Αρχειοθήκη ιστολογίου

Τρίτη 4 Σεπτεμβρίου 2018

The Role of Palliative Care in Oral Cavity Carcinoma

Abstract

Purpose of Review

The purpose of this study is to review the current and future role of palliative care in relation to oral cavity carcinoma (OCC).

Recent Findings

Palliative care for patients with OCC has traditionally been reserved for patients with advanced disease, recurrent disease, or poor performance status who are unable to undergo surgical or adjuvant treatments. Patients with early- or mid-stage disease were not typically offered palliative services. However, patients at all stages face quality of life issues including disruption of speech, eating, pain, mood, self-image, social interactions, work, and daily activities. This can directly affect performance status and has been shown to increase length of hospitalizations and decrease overall survival. Recent evidence suggests that involving palliative care earlier may decrease rates of depression, decrease cost, improve communication, and increase overall survival outcomes. Furthermore, new applications and innovations in radiation therapy, immunotherapy, and chemotherapy have broadened the palliative therapies available to patients with incurable disease.

Summary

Given the impact that OCC has on quality of life during all stages of disease, a paradigm shift is occurring to involve palliative care at earlier stages. Recent evidence has shown that upstream palliative care increases quality of life and ultimately overall survival.



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Book review—Diagnostic pathology: intraoperative consultation, 2nd edition



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Treatment of penile actinomycosis

Dermatologic Therapy, EarlyView.


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The clinical, biochemical, and ultrasonographic characteristics of patients with hidradenitis suppurativa in Northern Peninsular Malaysia: a multicenter study

International Journal of Dermatology, EarlyView.


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Mammalian meat allergy

International Journal of Dermatology, EarlyView.


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Shared decision making and decisional conflict in the Management of Vestibular Schwannoma: a prospective cohort study

Patients with vestibular schwannomas (VS) are faced with complex management decisions. Watchful waiting, surgical resection, and radiation are all viable options with associated risks and benefits. We sought t...

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Effectiveness of skull X-RAY to determine cochlear implant insertion depth

Cochlear implant (CI) insertion depth can affect residual hearing preservation, tonotopic range coverage, and Mapping. Therefore, determining insertion depth has the potential to maximize CI performance. A pos...

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Re-visiting the ATA 2015 sonographic guidelines - who are we missing?: A retrospective review

The American Thyroid Association published revised guidelines in 2015 on the management of differentiated thyroid cancer in adults. One of the key changes introduced in the revision proposes that diagnostic bi...

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Screening the Pathogen Box against Plasmodium sexual stages using a new nanoluciferase based transgenic line of P. berghei identifies transmission-blocking compounds. [Susceptibility]

Malaria remains an important parasitic disease with a large morbidity and mortality burden. Plasmodium transmission-blocking (TB) compounds are essential for achieving malaria elimination efforts. Recent efforts to develop high-throughput screening (HTS) methods to identify compounds that inhibit or kill gametocytes, the Plasmodium sexual stage infectious to mosquitoes, have yielded insight into new TB compounds. However, the activities of these compounds against gametes, formed in the first minutes of mosquito infection, are typically not assessed, unless screened in a standard membrane feeding assay (SMFA), a labor intensive assay. Here we demonstrate the generation of a Plasmodium model for drug screens against gametes and fertilization. The new P. berghei line, named Ookluc, was genetically and pharmacologically validated and scalable for HTS. Screening the Pathogen Box from the Medicines for Malaria Venture (MMV) using the new model identified promising TB compounds. The use of Ookluc in different libraries of compounds may aid in the identification of transmission-blocking drugs not assessed in screens against asexual stages or gametocytes.



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Absence of High Level of Duplication of the plasmepsin 2 Gene in Africa [Epidemiology and Surveillance]

Resistance to piperaquine has been associated with the amplification of the plasmepsin 2 gene in Cambodia. None of the 175 African isolates that we analyzed had plasmepsin 2 gene amplification (piperaquine inhibitory concentration 50% ranged from 0.94 to 137.5 nM), suggesting a low level of piperaquine reduced susceptibility prevalence in Africa. Additionally, the few isolates with reduced susceptibility to piperaquine did not harbor amplification of the plasmepsin 2 gene.



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Pharmacodynamic Evaluation of Rezafungin (CD101) Against Candida auris in the Neutropenic Mouse Invasive Candidiasis Model [Experimental Therapeutics]

Rezafungin (CD101) is a novel echinocandin under development for once-weekly intravenous (IV) dosing. We evaluated the pharmacodynamics (PD) of rezafungin against four Candida auris strains using the neutropenic mouse invasive candidiasis model. AUC/MIC was a robust predictor of efficacy (R2 0.76). The stasis free-drug 24-h AUC/MIC target exposure for the group was 1.88; whereas the 1-log kill free-drug 24-h AUC/MIC target exposure was 5.77. These values are very similar to previous rezafungin PD studies with other Candida spp. Based on recent surveillance susceptibility data, AUC/MIC targets are likely to be exceeded for >90% of C. auris isolates using the previously studied human dose of 400 mg IV once weekly.



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Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) Against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model [Pharmacology]

We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii (N=13) in the neutropenic murine lung infection model. Twelve isolates were meropenem-resistant. In control animals and those that received cefepime or zidebactam alone, mean bacterial growth at 24-h was >2 log10 CFU/lung compared with 0-h controls (6.32±0.33 log10 CFU/lung). WCK 5222 produced a decline in bacterial burden for all isolates (mean reduction, -3.34±0.85 log10 CFU/lung) and demonstrated remarkable potency.



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The effect of plasma protein binding on the anti-HBV activity and pharmacokinetic properties of NVR 3-778. [Antiviral Agents]

High plasma protein binding (PPB) not only affects drug-target engagement but can also impact exposure of hepatocytes to antivirals and thereby affect antiviral activity. In this study, we assessed the effect of PPB on the antiviral activity of NVR 3-778, a sulfamoylbenzamide capsid assembly modulator (CAM). To this end, primary human hepatocyte (PHH) medium was spiked with plasma proteins. At first, the effect of plasma proteins on the HBV-infection assay was evaluated. The addition of plasma proteins neither decreased cell viability nor affected HBV DNA secretion or intracellular HBV RNA accumulation. In contrast, the secretion and intracellular amount of HBV proteins were induced with increasing amounts of plasma proteins. Next, the antiviral activity of NVR 3-778 was demonstrated by multiple assays while PPB and the time-dependent disappearance of the parent drug were quantified by LC-MS/MS. Plasma proteins strongly decreased the free fraction of NVR 3-778 resulting in a physiologically relevant in vitro hepatocyte exposure. NVR 3-778 displayed high PPB, while the antiviral activity was only approximately 4-fold reduced. The disconnect between the high PPB and the only moderate shift of the antiviral activity was explained by the rapid hepatic clearance of NVR 3-778 in the absence of plasma proteins. This study highlights the use of PHHs as a model to accurately determine the antiviral activity by capturing PPB, clearance and liver distribution. It is advantageous to consider both pharmacokinetics and pharmacodynamics for selection of HBV antiviral drug candidates and successful extrapolation of in vitro data to clinical studies.



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In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates [Pharmacology]

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-Nuclear factor of activated T-cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with FK506. The four FK506 analogs generally possess lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus. Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of in vivo antifungal efficacy in the murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, its combination treatment with fluconazole significantly extended the survival of C. neoformans-infected mice, confirming synergistic in vivo antifungal efficacy between these two agents.



