Quiste del conducto torácico superior: un hallazgo incidental

Publication date: Available online 23 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Regina María Sánchez Jiménez, Francisca Velázquez Marín




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Subtotal Parathyroidectomy and Relocation of the Parathyroid Remnant for Renal Hyperparathyroidism: modification of a traditional operation

Abstract

Background

We describe a modification of the conventional subtotal parathyroidectomy operation where the parathyroid gland(s) remnant is repositioned with intact vascular supply to a plane superficial to the infrahyoid strap muscles and immediately under the skin incision. This technique called Subtotal Parathyroidectomy and Remnant Relocation (SPARE) retains all the metabolic advantages of the conventional operation with the added advantage of easier identification of a recurrent hyperplastic remnant if re-exploration becomes necessary.

Methods

In the SPARE technique, four parathyroid glands were identified and the quality of each gland and the length of each vascular pedicle to the parathyroid glands were assessed. The optimal parathyroid gland was relocated to a plane superficial to the strap muscles. The remainder of the glands were removed.

Results

In total, 30 patients with hyperparathyroidism secondary to renal failure (HSRF) underwent parathyroidectomy with the SPARE technique. The mean age was 53.1±12.5 years and median follow-up was 17.1 months (range 1-78.9 months). There were no recurrent laryngeal nerve (RLN) injuries or hematomas. The pre- and post-operative value for corrected calcium and PTH were 158.4±109.4 pmol/L and 11.4±12.1 pmol/L, respectively (p < 0.05). Three recurrences were noted (10.0%), with a mean time to recurrence of 15.3±6.6 months. One patient had excision of the remnant parathyroid glands performed under local anaesthetic (29 min); one had re-exploration performed under general anaesthetic (81 min), and one was managed medically.

Conclusion

We described a novel parathyroidectomy technique for patients with HSRF, which provides the advantages of conventional subtotal parathyroidectomy while mitigating the challenges of thyroid bed re-exploration when recurrences arise.

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Lymphatic malformation with acquired Horner syndrome in an infant

An infantpresented with right upper eyelid ptosis and was subsequently diagnosed with acquired Horner syndrome. Further evaluation revealed a right-sided cervicothoracic lymphatic malformation. At 13 weeks of age, the child underwent percutaneous intracystic sclerotherapy with a mixture of sodium tetradecyl sulphate and ethanol. Twenty-one weeks after initial treatment, ophthalmic examination showed complete resolution of the blepharoptosis and pupillary miosis. Percutaneous sclerotherapy not only effectively treated the space-occupying lymphatic malformation but also reversed the Horner syndrome that was presumably induced by neural tension (more likely) or compression.

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Leiomyosarcoma presenting as 'idiopathic unilateral lower limb lymphoedema

A 74-year-old woman presented with an 8-year history of unilateral swelling of her right lower limb, which was thought to be 'idiopathic' lymphoedema until she noticed a painless swelling in her right groin. Physical examination showed a painless, non-pulsatile, deep-seated mass in her right proximal thigh with significant lymphoedema distally. MRI scan showed a large mass at her right inguinal region, involving the common femoral vein. Histological examination on complete excision revealed leiomyosarcoma. It is important to exclude proximal obstructive lesion before making a diagnosis of unilateral idiopathic lower limb lymphoedema.

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Rhomboencephalosynapsis

Description

A baby boy was born to healthy, unrelated parents at 34 weeks gestation by caesarean section in view of an antenatal ultrasound diagnosis of hydrocephalus. Mother had a previous miscarriage at 13 weeks gestation of a twin pregnancy. At birth, the boy weighed 2.47 kg, was well and did not require resuscitation. Pregnancy was unremarkable with no significant events. At birth, a large head circumference was noted, but fontanelles were soft. The Apgar score was 9 at 1 and 10 min, baby had a good cry and was moving all four limbs. A CT scan of brain was done at 1-day old which showed obstructive hydrocephalus at the level of the cerebral aqueduct. A ventriculoperitoneal (VP) shunt was inserted at 1-week old. The boy showed slow development over the subsequent years, he never suffered from seizures, however required growth hormone therapy. A small atrial septal defect was noted on echocardiogram. An...

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Measurement of bone mineral density as an efficacy marker in denosumab treatment of giant cell tumour of bone

Three patients with giant cell tumour of bone (GCTB) in the lower extremity, where the only surgical treatment options were amputation or severe weakening of the bone, were treated with denosumab (D-mab) to strengthen the bone mass in the tumour. In order to quantify changes in bone mineral density (BMD) in the GCTB lesion during D-mab treatment, we did repeated dual-energy X-ray absorptiometry (DXA) scans. The patients underwent operation after 3, 4 and 8 months of D-mab treatment, respectively. The tumours in all three patients responded markedly to D-mab, and up to 50% BMD increase was observed. There was almost no BMD change in the control scans in the hip and spine of the same patients. DXA scans provide no information about local tumour response, but may be of value in evaluation of the time and size of the D-mab response in GCTB, and thereby aid in finding the best timing for surgery.

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Giant mediastinal parathyroid adenoma presenting as bilateral brown tumour of mandible: a rare presentation of primary hyperparathyroidism

Hyperparathyroidism (HPT) is becoming increasingly common endocrinopathy in clinical practice. Nowadays, it is mostly diagnosed in subclinical or early clinical stage. Bony involvement in HPT has seen significant fall in incidence. Brown tumour of bone is exceptionally rare as a first manifestation of primary HPT (PHPT). Its radiological and histopathological features may be mistaken for other bony pathologies. If possibility of underlying HPT is overlooked the disease is bound to recur after surgery adding to morbidity of the patient. Here we present a case of bilateral brown tumour of mandible which was mistakenly treated as giant cell granuloma by surgical curettage. That the patient was harbouring an ectopic parathyroid adenoma with hypercalcemia causing non-specific symptoms was missed by the referring physician. This led to recurrence of the lesion. On subsequent evaluation, a giant mediastinal parathyroid adenoma causing PHPT was detected at our centre and was removed via mini sternotomy approach.

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Transcatheter valve implantation to inferior vena cava to control carcinoid symptoms

Severe carcinoid syndrome and carcinoid heart disease in neuroendocrine tumours can have a significant impact on a patient's quality of life and are a major cause of morbidity and mortality. We present a novel approach to managing a patient with medically uncontrollable carcinoid syndrome. Inferior and superior vena cava placement of transcatheter heart valves has been used to treat patients with right heart failure due to severe tricuspid and pulmonary regurgitation. However, this procedure has not been attempted to specifically reduce hormone secretion, primarily from the liver, in order to control carcinoid syndrome symptoms. We attempted this procedure in a patient with severe carcinoid disease and tricuspid regurgitation as a bridge to later definitive therapy. The procedure was technically successful, but did not improve carcinoid symptoms. The possible reasons for the failure are discussed here.

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Birt-Hogg-Dube syndrome: awareness is important!

Birt-Hogg-Dubé (BHD) is a rare syndrome of inherited renal cell carcinomas, characterised by cutaneous lesions and pulmonary cysts and pneumothorax in a vast majority of the patients. Awareness of this syndrome is important in order to refer patients for genetic counselling and personalised follow-up as soon as possible. We describe a case of a 30-year-old female referred to our institution due to incidental discovery of solid bilateral renal masses. Renal biopsies were consistent with chromophobe tumour, and bilateral nephrectomy was performed. Gross examination revealed deformed kidneys with 28 brown and solid lesions, size variable between 0.1 and 6 cm, histologically corresponding to renal cell carcinomas, chromophobe type. Genetic test was required that showed a c.573delGAinsT frameshift mutation in heterozigosity at the folliculin gene, consistent with BHD diagnosis.

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Idiopathic catastrophic thrombosis with happy ending

A 59-year-old male patient suffered three life-threatening instent thromboses after an initial resuscitation due to an ST-segment elevation myocardial infarction of the anterior cardiac wall. With a high-risk profile for heparin-induced thrombocytopenia (HIT), he was placed on argatroban after the second reinfarction. Under this apparently appropriate treatment, a third reinfarction occurred, and the patient had to undergo high-risk cardiac bypass surgery. Later on, a deep vein thrombosis and an intracardiac thrombus formed. Despite a positive screening test for HIT and a single positive result in the heparin-induced platelet aggregation test, we are not convinced that HIT was the only underlying cause for this 'catastrophic thrombotic syndrome'. We speculate that a massive generation of thrombin, reflected in consistently high D dimers and the need of copious amounts of a direct thrombin inhibitor, triggered the set of events. With this case report, we want to raise awareness for cardiac complications in patients with complex clotting disorders and share our experience in the diagnostic and therapeutic management of such an unusual scenario.

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Neuroendocrine tumour in pancreatic dorsal agenesis: a rare association

Pancreatic dorsal agenesis (PDA) is a rare congenital anomaly, usually asymptomatic, that can present with abdominal pain, pancreatitis, diabetes mellitus and jaundice. Pancreatic tumours in PDA background are extremely rare, and when they occur are mainly pancreatic ductal adenocarcinoma. We present a case of a 48-year-old female patient with incidental detection of a 26x20 mm nodular lesion of the cephalic pancreas on ultrasound. Surgery was performed and gross examination revealed PDA with a tumour developed around the Wirsung duct. Histology showed a neuroendocrine tumour G1 with neural and vascular invasion. Two and half years later, the patient is alive and without tumour relapse. Awareness of the association of PDA and pancreatic tumours is fundamental in order to develop personalised follow-up programmes.

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Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts

A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient's mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night. Within an hour after taking her second suvorexant dose, the severity of patient's depression symptoms worsened and was accompanied by new onset of suicidal thoughts.

