The topic of e-cigarettes and oral health is of utmost importance and we were pleased to see this addressed by a recent review that was published in Oral Diseases (Javed et al., 2017). However, we would like to raise several concerns with this review.
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Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.
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Improper patient selection for septal surgery often has been found to result in therapeutic failure, and there needs to be an objective assessment of nasal obstruction before the surgery and for postoperative follow-up that can be applied in the routine otolaryngology practice. The purpose of this study is to assess the usefulness of a cost-effective device for objective measurement of the nasal airway partitioning in selecting patients for septal surgery and for postoperative outcome evaluation. A hospital-based, prospective, observational study was carried out in a tertiary-care teaching institution involving 74 patients waiting for septal surgery. Each patient was exposed to subjective assessment of nasal obstruction by the Nasal Obstruction Symptom Evaluation (NOSE) scale and objective measurement by Nasal Partitioning Ratio (NPR) using a new device, Nasal Airway Partition Meter (NAPM), once before and twice after surgery. Overall, average NOSE score and NPR values were 66.42 ± 9.42 and 0.57 ± 0.18, respectively, at preoperative assessment (correlation coefficient 0.441). Sixty of the 74 patients had high values for both NPR and NOSE scores (Group 1), but in the remaining 14, NPR values were found to be lower despite high NOSE scores (Group 2). Postsurgery, the NOSE score and NPR values were significantly reduced in Group 1. In contrast, participants in Group 2 showed no alteration in the values of both the parameters after the same operative maneuver. However, 2 patients in Group 1 had NOSE score and NPR values unaltered, while 1 patient in Group 2 had a reduced NOSE score after surgery. Therefore, the validity of the new equipment was calculated to be 96.7% sensitive and 92.9% specific to identify patients who needed to undergo septal surgery for their nasal obstruction. It can be deduced from the present study that NAPM can be a cost-effective device for clinicians to objectively measure nasal airway obstruction and screen patients for septal surgery.
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Fiddler's neck is a common dermatologic condition associated with instrument use in violin and viola players. It typically manifests as a submandibular and/or supraclavicular lesion. It is a benign condition, but it may be mistaken for lymphedema or a salivary gland malignancy. Otolaryngologists who treat patients with fiddler's neck should be aware of appropriate management protocols and the need to avoid surgical excision. We obtained informed consent from 3 violinists to present their cases as specific examples of fiddler's neck. In addition, we present a literature review based on our PubMed search for articles about this instrument-induced dermatitis. The literature suggests that submandibular fiddler's neck is caused by mechanical pressure and shear stress on the skin and that it can present as erythema, scarring, edema, and lichenification. Supraclavicular fiddler's neck, on the other hand, is caused by allergic contact dermatitis, and it can present as an eczematous, scaly, and/or vesicular lesion. In most cases, a good history (especially of string instrument use), physical examination, and a patch test are sufficient to diagnose this condition. Management of fiddler's neck includes a topical steroid, proper instrument handling, neck padding, changing the instrument's materials, and/or reducing the amount of playing time. Surgical excision is usually not advisable.
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To define the most successful and efficient manner to perform venous microvascular anastomoses, the effectiveness of mechanical venous anastomosis in head and neck microvascular reconstruction is reviewed. Head and neck reconstruction with free flap techniques has become the norm and gold standard for large defects. This retrospective, multicenter case series of a single microvascular surgeon's experience with mechanical venous anastomoses specifically assessed the effectiveness of head and neck reconstruction and the complications associated with it. Data were collected from two separate academic centers and are reported from a consecutive series of patients over the course of 10 years. All patients underwent microvascular reconstruction of the head and neck region using venous couplers and flap survival. Flap survival was greater than 98% using mechanical venous couplers as the primary means for venous outflow in this series of 402 consecutive patients and 431 total microvascular flaps. Venous couplers were performed in every instance. The study shows that mechanical venous anastomosis provides a highly effective and efficient means for venous outflow in head and neck microvascular reconstruction, and should be considered equivalent to the gold standard suture technique, even in the most difficult cases.
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Neoplasms located in the parotid region, temporal bone, infratemporal fossa, and lateral skull base represent a challenge due to their difficult anatomic location and surrounding neurovascular structures. A variety of surgical approaches are appropriate to access this area, although several of them can place the auricular blood supply in danger. If the auricular blood supply is compromised, ischemia and, eventually, avascular necrosis of the auricle can occur. Auricular necrosis often can cause patients a delay in adjuvant radiation therapy and result in the need for additional reconstructive procedures. Therefore, it is imperative to identify risk factors associated with the development of this disabling complication. We conducted a retrospective review of 32 individuals undergoing treatment of benign and malignant lesions in the parotid gland, infratemporal fossa, and lateral skull base. To identify potential risk factors for auricular necrosis, the patients were analyzed based on the type of neoplasm (malignant or benign), risk factors affecting blood flow (diabetes mellitus, smoking history, prior radiation, prior surgery), body mass index, and the length of surgery. In our population examined, 3 instances of auricular necrosis occurred. None of the potential risk factors proved to be statistically significant (although malignant pathology approached significance at p = 0.07). Two of the patients required an auriculectomy with reconstruction. The third had multiple postoperative clinic visits for surgical debridement. Although no potential risk factors were statistically significant, surgeons should remain cognizant of the auricular blood supply while performing surgery via preauricular and postauricular approaches to this area.
