History of NSAID Use in the Treatment of Headaches Pre and Post-industrial Revolution in the United States: the Rise and Fall of Antipyrine, Salicylic Acid, and Acetanilide

Abstract

Purpose of Review

Non-steroid anti-inflammatory drugs (NSAIDs) constitute a vital class of medications in today's headache regimen. However, up until the nineteenth century, they were largely unknown to most of the medical community. The purpose of this review is to explore the evolution of NSAIDs in the treatment of headaches spurred on by the Industrial Revolution in the USA.

Recent Findings

The currently available data on the impact of NSAIDs reflects their significant contribution to headache treatment.

Summary

The emergence of mass production spurred on by the Industrial Revolution, lead to widespread use of antipyrine, salicylic acid, and acetanilide. However, along with it came the growing awareness of consumer safety, leading to their ultimate downfall, and the subsequent birth of the Food and Drug Act.

http://bit.ly/2FRceHO

Unknown primary (CUP) of the head and neck : No advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment

Bilateral vs ipsilateral adjuvant radiotherapy in patients with cancer of unknown primary of the head and neck: An analysis of the clinical outcome and radiation‐induced side effects

Nguyen‐Son Le  Stefan Janik MD, PhD  Helmut Simmel MD  Boban M. Erovic MD, PD, MBA

First published: 19 January 2019 https://doi.org/10.1002/hed.25637

This work was presented at the 61st Annual Meeting of the Austrian Society of Oto‐Rhino‐Laryngology – Head and Neck Surgery, Vienna, Austria

Abstract

Background

The purpose of this study was to analyze and compare ipsilateral and bilateral adjuvant radiotherapy in patients with cancer of unknown primary (CUP) of the head and neck.

Methods

Overall survival, recurrence‐free survival, and radiation‐induced side effects were assessed in 76 patients with CUP who underwent ipsilateral (n = 29) or bilateral (n = 47) radiotherapy.

Results

At a median follow‐up of 41 months, the 5‐year overall survival and recurrence‐free rate were 67.9% and 71.5%, respectively. No statistically significant difference between ipsilateral and bilateral radiotherapy could be found regarding 5‐year overall survival, recurrence‐free survival, occurrence of a primary tumor, and distant metastasis. The analysis of radiation‐induced acute side effects showed a significant benefit of ipsilateral radiotherapy.

Conclusion

As the main parameters of the study regarding the outcome and radiation‐induced side effects showed no advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment of CUP patients.

Acanthosis Nigricans & Metabolic Syndrome : Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. High prevalence of Acanthosis Nigricans (AN) in subjects with metabolic syndrome. Also there was a positive correlation between severity of Acanthosis Nigricans (AN) and Metabolic syndrome.

Acanthosis nigricans: A cutaneous marker for metabolic syndrome p. 16

Nirali Girish Shah, Swapna S Khatu, Neeta R Gokhale, Yuvraj E More, Deepak Khismatrao

DOI:10.4103/mjdrdypu.mjdrdypu_44_18  

Background: Acanthosis Nigricans (AN) is an easily identifiable dermatoses characterized by thickened, hyperpigmented plaques. Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. AN is a skin marker associated with this syndrome. Aims and Objectives: This study aimed to determine the relationship between AN and metabolic syndrome by studying its clinico-epidemiological features and also the relation of severity of AN over neck with metabolic syndrome. Methodology: This is a case-control study. One hundred consecutive patients of AN attending dermatology OPD of a tertiary care hospital were included in this study. They were evaluated for AN and severity of AN over neck was assessed. Age and sex matched 100 controls were included in the study. Epidemiological, clinical and anthropometric characteristics (height, weight, waist circumference) were measured of all the cases and controls. Body Mass Index (BMI) was calculated. Fasting Blood Sugar, High Density Lipoprotein and Serum Triglyceride levels were estimated. Result: The average age of the patients was 32.4 years and females (62%) were more than the males (38%). Neck was involved in all the patients. There was statistically significant correlation of increasing severity of AN with each component of Metabolic syndrome. On comparing between cases and controls, each component of metabolic syndrome was raised in cases as compared to the controls. 70% cases had Metabolic syndrome which was statistically significant. Conclusion: There was a high prevalence of AN in subjects with metabolic syndrome. Also there was a positive correlation between severity of AN and Metabolic syndrome.

Salvage surgery for advanced stage head and neck squamous cell carcinoma following radiotherapy or chemoradiation

Abstract

Purpose

Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria.

Methods

Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation.

Results

16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30–45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (p_{heterogeneity} = 0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days.

Conclusions

Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.

http://bit.ly/2DtmwMw

Neuropsychiatric symptoms following sore throat in a young boy

A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children.

http://bit.ly/2Mrfs6i

Urachal Mucinous Cystadenocarcinoma

A 57-year-old man presented with a 6-month history of pelvic fullness. He had no lower urinary tract symptoms or altered bowel habits. On examination, there was a non-tender pelvic mass which extended from the pubic symphysis to the level of the umbilicus. CT scan of the abdomen demonstrated a 22x11x11 cm cystic mass arising from the pelvis extending into the midline and superiorly to the umbilicus. Other than raised carcinoembryonic antigen of 7.6 ng/mL (<5.0), the remainder of his blood test were unremarkable. Flexible cystoscopy demonstrated a convex deformity of the bladder wall in keeping with the compression and displacement as seen on the CT. The patient underwent an open excision of the cystic structure (urachal remnant), partial cystectomy, partial excision of anterior abdominal wall and pelvic lymphadenectomy. A check cystogram performed 12 days following the initial operation was unremarkable.

http://bit.ly/2sIp5US

Correction: Exclusively plant, whole-food diet for polypharmacy due to persistent atrial fibrillation, ischaemic cardiomyopathy, hyperlipidaemia and hypertension in an octogenarian

http://bit.ly/2MsddiX

Rare cutaneous myiasis of the face due to Lunds fly (Cordylobia rodhaini) in a British traveller returning from Uganda

We present a rare cause for cutaneous furuncular myiasis in a 55-year-old British traveller returning from Uganda. Initially presenting with what appeared to be a cellulitic furuncle on her forehead, she returned to the emergency department 3 days later with extensive preseptal periorbital swelling and pain. Occlusive treatment with petroleum jelly was applied and one larva manually extracted and sent to London School of Tropical Medicine for examination. It was identified as Lund's Fly (Cordylobia rodhaini), a rare species from the rainforests of Africa with only one other case reported in the UK since 2015. Ultrasound imaging identified another larva, necessitating surgical exploration and cleaning. The lesion subsequently healed completely and the patient remains well.

http://bit.ly/2sGT27V

Phenytoin-induced hypothermia

A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?

http://bit.ly/2MqZZmB

Anaphylaxis to patent blue dye in a 17-year-old boy

Patent blue V dye (PBV) is frequently used as a perioperative drug for lymphangiography, as well as a food additive. Hypersensitivity to PBV is poorly documented in adults and had not been previously described in children. The diagnosis of PBV allergy depends on corroboration of history consistent with an IgE-mediated reaction and confirmatory skin tests. We present in this paper a paediatric case of PBV anaphylaxis and of biphasic reaction that exemplifies the challenges involved in diagnosing and managing this rare but potentially life-threatening allergic reaction.

http://bit.ly/2sJ5DYk

Floating fetus: a rare complication of balloon tamponade treatment of caesarean scar ectopic pregnancy

http://bit.ly/2MqZWap

Spontaneous subcapsular haematoma: a rare cause of acute kidney graft dysfunction

http://bit.ly/2sF7yx3

Chylothorax in a patient with HIV-related Kaposis sarcoma

We present a case of a 33-year-old man with a background of HIV and Kaposi's sarcoma (KS), who presented with a right sided chylothorax. He was managed with percutaneous chest drainage and talc pleurodesis, in addition to his chemotherapy and antiretroviral therapy for KS and HIV, respectively. Good clinical control of the chylothorax remained 4 months post drainage. This case report summarises the approach to investigating and managing pleural effusion, and in particular chylothorax, in HIV patients.

http://bit.ly/2MqZUPP

Spontaneous spinal subdural haematoma in a patient on apixaban

A 68-year-old man on apixaban presented to the emergency department with back pain following a long-haul flight. Investigations for pulmonary embolus and aortic dissection were negative and he was discharged with analgesia for mechanical back pain. He presented three more times with worsening back pain, third time with urinary retention and the fourth time with lower limb weakness and loss of coordination. He was found to have a spinal subdural haematoma on MRI and transferred to a tertiary centre, where he was managed conservatively and discharged for rehabilitation with good neurological recovery.

http://bit.ly/2sEOn6m

Rectal adenocarcinoma presenting with thigh muscle metastasis as the only metastatic site

Rectal carcinoma with metastasis to skeletal muscle is a rare finding. According to literature review, 17 cases of skeletal muscle metastasis from colorectal carcinoma have been documented where only six cases were rectal carcinomas.