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Case of tumoral calcinosis on images: a rare clinicopathological entity

Description

We are presenting a case of tumoral calcinosis (TC) diagnosed on histopathology with characteristic X-ray, CT and MRI images. We acknowledge that although radiological and pathological descriptions are suggested as diagnostic criteria, mostly the term TC is saved for the condition caused by hereditary metabolic dysfunction of phosphate regulation associated with massive periarticular masses. Our patient had a normal phosphate. On review of literature, normophosphatemic TC has also been described.1

An 81-year-old Caucasian woman presented with left wrist pain and swelling, which first began approximately 3–4 years ago. As per patient, she saw her physician regarding this 1 year ago and was diagnosed with gout. Physical examination showed 4x3 cm left-sided volar ulnar wrist mass (figure 1).

Figure 1

Patient's picture showing swelling on the left wrist.

The patient's vital signs and rest of the examination were within normal limits....

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Metastatic meningioma: a rare cause of mediastinal lymphadenopathy.

Description

A 69-year-old man with known, stable atypical meningioma of the brain diagnosed 5 years previously presented with severe shortness of breath. The patient had previously been treated with surgery and radiotherapy to the brain. Chest X-ray revealed bulky mediastinal lymphadenopathy (figure 1). CT (figure 2) confirmed mediastinal and upper abdominal lymphadenopathy in addition to multiple pulmonary emboli. The patient underwent an endoscopic ultrasound and fine-needle aspiration (EUS-FNA), an established technique that enables prompt cytological sampling and assessment.1

Figure 1

Chest X-ray.

Figure 2

Contrast-enhanced CT image showing adenopathy at the level of the aortic arch.

The EUS-FNA preparations showed sheets and clusters of bland, polygonal epithelioid cells (figure 3). These demonstrated strong immunohistochemical positivity (figure 4) for epithelial membrane antigen. The final immunopanel was strongly supportive...

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Olfactory nerve hypertrophy: a clue to the presence of ipsilateral megalencephaly

Description

A boy aged 4 years presented with refractory focal seizures since 9 months of age. The seizures involved the left side of the body and consisted of clonic movements with frequent generalisation. MRI brain showed abnormal area with poor grey-white differentiation involving the right frontal lobe, especially the basifrontal region and the temporal lobe (figure 1A,B) suggesting the presence of a frontotemporal developmental malformation. Interestingly olfactory nerve hypertrophy was also noted on the same side (figure 1C,D). Video-electroencephalogram study demonstrated concurrence of the interictal (figure 2A) and ictal data (figure 2B) with the MRI defined abnormality. An 18-fluoro-2-deoxy-D-glucose positron emission tomography/CT of the brain showed severe right frontotemporal hypometabolism. The boy underwent a disconnection procedure involving the right frontal lobe sparing the motor cortex and the temporal lobe. Histopathology of the abnormal brain obtained during the surgery showed large...

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Necrotising pneumonia following influenza due to PVL-negative Staphylococcus aureus in a 64-year-old woman

Description

A 64-year-old immunocompetent woman presented to our institution during the 2016–2017 influenza A(H3N2) epidemic for cough and fever. She presented 10 days ago with an influenza syndrome, treated with ibuprofen 400 mg/day for 7 days. As the fever continued, with blood-streaked sputum, amoxicillin with clavulanic acid was prescribed for 3 days and then ceftriaxone (1 g/day). She had elevated transaminases and C reactive protein (184 mg/L). A chest X-ray was performed, showing a left pneumonia (figure 1A), and the patient was admitted in the infectious disease unit. There was no respiratory failure. Amphoric breath sound was heard at the top of the right lung. Antibiotics were modified, as levofloxacine (500 mg twice daily) was added to cefotaxime (1 g/8 hours). A CT scan of the chest was performed (figure 1B,C), showing a bifocal pneumonia involving the upper right and lower left lobes, and excavated bilateral nodules. The bronchoalveolar lavage showed a positive influenza...

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Correction: Out of the blue--finger ischaemia and occult colorectal cancer

Schattner A. Out of the blue finger ischaemia and occult colorectal cancer. BMJ Case Rep 2017 (Epub ahead of print 8 Mar 2017). doi:10.1136/bcr-2016-218779

The correct title of the article is: Out of the blue—finger ischaemia and occult colorectal cancer.

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Cellular subtype may predict survival outcomes in salivary adenoid cystic carcinoma patients—a single-institution experience

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Pre-emptive Diclofenac Versus Ketoprofen as a Transdermal Drug Delivery System: How They Face

Abstract

Aim

To compare the analgesic efficacy of Diclofenac vis-a-vis Ketoprofen transdermal patch, in the management of immediate post-operative pain following orthognathic procedures.

Material and Method

A prospective, double-blinded, randomised controlled study was conducted among 50 subjects, between 2012 and 2015. These patients were diagnosed clinically and cephalometrically as skeletal and dental class II malocclusion and underwent bi-jaw surgical procedure. In total, 25 Diclofenac and 25 Ketoprofen transdermal patches, sealed in envelopes and numbered, were administered to subjects. The patches used, contained 100 mg of either Diclofenac or Ketoprofen and administered by a nurse prior to induction. Duration of analgesia, severity of pain using Visual Analog Scale, necessity of rescue analgesia (spontaneous pain > 5 on a 10-cm scale) and any other adverse effect associated with the drug were evaluated.

Results

Mean duration of analgesia was significantly higher in the Ketoprofen group (20 h), compared to Diclofenac group (13 h) (p = 0.001). Rescue analgesia was required in 12% of subjects who received Diclofenac patch, compared to 4% in Ketoprofen group. None of the subjects showed any allergic reactions.

Conclusion

The study was designed to evaluate the efficacy of transdermal patch in reduction of post-operative pain in subjects undergoing bi-jaw surgeries. Subjects in both groups were comfortable and returned to early function. However, Ketoprofen transdermal patch had an edge over the Diclofenac transdermal patch with respect to analgesic efficacy.

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Re: “Assessing the Detection of Middle East Respiratory Syndrome Coronavirus IgG in Suspected and Proven Cases of Middle East Respiratory Syndrome Coronavirus Infection” by Alhetheel et al. (Viral Immunol 2017 [Epub ahead of print]; DOI: 10.1089/vim.2017.0091)

Viral Immunology , Vol. 0, No. 0.


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Endoscopic surgery of the olfactory cleft

Publication date: Available online 23 October 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): R. Jankowski, C. Rumeau, P. Gallet, D.T. Nguyen, A. Russel, B. Toussaint
The olfactory cleft is the specific site of development of many tumours (respiratory epithelial adenomatoid hamartoma, intestinal-type adenocarcinoma, neuroblastoma, inverted papilloma, glomangiopericytoma, etc.) and is also the site of CSF rhinorrhoea via the cribriform plate (cribri-rhinorrhoea). Olfactory cleft surgery must therefore be considered to be a specific type of surgery, complementary to ethmoidal labyrinth surgery and anterior skull base surgery. Olfactory cleft tumours can be resected according to five different surgical procedures: olfactory cleft mucosal resection, partial resection of the olfactory cleft, total resection of the olfactory cleft, unilateral endoscopic anterior skull base resection, and bilateral endoscopic anterior skull base resection. The diagnosis and closure of cribri-rhinorrhoea (i.e. documented CSF rhinorrhoea, demonstrated to arise from the cribriform plate during endoscopic examination of the olfactory cleft under general anaesthesia in a patient with no localizing signs on imaging) completes this range of treatment options.



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Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses

Abstract

Purpose

A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats.

Methods

Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1–10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro.

Results

In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001).

Conclusions

Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.

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CLARENCE CARNOT EVANS II, MD: A Statesman for Dermatology

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The role of psychological factors in the development of burning mouth syndrome

The psychiatric profiles of 50 patients diagnosed with burning mouth syndrome (BMS) were compared to those of 50 age- and sex-matched individuals as the control group. The Symptom Checklist-90-Revised (SCL-90-R) questionnaire was used to evaluate the role of psychological factors in the development of BMS. Somatization, obsessive-compulsive, depression, anxiety, hostility, phobic anxiety, psychoticism, global severity index (GSI), positive symptom total (PST), and positive symptom distress index (PSDI) scores were significantly higher in the patients with BMS than in the control group.

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Skeletal stability following bioresorbable versus titanium fixation in orthognathic surgery: a systematic review and meta-analysis

Despite developments in bioresorbable fixation over recent decades, controversy remains regarding skeletal stability following the use of this material in orthognathic surgery. This systematic review and meta-analysis investigated evidence from the international literature from studies comparing skeletal stability between bioresorbable and titanium fixation in orthognathic surgery. Key words were searched in MEDLINE, Embase, and Cochrane Library, and relevant journals and reference lists were searched for additional material, up to January 2017.

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VideoEndocrinology™ High-Impact Videos

VideoEndocrinology™
The Official Journal of: American Thyroid Association

FREE ACCESS through November 30, 2017

Watch now:

Transoral Endoscopic Thyroidectomy Vestibular Approach
Angkoon Anuwong, Thanyawat Sasanakietkul, Pornpeera Jitpratoom 

Transoral Endoscopic Thyroidectomy Vestibular Approach
Thanyawat Sasanakietkul, Tobias Carling 

Transoral Endoscopic Parathyroid Cyst Removal
Jonathon O. Russell, Mai G. Al Khadem, and Ralph P. Tufano 

Transoral Robotic Thyroidectomy
Jeremy D. Richmon, Ralph P. Tufano, Jon Russell, Andrew Day, Hamad M. Chaudhary, Salem I. Noureldine 

Transoral Endoscopic Total Parathyroidectomy in Renal Hyperparathyroidism Patient
Thanyawat Sasanakietkul, Wirada Wandee, Pornpeera Jitpratoom, Angkoon Anuwong 

Transoral Excision of Nodal Metastatic Papillary Thyroid Carcinoma
William M. Dougherty, Mark J. Jameson, David C. Shonka Jr. 

The post VideoEndocrinology™ High-Impact Videos appeared first on American Thyroid Association.