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The auricle, with its supersaturation of blood uric acid due to decreased temperature and reduced blood flow, is prone to develop gouty tophi.
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Most patients present with a mobile, painless midline neck mass, usually inferior to the hyoid bone, showing movement with tongue protrusion.
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Most of the bleeding in posterior epistaxis originates from the posterior end of the lateral aspect of the middle and inferior turbinates and the lateral wall of the meatuses.
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Amphotericin B deoxycholate (ABD) is the best therapeutic agent available for the treatment of most systemic fungal infections. However, some untoward adverse effects such as nephrotoxicity may limit its appropriate therapeutic use. We conducted a randomized, controlled trial ofthe infusion of fat emulsion (Intralipid) shortly after the infusion of ABD to evaluate its effects on reducing ABD-associated nephrotoxicity. Our patient population was made up of 31 patients who were randomized into two groups: an intervention group (n = 16) and a control group (15 patients). There were no statistically significant differences between the two groups in demographic or clinical variables. All patients received 1mg/kg/day of ABD in dextrose 5%. In addition, the patients in the intervention arm received Intralipid 10%, which was started as soon as possible within 1 hour after the infusion of ABD. ABD-associated nephrotoxicity was defined as a minimum 50% increase in baseline serum creatinine to a minimum of 2mg/dl. We also measured daily serum creatinine changes during the first 2 weeks of treatment, and we compared some other relevant indices of renal function, as well as ABD-related hypokalemia. We found no statistically significant differences between the two treatments in terms of ABD-associated nephrotoxicity or any of the other indices. We conclude that the administration of Intralipid 10% early after infusion of ABD in dextrose 5% does not have any effect in decreasing ABD-associated nephrotoxicity or hypokalemia.
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HRPM biofeedback therapy may be particularly beneficial for patients with sensory deficits by providing a visual mechanism for accurate exercise and strategy implementation.
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Atypical parathyroid adenomas are infrequently encountered and can present a diagnostic challenge, as they share overlapping clinical and histologic features with parathyroid carcinoma.
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Plasmoblastic lymphoma is a rare and aggressive subtype of diffuse large B cell lymphoma, which occurs usually in the jaw of immunocompromised subjects.
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Nicotinamide (vitamin B3) has a range of photoprotective effects in vitro and in vivo; it enhances DNA repair, reduces UV radiation-induced suppression of skin immune responses, modulates inflammatory cytokine production and skin barrier function and restores cellular energy levels after UV exposure. Pharmacological doses of nicotinamide have been shown to reduce actinic keratoses and nonmelanoma skin cancer incidence in high-risk individuals, making this a nontoxic and accessible option for skin cancer chemoprevention in this population.
Aleta Pupovac | Kim L Good-Jacobson
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Extended Endonasal Transsellar Transplanum Endoscopic Removal of Craniopharyngioma
Fan Zhao, Walavan Sivakumar, Amy Eisenberg, Garni Barkhoudarian, Chester F. Griffiths, Daniel F. Kelly
Management of Complex Airway Caused by Massive Retropharyngeal Goiter
Seth Kay, Mark A. Fritz, Gregory N. Postma, David J. Terris
Transoral Endoscopic Total Parathyroidectomy in Renal Hyperparathyroidism Patient
Thanyawat Sasanakietkul, Wirada Wandee, Pornpeera Jitpratoom, Angkoon Anuwong
Transoral Endoscopic Thyroidectomy Vestibular Approach
Thanyawat Sasanakietkul, Tobias Carling
Robotic Bilateral Cortical-Preserving Adrenalectomy in an MEN2A Patient with Steroid Allergy
Nisar Zaidi, Zanati Ahmed, Jesse Gutnick, Eren Berber
The post VideoEndocrinology™ High-Impact Videos appeared first on American Thyroid Association.
Juvederm Vollure XC (Allergan) is indicated for injection into facial tissue to correct moderate to severe facial wrinkles and folds in adults older than age 21 years.
FDA Approvals
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by Hyo Jeong Kim, So Young Kim, Jee Young Kwon, Yeo Jin Kim, Seung Hun Kang, Won-Hee Jang, Jun Ho Lee, Myung-Whan Suh, Jae-Jun Song, Young Rok Seo, Moo Kyun Park
No abstract available
Neurologic deterioration following acute injury to the central nervous system may be amenable to pharmacologic intervention, although, to date, no such therapy exists. Ketamine is an anesthetic and analgesic emerging as a novel therapy for a number of clinical entities in recent years, including refractory pain, depression, and drug-induced hyperalgesia due to newly discovered mechanisms of action and new application of its known pharmacodynamics. In this focused review, the evidence for ketamine as a neuroprotective agent in stroke, neurotrauma, subarachnoid hemorrhage, and status epilepticus is highlighted, with a focus on its applications for excitotoxicity, neuroinflammation, and neuronal hyperexcitability. Preclinical modeling and clinical applications are discussed.