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Effects of PERK eIF2{alpha} kinase inhibitor against Toxoplasma gondii [Experimental Therapeutics]

Toxoplasma gondii is an obligate intracellular parasite that has infected one third of the population. Upon infection of warm-blooded vertebrates, the replicating form of the parasite (tachyzoite) converts into a latent form (bradyzoite) present in tissue cysts. During immune deficiency, bradyzoites can reconvert into tachyzoites and cause life-threatening toxoplasmosis. We previously reported that translational control through phosphorylation of the α subunit of T. gondii eIF2 (TgIF2α) is a critical component of the parasite stress response. Diverse stresses can induce the conversion of tachyzoites to bradyzoites, including those disrupting the parasite's endoplasmic reticulum (ER stress). Toxoplasma possesses four eIF2 kinases, one of which (TgIF2K-A) localizes to the parasite ER analogous to PERK, the eIF2 kinase that responds to ER stress in mammalian cells. Here, we investigated the effects of a PERK inhibitor (PERKi) on Toxoplasma. Our results show that the PERKi GSK2606414 blocks the enzymatic activity of TgIF2K-A and reduces TgIF2α phosphorylation specifically in response to ER stress. PERKi also significantly impedes multiple steps of the tachyzoite lytic cycle and sharply lowers the frequency of bradyzoite differentiation in vitro. Pretreatment of host cells with PERKi prior to infection does not affect parasite infectivity, and PERKi still impairs parasite replication in host cells lacking PERK. In mice, PERKi confers modest protection from a lethal dose of Toxoplasma. Our findings represent the first pharmacological evidence supporting TgIF2K-A as an attractive new target for the treatment of toxoplasmosis.



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Bifunctional enzyme SpoT is involved in biofilm formation of Helicobacter pylori with multidrug resistance by upregulating efflux pump Hp1174 (gluP) [Mechanisms of Resistance]

The drug resistance of Helicobacter pylori (H. pylori) is gradually becoming a serious problem. Biofilm formation is an important factor that leads to multidrug resistance in bacteria. The ability of H. pylori to form biofilms on the gastric mucosa is known. However, there are few studies on the regulatory mechanisms of H. pylori biofilm formation and multidrug resistance. Guanosine 3'-diphosphate 5'-triphosphate and guanosine 3',5'-bispyrophosphate [(p)ppGpp] are global regulatory factors and are synthesized in H. pylori by the bifunctional enzyme SpoT. It has been reported that (p)ppGpp is involved in the biofilm formation and multidrug resistance of various bacteria. In this study, we found that SpoT also plays an important role in H. pylori biofilm formation and multidrug resistance. Therefore, it is necessary to carry out some further studies regarding its regulatory mechanism. Considering that efflux pumps are of great importance in the biofilm formation and multidrug resistance of bacteria, we tried to determine whether efflux pumps controlled by SpoT participate in these activities. We found that Hp1174 (glucose/galactose transporter, gluP), an efflux pump of the major facilitator superfamily (MFS), is highly expressed in biofilm-forming and multidrug-resistant (MDR) H. pylori and is upregulated by SpoT. Through further research, we determined that gluP involved in H. pylori biofilm formation and multidrug resistance. Furthermore, the average expression level of gluP in the clinical MDR strains (C-MDR) was considerably higher than that in the clinical drug-sensitive strains (C-DSS). Taken together, our results revealed a novel molecular mechanism of H. pylori resistance to multidrug exposure.



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First report of an OXA-48 and CTX-M-213-producing Kluyvera spp. clone recovered from patients admitted in a University Hospital in Madrid, Spain [Mechanisms of Resistance]

Enterobacterales species other than Klebsiella pneumoniae also contribute to OXA-48 carbapenemase endemicity. We study the emergence of OXA-48-producing Kluyvera spp., which expresses the novel CTX-M-213, colonizing patients in our Hospital. Rectal swabs from patients admitted in four wards (March-2014-March 2016, R-GNOSIS project) were seeded on ESBL and CARB/OXA-48 chromogenic agar plates. Carbapenemases and ESBLs were characterized (PCR, sequencing, cloning, site-directed mutagenesis) and antibiotic susceptibility was determined. Clonal relatedness was established (XbaI-PFGE) and plasmid content was studied [transformation, S1-PFGE, SB-Hybridization, RFLP (DraI, HpaI) and PCR (incompatibility group and repA, traU and parA genes)]. Whole genome sequencing (WGS, IlluminaHISeq-2500) and further bioinformatics analysis of plasmids (PLACNET, Plasmid SPAdes) were performed. Patients' charts were reviewed. Six unrelated patients (median age 75 years, range 59-81; 4/6 male) colonized with OXA-48-Kluyvera spp. (>95% similarity PFGE-pattern) were detected. Nosocomial acquisition was demonstrated. In two patients, OXA-48-Kluyvera spp. co-existed with OXA-48-producing Raoultella ornithinolytica, K. pneumoniae and Escherichia coli. The blaOXA-48 gene was located on a ~60kb IncL plasmid related to IncL/M-pOXA-48a and the novel blaCTX-M-213 in a conserved chromosomal region of Kluyvera spp. isolates. CTX-M-213 different from CTX-M-13 (K56E) but conferring a similar β-lactam resistance profile, was identified. Genomic analysis also revealed a 177 kb IncF plasmid (class I integronsul1 and aadA2) and an 8 kb IncQ (IS4-blaFOX-8). We describe the first blaOXA-48 plasmid in Kluyvera spp. and the novel chromosomal CTX-M-213 enzyme and highlight further nosocomial dissemination of blaOXA-48 through clonal lineages or plasmids related to IncL/M-pOXA-48a.



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Dysfunction of Prohibitin 2 Results in Reduced Susceptibility to Multiple Antifungal Drugs via Activating the Oxidative Stress Responsive Transcription Factor Pap1 in Fission Yeast [Mechanisms of Resistance]

The fight against resistance to antifungal drugs requires a better understanding of the underlying cellular mechanisms. To gain insight into the mechanisms leading to antifungal drug resistance, we performed a genetic screen to identify genes whose overexpression caused resistance to the antifungal drugs including clotrimazole and terbinafine using a model organism, Schizosaccharomyces pombe (S. pombe), and identified the phb2+ gene encoding a highly conserved mitochondrial protein prohibitin Phb2, as a novel determinant of multidrug resistance. Unexpectedly, deletion of the phb2+ gene also exhibited antifungal drug resistance. Overexpression of the phb2+ gene failed to cause the drug resistance when the pap1+ gene encoding an oxidative stress responsive transcription factor was deleted. Furthermore, pap1+ mRNA expression was significantly increased when the phb2+ gene was overexpressed or deleted. Importantly, either overexpression of phb2+ or deletion of its gene stimulated NO and ROS synthesis as measured by a cell-permeant fluorescent NO probe DAF-FM DA and a ROS probe DCFH-DA, respectively. Altogether, these results suggest that dysfunction of Phb2 results in multidrug resistance via increasing NO and ROS synthesis due to dysfunctional mitochondria, thereby activating transcription factor Pap1 in fission yeast.



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The small compound inhibitor K22 displays broad antiviral activity against different members of the family Flaviviridae and offers potential as pan-viral inhibitor [Antiviral Agents]

The virus family Flaviviridae encompasses several viruses, including (re)-emerging viruses which cause widespread morbidity and mortality throughout the world. Members of this virus family are positive-strand RNA viruses and replicate their genome in close association with reorganized intracellular host cell membrane compartments. This evolutionary conserved strategy facilitates efficient viral genome replication and contributes to evasion from host cell cytosolic defense mechanisms.