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Identification of IL-40, a Novel B Cell-Associated Cytokine [MUCOSAL IMMUNOLOGY]

We describe a novel B cell–associated cytokine, encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99), that is expressed in bone marrow and fetal liver and whose expression is also induced in peripheral B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (~27-kDa) secreted protein unrelated to other cytokine families, suggesting a function in mammalian immune responses. Accordingly, C17orf99 expression is induced in the mammary gland upon the onset of lactation, and a C17orf99^–/– mouse exhibits reduced levels of IgA in the serum, gut, feces, and lactating mammary gland. C17orf99^–/– mice have smaller and fewer Peyer's patches and lower numbers of IgA-secreting cells. The microbiome of C17orf99^–/– mice exhibits altered composition, likely a consequence of the reduced levels of IgA in the gut. Although naive B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL-4 and TGF-β1, suggesting that differentiation can result in the expansion of C17orf99-producing B cells during some immune responses. Taken together, these observations indicate that C17orf99 encodes a novel B cell–associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observations suggest that it may play a role in the pathogenesis of certain human diseases.

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Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse [INNATE IMMUNITY AND INFLAMMATION]

The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato–C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells. We found the strongest C5aR2 expression in the brain, bone marrow, and airways. All myeloid-derived cells expressed C5aR2, although with different intensities. C5aR2 expression in blood and tissue neutrophils was strong and homogeneous. Specific ligation of C5aR2 in neutrophils from tdTomato–C5aR2 mice blocked C5a-driven ERK1/2 phosphorylation, demonstrating functionality of C5aR2 in the reporter mice. In contrast to neutrophils, we found tissue-specific differences in C5aR2 expression in eosinophils, macrophages, and dendritic cell subsets. Naive and activated T cells stained negative for C5aR2, whereas B cells from different tissues homogeneously expressed C5aR2. Also, NK cell subsets in blood and spleen strongly expressed C5aR2. Activation of C5aR2 in NK cells suppressed IL-12/IL-18–induced IFN- production. Intratracheal IL-33 challenge resulted in decreased C5aR2 expression in pulmonary eosinophils and monocyte-derived dendritic cells. In summary, we provide a detailed map of murine C5aR2 immune cell expression in different tissues under steady-state conditions and upon pulmonary inflammation. The C5aR2 knock-in mouse will help to reliably track and conditionally delete C5aR2 expression in experimental models of inflammation.

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Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects [INFECTIOUS DISEASE AND HOST RESPONSE]

Select CMV epitopes drive life-long CD8⁺ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4⁺ T cells specific for human CMV (HCMV) are elevated in HIV⁺ HCMV⁺ subjects. To determine whether HCMV epitope–specific CD4⁺ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4⁺ T cells in coinfected HLA-DR7⁺ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4⁺ T cells were inflated among these HIV⁺ subjects compared with those from an HIV^– HCMV⁺ HLA-DR7⁺ cohort or with HLA-DR7–restricted CD4⁺ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4⁺ T cells consisted of effector memory or effector memory–RA⁺ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell–transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX₃CR1, CD38, or HLA-DR but less often coexpressed CD38⁺ and HLA-DR⁺. The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4⁺ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.

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HERP Binds TBK1 To Activate Innate Immunity and Repress Virus Replication in Response to Endoplasmic Reticulum Stress [INNATE IMMUNITY AND INFLAMMATION]

Host innate immunity is crucial for cellular responses against viral infection sensed by distinct pattern recognition receptors and endoplasmic reticulum (ER) stress. Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and neurological diseases. However, the exact mechanism underlying the link between ER stress induced by EV71 infection and host innate immunity is largely unknown. In this study, we demonstrated that EV71 infection induces the homocysteine-induced ER protein (HERP), a modulator of the ER stress response which is dependent on the participation of MAVS. Virus-induced HERP subsequently stimulates host innate immunity to repress viral replication by promoting type-I IFNs (IFN-α and IFN-β) and type-III IFN (IFN-1) expression. Through interacting with TANK-binding kinase 1, HERP amplifies the MAVS signaling and facilitates the phosphorylation and nuclear translocation of IFN regulatory factor 3 and NF-B to enhance the expression of IFNs, which leads to a broad inhibition of the replication of RNA viruses, including EV71, Sendai virus, influenza A virus, and vesicular stomatitis virus. Therefore, we demonstrated that HERP plays an important role in the regulation of host innate immunity in response to ER stress during the infection of RNA viruses. These findings provide new insights into the mechanism underlying the replication of RNA viruses and the production of IFNs, and also demonstrate a new role of HERP in the regulation of host innate immunity in response to viral infection.

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Reconstructing Antibody Repertoires from Error-Prone Immunosequencing Reads [NOVEL IMMUNOLOGICAL METHODS]

Transforming error-prone immunosequencing datasets into Ab repertoires is a fundamental problem in immunogenomics, and a prerequisite for studies of immune responses. Although various repertoire reconstruction algorithms were released in the last 3 y, it remains unclear how to benchmark them and how to assess the accuracy of the reconstructed repertoires. We describe an accurate IgReC algorithm for constructing Ab repertoires from high-throughput immunosequencing datasets and a new framework for assessing the quality of reconstructed repertoires. Surprisingly, Ab repertoires constructed by IgReC from barcoded immunosequencing datasets in the blind mode (without using information about unique molecular identifiers) improved upon the repertoires constructed by the state-of-the-art tools that use barcoding. This finding suggests that IgReC may alleviate the need to generate repertoires using the barcoding technology (the workhorse of current immunogenomics efforts) because our computational approach to error correction of immunosequencing data is nearly as powerful as the experimental approach based on barcoding.

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CD8+ T Cells Prevent Lethality from Neonatal Murine Roseolovirus Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

A recently described mouse homolog of the human roseoloviruses, murine roseolovirus (MRV), causes loss of peripheral and thymic CD4⁺ cells during neonatal infection of BALB/c mice. Despite significant disruptions to the normal adaptive immune response, infected BALB/c mice reproducibly recover from infection, consistent with prior studies on a related virus, mouse thymic virus. In this article, we show that, in contrast to published studies on mouse thymic virus, MRV appears to robustly infect neonatal C57BL/6 (B6) mice, causing severe depletion of thymocytes and peripheral T cells. Moreover, B6 mice recovered from infection. We investigated the mechanism of thymocyte and T cell loss, determining that the major thymocyte subsets were infected with MRV; however, CD4⁺ and CD4⁺CD8^– T cells showed increased apoptosis during infection. We found that CD8⁺ T cells populated MRV-infected thymi. These CD8⁺ T cells expressed markers of activation, had restricted TCR repertoire, and accumulated intracellular effector proteins, consistent with a cytotoxic lymphocyte phenotype and suggesting their involvement in viral clearance. Indeed, absence of CD8⁺ T cells prevented recovery from MRV infection and led to lethality in infected animals, whereas B cell–deficient mice showed CD4⁺ T cell loss but recovered from infection without lethality. Thus, these results demonstrate that CD8⁺ T cells are required for protective immunity against a naturally occurring murine pathogen that infects the thymus and establish a novel infection model for MRV in B6 mice, providing the foundation for detailed future studies on MRV with the availability of innumerable mutant mice on the B6 background.

http://ift.tt/2y0Wt9u

Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression [INNATE IMMUNITY AND INFLAMMATION]

TLR signaling is critical to innate immune system regulation; however, aberrant TLR signaling is involved in several diseases, including insulin resistance, Alzheimer's disease, and tumor metastasis. Moreover, a recent study found that TLR-4 signaling pathway inhibition might be a target for the suppression of chronic inflammatory disorders. In this article, we show that the green tea polyphenol epigallocatechin-3-O-gallate (EGCG) increases the expression of Toll interacting protein, a strong inhibitor of TLR4 signaling, by suppressing the expression of E74-like ETS transcription factor 1 (Elf-1). A mechanistic study revealed that EGCG suppressed Elf-1 expression via protein phosphatase 2A/cyclic GMP (cGMP)-dependent mechanisms. We also confirmed that orally administered EGCG and a cGMP inducer upregulated Toll interacting protein expression, increased intracellular levels of cGMP in macrophages, and suppressed Elf-1 expression. These data support EGCG and a cGMP inducer as potential candidate suppressors of TLR4 signaling.

http://ift.tt/2y0JODE

Interaction of Neutrophils with Macrophages Promotes IL-1{beta} Maturation and Contributes to Hepatic Ischemia-Reperfusion Injury [INNATE IMMUNITY AND INFLAMMATION]

Accumulating evidence suggests that IL-1β plays a pivotal role in the pathophysiology of hepatic ischemia–reperfusion (I/R) injury; however, the mechanism by which I/R triggers IL-1β production in the liver remains unclear. Recent data have shown that neutrophils contribute to hepatic I/R injury independently of the inflammasomes regulating IL-1β maturation. Thus, we investigated the role of neutrophils in IL-1β maturation and tissue injury in a murine model of hepatic I/R. IL-1β was released from the I/R liver and its deficiency reduced reactive oxygen species generation, apoptosis, and inflammatory responses, such as inflammatory cell infiltration and cytokine expression, thereby resulting in reduced tissue injury. Depletion of either macrophages or neutrophils also attenuated IL-1β release and hepatic I/R injury. In vitro experiments revealed that neutrophil-derived proteinases process pro–IL-1β derived from macrophages into its mature form independently of caspase-1. Furthermore, pharmacological inhibition of serine proteases attenuated IL-1β release and hepatic I/R injury in vivo. Taken together, the interaction between neutrophils and macrophages promotes IL-1β maturation and causes IL-1β–driven inflammation in the I/R liver. Both neutrophils and macrophages are indispensable in this process. These findings suggest that neutrophil-macrophage interaction is a therapeutic target for hepatic I/R injury and may also provide new insights into the inflammasome-independent mechanism of IL-1β maturation in the liver.