No abstract available
No abstract availableNKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA-binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell–specific ablation of the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2–deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog–deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and periphery.
Patients with mutations in inducible T cell kinase (ITK) are susceptible to viral infections, particularly EBV, suggesting that these patients have defective function of CD8+ CTLs. In this study, we evaluated the effects of ITK deficiency on cytolysis in murine CTLs deficient in ITK, and both human and murine cells treated with an ITK inhibitor. We find that ITK deficiency leads to a global defect in the cytolysis of multiple targets. The absence of ITK both affected CTL expansion and delayed the expression of cytolytic effectors during activation. Furthermore, absence of ITK led to a previously unappreciated intrinsic defect in degranulation. Nonetheless, these defects could be overcome by early or prolonged exposure to IL-2, or by addition of IL-12 to cultures, revealing that cytokine signaling could restore the acquisition of effector function in ITK-deficient CD8+ T cells. Our results provide new insight into the effect of ITK and suboptimal TCR signaling on CD8+ T cell function, and how these may contribute to phenotypes associated with ITK deficiency.
Adaptive immunity depends on mature thymocytes leaving the thymus to enter the bloodstream and the trafficking of T cells through lymphoid organs. Both of these require heterotrimeric Gαi protein signaling, whose intensity and duration are controlled by the regulator of G protein signaling (RGS) proteins. In this study, we show that RGS protein/Gαi2 interactions are essential for normal thymocyte egress, T cell trafficking, and homeostasis. Mature thymocytes with a Gαi2 mutation that disables RGS protein binding accumulated in the perivascular channels of thymic corticomedullary venules. Severe reductions in peripheral naive CD4+ T cells and regulatory T cells occurred. The mutant CD4+ T cells adhered poorly to high endothelial venules and exhibited defects in lymph node entrance and egress. The kinetics of chemokine receptor signaling were disturbed, including chemokine- induced integrin activation. Despite the thymic and lymph node egress defects, sphingosine-1-phosphate signaling was not obviously perturbed. This study reveals how RGS proteins modulate Gαi2 signaling to facilitate thymocyte egress and T cell trafficking.
Mycosis fungoides (MF) is characterized by a switch from indolent behaviour in the early stages to a worse clinical outcome in the advanced ones. Recently, various studies have investigated the role the microenvironment might play in such a switch. We have analysed the distribution of Langerhans cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells in 46 MF cases in various stages, aiming to assess whether changes occur from early to advanced stage. We have investigated the number of langerin, CD303 and arginase-1 positive cells and their distribution at high power. Data were analysed using t test for continuous variables, χ 2 tests or Fisher's exact test for categorical variables, as well as analysis of covariance. In comparing stages IA/B to IIB, we observed a significant decrease in Langerhans cells (p value 0.03) and a significant increase in CD303 and arginase-1 positive cells (p value <0.01 for both markers). Furthermore, a significant increase in Langerhans cells only was observed in stage IIB in comparison to stage III (p = 0.02), while in stage IV, a significant decrease in Langerhans cells was noted in comparison to stage III (p = 0.02). Our data suggest that changes in the microenvironment might influence disease progression, especially from stages IA/B to IIB, opening new scenarios in MF therapy.
No abstract available
No abstract available
BACKGROUND: It remains unknown whether continuous or scheduled intermittent bolus local anesthetic administration is preferable for transversus abdominis plane (TAP) catheters. We therefore tested the hypothesis that when using TAP catheters, providing local anesthetic in repeated bolus doses increases the cephalad-caudad cutaneous effects compared with a basal-only infusion. METHODS: Bilateral TAP catheters (posterior approach) were inserted in 24 healthy volunteers followed by ropivacaine 2 mg/mL administration for a total of 6 hours. The right side was randomly assigned to either a basal infusion (8 mL/h) or bolus doses (24 mL administered every 3 hours for a total of 2 bolus doses) in a double-masked manner. The left side received the alternate treatment. The primary end point was the extent of sensory deficit as measured by cool roller along the axillary line at hour 6 (6 hours after the local anesthetic administration was initiated). Secondary end points included the extent of sensory deficit as measured by cool roller and Von Frey filaments along the axillary line and along a transverse line at the level of the anterior superior iliac spine at hours 0 to 6. RESULTS: Although there were statistically significant differences between treatments within the earlier part of the administration period, by hour 6 the difference in extent of sensory deficit to cold failed to reach statistical significance along the axillary line (mean = 0.9 cm; SD = 6.8; 95% confidence interval –2.0 to 3.8; P = .515) and transverse line (mean = 2.5 cm; SD = 10.1; 95% confidence interval –1.8 to 6.8; P = .244). Although the difference between treatments was statistically significant at various early time points for the horizontal, vertical, and estimated area measurements of both cold and mechanical pressure sensory deficits, no comparison remained statistically significant by hour 6. CONCLUSIONS: No evidence was found in this study involving healthy volunteers to support the hypothesis that changing the local anesthetic administration technique (continuous basal versus hourly bolus) when using ropivacaine 0.2% and TAP catheters at 8 mL/h and 24 mL every 3 hours significantly influences the cutaneous effects after 6 hours of administration. Additional research is required to determine whether changing variables (eg, local anesthetic concentration, basal infusion rate, bolus dose volume, and/or interval) would provide different results.No abstract available