We have previously described the identification of a small compound inhibitor, K22, which exerts a potent antiviral activity against a broad range of coronaviruses by targeting membrane-bound viral RNA replication. To analyze the antiviral spectrum of this inhibitor, we assessed the inhibitory potential of K22 against several members of the Flaviviridae family, including the re-emerging Zika virus (ZIKV). We show that ZIKV is strongly affected by K22. Time of addition experiments revealed that K22 acts during a post-entry phase of the ZIKV life cycle, and combination regimens of K22 together with ribavirin (RBV) or interferon alpha (IFN-α) further increased the extent of viral inhibition. Ultrastructural electron microscopy studies revealed severe alterations of ZIKV-induced intracellular replication compartments upon infection of K22-treated cells. Importantly, the antiviral activity of K22 was demonstrated against several other members of the Flaviviridae family. It is tempting to speculate that K22 exerts its broad antiviral activity against several positive-strand RNA viruses via a similar mechanism, and thereby represents an attractive candidate for the development of a pan-viral inhibitor.



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Mechanism of macrolide-induced inhibition of pneumolysin release involves impairment of autolysin release in macrolide-resistant Streptococcus pneumoniae [Mechanisms of Action]

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Over the past two decades, macrolide resistance among S. pneumoniae has been increasing steadily and has escalated at an alarming rate worldwide. However, the use of macrolides in the treatment of community-acquired pneumonia has been reported to be effective regardless of antibiotic susceptibility of the causative pneumococci. Although previous studies suggested that sub-minimum inhibitory concentrations of macrolides inhibit the production of pneumolysin, a pneumococcal pore-forming toxin, by macrolide-resistant S. pneumoniae (MRSP), the underlying mechanisms of the inhibitory effect have not been fully elucidated. Here, we showed that the release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, was inhibited by treatment with azithromycin and erythromycin, whereas replenishing recombinant autolysin restored the release of pneumolysin from MRSP. Additionally, macrolides significantly downregulated ply transcription followed by a slight decrease of intracellular pneumolysin level. These findings suggested the mechanisms involved in the inhibition of pneumolysin in MRSP, which may provide additional explanation for the benefits of macrolides on the outcome of treatment for pneumococcal diseases.



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When designing vaccines, consider the starting material: the human B cell repertoire

Colin Havenar-Daughton | Robert K. Abbott | William R. Schief | Shane Crotty

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Dysmorphic features and cochlear implantation outcome in children with sensorineural hearing loss; the headmost study

Susan Amirsalari, Shahla Afsharpayman, Mohammad Ajalloueyan, Jaber Rasuli, Amin Saburi, Mohammad Torkaman

Indian Journal of Otology 2018 24(2):75-79

Introduction: Recently, treatment of children with severe-to-profound sensorineural hearing loss (SNHL) has been influenced by diagnostic improvements and technological treatment advances, specifically new cochlear implant prospects. Multiple handicaps children and children with syndromes and conditions resulting disabilities, such as dual sensory loss, cerebral palsy, somatic abnormalities, and autistic spectrum disorder, are now not routinely precluded from receiving a cochlear implant. The primary aim of this study was to determine the effects of dysmorphic feature on cochlear implant outcome. Materials and Methods: In this cohort study, we evaluated 336 cochlear implanted children from 2007 to 2009. The case group consists of 53 patients (15/7%) with dysmorphic features and control group consisted at 53 patients with normal features and without behavioral and developmental disorders. All patients received auditory and speech rehabilitation and we evaluated their speech and auditory outcome. One year after cochlear implantation, the patient was assessed by categories of auditory perception (CAP) and speech intelligibility rating (SIR) tests. Results: We included 106 out of 336 cochlear implanted children, with the mean age of 30.42 ± 12.16 (maximum 48 months), 52 cases (49.1%) were girls and 54 (50.9%) were boys. There was a significant difference in SIR between case and control groups (3.26 ± 0.98) versus (4.06 ± 0.94) (P < 0.001), and a significant difference in CAP (4.09 ± 1.26) versus (5.43 ± 1.23) as well (P < 0.001). Conclusion: In this study, the prevalence of dysmorphic feature in children with severe-to-profound SNHL is 15.7%. One year after cochlear implant SIR and categories of auditory perception in these patients are significantly lower than children without dysmorphic feature, but cochlear implant will help these children.

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A prospective, observational study of incidence of sensory neural hearing loss in diabetes mellitus patients

Swati Dadhich, Sushil G Jha, Vikas Sinha, TU Samanth

Indian Journal of Otology 2018 24(2):80-82

Aims and Objective: To find out the incidence of hearing loss among the type 2 diabetes mellitus patients. Materials and Methods: Study included 100 diabetic mellitus patients at least for 3 years. It is an observational study carried out for 1 year. Fasting blood sugar, PP2BS, random blood sugar, pure tone audiogram were done. Results: In this study, 100 diabetic patients were studied; out of them, 73 patients were having sensorineural hearing loss (SNHL). Out of 73 SNHL diabetic patients, 48 patients are having mild SNHL (65.75%), 21 patients are having moderate SNHL (28.76%), one patient of mod severe SNHL (1.37%), and three patients of severe SNHL (4.11%). Conclusion: The diabetic individuals had higher hearing threshold with bilateral mild to moderate degree SNHL. Gender of diabetic patient had no significant correlation with hearing loss. Duration of diabetes had significant correlation with hearing loss. Blood glucose level had strong association with SNHL.

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Papular mycosis fungoides: Three case reports and a comprehensive literature review

Jingcheng Zhang, Mingzhe Zhao, Huixian Hu

Indian Journal of Otology 2018 24(2):120-122

This study was to investigate the clinicopathological characteristics, treatments, and prognoses of papillary mycosis fungus (PMF). From May 2004 to September 2015, three cases of papular mycosis fungoides were analyzed at Jinhua Municipal Central Hospital. Diagnostic criteria refer to the World Health Organization 2005 Classification of Cutaneous Lymphoma. Factors that influenced patient survival and prognoses were analyzed. Skin papules were reduced, and skin color was lightened in three patients after a short treatment regimen. Follow-up for 4–7 years revealed few changes in pigmentation, no increase in skin papules, and neither organ nor lymph node involvement. Skin papular mycosis fungal disease can heal itself, and there is no need for excessive intervention.

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Determinants of holistic outcome in traumatic tympanic membrane perforation

Hemant Ahluwalia, Prem Narain, Arunabh Ahluwalia, Jaypal Singh, Ajay Singh

Indian Journal of Otology 2018 24(2):83-87

Objective: The goal of this study is to understand the perforation closure dynamics and to elucidate the factors playing vital role in closure of traumatic tympanic membrane perforation (TMP). Study Design: This was a prospective, sequential allocation, three armed, January 2015–June 2017 (30 months). Setting: This study was conducted at university teaching tertiary hospital. Sample Size: A sample size was 309 (291 patients and 294 ears). Results: The total number of patients included was 291 and the total ears were 294 being bilateral traumatic TMPs in three patients. The mean age of the patients was 27.9 years. Hearing loss and bleeding from ear were the most common presentation. In majority, the hearing loss was conductive. Slap being the most common etiology. Posteroinferior quadrant was the most common site of injury. The overall mean closure time of this study was 13.32 days. Three patients were lost to follow-up. Perforation healing rate in this study was 98.98% at 1 month, and there was a significant difference in healing rate for small and large perforations. We have studied all the three variables together, i.e., the impact of time of initiating treatment after injury, grade of perforation, and their closure time to understand the closure dynamics of traumatic TMPs which is unique and is first of its kind in literature. Conclusion: The carbolic acid to the edge and paper patch with soframycin is a noninvasive, patient-friendly and low-cost office procedure for traumatic TMP's and if performed within 72 h of injury gives 99%–100% closure rate.