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PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination [TUMOR IMMUNOLOGY]

The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8⁺ T cell (T_CD8) responses, and PD-1-based "checkpoint inhibitors" have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1–targeted therapies reverse T_CD8 exhaustion/anergy. However, whether they alter the epitope breadth of T_CD8 responses remains unclear. This is an important question because subdominant T_CD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity. We have addressed this question in an in vivo model of T_CD8 responses to well-defined epitopes of a clinically relevant oncoprotein, large T Ag. We found that unlike other coinhibitory molecules (CTLA-4, LAG-3, TIM-3), PD-1 was highly expressed by subdominant T_CD8, which correlated with their propensity to favorably respond to PD-1/PD-1 ligand-1 (PD-L1)-blocking Abs. PD-1 blockade increased the size of subdominant T_CD8 clones at the peak of their primary response, and it also sustained their presence, thus giving rise to an enlarged memory pool. The expanded population was fully functional as judged by IFN- production and MHC class I–restricted cytotoxicity. The selective increase in subdominant T_CD8 clonal size was due to their enhanced survival, not proliferation. Further mechanistic studies utilizing peptide-pulsed dendritic cells, recombinant vaccinia viruses encoding full-length T Ag or epitope mingenes, and tumor cells expressing T Ag variants revealed that anti–PD-1 invigorates subdominant T_CD8 responses by relieving their lysis-dependent suppression by immunodominant T_CD8. To our knowledge, our work constitutes the first report that interfering with PD-1 signaling potentiates epitope spreading in tumor-specific responses, a finding with clear implications for cancer immunotherapy and vaccination.

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Basic Fibroblast Growth Factor 2 Is a Determinant of CD4 T Cell-Airway Smooth Muscle Cell Communication through Membrane Conduits [CLINICAL AND HUMAN IMMUNOLOGY]

Activated CD4 T cells connect to airway smooth muscle cells (ASMCs) in vitro via lymphocyte-derived membrane conduits (LMCs) structurally similar to membrane nanotubes with unknown intercellular signals triggering their formation. We examined the structure and function of CD4 T cell–derived LMCs, and we established a role for ASMC-derived basic fibroblast growth factor 2 (FGF2b) and FGF receptor (FGFR)1 in LMC formation. Blocking FGF2b's synthesis and FGFR1 function reduced LMC formation. Mitochondrial flux from ASMCs to T cells was partially FGF2b and FGFR1 dependent. LMC formation by CD4 T cells and mitochondrial transfer from ASMCs was increased in the presence of asthmatic ASMCs that expressed more mRNA for FGF2b compared with normal ASMCs. These observations identify ASMC-derived FGF2b as a factor needed for LMC formation by CD4 T cells, affecting intercellular communication.

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IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression [MUCOSAL IMMUNOLOGY]

Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium. In this study we report that IL-22 signals exclusively through the basolateral side of polarized Caco-2 cell monolayers. IL-22 treatment does not affect the flux of uncharged macromolecules across cell monolayers but significantly reduces transepithelial electrical resistance (TEER), indicating an increase of paracellular permeability for ions. IL-22 treatment on Caco-2 monolayers and on primary human intestinal epithelium markedly induces the expression of Claudin-2, a cation–channel-forming tight junction protein. Furthermore, treatment of IL-22 in mice upregulates Claudin-2 protein in colonic epithelial cells. Knocking down Claudin-2 expression with small interfering RNA reverses the reduction of TEER in IL-22–treated cells. Moreover, IL-22–mediated upregulation of Claudin-2 and loss of TEER can be suppressed with the treatment of JAK inhibitors. In summary, our results reveal that IL-22 increases intestinal epithelial permeability by upregulating Claudin-2 expression through the JAK/STAT pathway. These results provide novel mechanistic insights into the role of IL-22 in the regulation and maintenance of the intestinal epithelial barrier.

http://ift.tt/2iuMaZp

NEMO-IKK{beta} Are Essential for IRF3 and NF-{kappa}B Activation in the cGAS-STING Pathway [INNATE IMMUNITY AND INFLAMMATION]

Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS–STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKβ. Activated IKKβ, but not IKKα, was required for TBK1 and NF-B activation. In contrast, TBK1 was reciprocally required for NF-B activation, probably by directly phosphorylating IKKβ. Thus, our findings identified a unique innate immune activation cascade in which TBK1–IKKβ formed a positive feedback loop to assure robust cytokine production during cGAS–STING activation.

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Stacking the Deck: Studies of Patients with Multiple Autoimmune Diseases Propelled Our Understanding of Type 1 Diabetes as an Autoimmune Disease [PILLARS OF IMMUNOLOGY]

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Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria [INFECTIOUS DISEASE AND HOST RESPONSE]

In elderly patients, bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (M) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that M exhibit age-related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and the ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The present study sought to determine changes in bacterial phagocytosis in aging alveolar M (AM) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AM through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 complex, an F-actin nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AM isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and actin-related protein-2/3 activation, as well as subsequent attenuation of F-actin polymerization, filopodia formation, and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AM is decreased. This study highlights a previously unidentified mechanism by which aging impairs M phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.

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Pillars Article: Islet-cell Antibodies in Diabetes Mellitus with Autoimmune Polyendocrine Deficiencies. Lancet. 1974. 304: 1279-1283 [PILLARS OF IMMUNOLOGY]

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Type III IFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection [INNATE IMMUNITY AND INFLAMMATION]

Type III IFNs (IFN-s) are secreted factors that are well-known for their antiviral activities. However, their regulation and functions during bacterial infections are unclear. In this article, we report that the regulation of IFN- genes did not track with mechanisms that control type I IFN expression in response to TLRs. Whereas type I IFNs were only expressed from TLRs present on endosomes, type III IFNs could be induced by TLRs that reside at the plasma membrane and that detect various bacterial products. The mechanisms that regulate type III IFN gene expression tracked with those that promote inflammatory cytokine and chemokine expression. Importantly, rIFN-s enhanced epithelial barriers in vitro, preventing transcellular bacteria dissemination. We therefore propose that in addition to their functions in cell-intrinsic antiviral immunity, type III IFNs protect epithelial barrier integrity, an activity that would benefit the host during any infectious encounter.

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Pillars Article: Antibodies to Pancreatic Islet Cells in Insulin-dependent Diabetics with Coexistent Autoimmune Disease. Lancet. 1974. 304: 1529-1531 [PILLARS OF IMMUNOLOGY]

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NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data [NOVEL IMMUNOLOGICAL METHODS]

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide–MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.

http://ift.tt/2iuM9Vl

Efficient Induction of Ig Gene Hypermutation in Ex Vivo-Activated Primary B Cells [ANTIGEN RECOGNITION AND RESPONSES]

Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes. How AID is targeted to the Ig V gene and switch region to trigger SHM and CSR remains elusive. Primary B cells stimulated with CD40L plus IL-4 or LPS plus IL-4 undergo efficient CSR, but it has been difficult to induce SHM in these cells. In the current study, we used B cells from B1-8^hi mice carrying a prerecombined V_H186.2DFL16.1J_H2 Ab gene to investigate the induction of SHM under in vitro culture conditions. B1-8^hi splenic B cells stimulated with CD40L plus IL-4 or LPS plus IL-4 underwent robust CSR to IgG₁, but failed to generate SHM in the V_H186.2 gene. Remarkably, ectopic expression of AID in AID-deficient, but not wild-type, B1-8^hi B cells induced efficient SHM at a rate close to that observed in germinal center B cells. We further established an AID-deficient CH12 B lymphoma line and found that ectopic expression of AID in the mutant line, but not in AID-sufficient CH12 cells, induced efficient point mutations and deletions in the V gene. These results demonstrate that the endogenous AID in ex vivo–activated primary B and B lymphoma cells not only cannot induce SHM but also inhibit the induction of SHM by the exogenous AID. Our results further suggest that the spatiotemporal distribution and/or posttranslational modification of AID strongly affects the induction of SHM in ex vivo–activated primary B cells.

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Phenotypic and Functional Characterization of Circulatory, Splenic, and Hepatic NK Cells in Simian Immunodeficiency Virus-Controlling Macaques [INFECTIOUS DISEASE AND HOST RESPONSE]

NK cells are key components of the immune system because of their rapid response potential and their ability to mediate cytotoxic and immunomodulatory functions. Additionally, NK cells have recently been shown to persist for long periods in vivo and to have the capacity to establish immunologic memory. In the current study, we assessed the phenotype and function of circulatory and tissue-resident NK cells in a unique cohort of SIV-controlling rhesus macaques that maintained low to undetectable levels of viremia in the chronic phase of infection. By contrasting NK responses of these macaques with those observed in SIV-noncontrolling and uninfected macaques, we aimed to identify markers and activities of NK subpopulations associated with disease control. We show in this article that most differences among NK cells of the three groups of macaques were observed in tissue-resident cells. Although SIV infection resulted in NK cell dysfunction, double-negative NK cells and those expressing CXCR3, NKG2D, and IL-18Rα were associated with viremia control, as was Ab-dependent cytotoxic function. Our results suggest several novel targets for therapeutic intervention.

http://ift.tt/2iuMfMH

Wnt/{beta}-Catenin Signaling Induces Integrin {alpha}4{beta}1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice [AUTOIMMUNITY]

The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4⁺ T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin–expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

http://ift.tt/2y1a7K9

The PYHIN Protein p205 Regulates the Inflammasome by Controlling Asc Expression [INNATE IMMUNITY AND INFLAMMATION]