BACKGROUND: Both pharmacologic and genetic approaches have been used to study the involvement of the muscarinic acetylcholine system in the regulation of chronic pain. Previous studies suggest that the M2 and M4 subtypes of muscarinic acetylcholine receptors (mAChRs) are important targets for the development of chronic pain. (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) has agonist effects on muscarinic M2 and M4 receptors and antagonist effects on muscarinic M1, M3, and M5 receptors. However, its analgesic effects have been less studied. METHODS: Male C57B L/6 mice were anesthetized, and left common peroneal nerve (CPN) ligation was performed to induce neuropathic pain. Before and after the application of PTAC systemically or specifically to the anterior cingulate cortex (ACC), the withdrawal thresholds to mechanical stimulation and static weight balance were measured, and the effects of PTAC on the conditioned place preference (CPP) were further evaluated. Western blotting was used to examine the expression of M1 and M2 in the striatum, ACC, and ventral tegmental area. RESULTS: The application of PTAC ([i.p.] intraperitoneal injection) increased the paw withdraw threshold in both the early (0.05 mg/kg, mean difference [95% confidence interval, CI]: 0.19 [0.05–0.32]; 0.10 mg/kg: mean difference [95% CI]: 0.34 [0.22–0.46]) and the late phases (0.05 mg/kg: mean difference [95% CI]: 0.45 [0.39–0.50]; 0.1 mg/kg: mean difference [95% CI]: 0.44 [0.37–0.51]) after nerve injury and rebalanced the weight distribution on the hind paws of mice (L/R ratio: before, 0.56 ± 0.03. 0.05 mg/kg, 1.00 ± 0.04, 0.10 mg/kg, 0.99 ± 0.03); however, it failed to induce place preference in the CPP (0.05 mg/kg, 2-way analysis of variance, P > .05; 0.2 mg/kg, 2-way analysis of variance, P > .05,). At the same doses, the analgesic effects at D3–5 lasted longer than the effects at D14–16. This may be due to the down-regulation of the M2 and M1 in tested brain regions. CONCLUSIONS: These observations suggested that PTAC has analgesic effects on the neuropathic pain induced by nerve injury.
BACKGROUND: To examine whether exposure to general anesthesia for procedures at age ≥40 years is associated with prevalent mild cognitive impairment (MCI) in the elderly. METHODS: A case–control study nested within a population-based cohort. Olmsted County, Minnesota, residents, aged 70–91 years, underwent baseline evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychologic testing. Individuals identified with MCI (cases) at enrollment were matched 1:2 on age, sex, education, and apolipoprotein genotype with participants who were cognitively normal at the time of the index visit. Medical records from age 40 years until the index visit were reviewed to determine exposures to general anesthesia. Conditional logistic regression, taking into account the matched set study design and adjusting for MCI risk factors, was used to assess whether exposure to anesthesia after the age of 40 years was associated with prevalent MCI. RESULTS: A total of 387 Mayo Clinic Study of Aging participants (219 males, 168 females) were diagnosed with MCI at enrollment with mean age of 81 ± 5 years. Exposure to general anesthesia after the age of 40 years was not significantly associated with prevalent MCI when analyzed as a dichotomous variable (any versus none, adjusted odds ratio, 0.97 [95% confidence interval, 0.68–1.40]) or the number of exposures (odds ratio, 1.13 [0.74–1.72], 0.81 [0.53–1.22], and 1.03 [0.67–1.58] for 1, 2–3, and ≥4 exposures, respectively, with no exposure as the reference). Similar results were obtained for exposure to anesthesia after the age of 60 years and during 5, 10, and 20 years before the first visit. CONCLUSIONS: Exposure to general anesthesia for procedures at age ≥40 years was not associated with prevalent MCI in the elderly.
Older adults make up an ever-increasing number of patients presenting for surgery, and a significant percentage of these patients will be frail. Frailty is a geriatric syndrome that has been conceptualized as decreased reserve when confronted with stressors, although the precise definition of frailty has not been easy to standardize. The 2 most popular approaches to define frailty are the phenotypic approach and the deficit accumulation approach, although at least 20 tools have been developed, which has made comparison across studies difficult. In epidemiologic studies, baseline frailty has been associated with poor outcomes in both community cohorts and hospitalized patients. Specifically in cardiac surgery (including transcatheter aortic valve implantation procedures), frailty has been strongly associated with postoperative mortality and morbidity, and thus frailty likely improves the identification of high-risk patients beyond known risk scores. For perioperative physicians then, the question arises of how to incorporate this information into perioperative care. To date, 2 thrusts of research and clinical practice have emerged: (1) preoperative identification of high-risk patients to guide both patient expectations and surgical decision-making; and (2) perioperative optimization strategies for frail patients. However, despite the strong association of frailty and poor outcomes, there is a lack of well-designed trials that have examined perioperative interventions with a specific focus on frail patients undergoing cardiac surgery. Thus, in many cases, principles of geriatric care may need to be applied. Further research is needed to standardize and implement the feasible definitions of frailty and examine perioperative interventions for frail patients undergoing cardiac surgery.Paragangliomas (PGL) develop from the parasympathetic system in the head and neck (HN) and arise primarily in four distinct areas: Carotid body, vagal, middle ear, and larynx. Globally, the diagnosis and morphologic features are the same regardless of anatomic site, however the incidence, frequency of genetic alterations/syndromes and differential diagnosis vary. It is now recognized that nearly 40% of all HN PGLs are hereditary, including a significant subset without a known family history. Now pathologists are central to the evaluation for diagnosis and further management of patients with HNPGLs. Specifically, SDHB immunohistochemical evaluation is an excellent screening tool to detect tumors with alterations in the SDH family of genes that represent the majority of hereditary cases in HNPGL. Similarly, SDHB immunohistochemical analysis allows for screening of PGL syndrome associated tumors (gastrointestinal stromal tumor (GIST), renal cell carcinoma (RCC), and pituitary adenomas) that have now been linked by their overlapping gene alterations. Awareness of the spectrum of these syndromes, and their associated tumors, positions the pathologist to augment patient care and surveillance.