We discuss a case of a middle-aged man with a known history of high-grade mucinous adenocarcinoma of the rectum, status post abdominoperineal resection followed by adjuvant radiotherapy and chemotherapy. During the planned chemotherapy course, a right proximal thigh subcutaneous mass was incidentally found which on subsequent biopsy proved to be metastatic from rectal primary site. On subsequent 18F-FDG (Fluorodeoxyglucose) positron emission tomography (PET)/CT scan after completion of chemotherapy for the purpose of treatment response evaluation, only FDG-avid lesion was residual right proximal thigh metastatic mass without involvement of other common sites, such as liver and lung. In this case, the 18F-FDG-PET/CT scan was able to exclude additional metastatic sites and also evaluate the patient's treatment response.

http://bit.ly/2MoWvRv

Radiation induced valvular disease: the internists prospective

Radiation-induced cardiac injury entails a wide spectrum of cardiovascular complications such as cardiomyopathy and valvular diseases among others. We present the internist's perspective and the challenges faced in managing these patients. There are guidelines addressing radiation-induced valvular disease (RIVD) including screening and treatment, but are often unrecognised by most internist's practice. A thorough cardiovascular examination and screening echocardiography may detect RIVD at an earlier stage. Early screening with transthoracic echocardiogram should be considered in asymptomatic or low-risk patients and more frequently in symptomatic and high-risk patients. The internists should educate their patients with prior chest irradiation, regarding the possible radiation related adverse cardiovascular effects and recommended screening. Lifestyle changes and aggressive cardiovascular risk modification should be emphasised, as concomitant hypertension, coronary artery disease and cardiomyopathy can have unfavourable effects in these patients.

http://bit.ly/2sI7CMh

Sacral schwannoma with intraosseous extension

http://bit.ly/2MplKDm

Rare case report of idiopathic gingival fibromatosis in childhood and its management

Idiopathic gingival fibromatosis (GF), also known as gingivomatosis, is a rare condition in childhood, with an unknown aetiology. The oral manifestations of the condition are varied and depend on the severity and age of involvement. This paper describe the case of a 5-year-old male child with extensive gingival enlargement covering almost all the maxillary and mandibular teeth resulted in difficulty with speech, mastication and poor aesthetics. Clinical and radiographic examination along with haematological investigations ruled out any systemic association. The case was managed with conventional scalpel blade surgery along with electrocautery under general anaesthesia yielding good results without any recurrence after a 12-month follow-up. The results revealed that the oral manifestations of GF depend on its severity and the age of onset. Timely intervention can help to prevent associated complications in a growing child.

http://bit.ly/2sGvvUs

Primary isolated hepatosplenic sarcoidosis mimicking malignancy and causing symptomatic hypercalcaemia

This is a case of a 67-year-old woman, known to have multiple medical problems, mainly papillary thyroid cancer status post-total thyroidectomy and cervical neck dissection in addition to radioactive iodine currently in remission for 1 year, who presented to the hospital with severe weakness and fatigue. The initial workup showed significant hypercalcaemia and suppressed Parathyroid hormone (PTH). The patient was treated with hydration and pamidronate and her hypercalcaemia and symptoms improved. The differential was wide, however, a CT scan of the chest, abdomen and pelvis did show multiple liver and splenic nodular lesions; therefore, malignancy was the highest possible diagnosis. Biopsy of the splenic lesion confirmed the diagnosis of sarcoidosis. Therefore, the patient was diagnosed with primary isolated nodular hepatosplenic sarcoidosis mimicking malignancy and causing significant symptomatic hypercalcaemia.

http://bit.ly/2MpZyZI

Frictional Keratosis, Contact Keratosis and Smokeless Tobacco Keratosis: Features of Reactive White Lesions of the Oral Mucosa

Abstract

White lesions of the oral cavity are quite common and can have a variety of etiologies, both benign and malignant. Although the vast majority of publications focus on leukoplakia and other potentially malignant lesions, most oral lesions that appear white are benign. This review will focus exclusively on reactive white oral lesions. Included in the discussion are frictional keratoses, irritant contact stomatitis, and smokeless tobacco keratoses. Leukoedema and hereditary genodermatoses that may enter in the clinical differential diagnoses of frictional keratoses including white sponge nevus and hereditary benign intraepithelial dyskeratosis will be reviewed. Many products can result in contact stomatitis. Dentrifice-related stomatitis, contact reactions to amalgam and cinnamon can cause keratotic lesions. Each of these lesions have microscopic findings that can assist in patient management.

http://bit.ly/2U9yVL4

Black and Brown: Non-neoplastic Pigmentation of the Oral Mucosa

Abstract

Black and brown pigmentation of the oral mucosa can occur due to a multitude of non-neoplastic causes. Endogenous or exogenous pigments may be responsible for oral discoloration which can range from innocuous to life-threatening in nature. Physiologic, reactive, and idiopathic melanin production seen in smoker's melanosis, drug-related discolorations, melanotic macule, melanoacanthoma and systemic diseases are presented. Exogenous sources of pigmentation such as amalgam tattoo and black hairy tongue are also discussed. Determining the significance of mucosal pigmented lesions may represent a diagnostic challenge for clinicians. Biopsy is indicated whenever the source of pigmentation cannot be definitively identified based on the clinical presentation.

http://bit.ly/2DsEw9V

Rule of thumb: a simple tool to estimate 1% scalp surface area

http://bit.ly/2T9UzyM

The Most Common Causes of Burnout among U.S. Academic Dermatologists Based on a Survey Study

http://bit.ly/2AYMGFw

Nail lichen planus

http://bit.ly/2T9Uviw

Letter to the Editor: Nail Lichen Planus: A True Nail Emergency

http://bit.ly/2AYMEgS

Therapeutic Pearl: Regenerative Healing Ability of the Digit Tip

Patient consent for publication available upon request. Ethics review board not required.

http://bit.ly/2T9UsTS

Screening for Depression and Suicidality in Psoriasis Patients: A Survey of U.S. Dermatologists

http://bit.ly/2R6Nnl6

Analysis of the association of IL4 polymorphisms with orthodontic mini-implant loss

The aim of this study was to investigate the association of clinical characteristics and IL4 tag single nucleotide polymorphisms (SNPs; rs2227284 and rs2243268) with orthodontic mini-implant (MI) failure. The sample included 135 subjects of both sexes, mean age 48.7±10years (range 20–76years): 104 in the control group (patients without any MI loss) and 31 in the study group (patients presenting ≥1 MI loss). Genotypes were determined by real-time PCR. Bivariate and multivariate analyses were performed (P<0.05).

http://bit.ly/2S0vARj

Port-wine stains on the neck respond better to a pulsed dye laser than lesions on the face: An intrapatient comparison study with histopathology

To the Editor: Neck port-wine stains (PWSs) usually respond better than facial PWSs to treatment with a pulsed dye laser (PDL).1 Until now, however, self-controlled studies with objective evaluation of efficacy and anatomic features have not been reported. In this study, we investigated the morphologic and anatomic features of both facial and neck PWS lesions and put forward a possible explanation for the difference in the therapeutic efficacy of PDL.

http://bit.ly/2FWrWkO

Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross [IMMUNOGENETICS]

Variations in the proportion and number of specific immune cell types among healthy individuals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight diverse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.

http://bit.ly/2DuFwdJ

IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-{beta}, Collagen Type I, and PD-L1/PD-1 [IMMUNOTHERAPY AND VACCINES]

IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-β. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-β-1 and collagen type I. Virus infection prevented IL-6/GM-CSF–mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer.

http://bit.ly/2Ua1aJL

IL-33 Augments Virus-Specific Memory T Cell Inflation and Potentiates the Efficacy of an Attenuated Cytomegalovirus-Based Vaccine [MUCOSAL IMMUNOLOGY]

Candidate vaccines designed to generate T cell–based immunity are typically vectored by nonpersistent viruses, which largely fail to elicit durable effector memory T cell responses. This limitation can be overcome using recombinant strains of CMV. Proof-of-principle studies have demonstrated the potential benefits of this approach, most notably in the SIV model, but safety concerns require the development of nonreplicating alternatives with comparable immunogenicity. In this study, we show that IL-33 promotes the accumulation and recall kinetics of circulating and tissue-resident memory T cells in mice infected with murine CMV. Using a replication-deficient murine CMV vector, we further show that exogenous IL-33 boosts vaccine-induced memory T cell responses, which protect against subsequent heterologous viral challenge. These data suggest that IL-33 could serve as a useful adjuvant to improve the efficacy of vaccines based on attenuated derivatives of CMV.

http://bit.ly/2FHPHOA

The Tale of IL-12 and IL-23: A Paradigm Shift [PILLARS OF IMMUNOLOGY]

http://bit.ly/2FQnR1G

Suppression of the IFN-{alpha} and -{beta} Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syndrome Bunyavirus Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Induction of type I IFNs during viral infection is crucial for host defense. IRF 3 and IRF7 play a critical role as key transcription factors in the activation of the IFN induction. Viruses have evolved a variety of strategies to evade innate immunity. Our previous studies have shown that the nonstructural protein (NSs) of the severe fever with thrombocytopenia syndrome virus (SFTSV) can suppress the IFN-β induction through its interaction with tank-binding kinase-1 and sequestering the inhibitor of nuclear factor kappa B kinase(IKK) complex into the inclusion bodies formed by NSs. In this study, we characterized the unique function of IRF7 in innate immunity and its role in inducing IFN-α in particular, regulated by NSs during the SFTSV infection in several cell types of human origin. Whereas IRF3 is constitutively expressed, IRF7 was significantly induced differentially in various cell types in response to SFTSV infection, promoted the induction of IFN-α2 and -α4, and further induced IFN-β, thus contributing to suppressing the viral replication. Our data indicate that NSs directly interacted with and sequestered IRF7 into the inclusion bodies, which is different from IRF3 indirectly interacting with NSs. Although interaction of NSs with IRF7 did not inhibit IRF7 phosphorylation, p-IRF7 was trapped in the inclusion bodies, resulting in a significant reduction of the IFN-α2 and -α4 induction and therefore enhanced viral replication. Interaction of the viral NSs with both IRF7 and IRF3 and subsequent sequestration of these transcription factors into viral inclusion bodies, a unique strategy used by this phlebovirus, may ensure effective evasion and suppression of host innate immunity.

http://bit.ly/2FEqJ2k

Manipulation of Ambient Housing Temperature To Study the Impact of Chronic Stress on Immunity and Cancer in Mice [BRIEF REVIEWS]

Mice are the preeminent research organism in which to model human diseases and study the involvement of the immune response. Rapidly accumulating evidence indicates a significant involvement of stress hormones in cancer progression, resistance to therapies, and suppression of immune responses. As a result, there has been a concerted effort to model human stress in mice. In this article, we discuss recent literature showing how mice in research facilities are chronically stressed at baseline because of environmental factors. Focusing on housing temperature, we suggest that the stress of cool housing temperatures contributes to the impact of other imposed experimental stressors and therefore has a confounding effect on mouse stress models. Furthermore, we propose that manipulation of housing temperature is a useful approach for studying the impact of chronic stress on disease and the immune response and for testing therapeutic methods of reducing the negative effects of chronic stress.

