OtoLaryngology New Articles

The role of cullin proteins in gastric cancer Abstract The cullin proteins are a family of scaffolding proteins that associate with RING proteins and ubiquitin E3 ligases and mediate substrate–receptor bindings. Thus, cullin proteins regulate the specificity of ubiquitin targeting in the regulation of proteins involved in various cellular processes, including proliferation, differentiation, and apoptosis. There are seven cullin proteins that have been identified in eukaryotes: CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, and CUL7/p53-associated parkin-like cytoplasmic protein. All of these proteins contain a conserved cullin homology domain that binds to RING box proteins. Cullin–RING ubiquitin ligase complexes are activated upon post-translational modification by neural precursor cell-expressed, developmentally downregulated protein 8. The aberrant expression of several cullin proteins has been implicated in many cancers though the significance in gastric cancer has been less well investigated. This review provides the first systematic discussion of the associations between all members of the cullin protein family and gastric cancer. Functional and regulatory mechanisms of cullin proteins in gastric carcinoma progression are also summarized along with a discussion concerning future research areas. Accumulating evidence suggests a critical role of cullin proteins in tumorigenesis, and a better understanding of the function of these individual cullin proteins and their targets will help identify potential biomarkers and therapeutic targets. Read More » ROCK inhibitor Y-27632 inhibits the growth, migration, and invasion of Tca8113 and CAL-27 cells in tongue squamous cell carcinoma Abstract The objective of this study is to determine the effects of Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor Y-27632 on the growth, invasion, and migration of Tca8113 and CAL-27 cells in tongue squamous cell carcinoma (TSCC). The methods of the study are as follows: After being routinely cultured for 24 h, Tca8113 and CAL-27 cells were treated with Y-27632 solution. The morphological change of Y-27632-treated cells was observed under an optical microscope and an inverted microscope; MTT assay was performed to measure the optical density (OD) of cells and calculate cell growth inhibition rate; the change of apoptosis was detected by AnnexinV-FITC/PI assay; cell invasion and migration were measured by Transwell assay. The results were as follows: (1) With increasing concentration of Y-27632, cell morphology changed and cell apoptosis appeared; (2) MTT assay showed that inhibition effect of Y-27632 on Tca8113 and CAL-27 cells was enhanced with increasing concentrations and time (all P < 0.01); (3) Apoptosis showed that, compared with controls, the number of apoptosis cells in experimental groups was significantly increased (all P < 0.01). Apoptosis rate was elevated with increasing concentrations of Y-27632; (4) Transwell assay showed, after a treatment with Y-27632, the number of migrated and invaded Tca8113 and CAL-27 cells in each group was statistically different (all P < 0.01); compared with controls, the number of migrated cell in groups treated with Y-27632 was decreased and less Tca8113 and CAL-27 cells in experimental groups passed through polycarbonate membrane (all P < 0.05). The study concludes that Y-27632 can inhibit the growth, invasion, and migration of Tca8113 and CAL-27 cells, suggesting that Y-27632 may be therapeutically useful in TSCC. Read More » Early downregulation of acute phase proteins after doxorubicin exposition in patients with breast cancer Abstract Chemotherapy remains the first-choice option for adjuvant therapy in breast cancer. Here, we investigated the impact of the first chemotherapic cycle of doxorubicin on the plasmatic–proteomic profiling of women diagnosed with breast cancer (n = 87). Blood samples were obtained from the same patient before and after doxorubicin infusion (1 h, 60 mg/m2) and processed for label-free LC-MS proteomic screening. A total of 80 proteins were downregulated after chemotherapy. In silico analysis revealed that the main biological process enrolled was inflammation and canonical pathways involving acute phase proteins. TNF-α, IL-1β, IL-12, TGF-β1, clusterin, and gelsolin were chosen as relevant for further validation. All selected targets presented reduced plasmatic levels after treatment. Our results indicate that doxorubicin downregulated acute phase proteins immediately after its infusion. Since such proteins are cancer promoting, its downregulation could support the effectiveness of doxorubicin along treatment. Read More » Down-expression of miR-152 lead to impaired anti-tumor effect of NK via upregulation of HLA-G Abstract It is known that chronic HBV infection (CHB) is the major risk factor for hepatocellular carcinoma (HCC) because CHB could not only cause liver tumorigenesis but also lead to change of local microenviroment and lower immune response to infected and cancerous cells (immune tolerance). Human leucocyte antigen-G (HLA-G) belongs to a non-classic MHC-I family and was considered to be an immune tolerance molecule, which could bind to immunosuppressive receptors of natural killer cell (NK) and T cells and trigger immunosuppressive signaling. Recently, numerous studies highlighted that microRNAs (miRNAs) were significantly differentially expressed in HCC tumorigenesis, and the expression was tissue-specific, indicating that miRNAs may cause great epigenetic changes in HCC tumorigenesis. In this study, we found that the expression of HLA-G was upregulated by hepatitis B virus (HBV) infection and miR-152; a HLA-G-targeting miRNA was downregulated by HBV infection. And high expression of HLA-G further suppressed NK against cancer cells, providing a new concept that miR-152 was involved in HBV-induced hepatocellular carcinoma. Read More » CD41 and CD45 expression marks the angioformative initiation of neovascularisation in human haemangioblastoma Abstract The initiation and formation of haemangioblastoma (HB) neovascularisation remain unknown, with concomitant controversy on its cytological origin. We detected HB-derived specific haematopoietic progenitors identified by surface expression of CD41 and CD45, which are similar to human embryonic vasculogenesis. CD41/CD45 cells expressed mesodermal markers, including SCL, Flk1 and c-kit. CD41 also seemed to appear before CD45 on haematopoietic progenitors. In vitro analysis showed that the CD41+/CD45 subpopulation gave rise to occasional primitive erythroid activity and endothelial marker expression. Meanwhile, kinetic investigation of the CD41+/CD45+ subpopulation showed that some molecules, including SCL, Flk1 and c-kit, were involved in vascular formation. The CD45+/c-kit+ population that lacked primitive haematopoiesis came from CD41+ cells. Acquisition of CD45 expression by the haematopoietic progenitors was associated with advanced differentiation towards the vascular cell lineage. Taken together, the present data suggested that CD41 and CD45 expression marked the onset of HB neovascularisation and the stepwise development of the angioformative period. Our findings provide new insights into the mechanisms of HB neovascularisation and the underlying therapeutic targets of anti-vascular treatment. Read More » Further considerations on hepatic lesion discrimination using diffusion MR imaging Abstract With great interest, we read the article "Differential diagnosis between hepatic metastases and benign focal lesions using DWI with parallel acquisition technique: a meta-analysis" (by Wei CG et al.). This article suggests that diffusion-weighted imaging was useful for differentiation between hepatic metastases and benign focal lesions. The result is encouraging. We would like to contribute regarding the value of DWI with parallel acquisition technique in the differentiation of metastases and benign hepatic lesions. Read More » Single nucleotide polymorphism rs11669203 in TGFBR3L is associated with the risk of neuroblastoma in a Chinese population Abstract With a primary mortality, neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Amplification of the MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) oncogene is observed in 20–30 % of NB cases, a feature which also characterizes a highly aggressive subtype of the disease. However, the systematic study of association between single nucleotide polymorphisms (SNPs) in MYCN-regulated genes and the risk of NB has not been investigated. In the current study, we scanned a set of 16 SNPs located within known or predicted MYCN binding sites in a cohort of 247 patients of Chinese origin with neuroblastic family tumors, including neuroblastoma (NB), ganglioneuroma (GN), and ganglioneuroblastoma (GNB), and in 290 cancer-free controls to determine whether any of the tested SNPs are associated with neuroblastic family tumors. We found that the rs11669203 G>C polymorphism, located in TGFBR3L promoter, is significantly associated with the risk of NB. Further, we found that this association is site specific to adrenal NB compared to non-adrenal NB. In addition, transcriptome analysis indicated that increased expression of TGFBR3L is strongly correlated with poor survival. The SNP rs11669203 located at the MYCN binding site of TGFBR3L is significantly associated with elevated risk of NB, and abnormal MYCN-regulated TGFBR3L expression may contribute to NB oncogenesis. Read More » Endoskopie bei der Versorgung von Fehlbildungspatienten Zusammenfassung Ziel der Arbeit Endoskopische Diagnostik und Therapiemaßnahmen haben einen festen Stellenwert bei der Behandlung von Fehlbildungen im Fachbereich der MKG-Chirurgie. Sowohl bei der Versorgung von kindlichen Patienten mit Lippen-Kiefer-Gaumen-Segel(LKGS)-Spalten als auch bei Risikopatienten mit syndromalen Erkrankungen ermöglicht die minimalinvasive Endoskopie eine sichere und wenig invasive Diagnostik. Auch die interdisziplinären Therapieergebnisse können mithilfe der Endoskopie verbessert werden. Material und Methoden Dargestellt werden typische Indikationen, standardisierte Techniken, interdisziplinäre Therapieansätze sowie Risiken der Endoskopie bei Neugeborenen, Kleinkindern und Heranwachsenden mit Fehlbildungen im Gesichtsbereich. Als zusätzlicher interdisziplinärer Ausblick werden minimalinvasive endoskopische Therapieverfahren der abführenden Tränenwege beschrieben, die sowohl bei Fehlbildungen im Gesichtsbereich als auch bei posttraumatischen Folgezuständen Anwendung finden können. Ergebnisse Bei der Planung endoskopischer Therapieverfahren müssen patienten- und altersspezifische Faktoren Berücksichtigung finden. Die endoskopische Behandlung von Patienten mit Fehlbildungen im MKG-Bereich sollte durch erfahrene Untersucher erfolgen oder begleitet werden. Schlussfolgerung Besonders bei Patienten mit LKGS-Spalten und syndromalen Erkrankungen des Kiefer-Gesicht-Bereichs sind die endoskopische Diagnostik und Therapie für die Prävention von spezifischen Komplikationen ebenso wie für den interdisziplinären Behandlungserfolg von sehr hohem Wert. Read More » In vitro and in vivo antidermatophytic activities of some Iranian medicinal plants In the last decades, the number of people suffering from dermatophytoses has seriously increased, which may be due to the development of resistant strains to a range of antifungal drugs. The present study was aimed to evaluate the antidermatophytic properties of eight extracts from the selected spices and herbs, which were ethno-medicinally used in Iran against Trichophyton mentagrophytes, Trichophyton interdigitale, Microsporum canis, and Microsporum gypseum (10 strain of each). The in vitro antifungal activities of the extracts from four spices and four plants were evaluated by the broth macro dilution method against four dermatophyte strains. In addition, the in vivo therapeutic effects of Myrtus communis L. and Cinnamomum zeylanicum Blume extracts (the most active extracts) on dermatophytosis induced by M. canis and T. mentagrophytes in guinea pigs were evaluated. Results of in vitro antifungal assay revealed that all the tested extracts demonstrated both fungistatic and fungicidal activities with the geometric mean (GM) MIC ranging from 0.058 to 3.73 mg/ml and GM (MFC) ranging from 0.058 to 7.46 mg/ml, respectively. Two extracts (M. communis and C. zeylanicum) significantly inhibited the growth of all the tested dermatophytes, while other extracts demonstrated weak (MICs of >0.625 mg/ml) to moderate (MICs ranging from 100 to 0.625 mg/ml) activities. In vivo antidermatophytic assay demonstrated that clotrimazole cured T. mentagrophytes and M. canis infection on days 21 and 17, respectively, whereas M. communis and C. zeylanicum extracts significantly (p < 0.05) cured T. mentagrophytes and M. canis infection on days 9 and 13 as well as 9, 11, respectively. Phytochemical screening showed the presence of flavonoids, tannins, phenols, and alkaloids in M. communis and alkaloids, flavonoids, and tannins in C. zeylanicum. Findings of the present study also provided the scientific evidence that natural plants could be used in traditional medicine for the prevention and treatment of dermatophytic infections. Read More » In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates In the present study, in vitro antifungal activities of five antipsychotic drugs (i.e., chlorpromazine hydrochloride, CPZ; trifluoperazine hydrochloride, TPZ; amantadine hydrochloride; R-(-)-deprenyl hydrochloride, and valproic acid sodium salt) and five conventional antifungal drugs (i.e., amphotericin B, AMB; caspofungin, CSP; itraconazole; terbinafine, TRB and voriconazole, VRC) were investigated in broth microdilution tests against four clinical and five environmental Scedosporium and Pseudallescheria isolates. When used alone, phenothiazines CPZ and TPZ exerted remarkable antifungal effects. Thus, their in vitro combinations with AMB, CSP, VRC, and TRB were also examined against the clinical isolates. In combination with antifungal agents, CPZ was able to act synergistically with AMB and TRB in cases of one and two isolates, respectively. In all other cases, indifferent interactions were revealed. Antagonism was not observed between the tested agents. These combinations may establish a more effective and less toxic therapy after further in vitro and in vivo studies for Scedosporium and Pseudallescheria infections. Read More » Does vaginal douching affect the type of candidal vulvovaginal infection? The normal vaginal microbiota is a dynamic system that continually fluctuates under the environmental changes and different physiological conditions. Yeast infections of the vagina are caused by one of the species of fungus called Candida (C.). The study aimed to evaluate the types of mycobiota in women with vulvovaginal candidiasis (VVC) who were performing vaginal douching (VD) or not. Furthermore, it studied the antifungal sensitivity toward different fungi isolated from the vagina. In a cross-sectional study conducted in Assiut University Hospital, Egypt, women with VVC were interviewed regarding relevant history including the habit of VD. Vaginal swabs were obtained and processed by direct microscope and by culture on CHROMagar Candida and other differential media. The types of Candida in women with the habit of VD were compared with those not having this habit. We found that VD habit was practiced by 67.4% of women with VVC, and Candida albicans was the commonest (78.3%) type observed. There was no significant difference in the percentage of non-albicans types between women performing VD (23.6%) and those not reporting this habit (18.9%). Harboring non-albicans types were significantly increased in regular performers of VD compared with those who had this procedure only after sexual intercourse or after the end of menstruation (36.8%,12.5%, and 16.7%, respectively) (P = .048). Thus, vaginal douching does not influence the type of Candida infection involved in VVC. Frequent performance of VD increases the likelihood of having non-albicans types and the resistance to the common antifungal agents. Read More » Reply to "Matrix-Assisted Laser Desorption Ionization-Time of Flight identification of Schizophyllum commune: Perspectives on the review by Chowdhary et al." Read More » Matrix-assisted laser desorption ionization-time of flight identification of Schizophyllum commune: perspectives on the review by Chowdhary et al. Read More » Diagnostic accuracy assessment of cytopathological examination of feline sporotrichosis Sporotrichosis is an implantation mycosis caused by pathogenic species of Sporothrix schenckii complex that affects humans and animals, especially cats. Its main forms of zoonotic transmission include scratching, biting and/or contact with the exudate from lesions of sick cats. In Brazil, epidemic involving humans, dogs and cats has occurred since 1998. The definitive diagnosis of sporotrichosis is obtained by the isolation of the fungus in culture; however, the result can take up to four weeks, which may delay the beginning of antifungal treatment in some cases. Cytopathological examination is often used in feline sporotrichosis diagnosis, but accuracy parameters have not been established yet. The aim of this study was to evaluate the accuracy and reliability of cytopathological examination in the diagnosis of feline sporotrichosis. The present study included 244 cats from the metropolitan region of Rio de Janeiro, mostly males in reproductive age with three or more lesions in non-adjacent anatomical places. To evaluate the inter-observer reliability, two different observers performed the microscopic examination of the slides blindly. Test sensitivity was 84.9%. The values of positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy were 86.0, 24.4, 2.02, 0.26 and 82.8%, respectively. The reliability between the two observers was considered substantial. We conclude that the cytopathological examination is a sensitive, rapid and practical method to be used in feline sporotrichosis diagnosis in outbreaks of this mycosis. Read More » {beta}-Aescin at subinhibitory concentration (sub-MIC) enhances susceptibility of Candida glabrata clinical isolates to nystatin Aescin (escin) derived from the seeds of horse chestnut (Aesculus hippocastanum L.) is a natural mixture of triterpene saponins exhibiting a wide variety of pharmacological properties, including antiinflammatory, analgesic, and antipyretic activities. However, data concerning antifungal activities of these compounds are limited. This study aims to evaluate the in vitro antifungal susceptibility of Candida glabrata clinical isolates to α-aescin sodium, β-aescin crystalline and β-aescin sodium using the disk diffusion (DD) and broth microdilution (BMD) methods. Moreover, the influence of subinhibitory concentration (0.5xMIC) of β-aescins on the nystatin MIC was also studied. In general, the results obtained by the DD assay correlated well with those obtained by the BMD method. Both β-aescins effectively inhibited the growth of all 24 strains tested. The minimum inhibitory concentration (MIC) values ranging from 8 to 32 μg/ml for β-aescin crystalline, whereas those of β-aescin sodium were slightly lower and ranged from 4 to 16 μg/ml. In contrast, α-aescin sodium was found to be completely ineffective against the strains studied. MIC values of nystatin were reduced 2–16-fold and 2–4-fold in the presence of subinhibitory concentration of β-aescin crystalline and β-aescin sodium, respectively. Results of the present study may suggest the additive interaction between β-aescin and nystatin. Read More » Pitfalls in Serological Diagnosis of Cryptococcus gattii Infections The detection of cryptococcal antigen by latex agglutination tests (LATs), enzyme-linked immunoassays (ELISA), or lateral flow assay (LFA) is an important tool for diagnosis of a Cryptococcus infection. Cerebrospinal fluid and/or serum samples of 10 patients with cryptococcosis due to Cryptococcus gattii or a hybrid of Cryptococcus neoformans and C. gattii were examined by three LATs (the IMMY Latex-Crypto® test, the PastorexTMCrypto Plus, and the Remel Cryptococcus Antigen Test Kit) and the LFA made by Immuno-Mycologics. LATs based on monoclonal antibodies (mAbs) like the PastorexTMCrypto Plus or the Remel Cryptococcus Antigen Test Kit turned out to have an insufficient sensitivity to detect four out of 10 C. gattii infections, including one infection by a hybrid between C. gattii and C. neoformans. Reflecting the ongoing expansion of C. gattii in geographical zones outside of tropical and subtropical areas like Mediterranean countries, Vancouver Island (British Columbia, Canada) and the Pacific Northwest region (USA), these findings are alarming because of the risk of delayed diagnosis of infections caused by C. gattii. Therefore, the preliminary serological screening for cryptococcal antigen in the case of a suspected Cryptococcus infection should be performed by using an assay with a broad range specificity and sensitivity for C. neoformans and C. gattii, including their hybrids. Read More » Novel in vivo observations