Members of the IFN-inducible PYHIN protein family, such as absent in melanoma-2 and IFN-–inducible protein (IFI)16, bind dsDNA and form caspase-1–activating inflammasomes that are important in immunity to cytosolic bacteria, DNA viruses, or HIV. IFI16 has also been shown to regulate transcription of type I IFNs during HSV infection. The role of other members of the PYHIN protein family in the regulation of immune responses is much less clear. In this study, we identified an immune-regulatory function for a member of the murine PYHIN protein family, p205 (also called Ifi205). Examination of immune responses induced by dsDNA and other microbial ligands in bone marrow–derived macrophages lacking p205 revealed that inflammasome activation by dsDNA, as well as ligands that engage the NLRP3 inflammasome, was severely compromised in these cells. Further analysis revealed that p205-knockdown cells showed reduced expression of apoptosis-associated speck-like molecule containing CARD domain (Asc) at the protein and RNA levels. p205 knockdown resulted in reduced binding of actively transcribing RNA polymerase II to the endogenous Asc gene, resulting in decreased transcription and processing of Asc pre-mRNA. Deletion of p205 in B16 melanoma cells using CRISPR/Cas9 showed a similar loss of Asc expression. Ectopic expression of p205 induced expression of an Asc promoter–luciferase reporter gene. Together, these findings suggest that p205 controls expression of Asc mRNA to regulate inflammasome responses. These findings expand on our understanding of immune-regulatory roles for the PYHIN protein family.

http://ift.tt/2iuMdEz

Pathogenic Role for {gamma}{delta} T Cells in Autoimmune Anti-Myeloperoxidase Glomerulonephritis [AUTOIMMUNITY]

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic Ab (ANCA)–associated vasculitis results from autoimmunity to MPO. IL-17A plays a critical role in generating this form of autoimmune injury but its cell of origin is uncertain. We addressed the hypothesis that IL-17A–producing T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN). We studied MPO-ANCA GN in wild type, αβ, or T cell–deficient (C57BL/6, βTCR^–/–, and TCR^–/– respectively) mice. Both T cell populations played important roles in the generation of autoimmunity to MPO and GN. Humoral autoimmunity was dependent on intact αβ T cells but was unaffected by T cell deletion. Following MPO immunization, activated T cells migrate to draining lymph nodes. Studies in TCR^–/– and transfer of T cells to TCR^–/– mice show that T cells facilitate the generation of anti-MPO autoimmunity and GN. TCR^–/– mice that received IL-17A^–/– T cells demonstrate that the development of anti-MPO autoimmunity and GN are dependent on T cell IL-17A production. Finally, transfer of anti-MPO CD4⁺ T cell clones to naive TCR^–/– and wild type mice with planted glomerular MPO shows that T cells are also necessary for recruitment of anti-MPO αβ CD4⁺ effector T cells. This study demonstrates that IL-17A produced by T cells plays a critical role in the pathogenesis of MPO-ANCA GN by promoting the development of MPO-specific αβ T cells.

http://ift.tt/2iwinPT

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor [INNATE IMMUNITY AND INFLAMMATION]

Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host–viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene-knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16–STING–type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that, in contrast to ALVAC, the Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate the STING–type I IFN pathway and to provide inflammasome-priming signals. In preconditioned APCs, the Ad5 vector could stimulate inflammasome activation through an AIM2-independent mechanism. Therefore, our study identifies the AIM2 inflammasome and cGAS/IFI16–STING–type I IFN pathway as a novel mechanism for host innate immunity to the ALVAC vaccine vector.

http://ift.tt/2ixj77p

NFAT1 Regulates Systemic Autoimmunity through the Modulation of a Dendritic Cell Property [AUTOIMMUNITY]

The transcription factor NFAT1 plays a pivotal role in the homeostasis of T lymphocytes. However, its functional importance in non-CD4⁺ T cells, especially in systemic immune disorders, is largely unknown. In this study, we report that NFAT1 regulates dendritic cell (DC) tolerance and suppresses systemic autoimmunity using the experimental autoimmune myasthenia gravis (EAMG) as a model. Myasthenia gravis and EAMG are T cell–dependent, Ab-mediated autoimmune disorders in which the acetylcholine receptor is the major autoantigen. NFAT1-knockout mice showed higher susceptibility to EAMG development with enhanced Th1/Th17 cell responses. NFAT1 deficiency led to a phenotypic alteration of DCs that show hyperactivation of NF-B–mediated signaling pathways and enhanced binding of NF-B (p50) to the promoters of IL-6 and IL-12. As a result, NFAT1-knockout DCs produced much higher levels of proinflammatory cytokines such as IL-1β, IL-6, IL-12, and TNF-α, which preferentially induce Th1/Th17 cell differentiation. Our data suggest that NFAT1 may limit the hyperactivation of the NF-B–mediated proinflammatory response in DCs and suppress autoimmunity by serving as a key regulator of DC tolerance.

http://ift.tt/2y12gfm

CD151 Expression Is Associated with a Hyperproliferative T Cell Phenotype [SYSTEMS IMMUNOLOGY]

The tetraspanin CD151 is a marker of aggressive cell proliferation and invasiveness for a variety of cancer types. Given reports of CD151 expression on T cells, we explored whether CD151 would mark T cells in a hyperactivated state. Consistent with the idea that CD151 could mark a phenotypically distinct T cell subset, it was not uniformly expressed on T cells. CD151 expression frequency was a function of the T cell lineage (CD8 > CD4) and a function of the memory differentiation state (naive T cells < central memory T cells < effector memory T cells < T effector memory RA⁺ cells). CD151 and CD57, a senescence marker, defined the same CD28^– T cell populations. However, CD151 also marked a substantial CD28⁺ T cell population that was not marked by CD57. Kinome array analysis demonstrated that CD28⁺CD151⁺ T cells form a subpopulation with a distinct molecular baseline and activation phenotype. Network analysis of these data revealed that cell cycle control and cell death were the most altered process motifs in CD28⁺CD151⁺ T cells. We demonstrate that CD151 in T cells is not a passive marker, but actively changed the cell cycle control and cell death process motifs of T cells. Consistent with these data, long-term T cell culture experiments in the presence of only IL-2 demonstrated that independent of their CD28 expression status, CD151⁺ T cells, but not CD151^– T cells, would exhibit an Ag-independent, hyperresponsive proliferation phenotype. Not unlike its reported function as a tumor aggressiveness marker, CD151 in humans thus marks and enables hyperproliferative T cells.

http://ift.tt/2ixj5wj

SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity [AUTOIMMUNITY]

Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10–competent B cell (B10) cell from Innp5d^fl/flAicda^Cre/+ mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID⁺ B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d^fl/flAicda^Cre/+ mouse model shows B cell–dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d^fl/fl mice, but not from the Innp5d^fl/flAicda^Cre/+ mice. This finding highlights the importance of defective B10 cells in Innp5d^fl/flAicda^Cre/+ mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d^fl/flAicda^Cre/+ mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.

http://ift.tt/2ixj9w3

Correction: IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection [CORRECTIONS]

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In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes [CLINICAL AND HUMAN IMMUNOLOGY]

Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition that increases the risk for preterm birth, death, and disability because of persistent systemic and localized inflammation. The immunological mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4⁺ T lymphocyte exometabolome. We cultured naive CD4⁺ T lymphocytes from HCA-positive and -negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6-h in vitro activation of naive CD4⁺ T lymphocytes with soluble staphylococcal enterotoxin B and anti-CD28. We analyzed samples by ultraperformance liquid chromatography ion mobility–mass spectrometry. We determined the impact of HCA on the CD4⁺ T lymphocyte exometabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: 1) CD4⁺ T lymphocytes exposed to HCA exhibit divergent exometabolomic profiles in both naive and activated states; 2) ~30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4⁺ T lymphocytes; 3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4⁺ T lymphocytes; and 4) flow cytometry and cytokine analyses suggested a bias toward a T_H1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exometabolomic profile of fetal CD4⁺ T lymphocytes. These exometabolomic changes may link HCA exposure to T_H1 polarization of the neonatal adaptive immune response.

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In This Issue [IN THIS ISSUE]

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Current opinions in office-based rhinology.

Purpose of review: The care of rhinologic patients has undergone a remarkable transformation in recent years. With the advent of endoscopic sinus surgery and high-tech image-guided computer systems, the surgical care of patients with benign sinonasal disease has successfully transitioned from the main hospital operating room to the outpatient ambulatory surgical center. Currently, there is yet another movement underway, in an attempt to care for these patients in the office setting. Recent findings: As the medical device sector continues to innovate at rapid speed, new technologies such as the radiofrequency ablator, microdebrider, balloon sinus dilator, and steroid-eluting stent have propelled the care of rhinologic patients into the clinic setting. Summary: In conjunction with an overall increased attention toward cost and time savings, the push to modernize instrumentation is now enabling the otolaryngologist to keep both the medical and surgical treatment of rhinologic patients, particularly those with chronic disease, within the office setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Risks and management of long-term corticosteroid use in chronic rhinosinusitis.

Purpose of review: The purpose of this review is to provide an update on the use and risks of long-term corticosteroids in the management of chronic rhinosinusitis (CRS). Recent findings: Long-term use of systemic corticosteroids is not indicated in the management of CRS due to the associated side effects and potential complications. Therefore, recent research has focused on the safety and efficacy of topical corticosteroid, particularly second-generation corticosteroids, and their modes of administration. Second-generation corticosteroids are more potent and have less systemic bioavailability than their first-generation counterparts. However, caution must be taken with concomitant use of more than two types of corticosteroids (topical, systemic, inhaled etc.) and also with their dosage and frequency of administration to avoid adrenal suppression, growth suppression in children, elevated intraocular pressure or epistaxis. Research is ongoing into therapies that may reduce corticosteroid resistance which has been demonstrated in some nasal polyps. Summary: Corticosteroids play an essential role in the management of CRS; however, use must be tailored to the patient-specific disease and requires ongoing review and regular reevaluation by their physician. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Opsoclonus myoclonus syndrome in a patient with Japanese encephalitis: a case report

Opsoclonus myoclonus syndrome is a rare neurological disorder that usually manifests as a paraneoplastic phenomenon. Although some viruses are reported to cause this condition, opsoclonus myoclonus syndrome by...