http://bit.ly/2FPx8XI

Human Anti-HIV-1 gp120 Monoclonal Antibodies with Neutralizing Activity Cloned from Humanized Mice Infected with HIV-1 [INFECTIOUS DISEASE AND HOST RESPONSE]

Broadly neutralizing, anti–HIV-1 gp120 mAbs have been isolated from infected individuals, and there is considerable interest in developing these reagents for Ab-based immunoprophylaxis and treatment. As a means to identify potentially new anti-HIV Abs, we exploited humanized NOD-scid IL2r^null mice systemically infected with HIV-1 to generate a wide variety of Ag-specific human mAbs. The Abs were encoded by a diverse range of variable gene families and Ig classes, including IgA, and several showed significant levels of somatic mutation. Moreover, the isolated Abs not only bound target Ags with similar affinity as broadly neutralizing Abs, they also demonstrated neutralizing ability against multiple HIV-1 clades. The use of humanized mice will allow us to use our knowledge of HIV-1 gp120 structure and function, and the immune response targeting this protein, to generate native human prophylactic Abs to reduce the infection and spread of HIV-1.

http://bit.ly/2FHgDxE

Dual TCR T Cells: Identity Crisis or Multitaskers? [BRIEF REVIEWS]

Dual TCR T cells are a common and natural product of TCR gene rearrangement and thymocyte development. As much as one third of the T cell population may have the capability to express two different TCR specificities on the cell surface. This discovery provoked a reconsideration of the classic model of thymic selection. Many potential roles for dual TCR T cells have since been hypothesized, including posing an autoimmune hazard, dominating alloreactive T cell responses, inducing allergy, and expanding the TCR repertoire to improve protective immunity. Yet, since the initial wave of publications following the discovery of dual TCR T cells, research in the area has slowed. In this study, we aim to provide a brief but comprehensive history of dual TCR T cell research, re-evaluate past observations in the context of current knowledge of the immune system, and identify key issues for future study.

http://bit.ly/2FWnToC

IRAK-M Associates with Susceptibility to Adult-Onset Asthma and Promotes Chronic Airway Inflammation [INNATE IMMUNITY AND INFLAMMATION]

IL-1R–associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN- concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN- production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.

http://bit.ly/2FIoOtx

Cutting Edge: Early Attrition of Memory T Cells during Inflammation and Costimulation Blockade Is Regulated Concurrently by Proapoptotic Proteins Fas and Bim [CUTTING EDGE]

Apoptosis of CD8 T cells is an essential mechanism that maintains immune system homeostasis, prevents autoimmunity, and reduces immunopathology. CD8 T cell death also occurs early during the response to both inflammation and costimulation blockade (CoB). In this article, we studied the effects of a combined deficiency of Fas (extrinsic pathway) and Bim (intrinsic pathway) on early T cell attrition in response to lymphocytic choriomeningitis virus infection and during CoB during transplantation. Loss of Fas and Bim function in Bcl2l11^–/–Fas^lpr/lpr mice inhibited apoptosis of T cells and prevented the early T cell attrition resulting from lymphocytic choriomeningitis virus infection. Bcl2l11^–/–Fas^lpr/lpr mice were also resistant to prolonged allograft survival induced by CoB targeting the CD40-CD154 pathway. These results demonstrate that both extrinsic and intrinsic apoptosis pathways function concurrently to regulate T cell homeostasis during the early stages of immune responses and allograft survival during CoB.

http://bit.ly/2FShyLa

Transthyretin Stimulates Tumor Growth through Regulation of Tumor, Immune, and Endothelial Cells [TUMOR IMMUNOLOGY]

Early detection of lung cancer offers an important opportunity to decrease mortality while it is still treatable and curable. Thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells, and alveolar myeloid cells of the CCSP-rtTA/(tetO)₇-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. Further analyses showed that TTR treatment enhanced the reactive oxygen species production in myeloid cells and enabled them to become functional myeloid-derived suppressive cells. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, these 13 Stat3 downstream inducible secretory protein biomarkers potentially can be used for lung cancer diagnosis, classification, and as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood.

http://bit.ly/2FHPM4Q

Classical Type 1 Dendritic Cells Dominate Priming of Th1 Responses to Herpes Simplex Virus Type 1 Skin Infection [ANTIGEN RECOGNITION AND RESPONSES]

CD4⁺ T cell responses are crucial for the control of many intracellular pathogens, yet the requirements for their induction are not fully understood. To better understand the role that various dendritic cell (DC) subtypes play in CD4⁺ T cell priming, we compared in vivo T cell responses to skin inoculation of mice with infectious or UV-inactivated HSV type 1. Localized infection elicited a Th1 response that was primed in skin-draining lymph nodes involving Ag presentation by migratory dermal and lymph node–resident DC. However, expansion and Th1 differentiation was impaired in response to UV-inactivated virus (UV-HSV), and this defect correlated with a restriction of Ag presentation to migratory CD103^– dermal DC. A similar differentiation defect was seen in infected mice lacking CD8α⁺ and CD103⁺ classical type 1 DC (cDC1). Finally, Th1 differentiation after UV-HSV inoculation was rescued by targeted Ag delivery to CD8α⁺ and CD103⁺ cDC1 using an anti-Clec9A Ab construct. This suggests that Ag presentation by cDC1 is crucial for optimal Th1 immunity to HSV type 1 infection and potentially other pathogens of the skin.

http://bit.ly/2FP5qdT

HIV Interferes with the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis-Specific CD4 T Cells into a Dysfunctional Phenotype [INFECTIOUS DISEASE AND HOST RESPONSE]

HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis–specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis–specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)–T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV–M. tuberculosis–infected (coinfected) human DCs can dysregulate the M. tuberculosis–specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-β and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

http://bit.ly/2FHaYrE

B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis [AUTOIMMUNITY]

The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using B6^{mir146a–/–} mice and a model of lymphoproliferative disease using the well-characterized lpr model. B6^lpr mice lacking ADAM10 on B cells (A10B^lpr) have decreased nodal proliferation and T cell accumulation compared with control B6^lpr mice. Additionally, A10B^lpr mice have a drastic reduction in autoimmune anti-dsDNA Ab production. In line with this, we found a significant reduction in follicular helper T cells and germinal center B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only show a role of B cell ADAM10 in control autoimmunity but also increase our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity.

http://bit.ly/2FRpEn7

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection [INNATE IMMUNITY AND INFLAMMATION]

Severe respiratory virus infections feature robust local host responses that contribute to disease severity. Immunomodulatory strategies that limit virus-induced inflammation may be of critical importance, notably in the absence of antiviral vaccines. In this study, we examined the role of the pleiotropic cytokine IL-6 in acute infection with pneumonia virus of mice (PVM), a natural rodent pathogen that is related to respiratory syncytial virus and that generates local inflammation as a feature of severe infection. In contrast to Influenza A, PVM is substantially less lethal in IL-6^–/– mice than it is in wild-type, a finding associated with diminished neutrophil recruitment and reduced fluid accumulation in lung tissue. Ly6C^hi proinflammatory monocytes are recruited in response to PVM via a CCR2-dependent mechanism, but they are not a major source of IL-6 nor do they contribute to lethal sequelae of infection. By contrast, alveolar macrophages are readily infected with PVM in vivo; ablation of alveolar macrophages results in prolonged survival in association with a reduction in virus-induced IL-6. Finally, as shown previously, administration of immunobiotic Lactobacillus plantarum to the respiratory tracts of PVM-infected mice promoted survival in association with diminished levels of IL-6. We demonstrated in this study that IL-6 suppression is a critical feature of the protective mechanism; PVM-infected IL-6^–/– mice responded to low doses of L. plantarum, and administration of IL-6 overcame L. plantarum–mediated protection in PVM-infected wild-type mice. Taken together, these results connect the actions of IL-6 to PVM pathogenesis and suggest cytokine blockade as a potential therapeutic modality in severe infection.

http://bit.ly/2FIN92D

Lupus-Associated Immune Complexes Activate Human Neutrophils in an Fc{gamma}RIIA-Dependent but TLR-Independent Response [AUTOIMMUNITY]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nucleic acids and nucleoproteins. Anti-dsDNA Abs are considered a hallmark of SLE, and previous studies have indicated that nucleic acid–containing immune complexes (ICs) induce B cell and dendritic cell activation in a TLR-dependent process. How ICs containing nucleic acids affect neutrophil function has not been well investigated. In this study, we report that nucleic acid–containing ICs derived from the sera of SLE patients induce human and mouse neutrophil activation through TLR-independent mechanisms. Soluble ICs containing Sm/RNP, an RNA Ag, activate human neutrophils to produce reactive oxygen species (ROS) and IL-8. In contrast, ICs containing DNA have to be immobilized to efficiently activate neutrophils. We found that deleting TLR7 or TLR9, the receptors for RNA and DNA, had no effect on mouse neutrophil activation induced by RNA-containing and immobilized DNA–containing ICs. Binding of ICs are mediated through FcRIIA and FcRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcRIIA, as blocking FcRIIA inhibited ROS release from neutrophils. RNA-containing ICs induce calcium flux, whereas TLR7/8 ligand R848 do not. Surprisingly, chloroquine inhibits calcium flux induced by RNA-containing ICs, suggesting that this lesser known function of chloroquine is involved in the neutrophil activation induced by ICs. These data indicate the SLE-derived ICs activate neutrophils to release ROS and chemokines in an FcRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.

http://bit.ly/2FQ1F82

IRF5 Is Required for Bacterial Clearance in Human M1-Polarized Macrophages, and IRF5 Immune-Mediated Disease Risk Variants Modulate This Outcome [INNATE IMMUNITY AND INFLAMMATION]