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Osteomyelitis of temporal bone: A case report of a rare disease

Bigyan Raj Gyawali, Pabina Rayamajhi

Indian Journal of Otology 2018 24(2):114-116

Osteomyelitis of temporal bone affecting the squamous portion is a very rare entity. We present here a case of osteomyelitis affecting the squamous portion of temporal bone following blunt trauma to the head.

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Effectiveness of multitalker babble over speech noise and its implications: A comparative study

Archana Gundmi, P Himaja, Alisha Dhamani

Indian Journal of Otology 2018 24(2):88-90

Introduction: Speech perception is a complex process. Many variables can affect speech perception; among that, background noise is one of the important factors where maximum interference for the speech perception happens. Perception of speech varies also with types of noise the individual is encountering. Aim: The present study was concentrated on effect of multitalker babble over speech noise in perceiving speech signal. Method: Twenty-four normal-hearing individuals participated in the present study were tested in two different conditions in different signal-to-noise ratio ratios. Result and Conclusion: Results revealed multitalker babble is more effective than speech noise thus can be used more relevantly in clinical practice.

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A therapeutic approach of isolated suppurative labyrinthitis complicated by meningitis

Erika Celis-Aguilar, Lucero Escobar-Aispuro, Jose M Alarid-Coronel, Alan Burgos-Paez

Indian Journal of Otology 2018 24(2):125-128

Suppurative labyrinthitis (SL), a major complication of otitis media, results from a bacterial infection spread through the round window to the inner ear. The most frequent symptoms are hearing loss, vertigo, nystagmus, nausea, and vomiting. This infection poses a significant risk of meningitis due to direct communication of the perilymph to the cerebrospinal fluid through the cochlear aqueduct. There are scarce data in the literature documenting isolated SL as the only cause of meningitis. There are no data describing which treatment is more effective, how often this complication occurs, or when to expect this fatal outcome. We report a case that developed from a labyrinthine suppurative infection to a late-onset meningeal infective disease. This case highlights the importance of correct and timely treatment of SL with early mastoidectomy. The indications of mastoidectomy in these cases are discussed, with a brief review of the literature.

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Clinical features of preauricular sinus and recurrence rate of supra-auricular approach

O Song-Hwan, In-Kyo So, Jin-Ho Kim

Indian Journal of Otology 2018 24(2):91-94

Objective: The objective of this study was to analyze the clinical features of preauricular sinus and the recurrence rate of supra-auricular approach. Materials and Methods: A total of 87 patients (96 ears) treated for preauricular sinus at the Department of Otolaryngology-Head and Neck Surgery, Pyongyang Medical College Hospital, Kim Il Sung University, between January 2007 and December 2016 were enrolled in this study. Results: The prevalence of preauricular sinus was more common in teenage group (55.2%). Preauricular sinus occurred more frequently in male (1.4 times). The most common type of preauricular sinus was marginal helicine type with 86.5%. The recurrence rate with supra-auricular approach was found to be 3.3% whereas simple sinusectomy was 17.1%. Conclusion: The most common type in the preauricular sinus was marginal helicine type and supra-auricular approach was a reliable technique which had significantly less recurrence rate.

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Measurement of speech in noise abilities in laboratory and real-world noise

Bhanu Shukla, B Srinivasa Rao, Udit Saxena, Himanshu Verma

Indian Journal of Otology 2018 24(2):109-113

Aim: The present study aimed to investigate speech in noise perception abilities in normal-hearing adults using different types of noise (i.e., speech babble, traffic noise, and speech spectrum noise) and at different signal-to-noise ratios (SNRs) (i.e., +5 dB, 0 dB, −5 dB, and −10 dB). Methods: A total of 109 individuals with mean age of 23 years were participated in the study. All participants had English as second language and Telugu as native and first language. English disyllabic words (Hrish et al.) were used as speech stimuli under different noises and different SNRs. Results: Results have shown that for any type of noise the speech perception scores changed with the variance in SNRs, the scores have decreased when the SNRs were decreased from 0 dB to −10 dB SNR, and the scores have increased when SNRs increased from 0 dB to +5 dB SNR. Conclusion: From this study, it can be concluded that speech perception score in noise depends on the type of noise used in testing the speech in noise abilities. This factor is very important in the selection of the noise type when measuring speech perception in the presence of noise. It was also seen that change in noise level also had a different impact on speech perception in noise abilities.

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Influence of mastoid drilling on otoacoustic emissions of the nonoperated ear

Sherien Badarudeen, Mubeena , Gangadhara Somayaji

Indian Journal of Otology 2018 24(2):95-97

Introduction: Drilling in mastoid surgeries can affect the nonoperated normal ear by transcranial transmission. This transient hearing loss can be assessed using distortion-product otoacoustic emissions (DPOAE). Objectives: To determine the effect of drilling on the DPOAE in the contralateral normal ear following mastoid surgeries and its relation with the duration of drilling. Study Design: This was a comparative, prospective, and case–control study. Materials and Methods: DPOAE was obtained for 20 patients who underwent mastoid surgery. DPOAE was measured at frequencies of 2, 3, 4, and 5 kHz with frequency ratio maintained at 1.22. DPOAE was recorded during the preoperative, immediate postoperative, 1st and 7th postoperative days. Twenty controls that underwent tympanoplasty were also analyzed pre- and post-operatively. Results: Significant deterioration in the DPOAE amplitudes was noticed during immediate postoperative period in all the four frequencies studied. No correlation was obtained between the duration of drilling and the change in amplitudes. Conclusion: A transient hearing loss is seen in the nonoperated ear following mastoid surgeries due to a drill-induced noise exposure.

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Double-Peak tympanometry in keratosis obturans

Azliana Aziz, Mohd Khairi Md Daud

Indian Journal of Otology 2018 24(2):117-119

Tympanometry is an effective objective tool used to identify problems in the middle ear. Keratosis obturans (KO) is a rare condition but may cause bony erosion and gradual expansion of the bony external auditory canal (EAC). We report a case of 32-year-old woman with KO who presented with bilateral hearing loss for a few years and right ear pain and discharge for 3 months before visit to an otorhinolaryngology clinic. She was treated by ear drops antibiotic and repeated ear toilet. Tympanometry done revealed a large EAC volume with a double-peak admittance. Double-peak tympanometry with an intact tympanic membrane may indicate diseases causing severe erosion in the EAC.

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Effect of below-damage-risk criteria environmental noise on auditory perception and working memory

Sandeep Maruthy, G Nike Gnanateja, Preethi C Chengappa, Sam A Publius, Varsha M Athreya

Indian Journal of Otology 2018 24(2):98-104

Background: The current research finding is the first in reporting impaired auditory and cognitive abilities consequent to chronic exposure to below-damage-risk criteria (DRC) environmental noise in humans. Objective: The objective of this study is to assess the chronic effects of occupational noise below DRC on auditory and cognitive abilities. Methods: A static-group comparison design was used, with three groups with varying levels of noise exposure below DRC. Shopkeepers working in busy areas exposed daily to environmental noise below DRC and shopkeepers working in quiet residential areas and college students in quiet environments. Speech perception in noise, acceptable noise levels, and concurrent vowel identification were used to assess auditory abilities, while Operation SPAN and Backward Digit Span were used to assess cognitive abilities. The data were analyzed using multivariate analysis of variance, Pearson's product-moment correlation, discriminant function analysis, and mediation analysis. Results: The results showed significantly poor auditory stream segregation abilities and working memory abilities in the shopkeepers exposed to environmental noise below DRC when compared to the other two groups with very low levels of occupational noise. The findings of the study are discussed in light of the deleterious effect of the supposedly safe (below DRC) levels of environmental noise on auditory and cognitive abilities. Conclusions: The novel results of affected auditory and cognitive abilities resulting from below-DRC occupational noise exposure as observed in the current study will have a great impact on the applicability to the general populace and also open up new avenues of research in ecological acoustics.