Sinonasal (Schneiderian) papillomas are benign neoplasms that arise in the sinonasal tract. Since their initial descriptions, sinonasal papillomas have triggered debate regarding their classification, etiology, rate or predictors of malignant transformation, and other issues. While significant strides have been made in recent years, there are still aspects of sinonasal papillomas that remain unclear even now. This review will serve to update the practicing pathologist on the current understanding of sinonasal papillomas.
Intestinal-type adenocarcinoma is the second most frequent sinonasal adenocarcinoma. High incidence of these tumors is seen among workers with occupational wood dust exposure, particularly of hardwood dusts. Intestinal-type adenocarcinoma has striking histomorphologic and immunophenotypic similarities with colorectal adenocarcinomas, but on the level of molecular pathologic mechanisms these tumors have their own specific features different from gastrointestinal tumors. This article provides an update on current histopathologic classification of intestinal-type adenocarcinomas, their immunophenotypic properties, recent advances in molecular pathologic features and differential diagnostic considerations.
More than 15 years ago, seminal studies by Dr. E. Leon Barnes and colleagues transformed our understanding of salivary duct carcinoma (SDC) and, in doing so, paved the way for contemporary diagnostic and therapeutic approaches to this aggressive salivary adenocarcinoma. In particular, attention to the apocrine phenotype of SDC and expression of androgen receptor (AR) by immunohistochemistry has improved the diagnostic accuracy and showed how SDC can be reliably distinguished from its morphologic mimics (i.e., other salivary gland carcinomas with high grade transformation, low grade cribriform cystadenocarcinoma, and squamous cell carcinomas involving parotid). Furthermore, the observation that SDC shares AR expression with prostate cancer and apocrine breast cancer foresaw the discovery of common molecular alterations between SDC and these tumor types and draw attention to androgen deprivation therapy for SDC patients.
Oxygen is supplied as a supportive treatment for patients suffering from acute respiratory distress syndrome. Unfortunately, high oxygen concentration increases reactive oxygen species generation, which causes DNA damage and ultimately cell death in the lung. Although 8-oxoguanine-DNA glycosylase (OGG-1) is involved in repairing hyperoxia-mediated DNA damage, the underlying molecular mechanism remains elusive. In this study, we report that ogg-1–deficient mice exhibited a significant increase of proinflammatory cytokines (TNF-α, IL-6, and IFN-) in the lung after being exposed to 95% oxygen. In addition, we found that ogg-1 deficiency downregulated (macro)autophagy when exposed to hyperoxia both in vitro and in vivo, which was evident by decreased conversion of LC3-I to LC3-II, reduced LC3 punctate staining, and lower Atg7 expression compared with controls. Using a chromatin immunoprecipitation assay, we found that OGG-1 associated with the promoter of Atg7, suggesting a role for OGG1 in regulation of Atg7 activity. Knocking down OGG-1 decreased the luciferase reporter activity of Atg7. Further, inflammatory cytokine levels in murine lung epithelial cell line cells were downregulated following autophagy induction by starvation and rapamycin treatment, and upregulated when autophagy was blocked using 3-methyladenine and chloroquine. atg7 knockout mice and Atg7 small interfering RNA-treated cells exhibited elevated levels of phospho–NF-B and intensified inflammatory cytokines, suggesting that Atg7 impacts inflammatory responses to hyperoxia. These findings demonstrate that OGG-1 negatively regulates inflammatory cytokine release by coordinating molecular interaction with the autophagic pathway in hyperoxia-induced lung injury.
Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that focal sites of inflammation around dying adipocytes, so-called crown-like structures, exhibit a unique microenvironment for macrophage proliferation. Interestingly, locally proliferating macrophages were not classically activated (M1), but they exhibited a rather alternatively activated (M2) immune phenotype. In this study, we established organotypic cell cultures of AT explants to study the impact of cytokine treatment on local ATM proliferation, without the bias of early monocyte recruitment. We show that exposure of AT to Th2 cytokines, such as IL-4, IL-13, and GM-CSF, stimulates ATM proliferation, whereas Th1 cytokines, such as TNF-α, inhibit local ATM proliferation. Furthermore, AT from obese mice exhibits an increased sensitivity to IL-4 stimulation, indicated by an increased phosphorylation of STAT6. In line with this, gene expression of the IL-4 receptor (Il4ra) and its ligand IL-13 are elevated in AT of obese C57BL/6 mice. Most importantly, Il4ra expression and susceptibility to IL-4 or IL-13 treatment depend on IL-6 signaling, which seems to be the underlying mechanism of local ATM proliferation in obesity. We conclude that IL-6 acts as a Th2 cytokine in obesity by stimulating M2 polarization and local ATM proliferation, presumably due to upregulation of the IL-4 receptor α.
Selective suppression of effector CD4+ T cell functions is necessary to prevent immune cell–mediated damage to healthy tissues. This appears especially true during pregnancy or in individuals predisposed to autoimmunity. Foxp3+ regulatory T (Treg) cells and induction of anergy, an acquired state of T cell functional unresponsiveness in Foxp3– cells, have both been implicated as mechanisms to suppress dangerous immune responses to tissue-restricted self-Ags. Anergic CD4+ T cells and Treg cells share a number of phenotypic and mechanistic traits—including the expression of CD73 and folate receptor 4, and the epigenetic modification of Treg cell signature genes—and an interesting relationship between these two subsets has recently emerged. In this review, we will compare and contrast these two subsets, as well as explore the role of anergy in the generation of peripheral Treg cells.
After foodborne transmission of the facultative intracellular bacterial pathogen Listeria monocytogenes, most of the bacterial burden in the gut is extracellular. However, we previously demonstrated that intracellular replication in an as yet unidentified cell type was essential for dissemination and systemic spread of L. monocytogenes. In this article, we show that the vast majority of cell-associated L. monocytogenes in the gut were adhered to Ly6Chi monocytes, a cell type that inefficiently internalized L. monocytogenes. With bone marrow–derived in vitro cultures, high multiplicity of infection or the use of opsonized bacteria enhanced uptake of L. monocytogenes in CD64– monocytes, but very few bacteria reached the cell cytosol. Surprisingly, monocytes that had upregulated CD64 expression in transition toward becoming macrophages fully supported intracellular growth of L. monocytogenes. In contrast, inflammatory monocytes that had increased CD64 expression in the bone marrow of BALB/c/By/J mice prior to L. monocytogenes exposure in the gut did not support L. monocytogenes growth. Thus, contrary to the perception that L. monocytogenes can infect virtually all cell types, neither naive nor inflammatory Ly6Chi monocytes served as a productive intracellular growth niche for L. monocytogenes. These results have broad implications for innate immune recognition of L. monocytogenes in the gut and highlight the need for additional studies on the interaction of extracellular, adherent L. monocytogenes with the unique subsets of myeloid-derived inflammatory cells that infiltrate sites of infection.
Lymphopenia-induced proliferation (LIP) occurs when resources for T cell survival in a host are in excess. LIP has been associated with the development of inflammatory disease in situations where an additional disease-predisposing cofactor is present during LIP. This has led to the view of LIP-driven autoimmunity as a two hit model; however, not all cofactors have equal ability to precipitate autoimmunity and we have recently shown that in some circumstances, such as the absence of the coinhibitory molecule PD-1, additional hits are required. Herein we review factors controlling LIP, including coinhibitory molecules and other attenuators of TCR signaling, with a focus on their contribution to LIP-driven autoimmunity. Rather than viewing LIP-associated autoimmunity as an n-hit model, we suggest a more quantitative view of lymphopenia with respect to the factors that promote LIP as a tool to predict autoimmune potential and to inform tumor immunotherapy approaches.
Neutrophil (PMN) infiltration of the intestinal mucosa often leads to severe epithelial injury; however, how this process occurs is unclear. This article describes a novel mechanism whereby membrane-derived microparticles released by tissue infiltrating PMNs (PMN-MPs) serve as shuttles to protect and deliver active mediators to locally modulate cellular function during inflammation. Specifically, myeloperoxidase (MPO), which is abundantly expressed in PMN azurophilic granules and is used for microbial killing, was found to be mobilized to the PMN surface and subsequently released in association with PMN-MPs upon PMN activation and binding to intestinal epithelial cells (IECs). The enzymatic activity of PMN-MP–associated MPO was enhanced compared with soluble protein, leading to potent inhibition of wound closure following PMN-MP binding to IECs. Importantly, localized microinjection of PMN-MPs into wounded colonic mucosa was sufficient to impair epithelial wound healing in vivo. PMN-MP/MPO–dependent inhibition of IEC wound healing was due to impaired IEC migration and proliferation, resulting from impeded actin dynamics, cell spreading, and cell cycle arrest. Thus, our findings provide new insight into mechanisms governing PMN-induced tissue injury and implicate PMN-MPs and MPO as important regulators of cellular function.
Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.