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A large bladder stone caused by the intravesical migration of an intrauterine contraceptive device: a case report

A wide variety of complications due to the extrauterine migration of intrauterine contraceptive devices have been reported in the literature. Here we describe the case of a large bladder stone formed around a ...

http://ift.tt/2yLbmAW

Urethrovaginal fistula following vaginal prolapse of a pedunculated uterine myoma: a case report

Urethrovaginal fistulas are usually secondary to a foreign body in the vagina or to vaginal gynecologic surgeries. We present a case of an urethrovaginal fistula secondary to vaginal prolapse of a huge peduncu...

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Current opinions in office-based rhinology.

Purpose of review: The care of rhinologic patients has undergone a remarkable transformation in recent years. With the advent of endoscopic sinus surgery and high-tech image-guided computer systems, the surgical care of patients with benign sinonasal disease has successfully transitioned from the main hospital operating room to the outpatient ambulatory surgical center. Currently, there is yet another movement underway, in an attempt to care for these patients in the office setting. Recent findings: As the medical device sector continues to innovate at rapid speed, new technologies such as the radiofrequency ablator, microdebrider, balloon sinus dilator, and steroid-eluting stent have propelled the care of rhinologic patients into the clinic setting. Summary: In conjunction with an overall increased attention toward cost and time savings, the push to modernize instrumentation is now enabling the otolaryngologist to keep both the medical and surgical treatment of rhinologic patients, particularly those with chronic disease, within the office setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2iwpeZL

Risks and management of long-term corticosteroid use in chronic rhinosinusitis.

Purpose of review: The purpose of this review is to provide an update on the use and risks of long-term corticosteroids in the management of chronic rhinosinusitis (CRS). Recent findings: Long-term use of systemic corticosteroids is not indicated in the management of CRS due to the associated side effects and potential complications. Therefore, recent research has focused on the safety and efficacy of topical corticosteroid, particularly second-generation corticosteroids, and their modes of administration. Second-generation corticosteroids are more potent and have less systemic bioavailability than their first-generation counterparts. However, caution must be taken with concomitant use of more than two types of corticosteroids (topical, systemic, inhaled etc.) and also with their dosage and frequency of administration to avoid adrenal suppression, growth suppression in children, elevated intraocular pressure or epistaxis. Research is ongoing into therapies that may reduce corticosteroid resistance which has been demonstrated in some nasal polyps. Summary: Corticosteroids play an essential role in the management of CRS; however, use must be tailored to the patient-specific disease and requires ongoing review and regular reevaluation by their physician. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2z2H5i7

Omalizumab Rapidly Improves Angioedema-Related Quality of Life in Adult Patients with Chronic Spontaneous Urticaria: X-ACT Study Data

Abstract

Background

The X-ACT study aims to examine the effect of omalizumab treatment on quality of life (QoL) in chronic spontaneous urticaria (CSU) patients with angioedema refractory to high doses of H₁-antihistamines.

Methods

In X-ACT, a phase III, double-blind, placebo-controlled study, CSU patients (18–75 years) with ≥4 angioedema episodes during the 6 months before inclusion were randomized (1:1) to receive omalizumab 300 mg or placebo every 4 weeks for 28 weeks. Angioedema-related QoL, skin-related QoL impairment, and psychological well-being were assessed.

Results

Ninety-one patients were randomized and 68 (omalizumab, n=35; placebo, n=33) completed the 28-week treatment period. At baseline, the mean (SD) total Angioedema QoL (AE-QoL; 56.2 [18.7] and 59.9 [19.2]) and Dermatology Life Quality Index (DLQI; 14.6 [5.7] and 16.6 [7.3]) score was high in the omalizumab and placebo group, respectively. At Week 4 (after the first treatment), the least squares mean difference in the AE-QoL and DLQI score between groups was −17.6 (P<0.001) and −7.2 (P<0.001), respectively. Significant QoL improvements in the omalizumab versus placebo groups continued until Week 28, but returned to placebo levels at the follow-up visit. The mean (SD) baseline 5-item World Health Organization Well-being Index was 10.0 (5.5, omalizumab) and 7.7 (5.3, placebo), which increased above the depression threshold (<13) from Week 4 and throughout with omalizumab but not placebo treatment. Compared to placebo, omalizumab was also associated with decreased fear of suffocation due to angioedema.

Conclusions

Our findings support omalizumab treatment in patients with severe H1-antihistamine-refractory CSU with angioedema.

This article is protected by copyright. All rights reserved.

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EPA Reduced Arsenic in Water, Prevented 1000s of Cancers

Exposure to arsenic in drinking water is significantly lower among people who drink mostly tap water, thanks to earlier protective legislation, resulting in meaningful reductions in related cancers.
Medscape Medical News

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Ipi Plus Nivo for Melanoma Patients With Brain Metastases

Two recent ASCO abstracts show important results, possibly practice-changing, on immunologic treatment in melanoma patients with brain metastases.
Medscape Oncology

http://ift.tt/2zwk4Ab

Handheld Microscopy May Improve Margin Mapping for Lentigo Maligna

Handheld reflectance confocal microscopy with radial video mosaicing may improve diagnostic accuracy and facilitate margin mapping for lentigo maligna and lentigo maligna melanoma, researchers suggest.
Reuters Health Information

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IL-10, TGF-β and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells

Publication date: Available online 23 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Noriko Ogasawara, Julie A. Poposki, Aiko I. Klingler, Bruce K. Tan, Ava R. Weibman, Kathryn E. Hulse, Whitney W. Stevens, Anju T. Peters, Leslie C. Grammer, Robert P. Schleimer, Kevin C. Welch, Stephanie S. Smith, David B. Conley, Joseph R. Raviv, Pejman Soroosh, Omid Akbari, Tetsuo Himi, Robert C. Kern, Atsushi Kato




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Evanescence Wave-Based Technology for the Rapid and Sensitive Quantification of Biological Analytes

Publication date: Available online 23 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Manfred Schawaller, Claudio Rhyner, Max Wiki, Gerald Quapil, Torsten Zuberbier, Cezmi A. Akdis, Reto Crameri




http://ift.tt/2yHYKbL

REirradiation and Programmed Cell Death Protein 1 (PD-1) Blockade On Recurrent Squamous Cell Head and Neck Tumors

Condition:   Head and Neck Squamous Cell Carcinoma
Interventions:   Drug: Nivolumab;   Radiation: Radiotherapy (RT)
Sponsors:   Oslo University Hospital;   Bristol-Myers Squibb
Recruiting

http://ift.tt/2y02cSc

Pilot Trial of Microsphere Oxycodone (Xtampza ER) for Pain Management in Patients Receiving Radiotherapy for Locally Advanced Head and Neck Cancer

Condition:   Locally Advanced Head and Neck Cancer
Intervention:   Drug: Xtampza ER
Sponsor:   University of Alabama at Birmingham
Not yet recruiting

http://ift.tt/2labUes

GenoType® HelicoDR test in comparison with histology and culture for Helicobacter pylori detection and identification of resistance mutations to clarithromycin and fluoroquinolones

Abstract

Background

There are several methods for Helicobacter pylori infection diagnosis.

Aim

The efficacies of three methods for H. pylori identification directly from a biopsy were compared: histology, culture, and molecular GenoType® HelicoDR test.

Materials & Methods

Eighty-five triplicates of stomach antrum biopsies were obtained during gastroscopy procedures for culture, histology, and molecular assay. In addition, we performed molecular identification of genes encoding resistance to clarithromycin and fluoroquinolones.

Results

The results have shown that the most specific method with the highest number of positive specimens was by molecular kit, compared to culture and histology (94.3%, 77.1%, and 71.4%, respectively). There was a higher rate of resistance mutations to clarithromycin than to fluoroquinolones (68.26% vs 20%). The most common mutations for clarithromycin and fluoroquinolones resistance were found in alleles A2143G and N87K, respectively. The highest rate of positive specimens was identified by the molecular.

Discussion

GenoType HelicoDR kit (94.3%), which has several advantages: direct identification, strain resistance characterization, mixture of genotypes detection, and no transport or storage limitations; thus, it is an excellent epidemiological screening tool. This work has demonstrated a lower resistance rate to fluoroquinolones; it is possible that in the investigated geographic area treatment with fluoroquinolones may be preferable to clarithromycin. GenoType® HelicoDR test eliminates the need for culture performance and susceptibility tests for several common antibiotic agents and enables optimal and specific antibiotic treatment adjustment.