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The inferior “transposition flap” in meatal nevus

Manish Munjal, Archana Arora, Amanjeet Singh, Porshia Rishi

Indian Journal of Otology 2018 24(2):123-124

Nevi and benign lesions of the epithelium of the cartilaginous meatus and refractory to multiple sessions of laser resections are ideal candidates for composite resection with transposition flap reconstitution, retaining thereby the esthetic appearance and dimensional configuration of the cartilaginous meatus. An inferiorly based flap transposed anteriorly and utilized in nevus of the floor and posterior wall gave excellent results.

https://ift.tt/2wIvK38

Role of cervical vestibular-evoked myogenic potentials in evaluating vestibular dysfunction in patients with Type II diabetes mellitus: A prospective institutional study

Sitaramaraju Kanumuri, Krishna Vemuru Chaitanya, Janardhan Nara, K Vasu Kumar Reddy

Indian Journal of Otology 2018 24(2):105-108

Introduction: Cervical Vestibular Evoked Myogenic Potentials (C VEMP) is new dimension of non-invasive investigation to evaluate integrity of Saccule and inferior vestibular nerve by means of sacculo-collic reflex. In this study, we intend to use cervical vestibular evoked Myogenic potential as tool to investigate prevalence of vestibular dysfunction in patients with type II diabetes mellitus. Objectives: To study the prevalence of vestibular dysfunction as measured by cervical Vestibular Evoked Myogenic Potentials in patients with type 2 diabetes mellitus. Results: Prospective study performed on patients presenting in Otorhinolaryngology department during 2013-2016. Patients in study with type 2 diabetes mellitus of greater than 5 years underwent vestibular assessment by using Cervical Vestibular Evoked Myogenic Potentials. It was observed that 4 (10.0%) patients had absent bilateral Cervical Vestibular Evoked Myogenic Potentials responses, 8(20.0%) patients had delayed Cervical Vestibular Evoked Myogenic Potentials responses with delayed p1 and n1 latencies. Discussion and Conclusion: In diabetic individuals who are asymptomatic in patients who never complained of giddiness, Cervical Vestibular Evoked Myogenic Potentials identified vestibular dysfunction in 25% of patients. In symptomatic diabetic mellitus individuals, Cervical Vestibular Evoked Myogenic Potentials was able to identify 33.3% of vestibular dysfunction, however in another 33.3% of patients where Cervical Vestibular Evoked Myogenic Potentials failed to identify.

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Management of unsafe type of chronic suppurative otitis media with extracranial complications at a tertiary care center

Vinod Tukaram Kandakure, Pradipkumar Digambarrao Khokle, Udit Rohit Shah

Indian Journal of Otology 2018 24(2):129-134

Chronic suppurative otitis media (CSOM) is a common disease in the developing countries and the complications associated with it still pose a major problem. Despite the reduction in the incidence of CSOM-related complications with the introduction of antibiotics, Gradenigo's syndrome, mastoid abscess, labyrinthine fistula, and other complications still do occur. Computed tomography scan is an inevitable part of diagnostic algorithm rendered when a patient with CSOM presents with complications. Otitis media although a common pathology,complications are rare and should be suspected when the picture is of torpid evolution with clinical worsening and manifestation of neurological signs. There is a need to emphasize the importance of accurate and early diagnosis followed by adequate surgical therapy with a multidisciplinary approach. Here, we look at such cases encountered at our institute and their management.

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Subsets of CD4+, CD8+, and CD25hi Lymphocytes Are in General Not Influenced by Isolation and Long-Term Cryopreservation [NOVEL IMMUNOLOGICAL METHODS]

Several key factors can affect the outcome of immunological studies; isolation/cryopreservation can possibly alter T, B, NK, and T-regulatory (Treg) cell marker expression patterns. Blood samples from 50 blood donors supplemented with Na-heparin or K2EDTA were handled within 4 and 24 h after blood sampling. PBMC were isolated with different density gradients. Flow cytometric analysis of intracellular and extracellular CD markers was performed on blood samples freshly isolated PBMC, and PBMC was thawed 6 and 12 mo post-cryopreservation for the purpose of identifying B, NK, Th, T-cytotoxic, and Treg cells. No differences were observed in the percentages for CD3+, CD3+CD4+, CD3+CD8+, CD19+, or CD56+CD16+ cells within 24 h of sampling regardless of which supplement or isolation techniques were used. Differentiated (diff) CD4+ cells were in general less affected by isolation and cryopreservation than diff CD8+ cells. Terminally diff effector CD4+ and CD8+ cells were not affected by either isolation of lymphocytes or cryopreservation. In contrast, naive and early-diff effector memory CD4+ and CD8+ cells were affected by isolation and cryopreservation. The percentages of Treg cells defined as CD4+CD25hi expressing CD101 or CD129, CD4+CD25hiCD127, and CD4+CD25hiCD127FOXP3+, respectively, remained stable after isolation and cryopreservation. Subsets expressing CD127, with or without FOXP3, were not affected by isolation/cryopreservation. Subsets expressing CD39, contrary to CD45RA, on CD4+CD25+CD127 cells with or without FOXP3 were not affected by either isolation or cryopreservation. In conclusion, subsets of CD4+, CD8+, and CD25hi lymphocytes are in general not influenced by isolation and long-term cryopreservation.



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Sweaty feet in adolescents—Early use of botulinum type A toxin in juvenile plantar hyperhidrosis

Pediatric Dermatology, EarlyView.


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Melanotic neuroectodermal tumor of infancy: A rare pediatric head and neck lesion

Pediatric Dermatology, EarlyView.


https://ift.tt/2Na99a3

Type 1 IFN and PD-L1 Coordinate Lymphatic Endothelial Cell Expansion and Contraction during an Inflammatory Immune Response [INNATE IMMUNITY AND INFLAMMATION]

Lymph node (LN) expansion during an immune response is a complex process that involves the relaxation of the fibroblastic network, germinal center formation, and lymphatic vessel growth. These processes require the stromal cell network of the LN to act deliberately to accommodate the influx of immune cells to the LN. The molecular drivers of these processes are not well understood. Therefore, we asked whether the immediate cytokines type 1 IFN produced during viral infection influence the lymphatic network of the LN in mice. We found that following an IFN-inducing stimulus such as viral infection or polyI:C, programmed cell death ligand 1 (PD-L1) expression is dynamically upregulated on lymphatic endothelial cells (LECs). We found that reception of type 1 IFN by LECs is important for the upregulation of PD-L1 of mouse and human LECs and the inhibition of LEC expansion in the LN. Expression of PD-L1 by LECs is also important for the regulation of LN expansion and contraction after an IFN-inducing stimulus. We demonstrate a direct role for both type 1 IFN and PD-L1 in inhibiting LEC division and in promoting LEC survival. Together, these data reveal a novel mechanism for the coordination of type 1 IFN and PD-L1 in manipulating LEC expansion and survival during an inflammatory immune response.



https://ift.tt/2NfUtWR

Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis [TRANSLATING IMMUNOLOGY]

Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17–producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.