on double acting points of luliconazole on Trichophyton rubrum: an ultrastructural study Scales from lesional skin of 12 patients with tinea pedis were investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to gain an insight into the spatial and morphological changes of dermatophytes after application of a clinical dosage of topical luliconazole 1% cream (Lulicon® cream 1%). In all cases, Trichophyton rubrum was identified. The scales from the lesions collected before and after topical luliconazole application were fixed with glutaraldehyde and subjected to SEM and TEM. For SEM, fixed specimens were first placed in 1N-KOH and then post-fixed and observed. SEM showed a swollen appearance of fungal hyphae as an early change, and then shrinkage of them showing a flattened and twisted appearance as a later change. TEM showed cell wall alterations with initial development of and accumulation of a granular structure in the outermost layer and subsequent amorphous and electron-lucent change of the thickened inner part of the cell wall. This is the first report of dramatic morphological changes of T. rubrum before and after topical luliconazole application in vivo demonstrated by SEM and TEM. We hypothesize that luliconazole has double acting points, on the plasma membrane and cell wall, of dermatophyte hyphae. Read More » In vitro interaction of antifungal and antibacterial drugs against Cryptococcus neoformans var. grubii before and after capsular induction This study evaluated the synergistic interactions between amphotericin B (AMB) and azithromycin (AZM), daptomycin (DAP), linezolid (LNZ), minocycline (MINO), fluconazole (FLZ), flucytosine (5FC), linezolid (LZD), or tigecycline (TIG) against clinical isolates of Cryptococcus neoformans var. grubii before and after capsule induction. High synergism (>75%) was observed for the combinations, AMB+5FC, AMB+TIG, AMB+AZM, AMB+LZD and AMB+MINO but only in the strains after capsule induction. The results show that the presence of the capsule may lower the minimum inhibitory concentrations (MICs) of antifungal agents, but antimicrobial activity can be improved by combining antifungal and antibacterial agents. Read More » Discovery of a sexual stage in Trichophyton onychocola, a presumed geophilic dermatophyte isolated from toenails of patients with a history of T. rubrum onychomycosis Trichophyton onychocola is a recently described geophilic dermatophyte that has been isolated from a toenail of Czech patient with a history of onychomycosis due to T. rubrum and clinical suspicion of relapse. In this study, we report a similar case from Denmark in an otherwise healthy 56-year-old man. The patient had a history of great toenail infection caused by T. rubrum in 2004 and presented with suspected relapse in 2011 and 2013. Trichophyton onychocola was the only microbial agent isolated at the second visit in 2013 and the identification was confirmed by DNA sequencing. Direct microscopic nail examination was positive for hyphae, however the etiological significance of T. onychocola was not supported by repeated isolation of the fungus. This new species may be an overlooked geophilic species due to the resemblance to some common species, for example, zoophilic T. interdigitale or some species of geophilic dermatophytes. We included differential diagnosis with phenotypically similar species; however, it is recommended that molecular methods are used for correct identification. The MAT locus of Danish strain was of opposite mating type than in the previously isolated Czech strain and the two isolates were successfully mated. The mating experiments with related heterothallic species T. thuringiense and Arthroderma melis were negative. The sexual state showed all typical signs of arthroderma-morph and is described by using optical as well as scanning electron microscopy. The sexual state was induced on a set of agar media, however low cultivation temperature and the presence of keratin source were crucial for the success rather than formulation of medium. Read More » Evaluation of two new enzyme immunoassay reagents for diagnosis of histoplasmosis in a cohort of clinically characterized patients The performance characteristics of the recently available analyte-specific reagent based enzyme immunoassay (ASR-EIA) and in vitro diagnostic (IVD) kit for urine Histoplasma antigen detection were evaluated in a cohort of 50 clinically characterized patients with histoplasmosis and 50 control patients. Overall sensitivity and specificity of the ASR-EIA were significantly improved compared with those of the IVD kit (sensitivity 72% vs. 22%, P<.001, specificity 98% vs. 84%, P = .014). Fourteen specimens from patients with clinically characterized histoplasmosis (five with pulmonary histoplasmosis and nine with progressive disseminated histoplasmosis) were falsely negative by ASR-EIA. All 10 specimens from patients with severe symptoms of progressive disseminated histoplasmosis were positive by ASR-EIA, although the average reading value of these 10 specimens was not significantly different from that of others with positive results. Compared to the MiraVista antigen assay, both the IVD kit and the ASR-EIA were significantly less sensitive in detecting Histoplasma antigen in the urine of patients with histoplasmosis. The ASR-EIA and MiraVista assay had comparable specificity. In conclusion, the ASR-EIA has improved performance compared with the IVD kit in the detection of Histoplasma antigen in the urine. However, users should be aware of the potential for false negative results using the currently recommended cutoff value. Read More » Dectin-2 polymorphism associated with pulmonary cryptococcosis in HIV-uninfected Chinese patients Dectin-2 is a C-type lectin receptor that can recognize critical structures of fungi and involve in the host immune response after pulmonary fungal infections. We aimed to investigate the association between Dectin-2 genetic polymorphisms and cryptococcosis among a series of human immunodeficiency virus (HIV)-uninfected Chinese patients. In this case control study, a total of 251 patients with cryptococcosis and 464 healthy controls were included. One tag-single nucleotide polymorphism (SNP) (rs11045418) located at 5'-flanking region of Dectin-2 gene was selected and genotyped in this study. Among 251 patients, there were 108 (43%) meningitis patients including 73 (67.7%) healthy ones, 74 (29.5%) pulmonary infected patients including 49 (66.2%) healthy ones, and 69 (27.5%) patients with both neural and pulmonary infection including 38 (55.1%) immunocompetent ones. One hundred and forty-three (74 plus 69) patients with pulmonary cryptococcosis and 177 (108 plus 69) patients with cryptococcal meningitis were compared with controls, respectively. Three samples from 143 pulmonary infected patients failed in genotyping. There was a significant difference between 86 immunocompetent pulmonary infected patients and controls in the overdominant model (C/T vs. T/T + C/C; OR, 0.59; 95%CI, 0.37–0.94; P, .026). Similar but not significant difference was found between the overall pulmonary infected patients and the controls in the overdominant model (OR, 0.77; 95%CI, 0.52–1.12; P, .17). No such difference was found between controls and patients with cryptococcal meningitis. Our study firstly showed a genetic association between Dectin-2 and pulmonary cryptococcosis. Read More » Molecular epidemiology of invasive Candida albicans at a tertiary hospital in northern Taiwan from 2003 to 2011 Candida albicans is a common cause of bloodstream fungal infections in hospitalized patients. To investigate its epidemiology, multilocus sequence typing (MLST) was performed on 285 C. albicans bloodstream isolates from patients in Chang Gung Memorial Hospital at Linkou (CGMHL), Taiwan from 2003 to 2011. Among these isolates, the three major diploid sequence types (DSTs) were 693, 659, and 443 with 19, 16, and 13 isolates, respectively. The 179 DSTs were classified into 16 clades by unweighted pair-group method using arithmetic averages (UPGMA). The major ones were clades 1, 4, 3, and 17 (54, 49, 31, and 31 isolates, respectively). Further analyses with eBURST clustered the 285 isolates into 28 clonal complexes (CC). The most common complexes were CC8, CC20, and CC9. DST 693 that had the highest number of isolates was determined to be the cluster founder of CC20, which belonged to clade 3. So far, 33 isolates worldwide including 29 from Taiwan and 4 from Korea, are CC20, suggesting that CC20 is an Asian cluster. Two fluconazole-resistant isolates belonging to CC12 and CC19 were detected. All other CGMHL isolates were susceptible to 5-flucytosine, amphotericin B, anidulfungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole, and voriconazole. However, CC20 isolates exhibited significantly lower susceptibility to fluconazole. In conclusion, the 285 CGMHL C. albicans isolates displayed geographically clustering with Asian isolates, and most of them are susceptible to common antifungal drugs. Isolates of DST 693, a Taiwanese major genotype belonging to MLST clade 3, were more resistant to fluconazole than other isolates. Read More » Aspergillus and aspergilloses in wild and domestic animals: a global health concern with parallels to human disease The importance of aspergillosis in humans and various animal species has increased over the last decades. Aspergillus species are found worldwide in humans and in almost all domestic animals and birds as well as in many wild species, causing a wide range of diseases from localized infections to fatal disseminated diseases, as well as allergic responses to inhaled conidia. Some prevalent forms of animal aspergillosis are invasive fatal infections in sea fan corals, stonebrood mummification in honey bees, pulmonary and air sac infection in birds, mycotic abortion and mammary gland infections in cattle, guttural pouch mycoses in horses, sinonasal infections in dogs and cats, and invasive pulmonary and cerebral infections in marine mammals and nonhuman primates. This article represents a comprehensive overview of the most common infections reported by Aspergillus species and the corresponding diseases in various types of animals. Read More » In vitro antifungal synergy between amphiphilic aminoglycoside K20 and azoles against Candida species and Cryptococcus neoformans Several azoles are widely used to treat human fungal infections. Increasing resistance to these azoles has prompted exploration of their synergistic antifungal activities when combined with other agents. The amphiphilic aminoglycoside, K20, was recently shown to inhibit filamentous fungi, yeasts and heterokonts, but not bacteria. In this study, in vitro synergistic growth inhibition by combinations of K20 and azoles (fluconazole, itraconazole, voriconazole, clotrimazole, or posaconazole) were examined against Candida species and Cryptococcus neoformans. Checkerboard microbroth dilution, time-kill curve, and disk diffusion assays revealed that K20 has synergistic inhibitory activities with all five azoles against C. albicans including azole-resistant C. albicans strains ATCC 64124 and ATCC 10231. Four (fluconazole, itraconazole, clotrimazole, posaconazole) and three (fluconazole, itraconazole, voriconazole) azoles were synergistically inhibitory with K20 against C. lusitaniae and C. tropicalis, respectively. Only posaconazole showed synergy with K20 against two Cryptococcus neoformans strains (90–26 and VR-54). Time-kill curves with azole-resistant C. albicans 64124 and azole-sensitive C. albicans MYA-2876 confirmed the K20-azole synergistic interactions with a ≥ 2 log10 decrease in colony-forming units (CFU)/ml compared with the corresponding azoles alone. These results suggest that combinations of K20 and azoles offer a possible strategy for developing therapies against candidiasis. Read More » Spektrografische Stimmtypenklassifizierung zur Beurteilung der Stimmqualität Laryngo-Rhino-Otol DOI: 10.1055/s-0035-1559678 Hintergrund: Neben der auditiv-perzeptiven Beurteilung, zählen auch objektiv-akustische Methoden als valides Evaluationsmittel für die Beurteilung der Stimmqualität. Die Spektrografie wird seit ca. 50 Jahren eingesetzt und kürzlich wurde ein neues Verfahren zur spektrografischen Stimmtypenklassifizierung nach Sprecher et al. (2010) vorgestellt. Das Ziel dieser Studie ist die Überprüfung der externen Validität beider Messverfahren mit einer größeren Stimmenanzahl. Material und Methoden: Es wurden 300 Stimmaufzeichnungen vom Vokal [a:] verwendet. 270 Aufnahmen stammten von Stimmpatienten mit unterschiedlichen Schweregraden einer Dysphonie und 30 Stimmgesunde. Alle Stimmen wurden von 7 Logopädinnen nach der RBH-Skala beurteilt und 2 Beurteiler analysierten die Stimmen nach der spektrografischen Stimmtypenklassifizierung. Ergebnisse: Die Intra- und Inter-Beurteiler-Zuverlässigkeit der RBH Parameter ergab nur eine durchschnittlich leichte Zuverlässigkeit (kappa=0,234–0,383). Die spektrografische-Beurteiler-Zuverlässigkeit war mäßig (kappa=0,457). Die Übereinstimmungsvalidität zwischen den auditiv-perzeptiven Parameter H und B und der spektrografischen Stimmtypenklassifizierung war hoch (H: r=0,746, p=0,000; B: r=0,746, p=0,000), jedoch für den Parameter R ergab sich nur eine leichte Übereinstimmung (r=0,370, p=0,000). Schlussfolgerung: Die spektrografische Stimmtypenklassifizierung nach Sprecher et al. (2010) scheint eine sinnvolle Ergänzung zur Beurteilung von Heiserkeit und Behauchtheit und bestätigt die Ergebnisse nach Sprecher et al. (2010). Das Verfahren ermöglicht eine objektivere Beurteilung von Stimmqualität für die angehaltene Phonation im klinischen Alltag sowie für die wissenschaftliche Arbeit. [...] © Georg Thieme Verlag KG Stuttgart · New York Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text Read More » Therapie von Blutungen bei Patienten unter oraler Antikoagulation Laryngo-Rhino-Otol 2015; 94: 697-709 DOI: 10.1055/s-0034-1564071 Sowohl unter einer Therapie mit klassischen Antikoagulanzien wie auch unter den direkten oralen Antikoagulanzien sind Blutungen die wichtigste klinische Komplikation. Deren Therapie unterscheidet sich zwischen den Substanzgruppen erheblich. [...] © Georg Thieme Verlag KG Stuttgart · New York Article in Thieme eJournals: Table of contents  |  Abstract  |  CME online  |  Full text Read More » Präaurikuläre Raumforderung bei einem 38-jährigen Patienten Laryngo-Rhino-Otol DOI: 10.1055/s-0035-1559691 © Georg Thieme Verlag KG Stuttgart · New York Article in Thieme eJournals: Table of contents  |  Full text Read More » Evaluation eines Klassifikationsmodells horizontaler Gefäßveränderungen der Stimmlippen Laryngo-Rhino-Otol DOI: 10.1055/s-0035-1559677 Hintergrund: Derzeit existiert keine valide Klassifikation von beginnenden Gefäßveränderungen der Stimmlippen. Wir testeten deshalb ein neues Klassifikationsmodell sichtbarer, beginnender, vaskulärer Veränderungen der Stimmlippen. Material und Methoden: 3 Gutachtern wurden 168 indirekte larynxendoskopische Aufnahmen der Stimmlippen als 84 Weißlicht-(WL) und 84 Narrow-Band-Imaging-Bilder (NBI) in zufälliger Reihenfolge zur Klassifikation vorgelegt (Graduierung in normal, leicht-, mittel-, hochgradig der Gefäßmerkmale Ektasie, Mäander, Gefäßkonvolut, Gefäßhäufigkeit, Grad der Verästelung und Richtungswechsel). Zudem mussten sie mittels Numerischer Rating-Skala ihre Sicherheit bei der Bewertung angeben. Die Validität der Gutachterangaben wurde anhand zufällig erneut angebotener WL- und NBI-Bilder überprüft. Ergebnisse: Eine Klassifizierung beginnender Gefäßmerkmale ist grundsätzlich möglich. Ektasie, Mäander, Gefäßhäufigkeit, Grad der Verästelung und Richtungswechsel eignen sich dafür (p<0,0001). NBI-Bilder zeigen die Gefäßmerkmale insgesamt höhergradig als die WL-Bilder (p<0,0001). Die Sicherheit bei der Bewertung der Gefäßmerkmale unterscheidet sich nicht signifikant (p=0,3529), differiert jedoch zwischen den Gutachtern höchst signifikant (p<0,0001). Bei dem Bewertungslaien ist der Zuwachs bei der Lernkurve am höchsten. Die Intra- sowie Interratervariabilität unterscheiden sich zwischen WL und NBI nur gering. Schlussfolgerungen: Beginnende, horizontale Gefäßmerkmale der Stimmlippen lassen sich sicher klassifizieren. Larynxendoskopische NBI-Bilder stellen die untersuchten Gefäßmerkmale nachweislich besser dar als WL-Bilder. Die Vertrautheit mit dem Klassifikationsmodell und der larynxendoskopischen Methode bestimmt die Sicherheit bei der Gefäßbeurteilung. [...] © Georg Thieme Verlag KG Stuttgart · New York Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text Read More » Die Sinusvenenthrombose – eine seltene Komplikation der akuten Mastoiditis und des Cholesteatoms Laryngo-Rhino-Otol DOI: 10.1055/s-0035-1555914 Hintergrund: Die Sinusvenenthrombose (SVT) ist eine seltene Komplikation der akuten Mastoiditis und des infizierten Cholesteatoms. In der internationalen Literatur wurde bisher wenig über die systematische Untersuchung bei V.a. eine SVT dokumentiert. In dieser Untersuchung wurden die klinischen, intraoperativen und therapeutischen Befunde der Patienten diskutiert. Patienten und Methoden: Es werden retrospektiv 7 Patienten mit radiologischem V.a. eine SVT dargestellt. Bei allen Patienten erfolgte eine Mastoidektomie mit Darstellung des Hirnsinus und Überprüfung dessen Blutführung. Ergebnisse: 4 Patienten hatten eine Thrombose des Sinus sigmoideus und 3 Patienten hatten eine Phlebitis des Sinus. Patienten mit einer SVT hatten zusätzlich zur Otalgie Schwindel, Cephalgien, Meningismus, Surditas oder eine Facialisparese. Postoperative MRT-Untersuchungen zeigten eine Rekanalisation des Sinus in allen Fällen. 2 Patienten entwickelten einen 2-zeitigen Kleinhirnabszess. Schlussfolgerung: Die Symptome der SVT sind unspezifisch. Neurologische Beschwerden können bei einer Mastoiditis hinweisend sein. Die Therapie besteht in der intravenösen Antibiotikagabe und der operativen Fokussanierung. Immer sollte im Rahmen der Mastoidektomie die Darstellung des Sinus erfolgen und dessen Blutführung überprüft werden. Im Falle einer Thrombose ist kann überdies die Antikoagulantientherapie indiziert sein. Zum Ausschluss eines 2-zeitigen Hirnabszesses empfiehlt sich eine Kontroll-MRT 7–14 Tage postoperativ. [...] © Georg Thieme Verlag KG Stuttgart · New York Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text Read More » Genexpressionsanalysen und ihr möglicher klinischer Nutzen in der Betrachtung der Kopf-Hals-Karzinome Zusammenfassung Systembiologische Ansätze für Mutationen (Exomanalysen und „targeted sequencing") und Genexpressionsanalysen (transkriptomweites „Genexpressions-Profiling") stellen in der Kopf-Hals-Onkologie ein neues wachsendes Gebiet dar, das neben medizinisch biologischer Kompetenz auch zunehmend bioinformatisches Spezialwissen erfordert. Für die Plattenepithelkarzinome des Kopf-Hals-Bereichs („head and neck squamous cell carcinoma", HNSCC) stellen die bisherigen molekulargenetischen Einzel-Gen- und Signalwegbetrachtungen Grundlagenforschung dar. Diese hat mittlerweile an verschiedenen Stellen wesentliche Erweiterungen durch systembiologische Ansätze, welche zu relevanten translationalen klinischen Forschungsfeldern herangewachsen sind. Heutzutage ist bekannt, dass Humanpapillomvirus(HPV)16 an verschiedenen Stellen mit genetischen Veränderungen assoziiert ist, aber auch auf der Methylierungsebene funktionellen Einfluss auf nicht in ihrer Basensequenz alterierte Gene ausübt. Verschiedene Konsortien fanden in Transkriptomanalysen übereinstimmende Cluster der Genexpression und HPV16-Assoziationen mit dem Spektrum somatischer Mutationen. Die bei HPV16-getriebenen HNSCC ermittelte differenzielle Methylierung von Genpromotoren erwies sich als prädiktiv für das Überleben auch bei HNSCC-Patienten ohne HPV-Nachweis. Die Autoren stellen eine Übersicht einiger translational relevanter Erkenntnisse dar und wagen einen Ausblick auf mögliche zukünftige klinische Entwicklungen. Read More » Comparison of the CAM2A and NAL-NL2 hearing-aid fitting methods for participants with a wide range of hearing losses 10.3109/14992027.2015.1095360<br/>Brian C. J. Moore Read More » Comment on: "The role of white matter dissection technique in modern neuroimaging: can neuroradiologists benefit from its use?" Read More » Neural connections between the nervus intermedius and the facial and vestibulocochlear nerves in the cerebellopontine angle: an anatomic study Abstract Purpose Unexpected clinical outcomes following transection of single nerves of the internal acoustic meatus have been reported. Therefore, this study aimed to investigate interneural connections between the nervus intermedius and the adjacent nerves in the cerebellopontine angle. Methods On 100 cadaveric sides, dissections were made of the facial/vestibulocochlear complex in the cerebellopontine angle with special attention to the nervus intermedius and potential connections between this nerve and the adjacent facial or vestibulocochlear nerves. Results A nervus intermedius was identified on all but ten sides. Histologically confirmed neural connections were found between the nervus intermedius and either the facial or