Conclusion

We recommend a combination of PCR assay and bacterial culture for a quick method of screening and more efficient identification of H. pylori strains and resistance patterns.

http://ift.tt/2it9JBI

Comparative Study of Outcome of Type I Tympanoplasty in Chronic Otitis Media Active Mucosal Disease (Wet Ear) Versus Chronic Otitis Media Inactive Mucosal Disease (Dry Ear)

Abstract

To compare the outcome of type I tympanoplasty with cortical mastoidectomy in chronic otitis media active mucosal disease (wet ear) versus chronic otitis media inactive mucosal disease (dry ear). An observational analytic study was conducted and data collection was done from August 2014 to August 2016. All patients of chronic otitis media with mucosal disease were divided into two groups, one with active disease (group A) and another with inactive disease (group B). The outcome was studied in the form of graft take up rate. Total 103 patients were studied, group A (wet ear) had 67 and group B (dry ear) had 36 patients. Graft take up rate was 94% in wet ear and 100% in dry ear and p value was 0.2. There was no statistically significant difference found between the two groups.

http://ift.tt/2xZhSjD

Ecthyma gangrenosum, an important cutaneous infection to recognize in the immunosuppressed patient

http://ift.tt/2h0mDDF

Itching for nail fashion: chronic urticaria and chronic hand dermatitis secondary to acrylate and methacrylate allergy in gel nail varnish

Summary

Allergic contact dermatitis (ACD) secondary to acrylates and methacrylates is a well- described occurrence, particularly in those who wear or handle gel nail varnish. Management involves avoidance of the identified allergen. The cause of chronic urticaria (CI) is often not identified, and CU is not known to be associated with acrylates or methacrylates. We report a case of a 50-year-old woman who initially presented with hand dermatitis exacerbated by gel nail varnish on a background of CU. Avoiding all nail varnishes because of her ACD also resulted in improvement of her CU. To our knowledge, this is the first documented case of CU secondary to the acrylates and methacrylates found in nail cosmetics.

http://ift.tt/2zwS2Vf

Treatment of molluscum contagiosum with hydrogen peroxide

http://ift.tt/2gZvcP9

Localized cluster of nodules in childhood

http://ift.tt/2zviGO9

A congenital naevus in a blaschkoid distribution

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Painful, violaceous plaques in a patient with pruritus

http://ift.tt/2zGkWTH

Human adipose-derived stem cell spheroid treated with photobiomodulation irradiation accelerates tissue regeneration in mouse model of skin flap ischemia

Abstract

Skin flap grafting is a form of transplantation widely used in plastic surgery. However, ischemia/reperfusion injury is the main factor which reduces the survival rate of flaps following grafting. We investigated whether photobiomodulation (PBM) precondition prior to human adipose-derived stromal cell (hASC) spheroid (PBM-spheroid) transplantation improved skin tissue functional recovery by the stimulation of angiogenesis and tissue regeneration in skin flap of mice. The LED had an emission wavelength peaked at 660 ± 20 nm (6 J/cm², 10 mW/cm²). The expression of angiogenic growth factors in PBM-spheroid hASCs was much greater than that of not-PBM-treated spheroid or monolayer-cultured hASCs. From immunochemical staining analysis, the hASCs of PBM-spheroid were CD31⁺, KDR⁺, and CD34⁺, whereas monolayer-cultured hASCs were negative for these markers. To evaluate the therapeutic effect of hASC PBM-spheroid in vivo, PBS, monolayer-cultured hASCs, and not-PBM-spheroid were transplanted into a skin flap model. The animals were observed for 14 days. The PBM-spheroid hASCs transplanted into the skin flap ischemia differentiated into endothelial cells and remained differentiated. Transplantation of PBM-spheroid hASCs into the skin flap ischemia significantly elevated the density of vascular formations through angiogenic factors released by the skin flap ischemia and enhanced tissue regeneration at the lesion site. Consistent with these results, the transplantation of PBM-spheroid hASCs significantly improved functional recovery compared with PBS, monolayer-cultured hASCs, and not-PBM-spheroid treatment. These findings suggest that transplantation of PBM-spheroid hASCs may be an effective stem cell therapy for the treatment of skin flap ischemia.

http://ift.tt/2yGF0oT

Should alcohol screening be a routine practice in alcohol-related facial trauma care? A narrative review

Abstract

The link between alcohol intoxication and Emergency Department (ED) attendance for management of alcohol-related injuries has been well documented. The acute settings such as ED and surgical wards may not be the most appropriate environment for treatment of chronic conditions, but traumatic episode presentation to ED may offer the most opportunistic time to focus on screening against harmful alcohol use in order to provide timely feedback and support. Although ED provides an opportunity to identify patients with alcohol problems, the initial challenge is finding suitable ways to identify and screen affected patients. This paper is a narrative review on methods of alcohol screening and its effectiveness and efficacy in trauma care setting. It is second part in a series on implementation of screening and brief intervention in managing trauma patients.

http://ift.tt/2yC6xKv

Pemphigus vegetans with the manifestations of acrodermatitis continua: A rare variant

http://ift.tt/2yHN1M0

Presymptomatic genetic diagnosis of two siblings with hereditary angioedema, presenting with unusual normal levels of serum C4

http://ift.tt/2xZsTkU

Pigmented Bowen disease: A challenging dermoscopic feature due to a traumatic disfigurement

http://ift.tt/2yHZLlD

Comparative Study of Outcome of Type I Tympanoplasty in Chronic Otitis Media Active Mucosal Disease (Wet Ear) Versus Chronic Otitis Media Inactive Mucosal Disease (Dry Ear)

Abstract

To compare the outcome of type I tympanoplasty with cortical mastoidectomy in chronic otitis media active mucosal disease (wet ear) versus chronic otitis media inactive mucosal disease (dry ear). An observational analytic study was conducted and data collection was done from August 2014 to August 2016. All patients of chronic otitis media with mucosal disease were divided into two groups, one with active disease (group A) and another with inactive disease (group B). The outcome was studied in the form of graft take up rate. Total 103 patients were studied, group A (wet ear) had 67 and group B (dry ear) had 36 patients. Graft take up rate was 94% in wet ear and 100% in dry ear and p value was 0.2. There was no statistically significant difference found between the two groups.

http://ift.tt/2xZhSjD

CD1a-positive cutaneous mastocytosis: Electron microscopic evidence of pleomorphic mast cell proliferation

http://ift.tt/2xZ6uEq

Generalized eruptive keratoacanthoma with vitiligo followed by the development of prurigo nodularis: A case report and published work review

Abstract

Herein, we report a unique case of generalized eruptive keratoacanthoma (GEKA) in a 47-year-old Chinese man presenting with extensive pruritic papules and nodules accompanied by oral lesions. He also had a 2-year history of vitiligo and long-term experience of working outdoors. Biopsies were consistent with keratoacanthoma . Interestingly, prurigo nodularis (PN) was found in histopathology at 1-year follow up. To our knowledge, this is the first report describing a case of GEKA with oral lesions complicated with vitiligo and developed with PN.

http://ift.tt/2yIjjqe

Dyskeratosis congenita associated with congenital hypothyroidism

http://ift.tt/2xZiWE9

Ductal cells of minor salivary glands in Sjögren's syndrome patients express LINE-1 ORF2p and APOBEC3B

Abstract

Background

Type I interferon activation is a hallmark event in Sjögren's syndrome. L1 retroelements stimulate plasmacytoid dendritic cells, activating the type I interferons, and are regulated by various mechanisms, including the APOBEC3 deaminases. As L1s are potential trigger factors in autoimmunity, we aimed to investigate the immunohistochemical localization of L1 ORF2 and its inhibitor APOBEC3B protein in minor salivary glands of Sjögren's syndrome patients.

Methods

Twenty minor salivary gland-tissue samples from 20 Sjögren's syndrome patients, classified according to Tarpley's histological criteria, and 10 controls were evaluated for L1 ORF2p and APOBEC3B expression via immunohistochemistry.

Results

L1 ORF2p was expressed in 17/20 SS patients and all controls. APOBEC3B expression was observed in 15/20 Sjögren's syndrome patients, 5/5 chronic sialadenitis and 3/5 normal minor salivary glands. Both antibodies stained the cytoplasm of the ductal epithelial cells. Negative staining was observed in the acinar cells. L1 ORF2p positive immunostaining was significantly lower in Tarpley IV Sjögren's syndrome patients than controls (p=0.039) and APOBEC3B positive staining was significantly lower in Tarpley I compared to Tarpley II Sjögren's syndrome patients (p=0.008) and controls (p=0.035).

Conclusions

L1 ORF2p and APOBEC3B are expressed in the ductal epithelial cells of minor salivary glands that are among the key targets in Sjögren's syndrome. L1 ORF2p expression may promote the L1 ability to act as an intrinsic antigen in Sjögren's syndrome. The potential future use of L1 ORF2-reverse transcriptase inhibitors in autoimmunity supports further investigation of L1 epigenetic regulation by APOBEC3 enzymes.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hXKaoI

Tumor-derived exosomes enhance invasion and metastasis of salivary adenoid cystic carcinoma cells

Abstract

Objectives

Tumor-derived exosomes (TDE) have been shown to participate in different steps of the dissemination of cancer cells. However, the role of salivary adenoid cystic carcinoma-derived (SACC-derived) exosomes had not been documented in SACC. The study aims to explore the functions of SACC-derived TDE in SACC progression and investigate potential mechanisms.

Methods

SACC cell line SACC-83 was used to generate TDE. Afterwards, SACC-83 or HUVECs was co-cultured with or without TDE. Tumor migration, tumor invasion, and endothelial permeability were examined by wound healing assay, tumor invasion assay, endothelial permeability assay, and tumor cell transendothelial migration assay, respectively. Moreover, the expression levels of cell junction related proteins were examined by qRT-PCR and Western Blot.

Results

SACC-83-derived exosomes were taken up by their host cells. Meanwhile, TDE increased migration and invasion capacity of SACC-83 cells and enhanced endothelial cell permeability. Furthermore, we demonstrated that the expression of cell junction related proteins (Claudins and ZO-1) was down-regulated, which is presumably involved in the TDE-mediated promotion of migration, invasion and metastasis.

Conclusion

The results suggested that SACC cells-derived exosomes were loaded with individual components that could enhance invasiveness and induce microenvironment changes, thus promoting SACC aggression.

This article is protected by copyright. All rights reserved.

http://ift.tt/2z0xE2O

Porphyromonas gingivalis lipopolysaccharide induces over production of CC chemokine ligand 2 via toll-like receptor-4 in oral lichen planus

Abstract

Background

We recently reported that the CC chemokine ligand 2 (CCL2)-CC receptor 2 (CCR2) axis was involved in the pathogenesis of oral lichen planus (OLP). However, the exact mechanism for the high expression of CCL2 in OLP specimens is not clear. Therefore, this study was designed to investigate the potential role of the toll-like receptor 4 (TLR-4) pathway in overproduction of CCL2 in OLP lesions.