Common IFN regulatory factor 5 (IRF5) variants associated with multiple immune-mediated diseases are a major determinant of interindividual variability in pattern recognition receptor (PRR)–induced cytokines in macrophages. PRR-initiated pathways also contribute to bacterial clearance, and dysregulation of bacterial clearance can contribute to immune-mediated diseases. However, the role of IRF5 in macrophage-mediated bacterial clearance is not well defined. Furthermore, it is unclear if macrophages from individuals who are carriers of low IRF5-expressing genetic variants associated with protection for immune-mediated diseases might be at a disadvantage in bacterial clearance. We found that IRF5 was required for optimal bacterial clearance in PRR-stimulated, M1-differentiated human macrophages. Mechanisms regulated by IRF5 included inducing reactive oxygen species through p40phox, p47phox and p67phox, NOS2, and autophagy through ATG5. Complementing these pathways in IRF5-deficient M1 macrophages restored bacterial clearance. Further, these antimicrobial pathways required the activation of IRF5-dependent MAPK, NF-B, and Akt2 pathways. Importantly, relative to high IRF5-expressing rs2004640/rs2280714 TT/TT immune-mediated disease risk-carrier human macrophages, M1-differentiated GG/CC carrier macrophages demonstrated less reactive oxygen species, NOS2, and autophagy pathway induction and, consequently, reduced bacterial clearance. Increasing IRF5 expression to the rs2004640/rs2280714 TT/TT levels restored these antimicrobial pathways. We define mechanisms wherein common IRF5 genetic variants modulate bacterial clearance, thereby highlighting that immune-mediated disease risk IRF5 carriers might be relatively protected from microbial-associated diseases.

http://bit.ly/2FKjrdm

High-Dose IL-2 Skews a Glucocorticoid-Driven IL-17+IL-10+ Memory CD4+ T Cell Response towards a Single IL-10-Producing Phenotype [CLINICAL AND HUMAN IMMUNOLOGY]

Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4⁺ T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-⁺IL-10⁺ cells was also observed despite overall downregulation of IFN- production. These dexamethasone-driven IL-10⁺ cells, and predominantly the IL-17⁺IL-10⁺ double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2–dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10⁺ cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10⁺ T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17⁺IL-10⁺–coproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic.

http://bit.ly/2FQ1DNs

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells [SYSTEMS IMMUNOLOGY]

T cell development depends on sequential interactions of thymocytes with cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells. PSMB11 is a catalytic proteasomal subunit present exclusively in cTECs. Because proteasomes regulate transcriptional activity, we asked whether PSMB11 might affect gene expression in cTECs. We report that PSMB11 regulates the expression of 850 cTEC genes that modulate lymphostromal interactions primarily via the WNT signaling pathway. cTECs from Psmb11^–/– mice 1) acquire features of medullary thymic epithelial cells and 2) retain CD8 thymocytes in the thymic cortex, thereby impairing phase 2 of positive selection, 3) perturbing CD8 T cell development, and 4) causing dramatic oxidative stress leading to apoptosis of CD8 thymocytes. Deletion of Psmb11 also causes major oxidative stress in CD4 thymocytes. However, CD4 thymocytes do not undergo apoptosis because, unlike CD8 thymocytes, they upregulate expression of chaperones and inhibitors of apoptosis. We conclude that PSMB11 has pervasive effects on both CD4 and CD8 thymocytes via regulation of gene expression in cTECs.

http://bit.ly/2FIZZOp

Expression of a Functional IL-2 Receptor in Vascular Smooth Muscle Cells [CLINICAL AND HUMAN IMMUNOLOGY]

Many nonlymphoid cell types express at least two, if not all three, subunits of the IL-2R; although, compared with lymphocytes, relatively little is known about how IL-2 affects the function of nonlymphoid cells. The limited information available suggests that IL-2 has a substantial impact on cells such as gastrointestinal epithelial cells, endothelial cells, and fibroblasts. In a previous report from our laboratory, we noted that IL-2 and IL-2Rβ–deficient mice lose smooth muscle cells over time, eventually resulting in aneurysmal aortas and ectatic esophagi. This finding, combined with our work showing that IL-2 surrounds vascular smooth muscle cells by association with perlecan, led us to ask whether vascular smooth muscle cells express an IL-2R. Toward this end, we reported the expression of IL-2Rβ on human and murine vascular smooth muscle cells. We now report that vascular smooth muscle cells express all three subunits of the IL-2R, and that expression of IL-2Rα varies with vascular smooth muscle cell phenotype. Furthermore, we show that, through a functional IL-2R, IL-2 initiates signaling pathways and impacts vascular smooth muscle cell function. Finally, we demonstrate that IL-2 expression increases upon initiation of conditions that promote intimal hyperplasia, suggesting a mechanism by which the IL-2/IL-2R system may impact this widespread vascular pathology.

http://bit.ly/2FXfemf

In This Issue [IN THIS ISSUE]

http://bit.ly/2FH6BwL

BCL6-Mediated Silencing of PD-1 Ligands in Germinal Center B Cells Maintains Follicular T Cell Population [IMMUNE REGULATION]

The programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2 on germinal center (GC) B cells deliver coinhibitory signals to follicular T cells. The PD-L1/L2–PD-1 axis modulates the quality and quantity of follicular T cells and has been shown to influence the GC responses. However, the transcriptional control of PD-1 ligands on GC B cells remains largely unknown. In this study, we report that the transcription factor BCL6 is a key negative regulator of the PD-1 ligands PD-L1 and PD-L2 in GC B cells. Acute deletion of Bcl6 in mature GC B cells resulted in marked upregulation of mRNA and protein abundance of PD-1 ligands. Moreover, the expression levels of BCL6 and PD-1 ligands were inversely correlated during GC B cell development and in human GC–derived lymphoma specimens. Mechanically, BCL6 directly bound to the promoter region of PD-L1 and intron 2 of PD-L2 to suppress their transcription. In addition, BCL6 indirectly inhibited the transcription of PD-1 ligands by repressing the expression of STAT1/STAT3 and IRF1. Moreover, BCL6 exerted these effects via its BTB domain. Finally, PD-1 blockade promoted cell survival to sustain the follicular T cell pool in the presence of Bcl6-deficinet GC B cells. In summary, B cell–specific expression of BCL6 dampens the PD-L1/L2–PD-1 signaling to maintain the size of follicular T cells during GC development.

http://bit.ly/2FSL5UW

Intensivist staffing and outcome in the ICU: daytime, nighttime, 24/7?

Purpose of review Many hospitals, particularly large academic centers, have begun to provide 24-h in-house intensive care attending coverage. Proposed advantages for this model include improved patient care, greater provider, nursing and patient satisfaction, better communication, and greater cost-effectiveness. This review will evaluate current evidence with respect to 24/7 coverage, including patient outcomes, cost-effectiveness, and impact on training/education. Recent findings Evidence surrounding 24-h intensivist staffing has been mixed. Although a subset of studies suggest a possible benefit to 24-h intensivist coverage, recent prospective studies have shown no difference in major patient outcomes, including mortality and ICU length of stay between patients in ICUs with and those without 24-h intensivist coverage. Summary Although some studies cite increased caregiver and patient satisfaction, outcome studies find no consistent effect on patient-centered outcomes such as mortality or length of stay. Downsides to in-house nighttime attending staffing include physician burnout, adverse effects on physician health, decreased trainee autonomy, and effects on trainee specialty choices because of undesirable lifestyle considerations. Tele-ICU and other novel approaches may allow for attending supervision without physical presence. Correspondence to Avery Tung, MD, 5841 S Maryland Ave MC 4028, Chicago, IL 60637, USA. Tel: +1 (773) 834 7937; E-mail: atung@dacc.uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2T6WGnd

Helicopter air ambulance services

Purpose of review Helicopter air ambulances are an integral component of modern trauma care, and are able to transport patients to facilities with greater capabilities, extract injured patients from hostile terrain, and speed transport to a trauma center. Recent findings HAA transport does not reduce the total time required to transport a patient, but it does reduce the time that the patient is between healthcare facilities. Factors that have been suggested to improve outcomes for trauma patients include the availability of advanced interventions, skilled personnel, speed, and trauma center access. Despite their potential benefits to the patient, HAA operations carry significant risks. HAA operations are among the most dangerous professions for both pilot and crew with a mortality rate greater than commercial fishing, loggers, and steelworkers. The US Federal Aviation Administration (FAA) has identified that the four most common causes of HAA accidents as inadvertent flight into instrument meteorological conditions, loss of control, controlled flight into terrain, and night conditions. Summary HAA operations are well tolerated and can improve patient care, but additional research is needed to improve our understanding of HAA operations and their effect on outcomes. Correspondence to Keith J. Ruskin, MD, FAsMA, FRAeS, Professor of Anesthesia and Critical Care and Biological Sciences Collegiate Division, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Avenue MC4028, Chicago, IL 60637, USA. Tel: +1 773 834 2369; e-mail: ruskin@uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2AZuSKg

Burn injury and blood transfusion

Purpose of review Blood transfusion is ubiquitous in major burn injury. The present article describes recent research findings directly impacting blood transfusion strategies in major burn injury both in the operating room and the ICU. Recent findings Transfusion strategies have been the focus of recent burn investigations. First, a randomized prospective trial encompassing both the ICU and operating room reported that a restrictive red blood cell transfusion threshold (7 g/dl) had equivalent outcomes to a traditional threshold (10 g/dl) for burns more than 20% in terms of mortality, infection, length of stay, duration of mechanical ventilation, and wound healing despite receiving significantly fewer transfusions. The second burn transfusion advance addresses coagulation. Although burn patients initially have elevated fibrinogen, thrombocytopenia and other coagulation disorders develop during excision. Blood product repletion should be based on measurements such as thromboelastography in addition to traditional tests. Finally, a recent randomized trial suggests that fresh-frozen plasma and platelets during burn excision more than 20% may decrease transfusion requirements. Summary A restrictive transfusion practice during burn excision and grafting is well tolerated and effective in reducing the number of transfusions without increasing complications. Repletion of coagulation products should focus on measured deficits of platelets, fibrinogen, and factors. Correspondence to Tina L. Palmieri, 2425 Stockton Blvd, Suite 718, Sacramento, CA 95817, USA. Tel: +1-916-453-2050; fax: +1-916-453-2373; e-mail: tlpalmieri@ucdavis.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2T7QATz

Resuscitative endovascular balloon occlusion of the aorta: an option for noncompressible torso hemorrhage?