vestibulocochlear nerves on 34 % of sides. The mean diameter of these small interconnecting nerves was 0.1 mm. The fiber orientation of these nerves was usually oblique (anteromedial or posterolateral) in nature, but 13 connections traveled anteroposteriorly. Connecting fibers were single on 81 % of sides, doubled on 16 %, and tripled on 3 %, six sides had connections both with the facial nerve anteriorly and the vestibular nerves posteriorly. On 6.5 % of sides, a connection was between the nervus intermedius and cochlear nerve. For vestibular nerve connections with the nervus intermedius, 76 % were with the superior vestibular nerve and 24 % with the inferior vestibular nerve. Conclusions Knowledge of the possible neural interconnections found between the nervus intermedius and surrounding nerves may prove useful to surgeons who operate in these regions so that inadvertent traction or transection is avoided. Additionally, unanticipated clinical presentations and exams following surgery may be due to such neural interconnections. Read More » First dwarf represented: ancient Egypt 2520 B.C. Read More » TNF-{alpha} enhancement of CD62E mediates adhesion of non-small cell lung cancer cells to brain endothelium via CD15 in lung-brain metastasis Background CD15, which is overexpressed on various cancers, has been reported as a cell adhesion molecule that plays a key role in non-CNS metastasis. However, the role of CD15 in brain metastasis is largely unexplored. This study provides a better understanding of CD15/CD62E interaction, enhanced by tumor necrosis factor-α (TNF-α), and its correlation with brain metastasis in non–small cell lung cancer (NSCLC). MethodsCD15 and E-selectin (CD62E) expression was demonstrated in both human primary and metastatic NSCLC cells using flow cytometry, immunofluorescence, and Western blotting. The role of CD15 was investigated using an adhesion assay under static and physiological flow live-cell conditions. Human tissue sections were examined using immunohistochemistry. ResultsCD15, which was weakly expressed on hCMEC/D3 human brain endothelial cells, was expressed at high levels on metastatic NSCLC cells (NCI-H1299, SEBTA-001, and SEBTA-005) and at lower levels on primary NSCLC (COR-L105 and A549) cells (P < .001). The highest expression of CD62E was observed on hCMEC/D3 cells activated with TNF-α, with lower levels on metastatic NSCLC cells followed by primary NSCLC cells. Metastatic NSCLC cells adhered most strongly to hCMEC/D3 compared with primary NSCLC cells. CD15 immunoblocking decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (P < .0001), confirming a correlation between CD15 and cerebral metastasis. Both CD15 and CD62E expression were detected in lung metastatic brain biopsies. ConclusionThis study enhances the understanding of cancer cell-brain endothelial adhesion and confirms that CD15 plays a crucial role in adhesion in concert with TNF-α activation of its binding partner, CD62E. Read More » Mentoring junior URM scientists to engage in sleep health disparities research: experience of the NYU PRIDE institute • Implementing training programs tailored to address specific needs of URM scientists is paramount in empowering them to address sleep-related cardiovascular diseases that disproportionately burden their communities.• The specific goals of the PRIDE Institute are to: select qualified junior URM faculty with potential to contribute to current knowledge of translational models to reduce sleep-related cardiovascular risk; increase mentees' knowledge, skills, and motivation to pursue a career in implementation of translational behavioral sciences; provide continuous mentorship to mentees and facilitate achievement of career independence; and dispense individualized coaching in acquiring proficiency in grant writing and understanding of the NIH review process. Read More » Vibratory Dynamics of Four Types of Excised Larynx Phonations There are four types of signals that are typical representations of vocal fold vibratory patterns. Type 1 signals are nearly periodic, type 2 signals contain subharmonic properties, type 3 signals are chaotic, and type 4 signals are characterized as white noise. High-speed imaging allows detailed observation of these vocal fold vibratory patterns. Therefore, high-speed imaging can explore the vibratory mechanism behind each of the four types of signals. Read More » Sex differences in hospital length of stay in children and adults hospitalized for asthma exacerbation Asthma prevalence remains at historically high levels, affecting 26 million Americans in 2010.1 The disease burden is uneven between women and men, with considerable differences in prevalence, chronic morbidity, and health care use (eg, higher risks of hospitalization).1–4 With regard to asthma hospitalizations, there are 372,000 annually in the United States.5 The limited literature on sex differences in acute morbidity among patients hospitalized for asthma exacerbation is conflicting, with hospital length of stay (LOS) among women found to be no different3 or longer than6,7 that among men. Read More » Outcome and Refractory Factor of Intensive Treatment for Geriatric Traumatic Brain Injury: Analysis of 1,165 cases registered in the Japan Neurotrauma Data Bank Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Shoji Yokobori, Masahiro Yamaguchi, Yutaka Igarashi, Kohei Hironaka, Hidetaka Onda, Kentaro Kuwamoto, Takashi Araki, Akira Fuse, Hiroyuki Yokota Read More » Immunohistochemical Analysis Sox17 Associated Pathway in Brain Arteriovenous Malformations Publication date: Available online 14 October 2015 Source:World Neurosurgery Author(s): Yulius Hermanto, Yasushi Takagi, Akira Ishii, Kazumichi Yoshida, Takayuki Kikuchi, Takeshi Funaki, Yohei Mineharu, Susumu Miyamoto BackgroundSox17 has emerged as an important factor in vascular remodeling, because of the potential linkage with Wnt/β catenin, notch and inflammatory pathway. Brain arteriovenous malformations (BAVMs) as an angiogenic and inflammatory disorder might possess an aberrant regulation of Sox17 associated pathway. Therefore, we sought to investigate the expression of Sox17 associated pathway in BAVMs.MethodsSixteen paraffin specimens of BAVMs nidus were analyzed by using immunohistochemical methods. Specimens were obtained from the patients during the surgical procedures.ResultsExpression of Sox17, Hey1, and β catenin were observed in all specimens. Large veins possessed distinct pattern of expression, thick walled had a stronger intensity, while thin walled had a weaker intensity of Sox17, Hey1, and β catenin (p < 0.001). The thick walled veins also had a higher expression of Sox 17, Hey1 and β catenin compared to large arteries (p < 0.05), furthermore the Hey1 and β catenin was also higher in the thick walled veins compared to brain microvessels (p < 0.01). In addition, the difference in expression of Sox17 associated pathway (Hey1 and β catenin) was also observed in medium and small arteries when compared to large arteries in BAVMs nidus and brain microvessels (p < 0.01).ConclusionSox17 associated pathway was activated in the BAVMs nidus. Our results indicate that arterial identity is gained in the thick walled veins, this might reflect the process of arterialization of the veins as a resultant of hemodynamic stress. In addition, high expression of Sox17 associated pathway in medium and small arteries indicates that BAVMs vessels active intrinsically. Read More » Serum B-Type Natriuretic Peptide: A Potential Marker for Neoplastic Edema in Brain Tumor Patients? Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Xi Chen, Yu Yao, Liang-Fu Zhou Read More » Successful preoperative endovascular embolization for an extreme hypervascular glioblastoma mimicking an arteriovenous malformation: a case report Publication date: Available online 14 October 2015 Source:World Neurosurgery Author(s): Tasuku Imai, Tomotaka Ohshima, Toshihisa Nishizawa, Shinji Shimato, Kyozo Kato BackgroundPreoperative endovascular embolization for hypervascular glioblastomas has not been established.Case DescriptionWe report the case of an extreme hypervascular glioblastoma mimicking an arteriovenous malformation that was successfully treated with preoperative embolization and subsequent removal. A 66-year-old man presented with progressive left hemiparesis and sensory aphasia. Cranial computed tomographic scans and magnetic resonance images revealed a left parietooccipital tumor with a ring enhancement. Digital subtraction angiography revealed an extreme high-flow arteriovenous shunt. The patient underwent presurgical endovascular embolization using n-butyl cyanoacrylate in a manner similar to embolization for arteriovenous malformations. The subsequent tumor removal was achieved with minimal blood loss.ConclusionThis is the first reported case of presurgical embolization for a glioblastoma with a high-flow shunt. Embolization for a malignant tumor with a high-flow shunt, in a manner similar to embolization for arteriovenous malformations, is feasible and effective. Read More » Ultrasound evaluation of peripheral nerves Publication date: Available online 14 October 2015 Source:World Neurosurgery Author(s): Zarina S. Ali, Jared M. Pisapia, Tracy S. Ma, Eric L. Zager, Gregory G. Heuer, Viviane Khoury There are a variety of imaging modalities available for evaluation of peripheral nerves. Of these, ultrasonography (US) is often under-utilized. There are several advantages of this imaging modality, including its cost-effectiveness, time-efficient assessment of long segments of peripheral nerves, ability to perform dynamic maneuvers, lack of contraindications, portability, and non-invasiveness. As such, it can provide diagnostic information that cannot be obtained by electrophysiological or, in some cases, magnetic resonance imaging studies. Ideally, the neurosurgeon can utilize US as a diagnostic adjunct in the preoperative assessment of a patient with traumatic, neoplastic, infective, or compressive nerve injury. Perhaps its most unique use is in intraoperative surgical planning. Here, the authors present a brief description of normal US nerve anatomy followed by a description of the US appearance of pathological peripheral nerves due to trauma, tumor, infection, and entrapment. Read More » Preoperative functional findings and surgical outcomes in patients with motor cortical arteriovenous malformation Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Fuxin Lin, Jun Wu, Bing Zhao, Xianzeng Tong, Zhen Jin, Yong Cao, Shuo Wang ObjectiveThe relationship between preoperative functional findings, derived from functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), and surgical outcomes in patients with motor cortical arteriovenous malformations (AVMs) has not been determined. The aim of this study was to determine the relationship between preoperative functional findings and surgical outcomes in patients with motor cortical AVM.Materials and MethodsFifteen patients with AVM involving precentral knob and/or paracentral lobule were reviewed. Each involved motor function was examined as an independent object. Preoperative functional findings included cortical reorganization, activation around the nidus, corticospinal tract (CST) reorganization, nidus involving the CST and the involved level of CST. The relationship between preoperative functional findings and surgical outcomes was statistically analyzed. A muscle strength≤grade 3 was defined as a poor outcome after surgery, and a muscle strength≥grade 4 was defined as a good outcome.ResultsEighteen objects were created and analyzed. Cortical reorganization (p=1.000) was not correlated with surgical outcomes. However, nidus involving the CST was significantly associated with poor short-term outcomes (1week after surgery) (p=0.028) and permanent muscle strength deficit (p=0.042). Most of the objects had good outcomes (16/18, 88.9%) at 6 months after surgery (long-term outcomes). Only one patient with CST ruptured at the corona radiata level and one patient who suffered from postoperative hemorrhage obtained poor long-term outcomes.ConclusionsNidus involving the CST and the involved level of the CST, rather than cortical reorganization, may be associated with surgical outcomes in patients with motor cortical AVM. Read More » Ruptured basilar tip aneurysm in a patient with bilateral internal carotid artery occlusion successfully treated with bilateral superficial temporal artery–middle cerebral artery anastomoses: case report Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Masahiro Indo, Soichi Oya, Toru Matsui Read More » Microvascular decompression of the optic nerve for paroxysmal phosphenes and visual field deficit Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Dirk De Ridder, Mary Jane Sime, Peter Taylor, Tomas Menovsky, Sven Vanneste BackgroundMicrovascular decompression surgery is standard neurosurgical practice for treating trigeminal neuralgia and hemifacial spasm. Most other cranial nerves have been decompressed for paroxysmal intermittent hyperactivity of the affected cranial nerve or in very longstanding compressions to treat cranial nerve hypo-functioning.Case descriptionWe here describe a case of intermittent paroxysmal unilateral phosphenes (i.e., light flashes) associated with worsening visual field defects. Magnetic resonance imaging (MRI) demonstrated a sandwiched optic nerve/chiasm between an inferior compression of the internal carotid artery (ICA) and a superior compression of the anterior communicating artery (ACoA). He was successfully treated by a microvascular decompression and anterior clinoidectomy plus optic canal unroofing.ConclusionThis case report adds to the few previous case reports in combining 2 previously described techniques, i.e. microvascular decompression and anterior clinoidectomy plus optic canal unroofing. Read More » Perioperative bioccipital watershed strokes in bilateral fetal posterior cerebral arteries during spinal surgery Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Gioia Mione, Guillaume Pische, Valérie Wolff, Romain Tonnelet, Lisa Humbertjean, Sébastien Richard BackgroundVision loss due to cerebral infarction during spinal surgery is less described. Intraoperative hypotension would be a leading cause. Patients with variation of the circle of Willis could be more prone to present stroke in this context but reports are lacking to sustain the theory. Bilateral occipital watershed ischemic strokes have never been described before. We report the case of a patient with a fetal origin of both posterior cerebral arteries (PCAs), presenting this particular anatomical stroke following lumbar laminectomy surgery for spinal stenosis during which intraoperative hypotension was observed. We discuss how this common anomaly associated with intraoperative hypotension could have promoted this serious complication.Case DescriptionA 55-year-old man woke up with cortical blindness after he had undergone lumbar surgery during which a marked decrease in blood pressure had occurred. Magnetic resonance imaging revealed bilateral symmetric infarctions of the occipital lobes, in the distal territory of both PCAs, and smaller anterior watershed ischemic strokes, suggesting a hemodynamic mechanism. Extended investigations, including conventional angiography, failed to find any cause of stroke, but revealed bilateral fetal PCAs supplied by internal carotid arteries only. Two years later, the patient has not recovered and remains severely visually impaired.ConclusionsThe standing hypothesis would be posterior low flow infarctions resulting from intraoperative hypotension on a variation of the circle of Willis more prone to decrease in cerebral blood flow. Moreover, this case supports the hypothesis of vascular insufficiency due to intraoperative hypotension as cause of stroke during spinal surgery. Read More » Rosai-Dorfman Disease of rare isolated spinal involement: report of four cases and literature review Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Bo Yuan Huang, Hua Zhang, Wen Jing Zong, Yan Hui Sun Rosai-Dorfman disease (RDD) is a rare histioproliferative disorder that only occasionally involves the central nervous system (CNS). We presented the diagnosis and treatment of four patients with isolated spinal RDD. All the four patients were treated by total or subtotal surgical resection and none of them experienced recurrence. Histopathological examination showed a characteristic emperipolesis, the lymphocytes were engulfed in the S-100-protein-positive histiocytes with no expression of CD1a. Preoperative diagnosis of spinal RDD is still challenging because the lesion is usually a dura-based lesion that mimics a meningioma. Surgical resection is an effective treatment and radiotherapy, steroid and chemotherapy has not demonstrated reliable therapeutic efficiency. Read More » Reply to a Letter to the Editor regarding, ""Occurrence of heropes simplex virus reactivation suggests a mechanism of trigeminal neuralgia surgical efficacy" Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Richard B. Tenser Read More » Efficacy of Three-Dimensional Endoscopy for Ventral Skull Base Pathology: A systematic review of the literature Publication date: Available online 14 October 2015 Source:World Neurosurgery Author(s): Hasan A. Zaidi, Aqib Zehri, Timothy R. Smith, Peter Nakaji, Edward R. Laws ObjectThe three-dimensional (3D) endoscope is a novel tool that provides stereoscopic vision and may allow for improved dexterity and safety during surgical resection of ventral skull base lesions. We describe here the cumulative experience available in the neurosurgical literature.MethodsA PubMed literature review was performed to identify and analyze all studies pertaining to 3D endoscopic endonasal skull base surgery.ResultsTwenty-six articles were identified: 14 clinical articles, 5 simulated environment studies, 5 human cadaveric studies, and 2 expert opinions. Among clinical studies, a total of 262 patients were treated for the following 257 pathologies listed in the articles: 190 suprasellar/parasellar lesions (73.9%), 41 ventral skull base lesions (16.0%), 19 sinonasal pathologies (7.4%), and 7 CSF leak repairs (2.7%). Complication rates, operative time, length of hospital stay, and extent of tumor resection were equivalent between 2D and 3D endoscopy. However, all studies report that subjective depth perception and spatial orientation were markedly improved with 3D technology. Three studies (11.5%) concluded that there was no clinically significant surgical benefit in switching from 2D to 3D endoscopy. All cadaveric studies and expert opinions concluded that 3D endoscopy improved identification of key anatomical structures and was superior to 2D endoscopy. Simulated environment studies demonstrated that 3D endoscopy improves speed and accuracy of endonasal tasks, more so in novice surgeons.ConclusionsOur findings suggest that this modality provides improved surgical dexterity by affording the surgeon with depth perception when manipulating tissue and maneuvering the endoscope in the endonasal corridor. Read More » Ruptured Infantile Myofibroma of the Head Presenting in a Neonate: Case Report and Review of the Literature Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Paul F. Koch, Tamara Fierst, Austin J. Heuer, Mariarita Santi, Gregory G. Heuer BackgroundInfantile myofibroma/myofibromatosis (IM/M) is a myofibroblastic proliferative disorder often seen in infants and children. IM/M can result in congenital tumors of the head and neck and may occasionally present to the neurosurgeon.Case DescriptionWe report a case of a solitary ruptured myofibroma of the head in a newborn patient. The lesion was initially suggestive of encephalocele. We describe the presentation and management of this patient, including relevant imaging, histopathological evaluation and surgical technique. We subsequently review the literature of IM/M of the head and neck, highlighting the three forms of the condition, each requiring a distinct management strategy.ConclusionWhile this tumor rarely presents to the neurosurgeon, it may do so in the process of ruling out other more dangerous conditions. It is therefore important to consider this diagnosis in masses that occur in the head and neck of newborns. Read More » Long-term Functional and Recurrence Outcomes of Surgical-treated Jugular Foramen Schwannoma: a 20-year Experience Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Xiao-Jun Zeng, Da Li, Shu-Yu Hao, Liang Wang, Jie Tang, Xin-Ru Xiao, Guo-Lu Meng, Gui-Jun Jia, Li-Wei Zhang, Zhen Wu, Jun-Ting Zhang Read More » Stereotactic Radiosurgery for Partially Resected Cerebral Arteriovenous Malformations Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Dale Ding, Zhiyuan Xu, Han-Hsun Shih, Robert M. Starke, Chun-Po Yen, Jason P. Sheehan ObjectiveIncomplete microsurgical resection of cerebral arteriovenous malformations (AVM) occurs uncommonly. However, such patients harboring postoperative residual nidi remain exposed to the risk of AVM hemorrhage and are, therefore, reasonable candidates for further intervention. The goals of this retrospective case-control study