The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3). FIP3 overexpression or silencing and its ability to interact with Rab11 modify Lck subcellular localization and its delivery to the immunological synapse. Importantly, FIP3-dependent Lck localization controls early TCR signaling events, such as tyrosine phosphorylation of TCR, ZAP70, and LAT and intracellular calcium concentration, as well as IL-2 gene expression. Interestingly, FIP3 controls both steady-state and poststimulation phosphotyrosine and calcium levels. Finally, our findings indicate that FIP3 modulates TCR-CD3 cell surface expression via the regulation of steady-state Lck-mediated TCR phosphorylation, which in turn controls TCR protein levels. This may influence long-term T cell activation in response to TCR-CD3 stimulation. Therefore, our data underscore the importance of finely regulated endosomal traffic in TCR signal transduction and T cell activation leading to IL-2 production.
The functions of activating members of the killer cell Ig-like receptor (KIR) family are not fully understood, as the ligands for these receptors are largely unidentified. In this study, we report that KIR2DS2 reporter cells recognize a ligand expressed by cancer cell lines. All cancer targets recognized by KIR2DS2 were also recognized by KIR2DL2 and KIR2DL3 reporters. Trogocytosis of membrane proteins from the cancer targets was observed with responding reporter cells, indicating the formation of KIR2DS2 ligand–specific immunological synapses. HLA-C typing of target cells showed that KIR2DS2 recognition was independent of the HLA C1 or C2 group, whereas targets cells that were only recognized by KIR2DL3 expressed C1 group alleles. Anti–HLA class I Abs blocked KIR2DL3 responses toward C1-expressing targets, but they did not block KIR2DS2 recognition of cancer cells. Small interfering RNA knockdown of β2-microglobulin reduced the expression of class I H chain on the cancer targets by >97%, but it did not reduce the KIR2DS2 reporter responses, indicating a β2-microglobulin–independent ligand for KIR2DS2. Importantly, KIR2DL3 responses toward some KIR2DS2 ligand–expressing cells were also undiminished after β2-microglobulin knockdown, and they were not blocked by anti–HLA class I Abs, suggesting that KIR2DL3, in addition to the traditional HLA-C ligands, can bind to the same β2-microglobulin–independent ligand as KIR2DS2. These observations indicate the existence of a novel, presently uncharacterized ligand for the activating NK cell receptor KIR2DS2. Molecular identification of this ligand may lead to improved KIR-HLA mismatching in hematopoietic stem cell transplantation therapy for leukemia and new, more specific NK cell–based cancer therapies.
Vaccine strategies to enhance CD8+ CTL responses remain a current challenge because they should overcome the plasmatic and endosomal membranes for favoring exogenous Ag access to the cytosol of APCs. As a way to avoid this hurdle, sticholysin (St) II, a pore-forming protein from the Caribbean Sea anemone Stichodactyla helianthus, was encapsulated with OVA into liposomes (Lp/OVA/StII) to assess their efficacy to induce a CTL response. OVA-specific CD8+ T cells transferred to mice immunized with Lp/OVA/StII experienced a greater expansion than when the recipients were injected with the vesicles without St, mostly exhibiting a memory phenotype. Consequently, Lp/OVA/StII induced a more potent effector function, as shown by CTLs, in vivo assays. Furthermore, treatment of E.G7-OVA tumor-bearing mice with Lp/OVA/StII significantly reduced tumor growth being more noticeable in the preventive assay. The contribution of CD4+ and CD8+ T cells to CTL and antitumor activity, respectively, was elucidated. Interestingly, the irreversibly inactive variant of the StI mutant StI W111C, encapsulated with OVA into Lp, elicited a similar OVA-specific CTL response to that observed with Lp/OVA/StII or vesicles encapsulating recombinant StI or the reversibly inactive StI W111C dimer. These findings suggest the relative independence between StII pore-forming activity and its immunomodulatory properties. In addition, StII-induced in vitro maturation of dendritic cells might be supporting these properties. These results are the first evidence, to our knowledge, that StII, a pore-forming protein from a marine eukaryotic organism, encapsulated into Lp functions as an adjuvant to induce a robust specific CTL response.
CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6 Faslpr mice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN- or IL-6 induced CD74 expression in kidney TECs in vitro. The presence of kidney TECs from Faslpr mice, rather than from wild-type mice, produced significantly stronger histones, dsDNA, and ribonucleoprotein-Smith Ag complex–induced CD4+ T cell activation. Splenocytes from CD74-deficient FaslprCd74–/– mice had muted responses in a MLR and to the autoantigen histones. Compared with FaslprCd74+/+ mice, FaslprCd74–/– mice had reduced kidney and spleen sizes, splenic activated T cells and B cells, serum IgG and autoantibodies, urine albumin/creatinine ratio, kidney Periodic acid–Schiff score, IgG and C3 deposition, and serum IL-6 and IL-17A levels, but serum IL-2 and TGF-β levels were increased. Study of chronic graft-versus-host C57BL/6 mice that received donor splenocytes from B6.C-H2bm12/KhEg mice and those that received syngeneic donor splenocytes yielded similar observations. CD74 deficiency reduced lupus-like autoimmunity and kidney pathology in chronic graft-versus-host mice. This investigation establishes the direct participation of CD74 in autoimmunity and highlights a potential role for CD74 in kidney TECs, together with professional APCs in systemic lupus erythematosus.
Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6–independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses.
Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell–derived autoantibody production. IL-21, a Tfh cell–derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus. We used blockade of IL-21 to dissect the mechanisms by which this cytokine promotes autoimmunity in murine lupus. Treatment of lupus-prone B6.Sle1.Yaa mice with an anti–IL-21 blocking Ab reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal-infiltrating Tfh and Th1 cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells coexpressing IL-21 and IFN-, and suppressed their production of the latter cytokine, albeit while not affecting their frequency. Anti–IL-21 treatment also led to a reduction in GC B cells, CD138hi plasmablasts, IFN-–dependent IgG2c production, and autoantibodies, indicating that Tfh cell–derived IL-21 is critical for pathological B cell cues in lupus. Normalization of GC responses was, in part, caused by uncoupling of Tfh–B cell interactions, as evidenced by reduced expression of CD40L on Tfh cells and reduced B cell proliferation in treated mice. Our work provides mechanistic insight into the contribution of IL-21 to the pathogenesis of murine lupus, while revealing the importance of T–B cellular cross-talk in mediating autoimmunity, demonstrating that its interruption impacts both cell types leading to disease amelioration.
Neutrophils are generally the first immune cells recruited during the development of sterile or microbial inflammation. As these cells express many innate immune receptors with the potential to directly recognize microbial or endogenous signals, we set out to assess whether their functions are locally influenced by the signals present at the onset of inflammation. Using a mouse model of peritonitis, we demonstrate that neutrophils elicited in the presence of C-type lectin receptor ligands have an increased ability to produce cytokines, chemokines, and lipid mediators in response to subsequent TLR stimulation. Importantly, we found that licensing of cytokine production was mediated by paracrine TNF-α-TNFR1 signaling rather than direct ligand sensing, suggesting a form of quorum sensing among neutrophils. Mechanistically, licensing was largely imparted by changes in the posttranscriptional regulation of inflammatory cytokines, whereas production of IL-10 was regulated at the transcriptional level. Altogether, our data suggest that neutrophils rapidly adapt their functions to the local inflammatory milieu. These phenotypic changes may promote rapid neutrophil recruitment in the presence of pathogens but limit inflammation in their absence.
Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN), but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic bead–purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupus-prone mice with spontaneous chronic glomerulonephritis (GN) and anti–glomerular basement membrane-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b+F4/80–I-A– macrophage population exhibiting the markers programmed death ligand-1 (PD-L1), Mac-2, and macrophage mannose receptor (CD206) and producing Klf4, Il10, Retnla, Tnf, and Il6 mRNA, which are known to be expressed by alternatively activated (M2b) macrophages, correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b+F4/80–I-A– intraglomerular macrophages and polymorphonuclear neutrophils (PMN) are important in inducing GN, as anti-CD11b and –ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b+F4/80–I-A– glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti–PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1– PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous chronic GN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and, to a less extent, dendritic cells as the major infiltrating leukocytes. Taken together, these data support the important pathogenic effect of CD11b+F4/80–I-A– M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment.
IL-10 limits the magnitude of inflammatory gene expression following microbial stimuli and is essential to prevent inflammatory disease; however, the molecular basis for IL-10–mediated inhibition remains elusive. Using a genome-wide approach, we demonstrate that inhibition of transcription is the primary mechanism for IL-10–mediated suppression in LPS-stimulated macrophages and that inhibited genes can be divided into two clusters. Genes in the first cluster are inhibited only if IL-10 is included early in the course of LPS stimulation and is strongly enriched for IFN-inducible genes. Genes in the second cluster can be rapidly suppressed by IL-10 even after transcription is initiated, and this is associated with suppression of LPS-induced enhancer activation. Interestingly, the ability of IL-10 to rapidly suppress active transcription exhibits a delay following LPS stimulation. Thus, a key pathway for IL-10–mediated suppression involves rapid inhibition of enhancer function during the secondary phase of the response to LPS.
Tissue-specific immune responses play an important role in the pathology of autoimmune diseases. In systemic lupus erythematosus, deposits of IgG-immune complexes and the activation of complement in the kidney have long been thought to promote inflammation and lupus nephritis. However, the events that localize cells in non-lymphoid tertiary organs and sustain tissue-specific immune responses remain undefined. In this manuscript, we show that BAFF promotes events leading to lupus nephritis. Using an inducible model of systemic lupus erythematosus, we found that passive transfer of antinucleosome IgG into AID–/–MRL/lpr mice elevated autoantibody levels and promoted lupus nephritis by inducing BAFF production in the kidneys, and the formation of renal tertiary lymphoid structures (TLSs). Reducing BAFF in vivo prevented the formation of TLSs and lupus nephritis; however, it did not reduce immune cell infiltrates, or the deposits of IgG and complement in the kidney. Mechanistically, lowering BAFF levels also diminished the number of T cells positioned inside the glomeruli and reduced inflammation. Thus, BAFF plays a previously unappreciated role in lupus nephritis by inducing renal TLSs and regulating the position of T cells within the glomeruli.
Cashew nut, pistachio nut and mango belong to the Anacardiaceae family and are botanically related. Therefore, cashew nut sensitised children are frequently advised to eliminate cashew nuts and pistachio nuts fro...
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