Purpose of review Hemorrhage is the major cause of early death in severely injured patients. In civilian emergency medical services, the majority of life-threatening bleedings are found in noncompressible body regions (e.g. abdomen and pelvis). Resuscitative endovascular balloon occlusion of the aorta (REBOA) has therefore been discussed in recent years as a possible lifesaving procedure and numerous studies, meta-analyses and guidelines have been published. In this review, the data situation of REBOA in the management of bleeding trauma patients is discussed and practical implementation is depicted. Recent findings The typical indication for REBOA is a traumatic life-threatening hemorrhage below the diaphragm in patients unresponsive or only transiently responsive to the usual conservative therapeutic measures. REBOA appears to be a safe and effective procedure to reduce blood loss and stabilize the patient's hemodynamic status. However, surgical hemostasis has to be achieved within 30–60 min after occlusion of the aorta. Data on clear advantages of REBOA over resuscitative thoracostomy are inconclusive. Summary REBOA could play an important role in the management of the severely bleeding patient in the future. Together with transfusion and therapy of coagulation disorders, REBOA may be an additional tool in the anesthetist's hands for trauma management in interprofessional care concepts. Correspondence to Dr Jürgen Knapp, Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. Tel: +41 31 632 04 96; e-mail: juergen.knapp@insel.ch Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2ATxj0P

The use of new procoagulants in blunt and penetrating trauma

Purpose of review Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use. Recent findings Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy. Summary There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies. Correspondence to Pratima Chowdary, Consultant Haematologist, KD Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK;. e-mails: p.chowdary@nhs.net, p.chowdary@ucl.ac.uk Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2TagE0q

Evaluation of Quality of Life and Pattern of Improvement of Bronchial Asthma in Chronic Rhinosinusitis Patients Treated by Functional Endoscopic Sinus Surgery

Abstract

Chronic inflammatory disorders of the upper airways are extremely prevalent and have a major impact on public health. Sinusitis and bronchial asthma are closely interrelated diseases and sinusitis is known to influence bronchial asthma in its severity and chronicity. Causal relationships have been proposed but not yet proved. The relationship between sinusitis and asthma is academically interesting and has important diagnostic and therapeutic implications. The present study is designed to evaluate the efficacy of functional endoscopic sinus surgery done as treatment for chronic rhinosinusitis on bronchial asthma patients, in terms of quality of life and pattern of improvement. Objectives of the study were to determine whether bronchial asthma and quality of life improved after functional endoscopic sinus surgery. This was an open labelled randomised control trial, done at ENT Department of Medical College, Thiruvananthapuram. Those in Group A underwent functional endoscopic sinus surgery and group B patients were given only medicines as per standard protocol. All of them received asthma treatment depending on asthma attacks and severity and followed up at specific intervals. Quality of life status and pattern of improvement of bronchial asthma among these patients were evaluated. Patients of chronic rhinosinusitis treated by functional endoscopic sinus surgery showed significant improvement in the mean asthma symptom score, asthma medication use score, pulmonary function test results, and quality of life assessment scores. Functional endoscopic sinus surgery could be considered early in the natural course of chronic rhinosinusitis with concomitant bronchial asthma.

http://bit.ly/2FHHo58

Salt, Hypertension, and the Lens

Metabolic Syndrome and Related Disorders, Ahead of Print.


http://bit.ly/2FGVV18

The Relationship Between Housing Types and Metabolic and Weight Phenotypes: A Nationwide Survey

Metabolic Syndrome and Related Disorders, Ahead of Print.


http://bit.ly/2FSxX2b

Influence of Porphyromonas gingivalis in gut microbiota of streptozotocin‐induced diabetic mice

Abstract

Objectives

Increasing evidence suggests that periodontitis can exacerbate diabetes, and gut bacterial dysbiosis appears to be linked with the diabetic condition. The present study examined the effects of oral administration of the periodontopathic bacterium, Porphyromonas gingivalis, on the gut microbiota and systemic conditions in streptozotocin‐induced diabetic mice.

Materials and Methods

Diabetes was induced by streptozotocin injection in C57BL/6J male mice (STZ). STZ and wild‐type (WT) mice were orally administered P. gingivalis (STZPg, WTPg) or saline (STZco, WTco). Feces were collected, and the gut microbiome was examined by 16S rRNA gene sequencing. The expression of genes related to inflammation, epithelial tight junctions, glucose/fatty acid metabolism in the ileum or liver were examined by quantitative PCR.

Results

The relative abundance of several genera, including Brevibacterium, Corynebacterium, and Facklamia, was significantly increased in STZco mice compared to WTco mice. The relative abundances of Staphylococcus and Turicibacter in the gut microbiome were altered by oral administration of P. gingivalis in STZ mice. STZPg mice showed higher concentrations of fasting blood glucose and inflammatory genes levels in the ileum, compared to STZco mice.

Conclusions

Oral administration of P. gingivalis altered the gut microbiota and aggravated glycemic control in streptozotocin‐induced diabetic mice.

This article is protected by copyright. All rights reserved.

http://bit.ly/2sFzv7K

Overexpression of EphrinB2 in Stem Cells from Apical Papilla Accelerates Angiogenesis

Abstracts

Objectives

we aimed to accelerate angiogenesis in pulp regeneration by modulating ephrinB2 expression in stem cells from apical papilla (SCAPs).

Materials and Methods

SCAPs were transducted with ephrinB2‐lentiviral expression vector in experimental group (ephrinB2‐SCAPs) and green fluorescent protein (GFP‐SCAPs) in control group. The transduction efficiency was confirmed by real‐time PCR and western blot assays. MTT assay was performed to detect the proliferative capacity of SCAPs after transduction. In vitro matrigel assay and in vivo matrigel plug assay were carried out to evaluate the angiogenic capacity.

Results

Results showed that ephrinB2‐SCAPs had significantly higher ephrinB2 expression than GFP‐SCAPs. EphrinB2‐SCAPs upregulated vascular endothelial growth factor (VEGF) secretion under hypoxia. In vitro matrigel assay demonstrated that human umbilical vein endothelial cells (HUVECs) cocultured with ephrinB2‐SCAPs under hypoxia formed vascular‐like structures earlier than GFP‐SCAPs. Animal experiments confirmed that SCAPs co‐transplanted with HUVECs enabled to generate greater amount of blood vessels than SCAPs alone. EphrinB2‐ SCAPs produced increased number of blood vessels with references to GFP‐SCAPs, and those co‐transplanted with HUVECs generated vessels with larger and functional tubule volumes.

Conclusions

Regulating ephrinB2 expression in SCAPs may act as a new avenue for enhancing angiogenesis in dental pulp regeneration.

This article is protected by copyright. All rights reserved.

http://bit.ly/2MoelnO

Eye movements and imaging in vestibular migraine

Publication date: Available online 22 January 2019

Source: Acta Otorrinolaringológica Española

Author(s): Mayada ElSherif, Mohamed Ihab Reda, Horeya Saadallah, Mona Mourad

Abstract

Background and objective

Migrainous dizziness is one of the most frequent complaints. Dizziness associated with migraine may be the result of abnormal eye movements. Brain imaging and changes in eye movements may explain the dizziness and highlight possible pathophysiological substrates in migraine dizziness. Our aim is to evaluate eye movement using videonystagmography (VNG) and video head impulse test (vHIT) and to study the occipital lobe metabolic profile in vestibular migraine patients (VM).

Materials and methods

There were 2 groups enrolled in the study; the first group consisted of 25 vestibular migraine patients (VM) according to the recent criteria of Barany society. The second group consisted of 20 age matched healthy subjects. Both groups underwent the following: (1) A detailed history, VNG test protocol, vHIT in three planes. (2) Magnetic resonance imaging (MRI) for the brain and inner ear using 1.5 T magnet and proton magnetic resonance spectroscopy (H1-MRS).

Results

Sixty eight percent of the patients complained of spontaneous vertigo and 28% complained of positional vertigo. Non-paroxysmal positional nystagmus was recorded in 92% during their dizzy spell. The brain MRI was unremarkable in 72% of the cases. Chemical shift in the occipital lobe was found in 92% of VM. Lactate peaks were statistically significant related with the presence of non-paroxysmal positional nystagmus.

Conclusions

A statistically significant relationship exists between non-paroxysmal positional nystagmus and presence of lactate peaks in the occipital lobe in VM patients.

Resumen

Antecedentes y objetivo

El mareo migrañoso es una de las quejas más frecuentes. Las pruebas de imagen del cerebro y los cambios en los movimientos oculares pueden explicar los mareos y destacar los posibles sustratos fisiopatológicos en la migraña vestibular. Nuestro objetivo fue evaluar el movimiento ocular utilizando videonistagmografía (VNG) y la prueba de impulso cefálico por vídeo (vHIT), y estudiar el perfil metabólico del lóbulo occipital en pacientes con migraña vestibular (VM).

Materiales y métodos

Se incluyeron dos grupos en el estudio; el primer grupo consistió en 25 pacientes con VM según los criterios recientes de la sociedad Bárány. El segundo grupo consistió en 20 sujetos sanos emparejados por edad. Ambos grupos se sometieron a lo siguiente: 1) Una historia detallada, protocolo de prueba de VNG y vHIT en 3 planos, y 2) Imágenes de resonancia magnética (IRM) para el cerebro y el oído interno con el imán de 1,5 tesla y la espectroscopía de resonancia magnética de protones (H1-MRS).