are to analyze the radiosurgery outcomes for partially resected AVMs and determine the effect of prior resection on AVM radiosurgery outcomes.MethodsWe evaluated a prospective database of AVM patients treated with radiosurgery from 1989-2013. Previously resected AVMs with radiologic follow-up ≥2 years or nidus obliteration were selected for analysis and matched, in a 1:1 fashion and blinded to outcome, to previously unresected AVMs. Statistical analyses were performed to assess relationship between prior resection and AVM radiosurgery outcomes.ResultsThe matching process yielded 88 patients in each of the previously resected and unresected AVM cohorts. In the resected AVM cohort, the actuarial AVM obliteration rates at 3 and 5 years were 47% and 75%, respectively; the rates of radiologic and symptomatic radiation-induced changes (RIC) were 10% and 3%, respectively; and the annual post-radiosurgery hemorrhage risk was 1.1%. The lack of prior AVM resection (P<0.001) and superficial AVM location (P=0.009) were independent predictors of radiologic RIC. The actuarial rates of obliteration (P=0.849) and post-radiosurgery hemorrhage (P=0.548) were not significantly different between the resected and unresected AVM cohorts.ConclusionsRadiosurgery affords a reasonable risk to benefit profile for incompletely resected AVMs. For those with a small volume residual nidus after resection, radiosurgery should be considered an effective alternative to repeat resection. Read More » En bloc resection and reconstruction using a frozen tumor-bearing bone for metastases of the spine and cranium from retroperitoneal paraganglioma Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Ryo Kitagawa, Hideki Murakami, Satoshi Kato, Mitsutoshi Nakada, Satoru Demura, Hiroyuki Tsuchiya BackgroundParagangliomas are neuroendocrine tumors that originate from autonomic nervous system-associated paraganglia, and are rare tumor accounting for only 0.3% of all neoplasms. Malignant paragangliomas frequently spread to the skeleton. The authors present a case of malignant paraganglioma with bone metastases to the spine and cranium, and excellent local control achieved with en bloc tumor resection and reconstruction using frozen tumor-bearing bone for the sites of the metastases.CaseThe patient was a 61-year-old woman underwent retroperitoneal paraganglioma resection 12 years previously. Nine years after the primary surgery, she began to experience back pain. Magnetic resonance imaging revealed an isolated metastasis in T6, and the following evaluation detected another metastasis in the left temporal bone. We performed curative surgeries for the metastases, including total en bloc spondylectomy of T6, and partial craniectomy for the cranial metastasis, and spinal and cranial reconstruction using frozen tumor-bearing bone for the sites of the metastases. At the 24-months follow-up examination, bone fusion was achieved between the frozen bone and the adjacent healthy bone in the spine and cranium. At 36 months postoperatively, an asymptomatic metastatic lesion was found in the pelvis. Nevertheless, no local recurrences at the surgical sites were detected. Her quality of life and performance in activities of daily living were well preserved. To the author's knowledge, this is the first report to present a case of cranioplasty achieved using a liquid nitrogen frozen, tumor-bearing autologous bone flap in a single-stage operation. Read More » Spinal Implants in Resource-Limited Settings: "Keep it Simple" Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Kee B. Park, Vycheth Iv Read More » Risk factors for low-flow related ischemic complications and neurological worsening in patients with complex internal carotid artery aneurysm treated by EC-IC high-flow bypass Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Hidetoshi Matsukawa, Rokuya Tanikawa, Hiroyasu Kamiyama, Toshiyuki Tsuboi, Kosumo Noda, Nakao Ota, Shiro Miyata, Go Suzuki, Rihee Takeda, Sadahisa Tokuda BackgroundThe revascularization technique has remained to be indispensable for complex aneurysms. However, risk factors for low-flow related ischemic complications (LRICs) and neurological worsening (NW) have been less well documented. We evaluated the risk factors for LRICs and NW in 67 patients treated with extracranial to intracranial (EC-IC) bypass graft using radial artery or saphenous vein graft for complex internal carotid artery (ICA) aneurysm with ICA occlusion.MethodsIntraoperative middle cerebral artery pressure (MCAP) by backup superficial temporal artery to middle cerebral artery bypass was measured. The MCAP ratio (MCAPR) was the ratio of the MCAP after release of the graft bypass to the initial MCAP. LRICs were defined as new neurological deficits and ipsilateral cerebral blood flow reduction in single photon emission computed tomography. Early and late NW were defined as an increase in 1 or more modified Rankin Scale at discharge and at the 12-month follow-up examination.ResultsDuring a median follow-up period of 13.3 months, LRICs were observed in 7 patients (10%). The Cox proportional hazards model showed a MCAPR ≦0.80 was significantly related to LRICs. Multivariate logistic regression analysis revealed perforating artery ischemia was significantly associated with early NW (n=13, 19%) and late NW (n=7, 13%). It also showed that LRICs were also significantly related to late NW.ConclusionsThe present study showed that regardless of the graft type, the MCAPR was associated with LRICs, which were related to late NW in patients with complex ICA aneurysms treated by EC-IC high-flow bypass graft. Read More » Vasa vasorum and the growing of thrombosed giant aneurysm of the vertebral artery: a case report Publication date: Available online 13 October 2015 Source:World Neurosurgery Author(s): Felix Hendrik Pahl, Eduardo de Arnaldo Silva Vellutini, Alberto Carlos Capel Cardoso, Matheus Fernandes de Oliveira BackgroundGiant aneurysms arising from the vertebral artery (VA) are often associated with thrombosis and present as mass lesions with slow progression of symptoms and signs. A consensus is still to be established on the underlying growth mechanisms and surgical management of thrombosed giant aneurysms of the vertebral artery.Clinical presentationHere we report the case of a 54-year-old man who searched neurosurgical care after 3 months of progressive cervical axial pain. He underwent cervical magnetic resonance imaging (MRI) and cerebral angiography, which revealed a giant VA aneurysm with thrombosed component. After failure of proximal and distal endovascular treatment, it was decided to perform surgical approach, which revealed a markedly developed vasa vasorum in aneurismal walls, raising the possibility of intraaneurismal nutrition from vasa vasorum. Patient recovered progressively and almost completely after surgery.Discussion and conclusionsAnother report have already described the case of a 58-year-old woman harboring a partially thrombosed giant aneurysm of VA. Interestingly, at the time of resection, a marked development of vasa vasorum on the occluded VA and the neck of the aneurysm was noted. We highlight the need to comprehend vasa vasorum as potential sources for aneurismal growth. Read More » Development and Pilot Testing of an Encounter Tool for Shared Decision Making About the Treatment of Graves' Disease Thyroid , Vol. 0, No. 0. Read More » Leaping to Conclusions: Why Premise Relevance Affects Argument Strength Abstract Everyday reasoning requires more evidence than raw data alone can provide. We explore the idea that people can go beyond this data by reasoning about how the data was sampled. This idea is investigated through an examination of premise non-monotonicity, in which adding premises to a category-based argument weakens rather than strengthens it. Relevance theories explain this phenomenon in terms of people's sensitivity to the relationships among premise items. We show that a Bayesian model of category-based induction taking premise sampling assumptions and category similarity into account complements such theories and yields two important predictions: First, that sensitivity to premise relationships can be violated by inducing a weak sampling assumption; and second, that premise monotonicity should be restored as a result. We test these predictions with an experiment that manipulates people's assumptions in this regard, showing that people draw qualitatively different conclusions in each case. Read More » Exploiting Listener Gaze to Improve Situated Communication in Dynamic Virtual Environments Abstract Beyond the observation that both speakers and listeners rapidly inspect the visual targets of referring expressions, it has been argued that such gaze may constitute part of the communicative signal. In this study, we investigate whether a speaker may, in principle, exploit listener gaze to improve communicative success. In the context of a virtual environment where listeners follow computer-generated instructions, we provide two kinds of support for this claim. First, we show that listener gaze provides a reliable real-time index of understanding even in dynamic and complex environments, and on a per-utterance basis. Second, we show that a language generation system that uses listener gaze to provide rapid feedback improves overall task performance in comparison with two systems that do not use gaze. Aside from demonstrating the utility of listener gaze in situated communication, our findings open the door to new methods for developing and evaluating multi-modal models of situated interaction. Read More » Cigarette Smoking and Activities of Daily Living in Ocular Myasthenia Gravis. Background: Myasthenia gravis is an autoimmune disease of the neuromuscular junction, commonly affecting the ocular muscles. Cigarette smoking has been shown to influence many autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, but its effect on myasthenia gravis has not been well studied. We sought to determine whether cigarette smoking influenced disease-related symptoms in ocular myasthenia gravis (OMG). Methods: We performed a prospective, clinic-based cross-sectional study in a single academic neuro-ophthalmology practice. All patients diagnosed with OMG between November 2006 and April 2014 were included. A prospective telephone survey was administered to determine smoking status and myasthenia gravis-related symptom severity. The main outcome measure was the myasthenia gravis-specific activities of daily living (MG-ADL) score, a well-validated marker of symptoms and quality of life in myasthenia gravis. Results: Forty-four patients were included in the analysis. Comparison of MG-ADL ocular subscores between current smokers (3.4 +/- 2.6), former smokers (1.8 +/- 2.1), and never smokers (1.1 +/- 1.5) revealed a statistically significant relationship (P = 0.031) where current smokers had the highest MG-ADL ocular subscores and never smokers the lowest. Comparison of MG-ADL total scores revealed the same relationship (current 5.6 +/- 4.5, former 2.9 +/- 3.1, never 1.4 +/- 2.5, P = 0.003). There were borderline significant correlations of pack years with MG-ADL ocular subscore (r = 0.27, P = 0.074) and MG-ADL total score (r = 0.30, P = 0.051). Conclusions: Our findings indicate an association between cigarette smoking and symptom severity in OMG. This association suggests that smoking cessation in OMG patients may lead to improved symptom-related quality of life. (C) 2015 by North American Neuro-Ophthalmology Society Read More » Brain Imaging in Idiopathic Intracranial Hypertension. Background: The primary role of brain imaging in idiopathic intracranial hypertension (IIH) is to exclude other pathologies causing intracranial hypertension. However, subtle radiologic findings suggestive of IIH have emerged with modern neuroimaging. This review provides a detailed description of the imaging findings reported in IIH and discusses their possible roles in the pathophysiology and the diagnosis of IIH. Evidence Acquisition: References were identified by searches of PubMed from 1955 to January 2015, with the terms "idiopathic intracranial hypertension," "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," "magnetic resonance imaging," "magnetic resonance venography," "computed tomography (CT)," "CT venography," "imaging," and "cerebrospinal fluid (CSF) leak." Additional references were identified by hand search of relevant articles. When possible, we extracted the number of patients and control subjects from each study for each radiological finding. When at least 2 studies used the same criteria to define a radiological finding, all patients from these studies were pooled to obtain a mean sensitivity and specificity with 95% confidence interval. Results: Specific neuroimaging findings may suggest long-standing IIH, including empty sella, flattening of the posterior globes, optic nerve head protrusion, distention of the optic nerve sheaths, tortuosity of the optic nerve, cerebellar tonsillar herniation, meningoceles, CSF leaks, and transverse venous sinus stenosis. Conclusion: Although IIH remains a diagnosis of exclusion, the most recently proposed diagnostic criteria have included neuroimaging findings to suggest IIH when major diagnostic criteria are not fulfilled. However, these findings are not diagnostic of IIH, and their presence is not required for the diagnosis of definite IIH. Their incidental discovery on brain imaging should not prompt invasive procedures, unless other signs of IIH, such as papilledema, are present. (C) 2015 by North American Neuro-Ophthalmology Society Read More » Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intra-arterial t-PA?: Response. No abstract available Read More » Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intra-arterial t-PA?: Comment. No abstract available Read More » Teaching Neuro-Ophthalmology in the Asia-Pacific Region and China: A Personal Perspective. Over the last 30 years, I have been involved in a number of projects helping to educate and train local ophthalmologists in many parts of Asia and the Pacific Islands, which lack adequate training and service in neuro-ophthalmology. In this article, I offer an overview of a number of different teaching initiatives and offer practical suggestions to anyone who might wish to become involved. (C) 2015 by North American Neuro-Ophthalmology Society Read More » The 12th European Neuro-Ophthalmology Society (EUNOS) Meeting, Ljubljana, Slovenia, June 21-24, 2015. No abstract available Read More » Is it the true incidence of IgE-cow's milk allergy (CMA) or CMA or IgE-CMA in some countries and CMA in others Read More » Dressing with epigallocatechin gallate-nanoparticles for wound regeneration Abstract Several reagents have been studied to overcome the problems encountered with anti-septic use, such as moderate cutaneous wound cytotoxicity and skin thinning. We successfully prepared a gelatin/chitosan/epigallocatechin gallate nanoparticle incorporated in a poly(γ-glutamic acid)/gelatin hydrogel, which comprised activated carbon fibers with gentamicin, to fabricate a sandwiched dressing to enhance wound regeneration. The inner-layer of activated carbon fibers with gentamicin was designed to prevent bacterial infection, and the outer-layer of gelatin/chitosan/epigallocatechin gallate nanoparticles incorporated in a poly(γ-glutamic acid)/gelatin hydrogel was designed to prevent inflammation and facilitate re-epithelialization. An in vitro study demonstrated that the dressing effectively inhibited target microorganisms, and scanning electron microscope and confocal laser scanning microscope indicated that the nanoparticles were homogeneously dispersed and migrated into the hydrogel. The in vivo study reported that the sandwiched dressing, comprising the poly(γ-glutamic acid)/gelatin hydrogel, was easy to remove from the wound and facilitated wound tissue regeneration and accelerated healing process. This article is protected by copyright. All rights reserved. Read More » Intradermal administration of ATP augments methacholine-induced cutaneous vasodilation but not sweating in young males and females Acetylcholine released from cholinergic nerves is a key neurotransmitter contributing to heat stress-induced cutaneous vasodilation and sweating. Given that sympathetic cholinergic nerves also release ATP, ATP may play an important role in modulating cholinergic cutaneous vasodilation and sweating. However, the pattern of response may differ between males and females given reports of sex-related differences in the peripheral mechanisms governing these heat loss responses. Cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated in 17 young adults (8 males, 9 females) at four intradermal microdialysis skin sites continuously perfused with: 1) lactated Ringer (Control), 2) 0.3 mM ATP, 3) 3 mM ATP, or 4) 30 mM ATP. At all skin sites, methacholine was coadministered in a concentration-dependent manner (0.0125, 0.25, 5, 100, 2,000 mM, each for 25 min). In both males and females, CVC was elevated with the lone infusion of 30 mM ATP (both P < 0.05), but not with 0.3 and 3 mM ATP compared with control (all P >0.27). However, 0.3 mM ATP induced a greater increase in CVC compared with control in response to 100 mM methacholine infusion in males (P < 0.05). In females, 0.3 mM ATP infusion resulted in a lower concentration of methacholine required to elicit a half-maximal response (EC50) (P < 0.05). In both males and females, methacholine-induced sweating was unaffected by any concentration of ATP (all P > 0.44). We demonstrate that ATP enhances cholinergic cutaneous vasodilation albeit the pattern of response differs between males and females. Furthermore, we show that ATP does not modulate cholinergic sweating. Read More » PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short- and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. Read More » Reduced sweet and fatty fluid intake after Roux-en-Y gastric bypass in rats is dependent on experience without change in stimulus motivational potency Here we assessed how intake reductions induced by Roux-en-Y gastric bypass surgery (RYGB) occur within and across access periods by examining drinking microstructure. After training, RYGB (n = 8–10) or sham-operated (SHAM, n = 12) rats were given 60-min access first to 0.3 M sucrose, then to 5% Intralipid, and finally to milk-chocolate Ensure Plus across 5 days each. Initially, total licks taken during the first meal of sucrose and Intralipid by RYGB and SHAM rats did not differ, but, across subsequent test periods, RYGB rats licked less than SHAM rats. First Ensure meal size also did not differ between RYGB and SHAM rats, but SHAM rats increased licking across test periods while the behavior of RYGB rats remained stable. The intake differences between the surgical groups, when they occurred, were most often due to smaller burst sizes in RYGB rats. Importantly, the surgical-group difference in sucrose and Intralipid intakes could not be explained by altered palatability of these solutions because, throughout testing, both groups had similar early meal licking behavior thought to represent the motivational potency of stimulus orosensory features. Although, overall, RYGB rats displayed lower early meal licking of Ensure relative to the SHAM rats, this appeared to be driven primarily by increases in the latter group across test periods; the RYGB group stayed relatively stable. Collectively, these results suggest that some level of postoral experience with these stimuli and/or their components is necessary before intake differences emerge between surgical groups, and, even when differences occur, often immediate taste-motivated ingestive behavior remains unaltered. Read More » Transient impairment of dynamic renal autoregulation in early diabetes mellitus in rats Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with NG-nitro-l-arginine methyl ester (l-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. l-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO-dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1. Read More » Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression Major depression is known to be associated with cardiovascular abnormalities, and oxidative stress has been suggested to play a role. We tested the hypothesis that antidepressant treatment reduces oxidative stress and endothelial dysfunctions in the chronic mild stress (CMS) model of depression in rats. Rats with >30% reduction in sucrose intake after 4 wk of CMS were defined in the study as CMS-susceptible and compared with unstressed controls. Sixteen CMS-susceptible and eight unstressed rats were treated during weeks 5 to 8 of the CMS protocol with escitalopram. Escitalopram-treated rats with >20% recovery in the sucrose consumption during the last 2 wk of treatment were defined as escitalopram responders. Rats that did not reach these criteria were defined as escitalopram nonresponders. In the open field test, escitalopram responders demonstrated anxiolytic effect of treatment. In mesenteric small arteries, escitalopram affected neither NO nor cyclooxygenase-1 (COX-1)-mediated