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Progression from the Common Lymphoid Progenitor to B/Myeloid PreproB and ProB Precursors during B Lymphopoiesis Requires C/EBP{alpha} [IMMUNE SYSTEM DEVELOPMENT]

The C/EBPα transcription factor is required for myelopoiesis, with prior observations suggesting additional contributions to B lymphopoiesis. Cebpa expression is evident in common lymphoid progenitor (CLP) and preproB cells but is absent in proB and preB cells. We previously observed that marrow lacking the Cebpa +37 kb enhancer is impaired in producing B cells upon competitive transplantation. Additionally, a Cebpa enhancer/promoter-hCD4 transgene is expressed in B/myeloid CFU. Extending these findings, pan-hematopoietic murine Cebpa enhancer deletion using Mx1-Cre leads to expanded CLP, fewer preproB cells, markedly reduced proB and preB cells, and reduced mature B cells, without affecting T cell numbers. In contrast, enhancer deletion at the proB stage using Mb1-Cre does not impair B cell maturation. Further evaluation of CLP reveals that the Cebpa transgene is expressed almost exclusively in Flt3+ multipotent CLP versus B cell–restricted Flt3 CLP. In vitro, hCD4+ preproB cells produce both B and myeloid cells, whereas hCD4 preproB cells only produce B cells. Additionally, a subset of hCD4 preproB cells express high levels of RAG1-GFP, as seen also in proB cells. Global gene expression analysis indicates that hCD4+ preproB cells express proliferative pathways, whereas B cell development and signal transduction pathways predominate in hCD4 preproB cells. Consistent with these changes, Cebpa enhancer–deleted preproB cells downmodulate cell cycle pathways while upregulating B cell signaling pathways. Collectively, these findings indicate that C/EBPα is required for Flt3+ CLP maturation into preproB cells and then for proliferative Cebpaint B/myeloid preproB cells to progress to Cebpalo B cell–restricted preproB cells and finally to Cebpaneg proB cells.



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The Intestinal Virome and Immunity [BRIEF REVIEWS]

The composition of the human microbiome is considered a major source of interindividual variation in immunity and, by extension, susceptibility to diseases. Intestinal bacteria have been the major focus of research. However, diverse communities of viruses that infect microbes and the animal host cohabitate the gastrointestinal tract and collectively constitute the gut virome. Although viruses are typically investigated as pathogens, recent studies highlight a relationship between the host and animal viruses in the gut that is more akin to host–microbiome interactions and includes both beneficial and detrimental outcomes for the host. These viruses are likely sources of immune variation, both locally and extraintestinally. In this review, we describe the components of the gut virome, in particular mammalian viruses, and their ability to modulate host responses during homeostasis and disease.



https://ift.tt/2NQfvZ0

Conventional Dendritic Cells Impair Recovery after Myocardial Infarction [SYSTEMS IMMUNOLOGY]

Ischemic myocardial injury results in sterile cardiac inflammation that leads to tissue repair, two processes controlled by mononuclear phagocytes. Despite global burden of cardiovascular diseases, we do not understand the functional contribution to pathogenesis of specific cardiac mononuclear phagocyte lineages, in particular dendritic cells. To address this limitation, we used detailed lineage tracing and genetic studies to identify bona fide murine and human CD103+ conventional dendritic cell (cDC)1s, CD11b+ cDC2s, and plasmacytoid DCs (pDCs) in the heart of normal mice and immunocompromised NSG mice reconstituted with human CD34+ cells, respectively. After myocardial infarction (MI), the specific depletion of cDCs, but not pDCs, improved cardiac function and prevented adverse cardiac remodeling. Our results showed that fractional shortening measured after MI was not influenced by the absence of pDCs. Interestingly, however, depletion of cDCs significantly improved reduction in fractional shortening. Moreover, fibrosis and cell areas were reduced in infarcted zones. This correlated with reduced numbers of cardiac macrophages, neutrophils, and T cells, indicating a blunted inflammatory response. Accordingly, mRNA levels of proinflammatory cytokines IL-1β and IFN- were reduced. Collectively, our results demonstrate the unequivocal pathological role of cDCs following MI.



https://ift.tt/2MNcegR

Cutting Edge: Glycolytic Metabolism and Mitochondrial Metabolism Are Uncoupled in Antigen-Activated CD8+ Recent Thymic Emigrants [CUTTING EDGE]

Recent thymic emigrants (RTEs) are peripheral T cells that have most recently completed selection and thymic egress and constitute a population that is phenotypically and functionally distinct from its more mature counterpart. Ag-activated RTEs are less potent effectors than are activated mature T cells, due in part to reduced aerobic glycolysis (correctable by exogenous IL-2), which in turn impacts IFN- production. Mitochondria serve as nodal regulators of cell function, but their contribution to the unique biology of RTEs is unknown. In this study, we show that activated mouse RTEs have impaired oxidative phosphorylation, even in the presence of exogenous IL-2. This altered respiratory phenotype is the result of decreased CD28 signaling, reduced glutaminase induction, and diminished mitochondrial mass in RTEs relative to mature T cells. These results suggest an uncoupling whereby IL-2 tunes the rate of RTE glycolytic metabolism, whereas the unique profile of RTE mitochondrial metabolism is "hard wired."



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CBLB Constrains Inactivated Vaccine-Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia [INFECTIOUS DISEASE AND HOST RESPONSE]

Fungal infections in CD4+ T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T cell responses and immunity to inactivated vaccine in the absence of CD4+ T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-) and type 17 (IL-17A) CD8+ T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb–/– mice. Augmented CD8+ T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8+ T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8+ T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients.



https://ift.tt/2NemX3a

Cutting Edge: Proper Orientation of CTCF Sites in Cer Is Required for Normal J{kappa}-Distal and J{kappa}-Proximal V{kappa} Gene Usage [CUTTING EDGE]

Ig locus contraction and V gene usage are controlled by Cer, a cis-acting sequence in the V–J intervening region. This effect is attributed to two CTCF-binding sites within Cer that are oriented toward the V gene region. However, the importance of Cer CTCF orientation in regulating VJ rearrangement is unknown. We used CRISPR/Cas9 editing to delete and invert Cer in murine Abl pro–B cell lines. This revealed that Cer orientation is critical because clones with either an inverted or deleted Cer element show skewing toward J-proximal V gene usage. However, only Cer deletion increased J-proximal V germline transcription, suggesting an insulating function of Cer. Lastly, circularized chromosome conformation capture interaction data show that Cer CTCF orientation regulates long-range interactions with inversion clones displaying fewer interactions with regions in the middle and distal parts of the V locus and more interactions to downstream regions compared with wild-type or deletion clones.



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Nucleotide Composition of Human Ig Nontemplated Regions Depends on Trimming of the Flanking Gene Segments, and Terminal Deoxynucleotidyl Transferase Favors Adding Cytosine, Not Guanosine, in Most VDJ Rearrangements [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The formation of nontemplated (N) regions during Ig gene rearrangement is a major contributor to Ab diversity. To gain insights into the mechanisms behind this, we studied the nucleotide composition of N regions within 29,962 unique human VHDJH rearrangements and 8728 unique human DJH rearrangements containing exactly one identifiable D gene segment and thus two N regions, N1 and N2. We found a distinct decreasing content of cytosine (C) and increasing content of guanine (G) across each N region, suggesting that N regions are typically generated by concatenation of two 3' overhangs synthesized by addition of nucleoside triphosphates with a preference for dCTP. This challenges the general assumption that the terminal deoxynucleotidyl transferase favors dGTP in vivo. Furthermore, we found that the G and C gradients depended strongly on whether the germline gene segments were trimmed or not. Our data show that C-enriched N addition preferentially happens at trimmed 3' ends of VH, D, and JH gene segments, indicating a dependency of the transferase mechanism upon the nuclease mechanism.



https://ift.tt/2NiKRuc

Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses [CUTTING EDGE]

Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in Ptpn6spin mice. In the current study we have identified a previously unknown role for CARD9 signaling as a critical regulator for Ptpn6spin-mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued the Ptpn6spin-mediated footpad inflammation. Mechanistically, enhanced IL-1α–mediated signaling in Ptpn6spin mice neutrophils was dampened in Ptpn6spinCard9–/– mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1α–driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.