Resultados

El 68% de los pacientes se quejó de vértigo espontáneo, y el 28% de vértigo posicional. El nistagmo posicional no paroxístico se registró en el 60% de los pacientes durante su mareo. La resonancia magnética cerebral no mostró alteraciones en el 72% de los casos. El cambio químico en el lóbulo occipital se encontró en el 92% de los casos de VM. Los picos de lactato fueron estadísticamente significativos con relación a la presencia de nistagmo posicional no paroxístico.

Conclusiones

Existe una relación estadísticamente significativa entre el nistagmo posicional no paroxístico y la presencia de picos de lactato en el lóbulo occipital en pacientes con VM.

http://bit.ly/2Dsw5vi

Microcurrent technology for rapid relief of sinus pain: a randomized, placebo‐controlled, double‐blinded clinical trial

Background

Transcutaneous electrical nerve stimulation has proven to be effective in alleviating chronic pain from facial myalgias. We evaluated the efficacy of a novel handheld microcurrent‐emitting device in short‐term, office‐based treatment of patients with sinus pain. This device, which is not yet U.S. Food and Drug Administration (FDA)‐cleared, detects and treats regions corresponding to nerve fibers.

Methods

Randomized, double‐blinded, placebo‐controlled trial. Seventy‐one participants with facial pain attributed to self‐reported nasal/sinus disease were recruited from a tertiary rhinologic practice and the surrounding community and randomly assigned to either office‐based use of an active (n = 38) or placebo (n = 33) microcurrent emitter. The study device was repetitively applied by each patient to the bilateral periorbital areas for 5 minutes. A visual analogue scale (VAS) for pain severity was administered before, and 10 minutes after, treatment.

Results

Active microcurrent‐treated patients had a reduction in mean pain score from 5.63 pretreatment to 3.97 posttreatment (mean difference, 1.66; 95% confidence interval [CI], 1.20 to 2.12). Patients using the sham device also reported sinus pain reductions (mean difference, 0.91; 95% CI, 0.61 to 1.21). However, the active device demonstrated a significantly greater reduction in pain compared to sham (0.75‐point difference, p = 0.007). Notably, 23.7% of patients using the active device had a reduction of 3 or more points by VAS compared to 0% of sham device patients (p = 0.003). One minor occurrence of transient facial skin erythema was noted.

Conclusion

This trial suggests that treatment of rhinologic facial pain using this noninvasive microcurrent device is safe and effective in providing rapid relief of nasal/sinus pain. Additional studies with longer term follow‐up are warranted.

http://bit.ly/2AUovba

Atopic dermatitis and cardiovascular disease: what are the clinical implications?

Publication date: Available online 22 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Aaron M. Drucker, Paula J. Harvey

http://bit.ly/2MrbCK6

Altered subsets and activities of B lymphocytes in polycystic ovary syndrome

Publication date: Available online 21 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Na Xiao, Ke He, Fei Gong, Qi Xie, Jing Peng, Xian Su, Yeping Lu, Xuefeng Xia, Ge Lin, Lamei Cheng

http://bit.ly/2sEFREj

Dilute bleach baths used for treatment of atopic dermatitis are not antimicrobial in vitro

Publication date: Available online 21 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Yu Sawada, Yun Tong, Mariam Barangi, Tissa Hata, Michael R. Williams, Teruaki Nakatsuji, Richard L. Gallo

http://bit.ly/2MoRbh5

PLATELET RICH PLASMA IN ANDROGENETIC ALOPECIA: A SYSTEMATIC REVIEW

In recent years, dozens of manufacturers and clinics have been promoting the use of platelet rich plasma (PRP) procedures for skin and hair regeneration. Well‐designed randomized controlled studies for these procedures are lacking. In this communication, we review the efficacy and safety of PRP procedures for androgenetic alopecia from multiple published peer‐reviewed studies. The conclusion of our analysis is that until the present moment there is not enough evidence for the use of PRP procedures in the treatment of androgenetic alopecia. We hope that this review will help practitioners and patients to make better‐informed treatment decisions.

This article is protected by copyright. All rights reserved.

http://bit.ly/2S0ypBL

Acute invasive fungal rhinosinusitis: our 2 year experience and outcome analysis

Abstract

Purpose

The incidence of Acute invasive fungal rhinosinusitis (AIFRS) is on the rise considering the multitude of comorbidities present in a single patient.The delay in suspecting the fungal etiology, presentation of the patient for an Otorhinolaryngology consult and lack of defined protocols affects outcome.This study looks in to the various aspects of treatment of AIFRS including sample collection, diagnosis and medicosurgical treatment. We propose a protocol for the management of these patients crafted from our outcome.

Methods

Between September 2015–September 2017, 14 patients presented with AIFRS. Targeted samples were taken for Potassium hydroxide mount, histopathological studies and fungal culture. Management was initiated with antifungals and multi-approach surgical debridement.

Results

Six of these patients had multiple comorbidities and most were uncontrolled diabetics. The average delay in presentation was 9 days. Potassium hydroxide mount was the screening test of choice. A minimum of two sittings of debridement was essential. In an average follow-up period of 15.12 months, all the patients are alive and disease free.

Conclusion

A high index of suspicion, awareness among medical fraternity and precise sample collection aids a firm diagnosis. Simultaneous initiation of surgical debridement and anti-fungals is fundamental.

http://bit.ly/2FOv9Tw

Combined mandibular and maxillary reconstruction: Managing sinus secretions and preventing infection

http://bit.ly/2FSMaMG

Laryngeal force sensor metrics are predictive of increased perioperative narcotic requirements

Objectives/Hypothesis

To determine the relationship between force metrics measured by the laryngeal force sensor (LFS) during suspension microlaryngoscopy (SML) and perioperative narcotic requirements.

Study Design

Prospective observational study.

Methods

Compressive tissue forces were recorded during SML using the LFS and correlated with postoperative narcotic requirements in the postanesthesia care unit (PACU) at an academic tertiary center. Patients were prospectively enrolled and had force metrics recorded throughout each procedure including maximum force, average force, suspension time, and total impulse. Narcotic administration in the intraoperative period and PACU were also recorded and converted into intravenous morphine equivalents (ME). Surgeons were blinded to the force recordings during surgery to prevent operator bias.

Results

Eighty‐two patients completed the study. Of these patients, the mean perioperative ME requirement was 16.96 mg (range, 0.15–79.82 mg). Univariate analysis demonstrated a positive correlation between perioperative narcotic requirements and total suspension time (P < .001) as well as total impulse (P = .007). A positive correlation was also seen with maximum force, although not significantly. On multiple linear regression, total suspension time was a significant predictive variable for perioperative narcotic use, with a marginal incremental increase of 0.273 mg of ME per minute of total suspension time (0.273 mg/min, 95% confidence interval: 0.040‐0.507 mg/min, P = .022).

Conclusions

Intraoperative force metrics including total suspension time are predictive of increased perioperative narcotic requirement after SML. Total impulse during SML may also correlate with increased perioperative narcotic requirements.

Level of Evidence

2 Laryngoscope, 2019

http://bit.ly/2FIwtbg

The Role of Elective Neck Dissection in Patients With Adenoid Cystic Carcinoma of the Head and Neck

Objective

To investigate the frequency and outcomes of elective neck dissection (END) for adenoid cystic carcinoma (ACC) of the head and neck.

Methods

The National Cancer Database was queried for a cohort study of patients with ACC of the major salivary glands, nasal cavity/nasopharynx, hard/soft palate, tongue, floor of mouth, larynx, and oral cavity who underwent primary surgical resection from 2004 to 2014. Multivariable logistic regression was used to identify predictors of END and occult nodal metastasis. Overall survival (OS) was estimated using the Kaplan‐Meier method and modeled with Cox proportional hazards regression.

Results

Among 2,807 patients with ACC treated surgically, 636 (22.7%) underwent END. Patients with ACC of the salivary glands and tongue most frequently underwent END; patients with hard/soft palate (odds ratio [OR] 0.06, P < 0.001) and nasal cavity/nasopharynx (OR 0.05, P < 0.001) ACC rarely underwent END compared to patients with major salivary gland cancer. Increasing tumor (T) stage (T4 vs. T1, OR 3.02, P < 0.001) was associated with END. Patients with advanced T3 to T4 ACC of the major salivary glands demonstrated extended OS associated with END (5‐year OS 78.1% vs. 70.4%, P = 0.041) on Kaplan‐Meier analysis and with END with adjuvant radiation therapy (hazard ratio 0.55, P = 0.027) using Cox proportional hazards regression. Elective neck dissection for T4 ACC of the salivary glands (21.3%) and tongue (25.5%) most consistently revealed occult nodal metastasis.

Conclusion

Elective neck dissection for ACC of the major salivary glands or tongue is most likely to reveal occult nodal metastasis. Elective neck dissection is associated with extended OS for advanced‐stage ACC of the major salivary glands.

Level of Evidence

NA. Laryngoscope, 2019

http://bit.ly/2FVj3rI

Pediatric Human Immunodeficiency Virus and Otolaryngologic Manifestations: An Analysis of Hospital Admissions From 1997 to 2012

Objectives/Hypothesis

Many human immunodeficiency virus (HIV)–infected pediatric patients develop otolaryngologic disease. We aimed to characterize their otolaryngologic manifestations by type and demographic variation, and model temporal trends.

Study Design

Retrospective cohort review.

Methods

A retrospective review utilizing the Kids' Inpatient Database (KID) was conducted. International Classification of Diseases, Ninth Revision, Clinical Modification codes for HIV and otolaryngologic diagnoses were used to query data from the triennially published KID files from 1997 to 2012. A subset analysis of infectious versus non‐infectious admitting otolaryngologic diagnoses was conducted.