vasodilation. Escitalopram potentiated endothelium-dependent hyperpolarization-like response, which was suppressed in the vehicle-treated CMS-susceptible rats and reduced COX-2-dependent relaxation, which was elevated in the vehicle-treated CMS-susceptible rats. Escitalopram did not affect blood pressure and heart rate, which were elevated in the vehicle-treated CMS-susceptible rats. Oxidative stress markers were changed in association with CMS in liver, heart, and brain. Escitalopram normalized oxidative stress markers in the majority of tissues. This study demonstrates that the antidepressant effect of escitalopram is associated with partial improvement of endothelial function in small arteries affecting COX-2 and endothelium-dependent hyperpolarization-like pathways. Read More » Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways The endocannabinoids are lipid-derived signaling molecules that control feeding and energy balance by activating CB1-type cannabinoid receptors in the brain and peripheral tissues. Previous studies have shown that oral exposure to dietary fat stimulates endocannabinoid signaling in the rat small intestine, which provides positive feedback that drives further food intake and preference for fat-rich foods. We now describe an unexpectedly broader role for cholinergic signaling of the vagus nerve in the production of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the small intestine. We show that food deprivation increases levels of 2-AG and its lipid precursor, 1,2-diacylglycerol, in rat jejunum mucosa in a time-dependent manner. This response is abrogated by surgical resection of the vagus nerve or pharmacological blockade of small intestinal subtype-3 muscarinic acetylcholine (m3 mAch) receptors, but not inhibition of subtype-1 muscarinic acetylcholine (m1 mAch). We further show that blockade of peripheral CB1 receptors or intestinal m3 mAch receptors inhibits refeeding in fasted rats. The results suggest that food deprivation stimulates 2-AG-dependent CB1 receptor activation through a mechanism that requires efferent vagal activation of m3 mAch receptors in the jejunum, which, in turn, may promote feeding after a fast. Read More » Gene expression of peripheral blood mononuclear cells is affected by cold exposure Because of the discovery of brown adipose tissue (BAT) in humans, there is increased interest in the study of induction of this thermogenic tissue as a basis to combat obesity and related complications. Cold exposure is one of the strongest stimuli able to activate BAT and to induce the appearance of brown-like (brite) adipocytes in white fat depots (browning process). We analyzed the potential of peripheral blood mononuclear cells (PBMCs) to reflect BAT and retroperitoneal white adipose tissue (rWAT) response to 1-wk cold acclimation (4°C) at different ages of rat development (1, 2, 4, and 6 mo). As expected, cold exposure increased fatty acid β-oxidation capacity in BAT and rWAT (increased Cpt1a expression), explaining increased circulating nonesterified free fatty acids and decreased adiposity. Cold exposure increased expression of the key thermogenic gene, Ucp1, in BAT and rWAT, but only in 1-mo-old animals. Additionally, other brown/brite markers were affected by cold during the whole developmental period studied in BAT. However, in rWAT, cold exposure increased studied markers mainly at early age. PBMCs did not express Ucp1, but expressed other brown/brite markers, which were cold regulated. Of particular interest, PBMCs reflected adipose tissue-increased Cpt1a mRNA expression in response to cold (in older animals) and browning induction occurring in rWAT of young animals (1 mo) characterized by increased Cidea expression and by the appearance of a high number of multilocular CIDE-A positive adipocytes. These results provide evidence pointing to PBMCs as an easily obtainable biological material to be considered to perform browning studies with minimum invasiveness. Read More » Influence of menopause and Type 2 diabetes on pulmonary oxygen uptake kinetics and peak exercise performance during cycling We investigated if the magnitude of the Type 2 diabetes (T2D)-induced impairments in peak oxygen uptake (Vo2) and Vo2 kinetics was affected by menopausal status. Twenty-two women with T2D (8 premenopausal, 14 postmenopausal), and 22 nondiabetic (ND) women (11 premenopausal, 11 postmenopausal) matched by age (range = 30–59 yr) were recruited. Participants completed four bouts of constant-load cycling at 80% of their ventilatory threshold for the determination of Vo2 kinetics. Cardiac output (CO) (inert gas rebreathing) was recorded at rest and at 30 s and 240 s during two additional bouts. Peak Vo2 was significantly (P < 0.05) reduced in both groups with T2D compared with ND counterparts (premenopausal, 1.79 ± 0.16 vs. 1.55 ± 0.32 l/min; postmenopausal, 1.60 ± 0.30 vs. 1.45 ± 0.24 l/min). The time constant of phase II of the Vo2 response was slowed (P < 0.05) in both groups with T2D compared with healthy counterparts (premenopausal, 29.1 ± 11.2 vs. 43.0 ± 12.2 s; postmenopausal, 33.0 ± 9.1 vs. 41.8 ± 17.7 s). At rest and during submaximal exercise absolute CO responses were lower, but the "gains" in CO larger (both P < 0.05) in both groups with T2D. Our results suggest that the magnitude of T2D-induced impairments in peak Vo2 and Vo2 kinetics is not affected by menopausal status in participants younger than 60 yr of age. Read More » IL-15R{alpha} is a determinant of muscle fuel utilization, and its loss protects against obesity IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα–/–) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα–/– mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα–/– are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity. Read More » Positive effect of combined exercise training in a model of metabolic syndrome and menopause: autonomic, inflammatory and oxidative stress evaluations. Background: It is now well-established that after menopause cardiometabolic disorders become more common. Recently, resistance exercise has been recommended as a complement to aerobic (combined training, CT) for the treatment of cardiometabolic diseases. Objective: To evaluate the effects of CT in hypertensive ovariectomized rats undergoing fructose overloadon blood pressure variability (BPV), inflammation and oxidative stress parameters. Methods:Wistar and spontaneously hypertensive (SHR) rats were divided into (n=8/group): Control (C), hypertensive ovariectomized undergoingfructose overload, sedentary (HOF) and trained (HOFT). CT was performed on a treadmill and ladder adapted to rats in alternate days (8 weeks; 40-60% maximal capacity). Arterial pressure (AP) signals were directly recorded. Oxidative stress and inflammation were measured on cardiac and renal tissues. Results: The association of risk factors (hypertension+ovariectomy+fructose) promoted an increase in mean AP (FHO: 174±4 vs. C: 108±1 mmHg) and heart rate (FHO: 403±12 vs. C: 352±11 bpm), induced impairment in insulin sensitivity, BVP, cardiac and renal oxidative stress and cardiac inflammation (TNF-α- FHO: 65.8±9.9 vs. C: 23.3±4.3pg/mg protein). However, CT was able to reduce MAP (FHOT: 158±4 mmHg) and heart rate (FHOT: 303±5 bpm), normalize insulin sensitivity and sympathetic modulation. Moreover, the trained rats presented reduced lipoperoxidation and increased antioxidant defenses in cardiac and renal tissues; reduced TNF- α (FHOT: 33.1±4.9 pg/mg protein) and increased IL-10 and nitric oxide bioavailability. Conclusion: The association of risk factors promoted an additional impairment in metabolic, cardiovascular, autonomic, inflammatory and oxidative stress parameters and combined exercise training was able to attenuate these dysfunctions. Read More » THE SODIUM-BICARBONATE COTRANSPORTER NBCe2 (SLC4A5) EXPRESSED IN HUMAN RENAL PROXIMAL TUBULES SHOWS INCREASED APICAL EXPRESSION UNDER HIGH SALT CONDITIONS The electrogenic sodium bicarbonate cotransporter (NBCe2) is encoded by SLC4A5, variants of which have been associated with salt sensitivity of blood pressure, which affects 25% of the adult population. NBCe2 is thought to mediate sodium bicarbonate cotransport primarily in the renal collecting duct, but NBCe2 mRNA is also found in the rodent renal proximal tubule (RPT). The protein expression or function of NBCe2 has not been demonstrated in the human RPT. We validated an NBCe2 antibody by shRNA and western blot, as well as overexpression of an epitope-tagged NBCe2 construct in both RPT cells (RPTCs) and HEK293 cells. Using this validated NBCe2 antibody, we found NBCe2 protein expression in the RPT of fresh and frozen human kidney slices, RPTCs isolated from human urine, and isolated RPTC apical membrane. Under basal conditions, NBCe2 was primarily found in the Golgi while NBCe1 was primarily found at the basolateral membrane. Following an acute short-term increase in intracellular sodium, NBCe2 expression was increased at the apical membrane in cultured slices of human kidney and polarized, immortalized RPTCs. Sodium bicarbonate transport was increased by monensin and overexpression of NBCe2, decreased by NBCe2 shRNA but not by NBCe1 shRNA, and blocked by 2,2'-(1,2-ethenediyl)bis[5-isothiocyanato-benzenesulfonic acid. NBCe2 appears to be important in apical sodium and bicarbonate cotransport under high salt conditions. Future studies will examine the role of NBCe2 in mediating increased renal sodium transport in humans whose blood pressures are elevated by an increase in sodium intake. Read More » Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O2 partial pressures (PmvO2) resulting from diabetes-induced cardiovascular dysfunction which alters the dynamic balance between O2 delivery and utilization rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO2 dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: Streptozotocin i.p.) and healthy (CONT) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O2) to 3.0 ATA at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO2 in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR) and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO2 increased faster than CONT. Subsequently, PmvO2 remained elevated at similar levels in CONT. Sympathetic nervous system, cardiac and respiratory responses to HBO were slower in DIA versus CONT. HBO treatment increases tibialis anterior muscle PmvO2 more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas, respiratory, cardiovascular and LSNA responses to HBO are profoundly slowed in DIA only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO2 kinetics. Read More » Folic acid supplementation during high fat diet feeding restores AMP-activated protein kinase (AMPK) activation via an AMP-LKB1 dependent mechanism The AMP-activated protein kinase (AMPK) is an endogenous energy sensor that regulates lipid and carbohydrate metabolism. Non-alcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome with impaired lipid and glucose metabolism, and increased oxidative stress. Our recent study showed that folic acid supplementation attenuated hepatic oxidative stress and lipid accumulation in high fat diet fed mice. The aim of the present study was to investigate the effect of folic acid on hepatic AMPK during high fat diet feeding and the mechanisms involved. Male C57BL/6J mice were fed a control diet (10% kcals fat), a high fat diet (60% kcals fat) or a high fat diet supplemented with folic acid (26mg/kg diet) for 5 weeks. Mice fed a high fat diet exhibited hyperglycemia, hepatic cholesterol accumulation and reduced hepatic AMPK phosphorylation. Folic acid supplementation restored AMPK phosphorylation (activation), and reduced blood glucose and hepatic cholesterol levels. Activation of AMPK by folic acid was mediated through an elevation of its allosteric activator AMP and activation of its upstream kinase, namely, liver kinase B1 (LKB1) in the liver. Consistent with in vivo findings, 5-methyltetrahydrofolate (bioactive form of folate) restored phosphorylation (activation) of both AMPK and LKB1 in palmitic acid-treated HepG2 cells. Activation of AMPK by folic acid might be responsible for AMPK-dependent phosphorylation of HMG-CoA reductase, leading to reduced hepatic cholesterol synthesis during high fat diet feeding. These results suggest that folic acid supplementation may improve cholesterol and glucose metabolism by restoration of AMPK activation in the liver. Read More » Impact of Blood Pressure Perturbations on Arterial Stiffness Although the associations between chronic levels of arterial stiffness and blood pressure (BP) have been fairly well studied, it is not clear if and how much arterial stiffness is influenced by acute perturbations in BP. The primary aim of this study was to determine magnitudes of BP-dependence of various measures of arterial stiffness during acute BP perturbation maneuvers. Fifty apparently healthy subjects, including 25 young (20-40 years) and 25 older adults (60-80 years), were studied. A variety of BP perturbations, including head-up tilt, head-down tilt, mental stress, isometric handgrip exercise, and cold pressor test, were used in order to encompass BP changes induced by physical, mental, and/or physiological stimuli. When each index of arterial stiffness was plotted with mean BP, all arterial stiffness indices, including cardio-ankle vascular index or CAVI (r=0.50), carotid-femoral pulse wave velocity or cfPWV (r=0.51), brachial-ankle pulse wave velocity or baPWV (r=0.61), arterial compliance (r=-0.42), elastic modulus (r=0.52), arterial distensibility (r=-0.32), β-stiffness index (r=0.19), and Young's modulus (r=0.35) were related to mean BP (all P<0.01). Changes in CAVI, cfPWV, baPWV, and elastic modulus were significantly associated with changes in mean BP in the pooled conditions while changes in arterial compliance, arterial distensibility, β-stiffness index, and Young's modulus were not. In conclusion, this study demonstrated that BP changes in response to various forms of pressor stimuli were associated with the corresponding changes in arterial stiffness indices and that the strengths of associations with BP varied widely depending on what arterial stiffness indices were examined. Read More » Direct Renal effects of a fructose-enriched diet: interaction with high salt intake Consumption of fructose has increase dramatically in the last 50 years. Excessive fructose consumption has a detrimental effect on mammalian health. In humans, a direct relationship exists between added sugars in the diet and increased risk for cardiovascular disease mortality. While the causes for this are unclear, we recently showed that fructose provided in the drinking water induces a salt-dependent increase in blood pressure in Sprague-Dawley rats in a matter of days. However, little is known about the effects of fructose per se in renal salt handling and whether these can lead to salt-sensitive hypertension prior to the development of metabolic abnormalities. The long-term effects of fructose intake (more than 4 weeks) in animals are not just due to fructose but also secondary to alterations in metabolism which may also impact kidney function. This mini-review focuses on the acute effect of fructose intake and its effect on salt regulation, as they affect blood pressure. Read More » Aging augments renal vasoconstrictor response to orthostatic stress in humans The ability of the human body to maintain arterial blood pressure (BP) during orthostatic stress is determined by several reflex neural mechanisms. Renal vasoconstriction progressively increases during graded elevations in lower body negative pressure (LBNP). This sympathetically mediated response redistributes blood flow to the systemic circulation to maintain BP. However, how healthy aging affects the renal vasoconstrictor response to LBNP is unknown. Therefore, ten young (25 ± 1 years; mean ± SE) and ten older (66 ± 2 years) subjects underwent graded LBNP (-15 and -30 mmHg) while beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), arterial blood pressures (BP; Finometer), and heart rate (HR; electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular variables were similar between groups, except diastolic BP was higher in older subjects (P < 0.05). Increases in RVR during LBNP were greater in the older group compared to the young group (older: -15 mmHg 10 ± 3%, -30 mmHg 20 ± 5%; young: -15 mmHg 2 ± 2%, -30 mmHg 6 ± 2%; P < 0.05). RBFV tended to decrease more (P = 0.10) and mean BP tended to decrease less (P = 0.09) during LBNP in the older group compared to the young group. Systolic and diastolic BP, pulse pressure, and HR responses to LBNP were similar between groups. These findings suggest that aging augments the renal vasoconstrictor response to orthostatic stress in humans. Read More » Relaxin increases sympathetic nerve activity and activates spinally-projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats Pregnancy is characterized by increased blood volume and baseline sympathetic nerve activity (SNA), vasodilation, and tachycardia. Relaxin (RLX), an ovarian hormone elevated in pregnancy, activates forebrain sites involved in control of blood volume and SNA through angiotensin (Ang II) dependent mechanisms, and contributes to adaptations during pregnancy. In anesthetized arterial baroreceptor denervated nonpregnant (NP) rats, RLX microinjected into the subfornical organ (SFO, 0.77 pmol in 50 nl) produced sustained increases in lumbar SNA (8 ± 3%) and mean arterial pressure (MAP, 26 ± 4 mmHg). Low dose intra-carotid artery (ica) infusion of RLX (155 pmol/ml/hr; 1.5 hr) had minor transient effects on arterial pressure and activated neurons (increased Fos-IR) in the SFO and in spinally-projecting (19 ± 2%) and AVP-IR (21 ± 5%) cells in the paraventricular nucleus of the hypothalamus (PVN) of NP, but not pregnant (P) rats. However, mRNA for RLX and Ang II AT1a receptors in the SFO were preserved in pregnancy. RLX receptor-IR is present in the region of the SFO in NP and P rats and is localized in astrocytes, the major source of angiotensinogen in the SFO. These data provide an anatomical substrate for a role of RLX in resetting of AVP secretion and increased baseline SNA in pregnancy. Since RLX and Ang II receptor expression was preserved in the SFO of P rats, we speculate that the lack of response to exogenous RLX may be due to maximal activation by elevated endogenous levels of RLX in near-term pregnancy. Read More » Postural influence on intracranial and cerebral perfusion pressure in ambulatory neurosurgical patients We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP: mean arterial pressure (MAP) - ICP) in neurosurgical patients undergoing 24-hour ICP monitoring as part of their diagnostic workup. We identified 9 patients (5 women, age 44±20 yrs.; mean±SD) who were "as normal as possible" i.e. without indication for neurosurgical intervention (e.g. focal lesions, global edema, abnormalities in ICP-profile or cerebrospinal fluid dynamics). ICP (tip-transducer probe, Raumedic) in the brain parenchyma (N=7) or in the lateral ventricles (N=2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared to the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4±3.8 to 14.3±4.7 and 19±4.7 mmHg, P<0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8±3.6 and 1.3±3.6 mmHg and ICP reached -2.4±4.2 mmHg when standing up (P<0.05). Concordant changes in MAP maintained CPP at 77±7 mmHg regardless of body position (P=0.95). During head-down tilt, the increase in ICP corresponded to a hydrostatic pressure gradient with reference just below the heart, likely reflecting the venous hydrostatic indifference point. When upright, the decrease in ICP was attenuated, corresponding to formation of a separate hydrostatic gradient with reference to the base of the skull, likely reflecting the site of venous collapse. ICP therefore seems to be governed by pressure in the draining veins and collapse of neck veins may protect the brain from being exposed to a large negative pressure when upright. Despite positional changes in ICP, MAP keeps CPP tightly regulated. Read More » Hypothalamic fatty acid sensing in Senegalese sole (Solea senegalensis):response to long-chain saturated, monounsaturated, and polyunsaturated (n-3) fatty acids We assessed the presence of fatty acid (FA) sensing mechanisms in hypothalamus of Senegalese sole (Solea senegalensis) and investigated their sensitivity to FA chain length and/or level of unsaturation. Stearate (SA, saturated FA), oleate (OA, monounsaturated FA of the same chain length), α-linolenate (ALA, a n-3 PUFA of the same chain length), and eicosapentanoate (EPA, a n-3 PUFA of a larger chain length) were injected intraperitoneally. Parameters related to FA sensing and neuropeptide expression in the hypothalamus were assessed after 3h and changes in accumulated food intake after 4, 24, and 48 h. Three FA sensing systems characterized in rainbow trout were also found in Senegalese sole, and were activated by OA in a way similar to that previously characterized in rainbow trout and mammals. These hypothalamic FA sensing systems were also activated by ALA, differing