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In This Issue [IN THIS ISSUE]



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Cutting Edge: IL-1R1 Mediates Host Resistance to Mycobacterium tuberculosis by Trans-Protection of Infected Cells [CUTTING EDGE]

IL-1R1 deficiency in mice causes severe susceptibility to Mycobacterium tuberculosis. Mice and macrophage cultures lacking IL-1R1 display increased bacterial growth, suggesting that phagocytes may require IL-1R1–dependent antimicrobial signals to limit intracellular M. tuberculosis replication directly. However, the myeloid-cell–intrinsic versus –extrinsic requirements for IL-1R1 to control M. tuberculosis infection in mice have not been directly addressed. Using single-cell analysis of infected cells, competitive mixed bone marrow chimeras, and IL-1R1 conditional mutant mice, we show in this article that IL-1R1 expression by pulmonary phagocytes is uncoupled from their ability to control intracellular M. tuberculosis growth. Importantly, IL-1R1–dependent control was provided to infected cells in trans by both nonhematopoietic and hematopoietic cells. Thus, IL-1R1–mediated host resistance to M. tuberculosis infection does not involve mechanisms of cell-autonomous antimicrobicidal effector functions in phagocytes but requires the cooperation between infected cells and other cells of hematopoietic or nonhematopoietic origin to promote bacterial containment and control of infection.



https://ift.tt/2NNGaG2

The Phagocyte Oxidase Controls Tolerance to Mycobacterium tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Protection from infectious disease relies on two distinct strategies: antimicrobial resistance directly inhibits pathogen growth, whereas infection tolerance protects from the negative impact of infection on host health. A single immune mediator can differentially contribute to these strategies in distinct contexts, confounding our understanding of protection to different pathogens. For example, the NADPH-dependent phagocyte oxidase (Phox) complex produces antimicrobial superoxide and protects from tuberculosis (TB) in humans. However, Phox-deficient mice display no sustained resistance defects to Mycobacterium tuberculosis, suggesting a more complicated role for NADPH Phox complex than strictly controlling bacterial growth. We examined the mechanisms by which Phox contributes to protection from TB and found that mice lacking the Cybb subunit of Phox suffered from a specific defect in tolerance, which was caused by unregulated Caspase-1 activation, IL-1β production, and neutrophil influx into the lung. These studies imply that a defect in tolerance alone is sufficient to compromise immunity to M. tuberculosis and highlight a central role for Phox and Caspase-1 in regulating TB disease progression.



https://ift.tt/2NOoji7

Syndecan-1 Regulates Psoriasiform Dermatitis by Controlling Homeostasis of IL-17-Producing {gamma}{delta} T Cells [ALLERGY AND OTHER HYPERSENSITIVITIES]

IL-17 is a potent proinflammatory cytokine that drives pathogenesis of multiple autoimmune diseases, including psoriasis. A major source of pathogenic IL-17 is a subset of T cells (T17) that acquires the ability to produce IL-17 while developing in the thymus. The mechanisms that regulate homeostasis of T17 cells and their roles in psoriasis, however, are not fully understood. In this paper, we show that the heparan sulfate proteoglycan syndecan-1 (sdc1) plays a critical role in regulating homeostasis of T17 cells and modulating psoriasis-like skin inflammation in mice. sdc1 was predominantly expressed by T17 cells (but not IL-17 T cells) in the thymus, lymph nodes, and dermis. sdc1 deficiency significantly and selectively increased the frequency and absolute numbers of T17 cells by mechanisms that included increased proliferation and decreased apoptosis. Adoptive transfer experiments ruled out a significant role of sdc1 expressed on nonhematopoietic cells in halting expansion and proliferation of sdc1-deficient T17 cells. When subjected to imiquimod-induced psoriasiform dermatitis, T17 cells in sdc1KO mice displayed heightened responses accompanied by significantly increased skin inflammation than their wild-type counterparts. Furthermore, transferred sdc1-deficient T cells caused more severe psoriasiform dermatitis than their sdc1-sufficient counterparts in TCR–β KO hosts. The results uncover a novel role for sdc1 in controlling homeostasis of T17 cells and moderating host responses to psoriasis-like inflammation.



https://ift.tt/2NldBm6

Glatiramer Acetate Enhances Myeloid-Derived Suppressor Cell Function via Recognition of Paired Ig-like Receptor B [INNATE IMMUNITY AND INFLAMMATION]

Glatiramer acetate (GA; Copaxone) is a copolymer therapeutic that is approved by the Food and Drug Administration for the relapsing-remitting form of multiple sclerosis. Despite an unclear mechanism of action, studies have shown that GA promotes protective Th2 immunity and stimulates release of cytokines that suppress autoimmunity. In this study, we demonstrate that GA interacts with murine paired Ig-like receptor B (PIR-B) on myeloid-derived suppressor cells and suppresses the STAT1/NF-B pathways while promoting IL-10/TGF-β cytokine release. In inflammatory bowel disease models, GA enhanced myeloid-derived suppressor cell–dependent CD4+ regulatory T cell generation while reducing proinflammatory cytokine secretion. Human monocyte-derived macrophages responded to GA by reducing TNF-α production and promoting CD163 expression typical of alternative maturation despite the presence of GM-CSF. Furthermore, GA competitively interacts with leukocyte Ig-like receptors B (LILRBs), the human orthologs of PIR-B. Because GA limited proinflammatory activation of myeloid cells, therapeutics that target LILRBs represent novel treatment modalities for autoimmune indications.



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Identification and Analysis of Islet Antigen-Specific CD8+ T Cells with T Cell Libraries [CLINICAL AND HUMAN IMMUNOLOGY]

Type 1 diabetes (T1D) is most likely caused by killing of β cells by autoreactive CD8+ T cells. Methods to isolate and identify these cells are limited by their low frequency in the peripheral blood. We analyzed CD8+ T cells, reactive with diabetes Ags, with T cell libraries and further characterized their phenotype by CyTOF using class I MHC tetramers. In the libraries, the frequency of islet Ag–specific CD45RO+IFN-+CD8+ T cells was higher in patients with T1D compared with healthy control subjects. Ag-specific cells from the libraries of patients with T1D were reactive with ZnT8186–194, whereas those from healthy control recognized ZnT8186–194 and other Ags. ZnT8186–194-reactive CD8+ cells expressed an activation phenotype in T1D patients. We found TCR sequences that were used in multiple library wells from patients with T1D, but these sequences were private and not shared between individuals. These sequences could identify the Ag-specific T cells on a repeated draw, ex vivo in the IFN-+ CD8+ T cell subset. We conclude that CD8+ T cell libraries can identify Ag-specific T cells in patients with T1D. The T cell clonotypes can be tracked in vivo with identification of the TCR gene sequences.



https://ift.tt/2NNxXBL

A Fundamental Role of Myh9 for Neutrophil Migration in Innate Immunity [INNATE IMMUNITY AND INFLAMMATION]