Results

A total of 11,150 cases met the inclusion criteria. Of these cases, 21.8% were admitted for otolaryngologic manifestations, with 18.0% presenting with infectious symptomatology, 4.8% with noninfectious disease, and 1.0% with both. On average, patients presenting with infectious disease were younger (8.17 years vs. 9.65 years, P < .001). Patients in the South were significantly more likely to be admitted for infection (54.8% vs. 42.0%, P < .001), with non‐infectious predominance in the Northeast and West. HIV‐infected children in 1997 were more likely to present with infectious otolaryngologic disease (56.3% vs. 45.8%, P < .001); however, there has been a decrease in the prevalence of infectious head and neck presentations (46.5%, 19.9%, 11.5%, 6.7%, 3.7%, and 1.9% from 1997 to 2012), and a gradual shift toward noninfectious manifestation with notable differences in 2000 and 2012 (19.9% vs. 25.2%; P = .017; and 1.9% vs. 4.8%, P < .001, respectively).

Conclusions

Otolaryngologic disease accounts for nearly one‐fifth of hospitalizations in HIV‐infected children; however, rates of hospitalization as well as otolaryngologic manifestations have progressively decreased over time. HIV‐infected children nowadays are more likely to present with noninfectious rather than infectious disease.

Level of Evidence

NA Laryngoscope, 2019

http://bit.ly/2FGlEql

The Association Between Disease Severity and Microbiome in Chronic Rhinosinusitis

Objective

The role of the microbiome in the etiology of chronic rhinosinusitis (CRS) is still in debate. Reductions in richness and diversity have been implicated in CRS; however, limited knowledge exists regarding the impact of the severity of disease on the microbiome. The associations between constituents of the microbiome and the degree of mucosal inflammation and tissue eosinophilia are described.

Methods

A cross‐sectional study of CRS and non‐CRS patients who underwent endoscopic sinus surgery was performed. Sinus mucosal biopsies were assessed for the degree of inflammation and tissue eosinophilia. Middle‐meatal swabs were subjected to 16S rRNA gene sequencing, which quantified the prevalence, mean relative abundance, richness, and diversity. Comparisons between the microbiome at the genus level and degree of inflammation (absent, mild, moderate, severe) and tissue eosinophilia (absent, < 10, 10–100, > 100 per high‐powered field) were performed.

Results

Eight‐nine patients (52.8 ± 14.21 years, 64.0% male) were assessed. Of those, 52 had CRS and 37 were controls. Corynebacterium and Staphylococcus were the most abundant genera in both the CRS (29% and 16%) and non‐CRS groups (40% and 20%). Richness decreased in more severely inflamed patients (23.2 ± 13.9 vs. 18.1 ± 16.1 vs. 16.8 ± 12.3 vs. 14.7 ± 10.9; P < 0.01), as did diversity (1.4 ± 0.7 vs. 1.2 ± 1.0 vs. 1.2 ± 0.8 vs. 0.9 ± 0.7; P = 0.05). Richness was associated with higher tissue eosinophilia (23.2 ± 13.9 vs. 19.3 ± 17.2 vs. 15.9 ± 11.6 vs. 13.4 ± 6.6; P < 0.01).

Conclusion

The loss of richness and diversity seen in the CRS microbiome appears to be a product of severity of inflammation and tissue eosinophilia. Whether this dysbiosis is causative or a result of the disease with impaired epithelial integrity requires ongoing research.

Level of Evidence

4. Laryngoscope, 2019

http://bit.ly/2FPe3Fe

Surgical management of juvenile nasopharyngeal angiofibroma

Publication date: Available online 21 January 2019

Source: Operative Techniques in Otolaryngology-Head and Neck Surgery

Author(s): Meghan N. Wilson, Daniel W. Nuss, Brad E. Zacharia, Carl H. Snyderman

Juvenile nasopharyngeal angiofibromas are benign yet aggressive anterior skull base tumors that occur almost exclusively in male adolescents. Diagnosis is typically made through radiographic findings and clinical characteristics; biopsy is not recommended due to the vascular nature of the disease. As with most tumors, there is a spectrum of tumor extent and invasion. In juvenile nasopharyngeal angiofibromas, one of the most important components of extent is the vascular supply. Once the vascular supply is identified, a systematic approach to resection can be planned. The majority of these tumors can be excised endoscopically, and those approaches are the focus of this article.

http://bit.ly/2CCCthP

Three-dimensional configuration of apical epithelial compartments including stem cell niches in guinea pig cheek teeth

Publication date: Available online 21 January 2019

Source: Journal of Oral Biosciences

Author(s): Yuta Seino, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Daisuke Koga, Tatsuo Ushiki, Hayato Ohshima

Abstract

Objectives

Continuously growing rodent incisors have an apically located epithelial stem cell compartment, known as an "apical bud" (AB). Few studies have described the morphological features of ABs and stem cell niches in continuously growing premolars/molars. We attempted to clarify the relationship between the three-dimensional configuration of ABs and the stem cell niches in guinea pig cheek teeth.

Methods

We perfusion-fixed four-week-old guinea pigs, then decalcified their premolars/molars to produce serial paraffin sections, which we immunostained for Sox2. We reconstructed the serial sections using image processing and analysis software. We processed undecalcified samples for scanning electron microscopy by KOH digestion.

Results

Two types of epithelia with M and Δ shapes surrounded the S-shaped dental papilla in the apical region of the premolars/molars, and there were three Sox2-positive epithelial bulges above the M- and Δ-shaped epithelia. Sox2-positive epithelial stem cell niches were restricted to the apical side, and cell proliferation and differentiation immediately proceeded in the crown-analogue dentin. The Sox2-positive epithelial stem cell niches were sparsely distributed and extended to the occlusal side. We also detected continuously proliferating cells in the cervical loop and Hertwig's epithelial root sheath of the root-analogue dentin.

Conclusions

Our findings suggest that guinea pig cheek teeth have three ABs, and the complex configuration of these types of teeth may be attributed to the prompt formation of crown-analogue dentin followed by the long-term formation of root-analogue dentin.

Graphical abstract

http://bit.ly/2FKWMxV

Is intensity-modulated radiotherapy superior to conventional techniques to prevent late ear complications of nasopharyngeal cancer?

Abstract

Purpose

This study analyzed the late ear complications of radiotherapy for nasopharyngeal cancer (NPC) and compared the conventional and intensity-modulated radiotherapy (2D-RT and IMRT, respectively).

Methods

At 2–21 years after the end of NPC treatment, 104 ears of 52 patients were evaluated with the otoscopic examination, pure tone audiometry test, tympanometry, and subjective complaints by being blinded to the radiotherapy technique.

Results

There were no differences in terms of the pathology of the external, middle or inner ear, air and bone-conduction hearing thresholds, and the air–bone (A–B) gap at 500, 1000, 2000, and 4000 Hz, and tympanometry types between 2D-RT and IMRT groups (p > 0.05). There were positive correlations between the values of A500 and A1000 thresholds; gap 500, 4000, and mean cochlear RT dose (p < 0.05). There were positive correlations between the values of A500, A1000, and A4000 thresholds; gap 500, 1000, 2000, 4000, and maximum cochlear RT dose (p < 0.05).

Conclusion

IMRT was not found to be superior to 2D-RT to prevent RT-induced ear complications. The solution of the middle ear problems must be the goal of the strategies for complications treatment.

http://bit.ly/2T399YN

CD300a expression is modulated in atopic dermatitis and could influence the inflammatory response

http://bit.ly/2Hrsn9d

Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti‐inflammatory drug‐induced urticaria

Abstract

Background

The role of arachidonic acid metabolites in NSAIDs‐induced hypersensitivity has been studied in depth for NSAIDs‐exacerbated respiratory disease (NERD) and NSAIDs‐exacerbated cutaneous disease (NECD). However, no information is available for NSAIDs‐induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAIDs‐hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single‐NSAID‐induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison.

Methods

Urine samples were taken from patients with confirmed NSAIDs‐induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high performance liquid chromatography‐tandem mass spectrometry and gas chromatography mass spectrometry.

Results

No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11β‐PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing towards initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups.

Conclusions

We present for the first time data regarding the role of COX‐1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

This article is protected by copyright. All rights reserved.

http://bit.ly/2RWhrog

Prognostic value of tumour-infiltrating CD8+ lymphocytes in rectal cancer after neoadjuvant chemoradiation: is indoleamine-2,3-dioxygenase (IDO1) a friend or foe?

Abstract

The prognostic value of the local immune phenotype in patients with colorectal cancer has been extensively studied. Neoadjuvant radiotherapy and/or chemotherapy may potentially influence these immune responses. In this study, we examined the prognostic role of indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) in locally advanced rectal carcinomas after neoadjuvant treatment. Expression of IDO1 and CD8 was evaluated by immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated along the tumour invasive front, in the tumour centre and within the neoplastic cells and expressed as total scores. Of the tumour specimens evaluable for immunohistochemistry, 100% showed CD8+ lymphocyte infiltration and 93.4% stained positive for IDO1. Total IDO1 score positively correlated with total CD8 score for all three subsites (p = 0.002, Kendall-tau-b 0.357). A high total CD8 score was positively correlated with lower ypUICC-stages (p = 0.047) and lower ypT-categories (p = 0.032). Total IDO1 expression showed a clear trend towards a lower risk of recurrence (p = 0.078). A high total IDO1 score was an independent prognostic marker for prolonged disease-free survival (HR 0.38, p = 0.046) and a high total CD8 score for favourable overall survival (HR 0.16, p = 0.029). Analysis of the local CD8 and IDO1 expression profile may be a helpful tool in predicting prognosis for patients with locally advanced rectal cancer following neoadjuvant chemoradiation.

http://bit.ly/2RJLGzx

Azithromycin and Erythromycin susceptibility and macrolide resistance genes in Prevotella from patients with periodontal disease

Abstract

Objectives

To study oral Prevotella spp. isolated from patients with chronic periodontitis, to determine their susceptibility to azithromycin and erythromycin and to screen the presence of macrolide resistance genes therein.