from mammals, where n-3 PUFA do not seem to activate FA sensors. This might suggest additional roles and highlights the importance of n-3 PUFA in fish diets, especially in marine species. The activation of FA sensing seems to be partially dependent on acyl chain length and degree of saturation, as no major changes were observed after treating fish with SA or EPA. The activation of FA sensing systems by OA and ALA, but not SA or EPA, is further reflected in the expression of hypothalamic neuropeptides involved in the control of food intake. Both OA and ALA enhanced anorexigenic capacity compatible with the activation of FA sensing systems. Read More » The role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure Heart Failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan ((a non-selective ETA and ETB receptor antagonist) (8 mg/kg/h) on resting levels of CSNA, arterial pressure and heart rate were determined in conscious normal sheep (n= 6) and sheep with pacing induced HF (n= 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts / 100 heart beats, P < 0.01). Infusion of tezosentan for 60 minutes significantly decreased resting MAP in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg respectively; p<0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals, but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF. Read More » Sex and Gender Differences in Cardiovascular, Renal and Metabolic Diseases N/A Read More » Effects of passive heat stress on human somatosensory processing We herein investigated the effects of passive heat stress on human somatosensory processing recorded by somatosensory-evoked potentials (SEPs). Fifteen healthy subjects received a median nerve stimulation at the left wrist under two thermal conditions: Heat stress and normothermic Time Control. The latencies and amplitudes of P14, N20, P25, N35, P45, and N60 at C4' and P14, N18, P22, and N30 at Fz were evaluated. Under the Heat stress condition, SEPs were recorded at normothermic baseline (1st), early in heat stress (2nd), when esophageal temperature had increased by ~1.0 °C (3rd) and ~2.0 °C (4th), and after heat stress (5th). In the Time control condition, SEPs were measured at the same time intervals as those in the Heat stress condition. The peak latencies and amplitudes of SEPs did not change early in heat stress. However, the latencies of P14, N20, and N60 at C4' and P14, N18, and P22 at Fz were significantly shorter in the 4th session than in the 1st session. Furthermore, the peak amplitudes of P25 and N60 at C4', and P22 and N30 at Fz decreased with increases in body temperature. On the other hand, under the Time control condition, no significant differences were observed in the amplitudes or latencies of any component of SEPs. These results suggested that the conduction velocity of the ascending somatosensory input was accelerated by increases in body temperature, and hyperthermia impaired the neural activity of cortical somatosensory processing. Read More » Editorial Focus: Cardiac responses to hypoxia and reoxygenation in Drosophila. New insights into evolutionary conserved gene responses N/A Read More » In vivo evidence for unidentified leptin-induced circulating factors that control white fat mass Fat transplants increase body fat mass without changing the energy status of an animal and provide a tool for investigating control of total body fat. Early transplant studies found that small pieces of transplanted fat took on the morphology of the transplant recipient. Experiments described here tested whether this response was dependent upon expression of leptin receptors in either transplanted fat or the recipient mouse. Fat from leptin receptor deficient db/db mice or wild type mice was placed subcutaneously in db/db mice. After 12 weeks cell size distribution in the transplant was the same as in endogenous fat of the recipient. Thus wild type fat cells, which express leptin receptors, were enlarged in a hyperleptinemic environment indicating that leptin does not directly control adipocyte size. By contrast, db/db or wild type fat transplanted into wild type mice decreased in size, suggesting that a functional leptin system in the recipient is required for body fat mass to be controlled. In the final experiment wild type fat was transplanted into a db/db mouse parabiosed to either another db/db mouse to an ob/ob mouse or in control pairs in which both parabionts were ob/ob mice. Transplants increased in size in db/db-db/db pairs, decreased in db/db-ob/ob pairs and did not change in ob/ob-ob/ob pairs. We propose that leptin from db/db parabionts activated leptin receptors in their ob/ob partners. This in turn stimulated release of unidentified circulating factors which travelled back to the db/db partner and acted on the transplant to reduce fat cell size. Read More » Chronic hypoxia during development does not trigger pathologic remodeling of the chicken embryonic heart but reduces cardiomyocyte number Fetal growth restriction programs an increased risk of cardiovascular disease in adulthood but the actual mechanisms of this developmental programming are not fully understood. Previous studies in mammalian models suggest that hearts of growth-restricted fetuses have reduced cardiomyocyte number due to reduced proliferation and premature cardiomyocyte maturation. Chicken embryos incubated under chronic hypoxia are also growth-restricted, have smaller hearts and show signs of cardiac insufficiency post-hatching. The aim of the present study was to investigate how chronic hypoxia (14% O2) during development affects cardiomyocyte mass and how myocardial structure is altered. Hypoxic incubation reproduced the well-characterized embryonic growth restriction and an increased ventricle-to-body mass ratio (at E11, E15, E17 and E19) with reduced absolute heart mass only at E19. Cell density, apoptosis and cardiomyocyte size were insensitive to hypoxia at E15 and E19 and no signs of ventricular wall remodeling or myocardial fibrosis were detected. Bayesian modeling provided strong support for hypoxia affecting absolute mass and proliferation rates at E15, indicating that the growth impairment, at least partly, occurs earlier in development. Neither E15 nor E19 hearts contained binucleated cardiomyocytes, indicating that fetal hypoxia does not trigger early maturation of cardiomyocytes in the chicken, which contrasts with previous results from hypoxic rat pups. In conclusion, prenatal hypoxia in the chick embryo results in a reduction in the number of cardiomyocytes without inducing ventricular remodeling, cell hypertrophy or premature cardiomyocyte maturation. Read More » Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses. The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 hours of water deprivation (WD), which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis. The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of WD rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses. Although the administration of ACEA or AM251 did not produce any effects on WD-induced vasopressin (AVP) secretion, oxytocin (OXT) plasma concentrations were significantly decreased in WD rats treated with ACEA. At the genomic level, ACEA significantly decreased AVP and OXT mRNA expression in the hypothalamus of WD rats, whereas AM251 potentiated both basal and WD-induced stimulatory effects on the transcription of AVP and OXT genes. In addition, we showed that WD alone upregulates proopiomelanocortin, Agouti-related protein, melanin-concentrating hormone and Orexin A mRNA levels in the hypothalamus, and that CB1Rs regulate main central peptidergic pathways controlling food intake, being most of these effects also significantly influenced by the hydration status. In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during WD. Read More » Prolonged blood pressure elevation following continuous infusion of angiotensin-II - a baroreflex study in healthy humans Background: Angiotensin-II (Ang-II) interacts with the sympathetic nervous system at central nervous blood pressure regulating structures including the baroreflex. It is unknown whether prolonged BP elevation mediated by high Ang-II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short Ang-II plasmatic half time of few seconds, thereby consolidating elevated BP and / or increased SNA in healthy humans. Methods: In a blinded cross-over design Ang-II or placebo (saline) was infused for a 6-hour period in 12 resting normotensive students (6 males) raising BP to borderline hypertensive levels. Between 60-120 minutes after the infusion period muscle sympathetic nerve activity (MSNA) was assessed microneurographically, and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Results: Infusion of Ang-II increased BP to borderline-hypertensive levels, as intended whereas heart rate remained unaltered. At baroreflex assessment (i.e. 60-120 minutes after end of infusion period), systolic BP was significantly higher compared to placebo (8.4±3.1 mmHg; p<0.05), whereas diastolic values were near equal between conditions. Baseline MSNA was neither decreased nor increased and baroreflex sensitivity to vasoactive drug challenge was not altered. Conclusion: Our results show that elevation of Ang-II plasma levels over 6-hours was able to increase systolic but not diastolic BP far beyond blood-mediated Ang-II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that Ang-II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input-signals without counter-regulatory response. Read More » Increased risk for the development of preeclampsia in obese pregnancies: Weighing in on the mechanisms Preeclampsia (PE) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNFα and AT1-AA, which promote endothelial dysfunction by reducing levels of the pro-vasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors. Read More » Placental Ischemia-induced Increases in Brain Water Content and Cerebrovascular Permeability: Role of TNF{alpha} Cerebrovascular complications and increased risk of encephalopathies are characteristic of preeclampsia and contribute to 40% of preeclampsia/ eclampsia related deaths. Circulating tumor necrosis factor α (TNFα) is elevated in preeclamptic women and infusion of TNFα into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNFα has a mechanistic role to promote preeclampsia, the impact of TNFα on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNFα contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNFα in pregnant rats (200 ng/day i.p, from gestational day 14 to 19), at levels to mimic those reported in preeclamptic women. TNFα increased mean arterial pressure (MAP, p<0.05) and brain water content in the anterior cerebrum (p<0.05), however, TNFα infusion had no effect on blood-brain barrier (BBB) permeability in the anterior cerebrum or posterior cerebrum. We then assessed the role of endogenous TNFα in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNFα receptor (etanercept, 0.8 mg/kg, sc.) on gestational day 18. Etanercept reduced placental ischemia-mediated increases in MAP, anterior brain water content (p<0.05), and BBB permeability (202±44% in placental ischemic rats to 101±28% of normal pregnant rats). Our results indicate that TNFα mechanistically contributes to cerebral edema by increasing BBB permeability and is an underlying factor in the development of cerebrovascular abnormalities associated with preeclampsia complicated by placental ischemia. Read More » Are Episodic and Chronic Migraine One Disease or Two? Abstract Migraine is a debilitating headache disorder that has a significant impact on the world population, in both economic and sociologic capacities. Migraine has two main categories: (1) chronic migraine (CM), defined as the patient having 15 or more headache days per month, with at least five attacks fulfilling measures for EM with aura or EM without aura, and (2) episodic migraine (EM), defined as less than 15 headache days per month. With this definition, CM can only exist in the presence of EM, and it questions whether the two are separate diseases. Migraine has a significant impact on the population, as each year, about 2.5 % of patients with EM develop new-onset CM (Manack et al., Curr Pain Headache Rep 15:70–78, 2011) (Loder et al. Headache 55:214–228, 2015), with certain risk factors being evident only with CM. In addition, there are comorbid diseases that are only associated with CM, suggesting two separate diseases rather than one. Differentiation in response to treatments, both preventive and abortive, demonstrates both a similarity and a difference in EM versus CM. Also, comparing the two processes based upon functional imaging has been a recent development, beginning to show a physiological difference in regional cortical thickness, cortical surface area, and regional volumes in patients with EM and CM. Evidence regarding whether EM and CM demonstrate one disease with a significant level of complication or if two independent processes is inconclusive, and additional research must be performed to further characterize their relationship. Read More » Are Episodic and Chronic Migraine One Disease or Two? Abstract Migraine is a debilitating headache disorder that has a significant impact on the world population, in both economic and sociologic capacities. Migraine has two main categories: (1) chronic migraine (CM), defined as the patient having 15 or more headache days per month, with at least five attacks fulfilling measures for EM with aura or EM without aura, and (2) episodic migraine (EM), defined as less than 15 headache days per month. With this definition, CM can only exist in the presence of EM, and it questions whether the two are separate diseases. Migraine has a significant impact on the population, as each year, about 2.5 % of patients with EM develop new-onset CM (Manack et al., Curr Pain Headache Rep 15:70–78, 2011) (Loder et al. Headache 55:214–228, 2015), with certain risk factors being evident only with CM. In addition, there are comorbid diseases that are only associated with CM, suggesting two separate diseases rather than one. Differentiation in response to treatments, both preventive and abortive, demonstrates both a similarity and a difference in EM versus CM. Also, comparing the two processes based upon functional imaging has been a recent development, beginning to show a physiological difference in regional cortical thickness, cortical surface area, and regional volumes in patients with EM and CM. Evidence regarding whether EM and CM demonstrate one disease with a significant level of complication or if two independent processes is inconclusive, and additional research must be performed to further characterize their relationship. Read More » Features of autosomal recessive nonsyndromic hearing impairment; a review to serve as a reference Abstract Objective nonsyndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counseling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient. Type of review traditional literature review. Data Source all articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed. Conclusion This review aims to serve as a summary and a reference for counseling purposes when a causative gene has been identified in a patient with a nonsyndromic autosomal recessively inherited sensorineural hearing impairment. This article is protected by copyright. All rights reserved. Read More » Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis Abstract Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need. Read More » Reply to: Comment on Dornoff et al.: re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck Read More » Comment on Dornoff et al.: Re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck Read More » Novel Use of a Percutaneous Endoscopic Gastrostomy Tube Fastener for Securing Silicone Tracheal Stents in Patients With Benign Proximal Airway Obstruction Background: Benign tracheal obstruction occurs for a variety of reasons. Bronchoscopic intervention includes silicone stent placement, which effectively maintains airway patency. Stent migration is a common complication, particularly when placed in the proximal trachea. We used a novel technique of securing tracheal stents with a percutaneous endoscopic gastrostomy tube fastener (PEG-TF) to prevent stent migration. The purpose of this study was to determine the feasibility of securing silicone stents in the proximal trachea with PEG-TF. Methods: Silicone stents were placed under general anesthesia by rigid bronchoscopy in 7 consecutive patients with inoperable benign proximal tracheal obstruction. PEG-TFs were placed under sterile conditions with direct bronchoscopic visualization. A needle was inserted through the anterior neck and silicone stent wall allowing stylet introduction of a T-fastener into the interior of the stent. The T-fastener was secured externally by a metal clamp and cotton pledget at the surface of the neck. Patients had routine outpatient follow-up and covered the external portion of the PEG-TF with a waterproof dressing when showering. Results: All 7 PEG-TFs were placed without complications. The PEG-TFs were left in for 1 to 25 weeks. Complications of the PEG-TF included localized cellulitis and suture breakage. No stent migration occurred while the fastener was in place. Two stents were removed within 2 weeks due to patient's difficulty tolerating the stent. Conclusions: Securing silicone stents in the proximal trachea is feasible and may prevent stent migration, but further study and possible modification of the PEG-TF device are needed. Read More » Impact of Pleural Manometry on the Development of Chest Discomfort During Thoracentesis: A Symptom-based Study Background: Routine manometry is recommended to prevent complications during therapeutic thoracentesis, but has not definitively been shown to prevent pneumothorax or reexpansion pulmonary edema. As chest discomfort correlates with negative pleural pressures, we aimed to determine whether the use of manometry could anticipate the development of chest discomfort during therapeutic thoracentesis. Methods: A retrospective chart review of 214 consecutive adults who underwent outpatient therapeutic thoracentesis at our institution between January 1, 2011 and June 30, 2013 was performed. We compared preprocedural to postprocedural discomfort (using a linear analog scale from 0 to 10) in patients undergoing thoracentesis with or without manometry. We used a multivariate model to adjust for possible confounders. Changes of dyspnea scores were also analyzed. Results: Manometry was performed in 82/214 patients (38%). On univariate and multivariate analyses, neither the change in chest discomfort nor dyspnea scores was significantly different in the manometry versus the control group (P=0.12 and 0.24, respectively). Similar results were also found in the subgroup of large-volume thoracentesis (P=0.32 for discomfort, P=1.0 for dyspnea). Conclusions: In our retrospective study, the use of manometry did not appear to anticipate the development of chest discomfort during therapeutic thoracentesis. Prospective studies are needed to confirm these findings. Read More » Exacerbation of SUNCT and SUNA syndromes during intravenous dihydroergotamine treatment: A case series Background The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) remains challenging in view of the limited understanding of their pathophysiological mechanisms. MethodsAn initial observation that patients with both chronic migraine (CM) or cluster headache (CH) and SUNCT/SUNA receiving intravenous dihydroergotamine (IV DHE) had complained of dramatic worsening of the latter led to review of the case notes of patients with CM or CH and co-existent SUNCT/SUNA seen between 2008 and 2013 and who had a trial of IV DHE. ResultsTwenty-four patients were identified. IV DHE was ineffective for SUNCT/SUNA in 16 patients, while one patient reported a marginal improvement. Five patients reported dramatic worsening of the SUNCT/SUNA. Moreover, two patients developed new-onset SUNA during their first IV DHE infusion. Out of these seven patients, those requiring repeated courses of IV DHE consistently experienced exacerbations of SUNCT/SUNA which were suppressed with IV lidocaine. ConclusionsDHE is an ineffective treatment option for SUNCT and SUNA. Physicians who intend to offer IV DHE to CH or CM patients should warn them that IV DHE could exacerbate and possibly even lead to a de novo onset of SUNCT/SUNA. In view of the reported worsening or new onset of SUNCT/SUNA in patients using dopamine agonists for the treatment of pituitary prolactinomas, we speculate that DHE might worsen or induce SUNCT and SUNA, at least in a sub-group of patients, through a perturbation in the dopaminergic system. Read More » Fulminant acephalgic giant cell arteritis with basal cerebral artery occlusion: A radiological and clinico-pathological study Read More » Rhinitis-induced anosmia leads to the disappearance of olfactory-triggered migraine attacks Read More » Meningeal norepinephrine produces headache behaviors in rats via actions both on dural afferents and fibroblasts Background Stress is commonly