Methods

Immunohistochemical staining and real-time RT-PCR were used to detect TLR-4, CCL2, and CCR2 expression in OLP lesions. Then, gingival epithelial cells from OLP lesions were established and treated with Porphyromonas gingivalis (P. gingivsalis) lipopolysaccharide (LPS). CCL2 expression in epithelial cells was determined by Western blotting and real-time RT-PCR. In some experiments, TAK-242, a specific inhibitor of TLR-4, was used to block the TLR-4 pathway before cells were stimulated with LPS.

Results

We found that TLR-4 was significantly increased in the epithelium of OLP specimens, compared with controls. Moreover, LPS can induce the over production of CCL2 in epithelial cells of OLP, in vitro. TAK-242 effectively eliminated the increase in CCL2 expression induced by LPS by blocking the TLR-4/NF-κB pathway. In addition, we again confirmed that expression of CCL2 and CCR2 was increased in OLP specimens.

Conclusion

Increased TLR-4 expression contributes to the upregulated expression of CCL2 in the epithelium of OLP lesions, which suggests that oral bacteria participate in the pathogenesis of OLP via the TLR-4 pathway.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hXFSgQ

Should alcohol screening be a routine practice in alcohol-related facial trauma care? A narrative review

Abstract

The link between alcohol intoxication and Emergency Department (ED) attendance for management of alcohol-related injuries has been well documented. The acute settings such as ED and surgical wards may not be the most appropriate environment for treatment of chronic conditions, but traumatic episode presentation to ED may offer the most opportunistic time to focus on screening against harmful alcohol use in order to provide timely feedback and support. Although ED provides an opportunity to identify patients with alcohol problems, the initial challenge is finding suitable ways to identify and screen affected patients. This paper is a narrative review on methods of alcohol screening and its effectiveness and efficacy in trauma care setting. It is second part in a series on implementation of screening and brief intervention in managing trauma patients.

http://ift.tt/2yC6xKv

Staphylococcal Biofilms in Atopic Dermatitis

Abstract

Purpose of Review

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that is a major public health burden worldwide. AD lesions are often colonized by Staphylococcus aureus and Staphylococcus epidermidis. An important aspect of Staphylococcus spp. is their propensity to form biofilms, adhesive surface-attached colonies that become highly resistant to antibiotics and immune responses, and recent studies have found that clinical isolates colonizing AD skin are often biofilm-positive. Biofilm formation results in complex bacterial communities that have unique effects on keratinocytes and host immunity. This review will summarize recent studies exploring the role of staphyloccocal biofilms in atopic dermatitis and the implications for treatment.

Recent Findings

Recent studies suggest an important role for biofilms in the pathogenesis of numerous dermatologic diseases including AD. S. aureus biofilms have been found to colonize the eccrine ducts of AD skin, and these biofilms influence secretion of keratinocyte cytokines and trigger differentiation and apoptosis of keratinocytes. These activities may act to disrupt barrier function and promote disease pathogenesis as well as allergen sensitization.

Summary

Formation of biofilm is a successful strategy that protects the bacteria from environmental danger, antibiotics, and phagocytosis, enabling chronic persistence in the host. An increasing number of S. aureus skin isolates are resistant to conventional antibiotics, and staphylococcal biofilm communities are prevalent on the skin of individuals with AD. Staphylococcal colonization of the skin impacts skin barrier function and plays multiple important roles in AD pathogenesis.

http://ift.tt/2yK5Zlz

Staphylococcal Biofilms in Atopic Dermatitis

Abstract

Purpose of Review

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that is a major public health burden worldwide. AD lesions are often colonized by Staphylococcus aureus and Staphylococcus epidermidis. An important aspect of Staphylococcus spp. is their propensity to form biofilms, adhesive surface-attached colonies that become highly resistant to antibiotics and immune responses, and recent studies have found that clinical isolates colonizing AD skin are often biofilm-positive. Biofilm formation results in complex bacterial communities that have unique effects on keratinocytes and host immunity. This review will summarize recent studies exploring the role of staphyloccocal biofilms in atopic dermatitis and the implications for treatment.

Recent Findings

Recent studies suggest an important role for biofilms in the pathogenesis of numerous dermatologic diseases including AD. S. aureus biofilms have been found to colonize the eccrine ducts of AD skin, and these biofilms influence secretion of keratinocyte cytokines and trigger differentiation and apoptosis of keratinocytes. These activities may act to disrupt barrier function and promote disease pathogenesis as well as allergen sensitization.

Summary

Formation of biofilm is a successful strategy that protects the bacteria from environmental danger, antibiotics, and phagocytosis, enabling chronic persistence in the host. An increasing number of S. aureus skin isolates are resistant to conventional antibiotics, and staphylococcal biofilm communities are prevalent on the skin of individuals with AD. Staphylococcal colonization of the skin impacts skin barrier function and plays multiple important roles in AD pathogenesis.

http://ift.tt/2yK5Zlz

Cystic Lymphangioma of the Chest Wall in a 5-Year-Old Male Patient: A Rare and Atypical Localization—A Case Report and Comprehensive Review of the Literature

Lymphangioma is a benign congenital malformation. The extremely rare and atypical localization of a lymphangioma in the chest wall was the real motive for the present case study. A 5-year-old boy was admitted to the Emergency Department of the 1st Department of Pediatric Surgery, Aristotle University of Thessaloniki, due to the presence of a mildly painful swelling in the left lateral chest wall, which was first noticed three months ago, after a blunt injury during sport. Physical examination revealed the presence of a palpable, spherical, painful, nut-sized subcutaneous lesion in the left lateral chest wall, respectively, with the anterior axillary line, at the height of the 6th to 7th intercostal space. Presence of ecchymosis on the overlying skin was also noticed. During palpation, we did not notice fluctuation, while transillumination was not feasible. Performance of ultrasonography, including Doppler color flow imaging, followed, depicting a subcutaneous cystic lesion,  cm in dimensions, without extension to the thoracic cavity. Scheduled surgical excision of the lesion was decided. Histopathological examination documented the diagnosis of cystic lymphangioma. Patient is still followed up on a 6-month basis. He remains asymptomatic, after 2 years, without indication of relapse.

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Clinical Snippets

http://ift.tt/2zv4t3L

Issue Information

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Speech-language pathology care and short- and long-term outcomes of oropharyngeal cancer treatment in the elderly

Objective

To examine associations between speech-language pathology (SLP) care and pretreatment variables, short-term and long-term swallowing and airway impairment, and survival in elderly patients treated for oropharyngeal squamous cell cancer (SCCA).

Study Design

Retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data.

Methods

We evaluated longitudinal data from 666 patients diagnosed with oropharyngeal SCCA from 2004 to 2007 using cross-tabulations, multivariate logistic regression, and survival analysis.

Results

SLP care was documented in 25% of patients. High-volume hospital care (odds ratio (OR) = 3.2 [1.0–10.0]) and dysphagia during treatment (OR = 13.0 [3.6–47.1]) were the only significant predictors of SLP care during the initial treatment period. SLP care was significantly more likely during the first year (OR = 5.3 [3.1–9.1]) and second year (OR = 4.5 [2.4–8.2]) following initial treatment. Subsequent dysphagia (OR = 32.5 [16.9–62.4]), stricture (OR = 2.2 [1.2–4.0]), gastrostomy (OR = 1.7 [1.1–2.7]), and tracheostomy tube use (OR = 2.4 [1.2–4.8]) were significantly associated with long-term SLP care. After controlling for patient, tumor, and treatment-related variables, SLP care was associated with significant relative attenuation of the OR for dysphagia (93%), stricture (35%), weight loss (8%), and airway obstruction (34%). Survival analysis, controlling for all other variables, demonstrated improved survival for patients under SLP care (hazard ratio = 0.73 [0.57–0.95]).

Conclusion

SLP care is underutilized in elderly oropharyngeal SCCA patients and largely utilized after the onset of impaired airway and swallowing function, but is associated with improved outcomes. These data suggest a need for treatment guidelines that incorporate the routine use of SLP care in this population during the initial treatment period and beyond.

Level of Evidence

2c. Laryngoscope, 2017

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Successful treatment of refractory cholinergic urticaria with omalizumab

http://ift.tt/2yCvA0k

A 71-year-old man with a hemorrhagic vesicular eruption

http://ift.tt/2gBK2yj

Psoriasis and small intestine bacterial overgrowth

http://ift.tt/2yCxWMA

Dermoscopic features of Orf disease

http://ift.tt/2gCbsUY

Support needs of people living with Mycobacterium ulcerans (Buruli ulcer) disease in a Ghana rural community: a grounded theory study

Abstract

Introduction/Background

Mycobacterium ulcerans (also known as Buruli ulcer) disease is a rare skin disease which is prevalent in rural communities in the tropics mostly in Africa. Mortality rate is low, yet morbidity and consequent disabilities affect the quality of life of sufferers.

Aims

The aim of this paper is to use the grounded theory method to explore the support needs of people living with the consequences of Buruli ulcer in an endemic rural community in Ghana.

Methods

We used the grounded theory research approach to explore the experiences of people living with Mycobacterium ulcerans in a rural district in Ghana and provide a basis to understand the support needs of this group.

Results

The key support needs identified were: functional limitations, fear and frequency of disease recurrence, contracture of limbs and legs, loss of sensation and numbness in the affected body area, lack of information from health professionals about self-care, feeling tired all the time, insomnia, lack of good diet, lack of access to prostheses, having to walk long distances to access health services, and loss of educational opportunities.

Discussions

The study discusses how the systematically derived qualitative data has helped to provide a unique insight and advance our understanding of the support needs of people living with BU and how they live and attempt to adapt their lives with disability. We discuss how the availability of appropriate interventions and equipment could help them self-manage their condition and improve access to skin care services.

Conclusions

The support needs of this vulnerable group were identified from a detailed analysis of how those living with BU coped with their lives. A key issue is the lack of education to assist self-management and prevent deterioration. Further research into the evaluation of interventions to address these support needs is necessary including self-management strategies.

http://ift.tt/2yCxWw4