Material and Methods

Isolates with a Prevotella‐like morphology were obtained from subgingival samples of 52 patients with chronic periodontitis. Each isolate was identified to the species level by sequencing of the 16S rRNA gene. In 100 Prevotella spp. isolates, azithromycin and erythromycin susceptibility was determined using the E‐test method, and the screening of erm(A), erm(B), erm(C), erm(F), erm(G), erm(Q) and mef(A) genes was done by PCR.

Results

Prevotella intermedia and Prevotella nigrescens were the most identified species (33% each). MIC ranges for both antibiotics were 0.016/0.032 ‐ >256 μg/mL. MIC₅₀ values for azithromycin and erythromycin were 1.5 and 1 μg/mL, respectively, and MIC₉₀ values were >256 μg/mL for both antibiotics. Nineteen percent of the isolates carried erm(B) and 51% carried erm(F).

Conclusions

The MIC values found were high compared to previous studies. erm(F) was greatly prevalent and we describe for the first time the erm(B) gene in Prevotella spp. The presence of either of the genes seems to be associated with a higher degree of resistance to azithromycin and erythromycin.

This article is protected by copyright. All rights reserved.

http://bit.ly/2RJL111

Colloid milium, an expression of excessive sun exposure in Ecuadorian patients

http://bit.ly/2CDF4rM

A review of N‐acetylcysteine in the treatment of grooming disorders

Abstract

Background

Pathologic grooming disorders can lead to clinically significant distress and functional impairment. Studies on treatment of these disorders with selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants have led to inconsistent findings. N‐acetylcysteine (NAC) has shown promise in treatment of obsessive‐compulsive and related disorders. The objective of this article is to perform an updated review of NAC in the treatment of grooming disorders.

Methods

PubMed was searched from inception to October 2017 to identify literature on the use of NAC in the management of trichotillomania, onychophagia, and pathological skin picking. Case reports, case series, and randomized controlled trials were included. Data on study design, dosing regimens, comorbidities, concurrent treatment, and side effects were extracted from the included articles.

Results

Fifteen articles were included in this review, which consisted of 10 case reports, one case series, and four randomized controlled trials. Dosing of oral NAC ranged from 450 to 2,400 mg per day, and treatment periods lasted from 1 to 8 months. Side effects were uncommon, mild, and usually gastrointestinal in nature, with severe aggression reported in one child.

Conclusions

While there are multiple reports of the safety and efficacy of NAC in the treatment of grooming disorders, there are currently few randomized controlled trials on this topic, and more research is needed to develop a formal treatment algorithm. While current data should be considered very preliminary, case reports have demonstrated mostly positive results and a lack of significant side effects. A trial of NAC may be a viable option for pathologic grooming disorders, especially in patients who have failed prior psychologic or pharmacologic treatment.

http://bit.ly/2RGn22x

Cure of recurring Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae septic shock episodes due to complicated soft tissue infection using a ceftazidime and avibactam-based regimen: a case report

Infections caused by multidrug-resistant Enterobacteriaceae are hard to treat and life-threatening due to reduced therapeutic options. Systemic infections caused by Klebsiella pneumoniae carbapenemase-producing K...

http://bit.ly/2sF2ys0

Total Glossectomy With Free Flap Reconstruction: Twenty‐Year Experience at a Tertiary Medical Center

Objectives/Hypothesis

To characterize the demographics, clinicopathologic characteristics, and treatment and reconstructive outcomes of patients who underwent total glossectomy

Study Design

Retrospective chart review at an academic tertiary‐care medical center.

Methods

All patients who had undergone total glossectomy (as an individual procedure or as part of a more extensive resection) between January 1, 1995 and December 31, 2014 were included in the analysis. Patient characteristics and clinical outcomes were reviewed.

Results

Forty‐eight patients underwent total glossectomy for oral tongue and base of tongue cancer. The mean age of the patients was 56 (range, 29–92 years). History of tobacco and heavy alcohol use was found in 76% and 11% of patients, respectively. The majority of patients had advanced cancer (91.7% at stage IV), and 60.4% had salvage therapy for recurrent disease. T4 disease comprised 81% of patients. Sixty percent had clinical or radiographic evidence of nodal metastasis. Reconstruction of the defect was performed with free flaps from the rectus abdominus (40%), fibula (25%), anterolateral thigh (23%), and other donor tissues. One‐ and 5‐year survival rates were 42% and 26%, with locoregional and distant recurrence reported at 36% and 25%, respectively.

Conclusions

Total glossectomy for oncologic control is most commonly performed in patients who have stage IV cancers. Despite high reconstructive success rates, the likelihood of locoregional and distance recurrence was high. Most patients can communicate intelligibly and achieve decannulation, but swallowing outcomes remain guarded, especially considering previous irradiation and resection of the base of tongue.

Level of Evidence

4 Laryngoscope, 2019

http://bit.ly/2RIZdqM

Comparison of inducible nitric oxide synthase mRNA expression in different airway portions and association with nitric oxide parameters from patients with asthma

Abstract

Background

Fractional exhaled nitric oxide concentration (FeNO) is widely used to support diagnosis and monitoring of bronchial asthma (BA). Tsoukias and George proposed a two‐compartment model (2CM) for assessing the alveolar concentration of NO, referred to as CANO(2CM), while Condorelli et al. proposed a model based on the trumpet shape of the airway tree and axial diffusion (TMAD), referred to as CANO(TMAD). In addition, Högman et al. proposed non‐linear model, referred to as CANO(non‐linear).

Objective

We examined associations between the expression of inducible nitric oxide synthase (iNOS) mRNA in airway cells (ACs) by bronchoscopy and NO‐parameters calculated by the three methods and identified which of them accurately reflected expression of iNOS mRNA from different airway portions.

Methods

We retrospectively analyzed data of 18 patients with stable, mild‐moderate asthma, including 10 steroid‐naïve BA (snBA) patients. Samples were obtained from airway brushings and bronchoalveolar lavage (BAL). Expressions of iNOS protein in tissue samples were evaluated by immunostaining. The iNOS mRNA in ACs was measured by qPCR. NO‐parameters calculated by the three methods above and evaluated whether they were associated with iNOS mRNA in ACs derived from proximal (2nd carina), distal (10‐15^th) airways and alveolar regions.

Results

Immunostaining revealed expression of iNOS proteins mainly in epithelial cells in the airways, while it was mainly expressed in macrophages in the alveolar region in the snBA group. The iNOS mRNA expression was increased in both proximal and distal ACs in the snBA group compared with steroid treated BA group (stBA). CANO(2CM) negatively associated with FEV₁ (%predicted) and also associated with iNOS mRNA in distal ACs significantly. However, CANO(TMAD) and CANO(non‐linear) showed no correlation with lung function nor iNOS mRNA expression in any portions of ACs.

Conclusions

These results suggested that CANO(2CM) reflected distal airway inflammation in steroid‐naïve asthma.

This article is protected by copyright. All rights reserved.

http://bit.ly/2MmAAKT

Lichenoid Characteristics in Premalignant Verrucous Lesions and Verrucous Carcinoma of the Oral Cavity

Abstract

Verrucous hyperkeratosis (VH), verrucous carcinoma (VC) and the relentless, truly pre-malignant variant proliferative verrucous leukoplakia often exhibit lichenoid histologic features that may create a diagnostic dilemma for pathologists. This study aims to evaluate and categorize the frequency and the histopathologic patterns of lichenoid features seen in these lesions. Following IRB approval, cases of VH and VC from 1994 to 2014 were retrieved from the archives of UF Oral Pathology Biopsy Service. A panel of 4 board-certified oral and maxillofacial pathologists reviewed and scored the presence or absence of 5 lichenoid features: band-like infiltrate (BLI), saw tooth rete ridges (STRR), interface stomatitis (IS), civatte bodies (CB), and basement membrane degeneration (BMD). Cases not fulfilling the stringent selection criteria were excluded. A total of 70 cases of VH and 56 cases of VC were included. Approximately 25% of both VH and VC cases exhibited 3 or more lichenoid features. By Chi square testing, BLI (p = 0.000), IS (p = 0.005), and CB (p = 0.026) were significantly more common in VC than VH. Gingival lesions had significantly less frequent BLI (p = 0.004) and IS (p = 0.024) versus other sites. However, STRR was significantly more common in VH than VC (p = 0.000) in the gingiva. (p = 0.002). Statistical analysis revealed that the only significant valid association was the increased presence of band-like infiltrate in VC over VH (p = 0.001). Lichenoid features are common in both VH and VC and may represent a nonspecific inflammatory response to the dysplasia or malignancy rather than concomitant lichenoid disease. This could lead to significant under diagnoses of these premalignant or potentially malignant lesions by pathologists.

http://bit.ly/2U87q4B

Effect of antiangiogenic targeted chemotherapy on the osseointegration of titanium implants in rabbits

Publication date: Available online 22 January 2019

Source: British Journal of Oral and Maxillofacial Surgery

Author(s): B. Al-Jandan

Abstract

Patients with cancer have recently been treated with more advanced targeted chemotherapies that have greater specificity towards the cancer cells and fewer side effects. However, the periods of treatment take longer than those of traditional cytotoxic treatments. The aim of this study was to examine the effect of antiangiogenic targeted chemotherapy on the osseointegration of titanium implants. Fourteen white New Zealand rabbits were allocated randomly into two groups of seven: the placebo control group and the Avastin^® group. Animals in the Avastin^® group had five doses of bevacizumab intraperitoneally (3 mg/kg/week). The first was given two days before the implant was inserted and the remaining four were given weekly for four weeks. One titanium implant was inserted in the right distal femoral condyle of each rabbit. Osseointegration of the implants was measured using microcomputed tomography (CT) and histomorphometric evaluation. Both of these showed less osseointegration in the Avastin^® group than in the controls. The pharmacological inhibition of angiogenesis by bevacizumab may negatively affect the osseointegration of titanium implants in rabbits.

http://bit.ly/2S1Lafr