reported to contribute to migraine although mechanisms by which this may occur are not fully known. The purpose of these studies was to examine whether norepinephrine (NE), the primary sympathetic efferent transmitter, acts on processes in the meninges that may contribute to the pain of migraine. MethodsNE was applied to rat dura using a behavioral model of headache. Primary cultures of rat trigeminal ganglia retrogradely labeled from the dura mater and of rat dural fibroblasts were prepared. Patch-clamp electrophysiology, Western blot, and ELISA were performed to examine the effects of NE. Conditioned media from NE-treated fibroblast cultures was applied to the dura using the behavioral headache model. ResultsDural injection both of NE and media from NE-stimulated fibroblasts caused cutaneous facial and hindpaw allodynia in awake rats. NE application to cultured dural afferents increased action potential firing in response to current injections. Application of NE to dural fibroblasts increased phosphorylation of ERK and caused the release of interleukin-6 (IL-6). ConclusionsThese data demonstrate that NE can contribute to pro-nociceptive signaling from the meninges via actions on dural afferents and dural fibroblasts. Together, these actions of NE may contribute to the headache phase of migraine. Read More » Gender aspects of the relationship between migraine and cardiovascular risk factors: A cross-sectional evaluation in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Background The relationship between cardiovascular risk factors (CVRF) and migraine is controversial and might be different in both genders. These associations were evaluated in Brazilian middle-aged men and women from the Longitudinal Study of Adult Health (ELSA-Brasil). MethodsThe cross-sectional relationship between our main outcome, which was migraine headache (definite, probable and overall), and CVRF was evaluated in the total sample and according to gender. We calculated frequencies and odds ratios (95% CI) for this relationship using binary and multinomial logistic regression analyses in crude, age-adjusted and multivariable models adjusted by potential confounders. ResultsOf 14,953 individuals who completed the data about headache and CVRF, the frequency of one-year migraine was of 29.5% (22.5% in women and 7.0% in men). In the multivariable-adjusted regression analyses, an inverse association between hypertension (OR, 0.53; 95% CI, 0.36–0.79), metabolic syndrome (OR, 0.65; 95% CI, 0.43–0.99) and definite migraine were confirmed for men, but not for women. In the opposite direction, a positive association between migraine headaches (definite, probable and overall) and dyslipidemia (overall migraine OR, 1.25; 95% CI, 1.13–1.38) was observed only for women, but not for men. ConclusionsA gender influence on the relationship between migraine and CVRF was verified in the ELSA-Brasil. Read More » Can nitric oxide induce migraine in normal individuals? Introduction For many years, scientists have debated the possibility that an individual "migraine threshold" determines the likelihood with which individuals may express migraine attacks. DiscussionRecent discoveries provided evidence for both genetic and environmental influences on individual migraine expression. The question is whether any person may express a migraine attack given a sufficiently strong stimulus or provocation. Here, we reviewed and discussed the ability of nitric oxide to induce migraine-like attacks in normal individuals. ConclusionExperimental data show that normal individuals may develop a migraine-like attack and that the human data point to different ways of further developing existing animal and human models. Read More » Association between neurovascular contact and clinical characteristics in classical trigeminal neuralgia: A prospective clinical study using 3.0 Tesla MRI Background Previous studies demonstrated that a severe neurovascular contact (NVC) causing displacement or atrophy of the trigeminal nerve is highly associated with classical trigeminal neuralgia (TN). There are no studies describing the association between the clinical characteristics of TN and severe NVC. MethodsClinical characteristics were prospectively collected from consecutive TN patients using semi-structured interviews in a cross-sectional study design. We evaluated 3.0 Tesla MRI blinded to the symptomatic side. ResultsWe included 135 TN patients. Severe NVC was more prevalent in men (75%) compared to women (38%) (p < 0.001), and the odds in favor of severe NVC on the symptomatic side were 5.1 times higher in men compared to women (95% CI 2.3–10.9, p < 0.001). There was no difference between patients with and without severe NVC in age (≥60 years vs. <60) (OR 1.6 95% CI (0.8–3.4), p = 0.199) or duration of disease (p = 0.101). ConclusionsSevere NVC was much more prevalent in men than in women, who may more often have other disease etiologies causing or contributing to TN. Severe NVC was not associated with age or with duration of disease. Read More » Effects of peripheral FAAH blockade on NTG-induced hyperalgesia--evaluation of URB937 in an animal model of migraine Background Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)—the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. AimWe evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. ResultsDuring the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. ConclusionsThe data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine. Read More » Ambient air pollution, weather and daily emergency department visits for headache Background Headache is a common condition, and a common complaint leading patients to emergency departments (ED). There have been a number of studies of the effect of environmental factors on headache, such as weather and air pollutants. MethodsThis retrospective cohort study included data on daily ED visits with a chief complaint of headache in Soroka University Medical Center (SUMC) during 2002–2012. Data on weather and air pollutants were obtained from monitor station in Be'er-Sheva. To estimate the short-term effects of air pollution and temperature on number of daily headache ED visits, we applied generalized linear mixed models (GLMM). ResultsA total of 22,021 ED visits were included in the analysis. An increase in 5℃ in temperature was associated with an increase in ED visits, relative risk (RR) = 1.042, (95% CI 1.009; 1.076). RR for headache was associated with an increase in 10 units of nitrogen dioxide (NO2), RR = 1.110 (95% CI 1.057; 1.167), with a higher effect for older patients. DiscussionThe current findings give evidence of an association between air pollution, weather and ED visits for headache, especially for NO2. Short-term increases in air pollution exposure may trigger headache by increasing pulmonary and systemic inflammation, increasing blood coagulability or altering endothelial function. Read More » Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs Background During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. MethodsForty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1–C3) for infusions of 5-HT. ResultsThe external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. ConclusionsChronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action. Read More » Sleep disturbances among pregnant women with history of migraines: A cross-sectional study Background Migraine is associated with sleep disturbances in men and non-pregnant women. However, relatively little is known about sleep disturbances among pregnant migraineurs. We investigated sleep disturbances among pregnant women with and without history of migraine. MethodsThis cross-sectional study was conducted among 1324 women who were recruited during early pregnancy. Migraine diagnoses were based on the International Classification of Headache Disorders-II criteria. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to evaluate sleep-related characteristics including sleep duration, sleep quality, excessive daytime sleepiness, and other sleep traits. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs). ResultsMigraineurs were more likely than non-migraineurs to report short sleep duration (<6.5 hours) (AOR = 1.47, 95% CI 1.07–2.02), poor sleep quality (PSQI>5) (AOR = 1.73, 95% CI 1.35–2.23), and daytime dysfunction due to sleepiness (AOR = 1.51, 95% CI 1.12–2.02). Migraineurs were also more likely than non-migraineurs to report taking sleep medication during pregnancy (AOR = 1.71, 95% CI 1.20–2.42). Associations were generally similar for migraine with or without aura. The odds of sleep disturbances were particularly elevated among pre-pregnancy overweight migraineurs. ConclusionMigraine headache and sleep disturbances are common comorbid conditions among pregnant women. Read More » An unusual case of CSF leak following post-traumatic rupture of a sacral meningeal cyst Read More » Observations of backscatter from sand and gravel seafloors between 170 and 250 kHz Interpreting observations of frequency-dependence in backscatter from the seafloor offers many challenges, either because multiple frequencies are used for different observations that will later be merged or simply because seafloor scattering models are not well-understood above 100 kHz. Hindering the understanding of these observations is the paucity of reported, calibrated acoustic measurements above 100 kHz. This manuscript seeks to help elucidate the linkages between seafloor properties and frequency-dependent seafloor backscatter by describing observations of backscatter collected from sand, gravel, and bedrock seafloors at frequencies between 170 and 250 kHz and at a grazing angle of 45°. Overall, the frequency dependence appeared weak for all seafloor types, with a slight increase in seafloor scattering strength with increasing frequency for an area with unimodal, very poorly to moderately well sorted, slightly granular to granular medium sand with significant amounts of shell debris and a slight decrease in all other locations. Read More » REVIEWS OF ACOUSTICAL PATENTS Read More » Immunophenotyping of patients with oral squamous cell carcinoma in peripheral blood and associated tumor tissue Abstract The immune system is important for elimination of cancer cells. Tumors including oral squamous cell carcinoma (OSCC) are capable of escaping detection by host immune cells through apoptotic depletion of tumor-infiltrating lymphocytes (TILs). Circulating peripheral blood lymphocytes (PBLs) and corresponding TILs of tumor specimen were evaluated before and after curative tumor resection (n = 30) compared with PBLs of controls (n = 87). PBLs were characterized for the total number of T cells (CD3+), T helper cells (Th, CD3+/CD4+), regulatory T cells (Treg, CD4+/CD25+/CD127low), cytotoxic T cells (Tc, CD3+/CD8+), activated T cells (CD3+/HLA-DR+), and natural killer (NK) cells (CD3−/CD16+/CD56+). In tumor tissue, the prevalence of CD3+, CD4+, and CD8+ TILs was assessed using immunohistochemistry, whereas the incidence of apoptosis was assessed using terminal deoxynucleotidyl transferase deoxyuridinetriphosphate nick-end labeling (TUNEL) assay. In PBLs of pretreated OSCC patients, a highly significant decrease in total number of T cells (p = 0.0001), Th cells (p < 0.0001), Treg cells (p < 0.0001), Tc cells (p < 0.0001), and NK cells (p = 0.0037) were found compared with controls. Decreased PBLs of OSCC patients were correlated with decreased numbers of corresponding TILs, which were associated with increased detection of apoptosis in the tumor tissue. Compared with the controls, the total number of T cells remained unchanged after surgery but the total number of NK cells significantly increased. Standardized immunophenotyping of OSCC may help to identify patients likely to benefit from cancer immunotherapy strategies and/or chemoradiation. Finally, future attempts to enhance an effective tumor-reactive immune response by immunotherapy or vaccination should be made by promoting tumor-specific Th and/or Tc cell/NK cell responses. Read More » Interleukin-3 receptor α chain (CD123) is preferentially expressed in immature T-ALL and may not associate with outcomes of chemotherapy Abstract Interleukin-3 (IL-3) receptor α chain (CD123) plays an essential role in regulating the proliferation of hematopoietic stem cells. In the hematopoietic malignancies, CD123 expression has been found in acute myeloid leukemia (AML), B-precursor acute lymphoblastic leukemia (B-ALL), as well as dendritic cell malignancies. However, whether CD123 is also expressed in T-acute lymphoblastic leukemia (T-ALL) remains unknown. Using multi-parameter flow cytometry, we analyzed CD123 expression in 160 consecutive diagnostic T-ALL patients, including 88 pediatric T-ALL cases and 72 adult T-ALL cases. The minimal residual disease (MRD) was detected after one course of induction therapy to evaluate the treatment effects. CD123 expression was detected in 24 out of 88 (27 %) pediatric T-ALLs and 30 out of 72 (42 %) adult T-ALLs. Further analysis revealed that CD123 expression is associated with the maturation stage of T-ALLs. The frequencies of CD123-positive cases decreased from 83 to 40 % and 21 % in early T-precursor ALLs, T-precursor ALLs, and mature T-ALLs, respectively. Interestingly, we detected the CD4+CD8+ double-positive leukemic cells in 22 immature and 34 mature T-ALL patients. Of note, only 4 % of these patients expressed CD123. In addition, we found that 79 % of CD33+ and 64 % of CD117+ immature T-ALL patients also expressed CD123. However, CD123 expression did not predict the outcomes of the first course of induction therapy in T-ALL patients. In conclusion, we found that CD123 is preferentially expressed in immature T-ALL. Moreover, CD123 expression is strongly associated with cross-lineage expression of myeloid markers in early T-precursor ALL. Read More » MicroRNA-608 acts as a prognostic marker and inhibits the cell proliferation in hepatocellular carcinoma by macrophage migration inhibitory factor Abstract Human hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Research on HCC has recently focused on microRNAs (miRNAs) that play crucial roles in cancer development and progression of HCC. In this study, we aimed to analyze the expression and function of a metastasis-associated microRNA-608 (miR-608) in HCC. Samples of human HCC and matched adjacent normal tissues were surgically removed, and miR-608 expression and the pathological characteristics of HCC were investigated. In this study, we found that miR-608 expression was significantly reduced in HCC and its expression levels were highly associated with tumor size, differentiation, clinical stage, and overall and disease-free survival of HCC. Overexpression of miR-608 in HCC cell lines HepG2 and SK-Hep-1 inhibited cell proliferation by G1 arrest. Macrophage migration inhibitory factor (MIF), a potential target gene of miR-608, was inversely correlated with miR-608 expression in HCC tissues and cell lines. Furthermore, we demonstrated that MIF was directly regulated by miR-608 and the restoration of MIF expression reversed the inhibitory effects of miR-608 on HCC cell proliferation. Taken together, these findings collectively demonstrate that miR-608 exerts its anti-cancer function by directly targeting MIF in HCC, indicating a potential novel prognostic biomarker and therapeutic target for HCC. Read More » Diagnostic and prognostic potentials of KLF6 and HER3 expression alterations in cutaneous malignant melanoma Abstract In this study, we evaluated the presence of Kruppel-like factor 6 (KLF6) and human epidermal growth factor receptor 3 (HER3) in patients with cutaneous malignant melanoma and clinical significance of these markers. Real-time PCR was used to quantify the expression levels of KLF6 and HER3 in collected tissues. Our data revealed that no or low expression levels of KLF6 were detected in 38 of 48 patients (79.16 %) and moderate to high expression levels of KLF6 were detected in 10 patients (7 cases = moderate [14.58 %] and 3 cases = high [6.25 %]). Moreover, moderate to high expression levels of HER3 were detected in 29 of 48 patients (60.41 %; 11 cases = moderate [22.91 %] and 18 cases = high [37.5 %]), and no or low expression levels were detected in 19 patients (39.58 %). The KLF6 expression levels were lower in the malignant melanoma when compared to normal healthy tissues of the patients (P < 0.05). As matter of fact, the KLF6 levels were detected more frequently in normal healthy skin tissue when compared with cutaneous melanoma lesions. HER3 expression was higher in malignant melanoma compared to normal tissues (P < 0.05). Our findings showed that the KLF6 expression levels in cutaneous malignant melanoma were significantly linked to tumor node metastasis (TNM) stage (P < 0.003) and size of tumor (P < 0.03). We found that HER3 expression levels in cutaneous malignant melanoma were significantly associated with TNM stage (P < 0.015). Our results showed that KLF6 expression is decreased in cutaneous malignant melanoma than healthy control tissues, suggesting that KLF6 may have its role in tumor progression and may act as a prognostic marker. Moreover, HER3 may contribute to development of melanoma and progression. Read More » Methyl methanesulfonate induces necroptosis in human lung adenoma A549 cells through the PIG-3-reactive oxygen species pathway Abstract Methyl methanesulfonate (MMS) is an alkylating agent that can induce cell death through apoptosis and necroptosis. The molecular mechanisms underlying MMS-induced apoptosis have been studied extensively; however, little is known about the mechanism for MMS-induced necroptosis. Therefore, we first established MMS-induced necroptosis model using human lung carcinoma A549 cells. It was found that, within a 24-h period, although MMS at concentrations of 50, 100, 200, 400, and 800 μM can induce DNA damage, only at higher concentrations (400 and 800 μM) MMS treatment lead to necroptosis in A549 cells, as it could be inhibited by the specific necroptotic inhibitor necrostatin-1, but not the specific apoptotic inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-fmk). MMS-induced necroptosis was further confirmed by the induction of the necroptosis biomarkers including the depletion of cellular NADH and ATP and leakage of LDH. This necroptotic cell death was also concurrent with the increased expression of p53, p53-induced gene 3 (PIG-3), high mobility group box-1 protein (HMGB1), and receptor interaction protein kinase (RIP) but not the apoptosis-associated caspase-3 and caspase-9 proteins. Elevated reactive oxygen species (ROS) level was also involved in this process as the specific ROS inhibitor (4-amino-2,4-pyrrolidine-dicarboxylic acid (APDC)) can inhibit the necroptotic cell death. Interestingly, knockdown of PIG-3 expression by small interfering RNA (siRNA) treatment can inhibit the generation of ROS. Taken together, these results suggest that MMS can induce necroptosis in A549 cells, probably through the PIG-3-ROS pathway. Read More » E-cadherin mediates adhesion of Aspergillus fumigatus to non-small cell lung cancer cells Abstract A spergillus fumigatus is a widely distributed microorganism, and recently, A. fumigatus culture filtrate has been shown to trigger apoptotic cell death in several human cancer cell lines, including non-small lung cancer (NSCLC) cells, A549. Nevertheless, the molecular adhesion of A. fumigatus to these cancer cells to trigger cell death remains unknown. Here, we knocked down E-cadherin in A549 cells and examined its effects on A. fumigatus. The blastospores of A. fumigatus were incubated with the complete protein extracts from A549 cells, using an affinity purification procedure. Preliminary exploration of E-cadherin-interacting protein on the surface of Aspergillus fumigates was done by immunoprecipitation and mass spectrometry analysis. We found that the adhesion of the blastospores to A549 cells was significantly reduced by E-cadherin suppression in A549 cells, suggesting that E-cadherin of A549 cells may mediate the surface adhesion of A. fumigatus blastospore. Mass spectrometry (MS) analysis predicted two binding proteins for E-cadherin on A. fumigatus, AfA24A6.130c and XP_747789. Finally, the growth of E-cadherin-depleted A549 cells significantly increased by infection of A. fumigatus in vivo. Thus, our study suggests that E-cadherin mediates adhesion of A. fumigatus to NSCLC cells to trigger cell death and provides molecular evidence for the treatment of NSCLC with controlled A. fumigatus infection. Read More » The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study Abstract Delta-like ligand-4 (DLL4)-Notch signaling is known to play a pivotal role in the regulation of tumor angiogenesis. We had previously found that DLL4 was overexpressed, while Notch1 receptor, which binds to DLL4 during angiogenesis, was absent in the majority of human primary glioblastomas. Thus, DLL4-Notch signaling pathway in the regulation of tumor angiogenesis in primary glioblastoma remains unknown. Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for expression of components of DLL4-Notch signaling, vascular endothelial growth factor (VEGF), and microvessel density (MVD). Immunohistochemistry results showed that the positive staining of DLL4 and Notch4 was primarily distributed in tumor vascular endothelial cells but rarely detected in tumor cells. However, VEGF, hairy/enhancer of split-1 (HES1; a target gene of Notch signaling), and Notch1–3 expression was seen in both tumor vascular endothelial cells and tumor cells. Univariate analysis showed that the expression levels of VEGF and DLL4, HES1, and Notch4 in tumor endothelial cells were significantly associated with MVD in primary glioblastoma (P < 0.001). Binary logistic regression analysis showed that high expression levels of DLL4, HES1, and Notch4 in tumor endothelial cells were associated with a decrease of MVD in primary glioblastoma, while MVD increased with elevated VEGF expression in contrast. In addition, DLL4, Notch4, and HES1 expression were positively correlated in tumor vascular endothelial cells (P < 0.05). We conclude that the vascular DLL4-Notch4 signaling and VEGF signaling complementing each other plays an important role in the progression of tumor angiogenesis in primary glioblastoma. Graphical abstract A, positive staining of DLL4 in human kidney; B, positive staining of VEGF in human breast cancer; C, positive staining of CD34 in human lung cancer; D, positive staining of HES1 in human breast cancer; E-H, positive staining of Notch1-4: E-F in human lung cancer; G-H in human kidney Read More » MiR-429 regulates gastric cancer cell invasiveness through ZEB proteins Abstract MicroRNAs (miRNAs) play an essential role in the tumorigenesis of gastric carcinoma (GC). MiR-429 has been recently reported to inhibit GC growth; however, whether miR-429 may also regulate the invasion of GC cells is unknown. Here, we showed that miR-429 levels were significantly decreased and ZEB1 and ZEB2 levels were significantly increased in GC specimens, compared to the paired adjacent non-tumor gastric tissue. Moreover, the levels of miR-429 and ZEB1 or ZEB2 inversely correlated in GC specimens. Bioinformatics analyses showed that miR-429 targeted the 3′-untranslated region of both ZEB1 and ZEB2 mRNA to inhibit their translation, which was confirmed by luciferase reporter assay. Overexpression of miR-429 inhibited ZEB1/2-mediated cell invasiveness, while depletion of miR-429 augmented it. Together, our data suggest that miR-429 suppression in GC promotes ZEB1/2-mediated cancer cell invasion. Read More » Naringin inhibits the invasion and migration of human glioblastoma cell via downregulation of MMP-2 and MMP-9 expression and inactivation of p38 signaling pathway Abstract Gliomas are the most common and malignant primary brain tumors. They are associated with a poor prognosis despite the availability of multiple therapeutic options. Naringin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative and anti-cancer properties. However, there are no reports describing its effects on the invasion and migration of glioblastoma cell lines. Our results showed that the treatment of U251 glioma cell lines with different concentrations of naringin inhibited the invasion and migration of these cells. In addition, we revealed a decrease in the levels of matrix metalloproteinases (MMP-2) and (MMP-9) expression as well as proteinase activity in U251 glioma cells. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP-1) and (TIMP-2) was increased. Furthermore, naringin treatment decreased significantly the phosphorylated level of p38. Combined treatment with a p38 inhibitor (SB203580) resulted in the synergistic reduction of MMP-2 and MMP-9 expressions correlated with an increase of TIMP-1 and TIMP-2 expressions and the anti-invasive properties. However, p38 chemical activator (anisomycin) could block these effects produced by naringin, suggesting a direct downregulation of the p38 signaling pathway. These data suggest that naringin may have therapeutic potential for controlling invasiveness of malignant gliomas by inhibiting of p38 signal transduction pathways. Read More » Structure, Processes, and Retrospective Outcomes From an Intensive Comprehensive Aphasia Program Purpose This study describes the structure, processes, and outcomes of an intensive comprehensive aphasia program (ICAP). The aim was to identify treatment gains and determine if outcomes were significantly different between participants grouped according to severity and type of aphasia, and time postonset. Method Data from 74 first-time ICAP participants were analyzed. Pre- and posttreatment scores on the Western Aphasia Battery–Revised and other impairment and participation measures were compared using paired t tests. Analyses of variance were used to compare outcomes related to aphasia severity (severe, moderate, and mild aphasia), aphasia type (fluent, nonfluent), and chronicity (0–6 months postonset, 7–12 months postonset, and 12+ months postonset). Results Participants made significant changes on all impairment and participation measures. Large effect sizes were noted for one participation and three impairment measures. Medium effect sizes were noted for one impairment and three participation measures. There was no significant difference among groups on any factor. Conclusion ICAPs can have a significant effect on the language impairment and participation of people with aphasia, but further research is required to determine if the effect is comparable to other types of service delivery. Read More » Sound Production Treatment: Synthesis and Quantification of Outcomes Purpose This investigation was designed to provide a quantification and synthesis of a series of single-case experimental design investigations into the effects of sound production treatment, an articulatory-kinematic treatment for acquired apraxia of speech (AOS). The main purpose was to perform a meta-analysis of aggregated sound production treatment data in order to provide benchmarks to serve as indicators of magnitude of change. Additional analyses explored various factors influencing effect sizes and level of performance. Method Effect sizes were calculated for treated and untreated items for 24 participants across 10 investigations. Benchmarks were calculated as the quartiles of the distributions of the effect sizes. Correlational analyses were performed to examine (a) end-of-treatment performance relative to follow-up performance, (b) response of trained items relative to untrained items, and (c) effect size relative to participant variables. Results Effect sizes were predominantly large and positive; benchmarks for treated items were larger than those for untreated items. End of treatment and follow-up performance were positively correlated, and response generalization was positively correlated with AOS severity. Conclusion These benchmarks may assist in evaluating the effects of interventions for individuals with AOS utilizing similar outcome measures in both clinical and research settings. Read More » A combined endoscopic and external approach for extraction of large stones with preservation of parotid and submandibular glands Read More » Interventional sialendoscopy Read More » Issue Information Read More » Editor's Note: Trials and Tribulations Read More » Using Errors by Guard Honeybees (Apis mellifera) to Gain New Insights into Nestmate Recognition Signals Although the honeybee (Apis mellifera) is one of the world most studied insects, the chemical compounds used in nestmate recognition, remains an open question. By exploiting the error prone recognition system of the honeybee, coupled with genotyping, we studied the correlation between cuticular hydrocarbon (CHC) profile of returning foragers and acceptance or rejection behavior by guards. We revealed an average recognition error rate of 14% across 3 study colonies, that is, allowing a non-nestmate colony entry, or preventing a nestmate from entry, which is lower than reported in previous studies. By analyzing CHCs, we found that CHC profile of returning foragers correlates with acceptance or rejection by guarding bees. Although several CHC were identified as potential recognition cues, only a subset of 4 differed consistently for their relative amount between accepted and rejected individuals in the 3 studied colonies. These include a unique group of 2 positional alkene isomers (Z-8 and Z-10), which are almost exclusively produced by the bees Bombus and Apis spp, and may be candidate compounds for further study. Read More » Table of Contents Read More » Identification of Odorant Binding Proteins and Chemosensory Proteins in Antennal Transcriptomes of the Jumping Bristletail Lepismachilis y-signata and the Firebrat Thermobia domestica: Evidence for an Independent OBP-OR Origin Chemosensory protein (CSP) and gustatory receptor genes have been identified in all major arthropod groups. However, odorant binding proteins (OBP) and olfactory receptor genes are insect specific, suggesting that both gene families originated after the Hexapoda–Crustacea split (~470 million years ago). The seemingly parallel diversification of OBP and olfactory receptors has been suggested as coevolution between these genes after insect terrestrialization. To test this hypothesis we used the recently published transcriptomes of the jumping bristletail Lepismachilis y-signata and the firebrat Thermobia domestica to search for putative OBP and CSP sequences and analyzed their relationship to binding proteins of other insects and crustaceans. Our results suggest an evolution and expansion of OBPs as an adaptation to a terrestrial insect lifestyle, independently from the emergence of olfactory receptors. Read More » Editorial Board Read More » Cover Read More » Chemosensory Dysfunction in Alcohol-Related Disorders: A Joint Exploration of Olfaction and Taste Chemosensory (olfaction–taste) dysfunctions are considered as reliable biomarkers in many neurological and psychiatric states. However, experimental measures of chemosensory abilities are lacking in alcohol-dependence (AD) and Korsakoff Syndrome (KS, a neurological complication of AD), despite the role played by alcohol-related odors and taste in the emergence and maintenance of AD. This study thus investigated chemosensory impairments in AD and KS. Olfactory–gustatory measures were taken among 20 KS, 20 AD, and 20 control participants. Olfaction (odor detection–discrimination–identification) was assessed using the "Sniffin Sticks" battery and taste was measured using the "Taste Strips" task. Impairments were found for high-level olfaction in AD (odor discrimination) and KS (odor discrimination–identification), even after controlling for psychopathological comorbidities. Gustatory deficits were also observed in both groups, indexing a global deficit for chemosensory perception. Finally, the gradient of impairment between the successive disease stages for odor identification suggests that the hypothesis of a continuum between AD and KS regarding cognitive deficits can be generalized to chemosensory perception. AD and KS are thus characterized by deficits in chemosensory abilities, which could constitute a marker of the AD–KS transition. In view of its deleterious influence on everyday life, chemosensory dysfunction should also be taken into account in clinical settings. Read More » The Insect Chemoreceptor Superfamily Is Ancient in Animals The insect chemoreceptor superfamily consists of 2 gene families, the highly diverse gustatory receptors (GRs) found in all arthropods with sequenced genomes and the odorant receptors that evolved from a GR lineage and have been found only in insects to date. Here, I describe relatives of the insect chemoreceptor superfamily, specifically the basal GR family, in diverse other animals, showing that the superfamily dates back at least to early animal evolution. GR-Like (GRL) genes are present in the genomes of the placozoan Trichoplax adhaerens, an anemone Nematostella vectensis, a coral Acropora digitifera, a polychaete Capitella teleta, a leech Helobdella robusta, the nematode Caenorhabditis elegans (and many other nematodes), 3 molluscs (a limpet Lottia gigantea, an oyster Crassostrea gigas, and the sea hare Aplysia californica), the sea urchin Strongylocentrotus purpuratus, and the sea acorn Saccoglossus kowalevskii. While some of these animals contain multiple divergent GRL lineages, GRLs have been lost entirely from other animal lineages such as vertebrates. GRLs are absent from the ctenophore Mnemiopsis leidyi, the demosponge Amphimedon queenslandica, and 2 available chaonoflagellate genomes, so it remains unclear whether this superfamily originated before or during animal evolution. Read More » Subscriptions Read More » Cre-Mediated Recombination in Tas2r131 Cells--A Unique Way to Explore Bitter Taste Receptor Function Inside and Outside of the Taste System The type 2 taste receptors (Tas2rs) comprise a large family of G protein-coupled receptors that recognize compounds bitter to humans and aversive to vertebrates. Tas2rs are expressed in both gustatory and nongustatory tissues, however, identification and functional analyses of T2R-expressing cells have been difficult in most tissues. To overcome these limitations and to be able to manipulate Tas2r-expressing cells in vivo, we used gene-targeting to generate a Tas2r131-specific Cre knock-in mouse strain. We then employed a binary genetic approach to characterize Cre-mediated recombination in these animals and to investigate Tas2r131 expression during postnatal development. We demonstrate that a Cre-activated fluorescent reporter reliably visualizes Tas2r131-cells in gustatory tissue. We show that the onset of Tas2r131 as well as of α-Gustducin expression is initiated at different developmental stages depending on the type of taste bud. Furthermore, the number of Tas2r131- and α-Gustducin-expressing cells increased during postnatal development. Our results demonstrate that the Tas2r131-expressing cells constitute a subpopulation of α-Gustducin positive cells at all stages. We detected Tas2r131-expressing cells in several nongustatory tissues including lung, trachea, ovary, ganglia, and brain. Thus, the Tas2r131-Cre strain will help to dissect the functional role of Tas2r131 cells in both gustatory and nongustatory tissues in the future. Read More » Female Mice Avoid Male Odor from the Same Strain via the Vomeronasal System in an Estrogen-Dependent Manner Inbreeding avoidance is essential to providing offspring with genetic diversity. Females' mate choice is more crucial than males' for successful reproduction because of the high cost of producing gametes and limited chances to mate. However, the mechanism of female inbreeding avoidance is still unclear. To elucidate the mechanism underlying inbreeding avoidance by females, we conducted Y-maze behavioral assays using BALB/c and C57BL/6 female mice. In both strains, the avoidance of male urine from the same strain was lower in the low estrogen phase than in the high estrogen phase. The estrous cycle-dependent avoidance was completely prevented by vomeronasal organ (VNO) removal. To assess the regulation of the vomeronasal system by estrogen, the neural excitability was evaluated by immunohistochemistry of the immediate early gene products. Although estrogen did not affect neural excitability in the VNO, estrogen enhanced the neural excitability of the mitral cell layer in the AOB induced by urine from the cognate males. These results suggest that female mice avoid odor from genetically similar males in an estrogen-dependent manner via the vomeronasal system and the excitability of the mitral cells in the AOB is presumed to be regulated by estrogen. Read More » Immunohistochemical Analysis of Human Vallate Taste Buds The morphology of the vallate papillae from postmortem human samples was investigated with immunohistochemistry. Microscopically, taste buds were present along the inner wall of the papilla, and in some cases in the outer wall as well. The typical taste cell markers PLCβ2, GNAT3 (gustducin) and the T1R3 receptor stain elongated cells in human taste buds consistent with the Type II cells in rodents. In the human tissue, taste bud cells that stain with Type II cell markers, PLCβ2 and GNAT3, also stain with villin antibody. Two typical immunochemical markers for Type III taste cells in rodents, PGP9.5 and SNAP25, fail to stain any taste bud cells in the human postmortem tissue, although these antibodies do stain numerous nerve fibers throughout the specimen. Car4, another Type III cell marker, reacted with only a few taste cells in our samples. Finally, human vallate papillae have a general network of innervation similar to rodents and antibodies directed against SNAP25, PGP9.5, acetylated tubulin and P2X3 all stain free perigemmal nerve endings as well as intragemmal taste fibers. We conclude that with the exception of certain molecular features of Type III cells, human vallate papillae share the structural, morphological, and molecular features observed in rodents. Read More » Articles highlighted Read More » Frequency Importance Functions in Quiet and Noise for Adults With Cochlear Implants Purpose Several studies have been devoted to understanding the frequency information available to adult users of cochlear implants when listening in quiet. The objective of this study was to construct frequency importance functions for a group of adults with cochlear implants and a group of adults with normal hearing both in quiet and in a +10 dB signal-to-noise ratio. Method Two groups of adults, 1 with cochlear implants and 1 with normal hearing, were asked to identify nonsense syllables in quiet and in the presence of 6-talker babble while "holes" were systematically created in the speech spectrum. Frequency importance functions were constructed. Results Results showed that adults with normal hearing placed greater weight on bands 1, 3, and 4 than on bands 2, 5, and 6, whereas adults with cochlear implants placed equal weight on all bands. The frequency importance functions for each group did not differ between listening in quiet and listening in noise. Conclusions Adults with cochlear implants assign perceptual weight toward different frequency bands, though the weight assignment does not differ between quiet and noisy conditions. Generalizing these results to the broader population of adults with implants is constrained by a small sample size. Read More » Audiometric Thresholds: Stimulus Considerations in Sound Field and Under Earphones Purpose This study evaluates a new stimulus, FREquency Specific Hearing assessment (FRESH) noise, to obtain hearing thresholds and reviews the potential pitfalls of using narrow band noise. Method Twelve adults with simulated gradually sloping hearing loss and 12 adults with steeply sloping hearing loss participated. Hearing thresholds were measured in sound field and under a supraaural earphone for FRESH noise, warbled tones, and narrowband noise. Pure-tone thresholds were also measured under the supraaural earphone. Results FRESH noise thresholds were similar to pure-tone and warbled-tone thresholds regardless of audiometric configuration. For the group with gradually sloping hearing loss, thresholds obtained with narrowband noise were approximately 4 dB better than those obtained with the other test stimuli. For the group with steeply sloping hearing loss, narrowband noise significantly underestimated hearing thresholds—the steeper the hearing loss, the greater the underestimation. Conclusions When hearing loss is suspected, FRESH noise is appropriate for accurately determining audiometric thresholds in sound field and under earphones. A wider band, attention-getting stimulus such as narrowband noise can result in thresholds that are inaccurate. Clinical decision making regarding choice of test stimulus is discussed. Read More » Resource Paper: Sonoluminescence Sonoluminescence is the production of electromagnetic radiation, much of it in the form of visible light, that is emitted from a gas-filled cavity that has grown and collapsed under the influence of a varying pressure field. This resource paper provides a guide to the literature of sonoluminescence, from its early history to the present. Read More » On cross-language consonant identification in second language noise Speech perception in everyday conditions is highly affected by the presence of noise of a different nature. The presence of overlapping speakers is considered an especially challenging scenario, as it introduces both energetic and informational masking. The efficacy of the masking also depends on the familiarity with the language of both the target and masking stimuli. This work analyses consonant identification by non-native English speakers in N-talker natural babble noise and babble-modulated noise, by varying the number of talkers in the babble. In particular, only English consonants that are also present in all the native languages of the subjects are used. As the subjects are familiar with the consonants used, this study can be considered a step towards a deeper analysis on perception of first language speech in the presence of second language maskers. Read More »