Neutrophils are the first leukocytes to arrive at sites of injury during the acute inflammatory response. To maintain the polarized morphology during migration, nonmuscle myosins class II are essential, but studies using genetic models to investigate the role of Myh9 for neutrophil migration were missing. In this study, we analyzed the functional role of Myh9 on neutrophil trafficking using genetic downregulation of Myh9 in Vav-iCre+/Myh9wt/fl mice because the complete knockout of Myh9 in the hematopoietic system was lethal. Migration velocity and Euclidean distance were significantly diminished during mechanotactic migration of Vav-iCre+/Myh9wt/fl neutrophils compared with Vav-iCre/Myh9wt/fl control neutrophils. Similar results were obtained for transmigration and migration in confined three-dimensional environments. Stimulated emission depletion nanoscopy revealed that a certain threshold of Myh9 was required to maintain proper F-actin dynamics in the front of the migrating cell. In laser-induced skin injury and in acute peritonitis, reduced Myh9 expression in the hematopoietic system resulted in significantly diminished neutrophil extravasation. Investigation of bone marrow chimeric mice in the peritonitis model revealed that the migration defect was cell intrinsic. Expression of Myh9-EGFP rescued the Myh9-related defects in two-dimensional and three-dimensional migration of Hoxb8-SCF cell–derived neutrophils generated from fetal liver cells with a Myh9 knockdown. Live cell imaging provided evidence that Myh9 was localized in branching lamellipodia and in the uropod where it may enable fast neutrophil migration. In summary, the severe migration defects indicate an essential and fundamental role of Myh9 for neutrophil trafficking in innate immunity.



https://ift.tt/2NLMgql

SAMHD1 Posttranscriptionally Controls the Expression of Foxp3 and Helios in Human T Regulatory Cells [IMMUNE REGULATION]

Clinical application of Ag-specific T regulatory cells (Tregs) offers promise for the treatment of undesirable immune diseases. To achieve this goal, long-term expansion of Tregs is required to obtain sufficient numbers of cells. However, human Tregs are not stable ex vivo. Therefore, we previously developed an innovative Treg expansion protocol using 25mer-phosphorothioated random oligonucleotides (ODNps25). The addition of ODNps25 successfully resulted in the stabilization of engineered Ag-specific Tregs; however, the mechanism is not fully characterized. We first identified sterile α motif histidine-aspartate–domain containing protein 1 (SAMHD1) as an ODNps25-binding protein using a UV–cross-linking pull-down strategy. SAMHD1 physically interacted with the 3' untranslated region of Foxp3 mRNA and was translocated from nucleus to cytoplasm after ODNps25 treatment. Importantly, addition of ODNps25 enhanced the interaction of SAMHD1 and Foxp3 mRNA significantly, and this interaction was increased by TCR stimulation. Because ODNps25 binds to the nuclease (HD) domain of SAMHD1, we then established that overexpression of a dNTPase-deficient mutant (D137N) in Tregs significantly stabilized the expression level of the Foxp3 protein. Furthermore, we found that TCR stimulation upregulates phosphorylation of the threonine residue (Thr592), which is a regulatory site to control SAMHD1 activity, and phosphorylation of Thr592 is critical to control SAMHD1 activity to stabilize the expression of Foxp3 and Helios in Tregs. Taken together, we suggest that the interaction of ODNPs25 in HD or phosphorylation of Thr592 by TCR stimulation interferes with nuclease activity of SAMHD1, thereby stabilizing 3' untranslated region of Foxp3 and Helios mRNAs in long-term culture.



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Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor {gamma} Regulates Inflammation and Mucin Expression in Allergic Airway Disease [MUCOSAL IMMUNOLOGY]

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator–activated receptor (PPAR) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPAR agonists antagonize exaggerated inflammatory responses, yet PPAR's precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPAR (AEC-PPAR) deletion to investigate PPAR's functions in a murine model of allergic airway disease. AEC-PPAR deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPAR directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPAR regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies' limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPAR's role as a transcriptional repressor of MUC5AC highlights this receptor's potential as a pharmacological target for asthma.



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ERK Signaling Controls Innate-like CD8+ T Cell Differentiation via the ELK4 (SAP-1) and ELK1 Transcription Factors [IMMUNE SYSTEM DEVELOPMENT]

In mouse thymocyte development, signaling by the TCR through the ERK pathway is required for positive selection of conventional naive T cells. The Ets transcription factor ELK4 (SAP-1), an ERK-regulated cofactor of the SRF transcription factor, plays an important role in positive selection by activating immediate-early genes such as the Egr transcription factor family. The role of ELK4–SRF signaling in development of other T cell types dependent on ERK signaling has been unclear. In this article, we show that ELK4, and its close relative ELK1, act cell autonomously in the thymus to control the generation of innate-like αβ CD8+ T cells with memory-like characteristics. Mice lacking ELK4 and ELK1 develop increased numbers of innate-like αβ CD8+ T cells, which populate the periphery. These cells develop cell autonomously rather than through expansion of PLZF+ thymocytes and concomitantly increased IL-4 signaling. Their development is associated with reduced TCR-mediated activation of ELK4–SRF target genes and can be partially suppressed by overexpression of the ELK4–SRF target gene EGR2. Consistent with this, partial inhibition of ERK signaling in peripheral CD8+T cells promotes the generation of cells with innate-like characteristics. These data establish that low-level ERK signaling through ELK4 (and ELK1) promotes innate-like αβ CD8+ T cell differentiation, tuning conventional versus innate-like development.



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Safe Touch Conversations and Sexual Abuse Prevention for Children

Talking to your kids about safety is not always an exciting or easy conversation, but it's necessary in the world we live in.  Most basic safety rules are shared with children naturally in our daily lives.  When I get in the car with my two kids, the very first thing we do is "buckle up for safety."  Before my 5-year-old daughter grabs her bike from the garage, I ask, "Are you forgetting something?"  She replies, "My helmet to keep my head and brain safe."  When my 3-year-old son drags a stool over to the kitchen counter to snag some watermelon I am cutting, I remind him, "Don't reach.  I'm using a very sharp knife!"

Initiating Safe Touch Conversations

Talking about sexual abuse precautions, however, is a different story.  First off, it doesn't tend to come up in daily situations to enable us to naturally bring up the topic.  Most of us wouldn't say talking about sex with our children and especially deviant sexual behavior is exactly comfortable.  We don't like to think about it.  And really it doesn't happen that often.  But does it?  Approximately one in 10 children will be sexually abused before their 18th birthday.  Nearly 70% of all reported sexual assaults occur to children ages 17 and younger.

Why am I sharing these awful statistics?  Because as parents we have the responsibility and privilege to protect our children, and close supervision and monitoring is not enough. We need to teach and inform our children about ways to protect themselves from danger, including sexual abuse.  I encourage you to make a conscious effort to initiate these challenging but vitally important conversations with your children.  Here are some starting points to keep in mind:

Don't just talk about "stranger danger."

About 90% of children who are victims of sexual abuse know their abuser, and 60% are abused by people the family trusts, including family members (about 30% of child abuse perpetrators).  Unfortunately, there are no physical markers that distinguish child sexual abusers.  They can be familiar people in your neighborhood, school, church and community sports leagues.

Identifying Their Private Parts

Teach your children to identify their private parts using anatomically correct terms. It is important that children feel empowered to talk about their bodies accurately.  This encourages positive body image, self-confidence, open communication and ease to talk about any issues of sexual abuse that may arise.

What is Safe Touch?

Define safe vs. unsafe touch. Talk to your children about what constitutes safe and appropriate touch from family members, teachers, peers, and others, and what constitutes unsafe touch.  The "swimsuit" guide is useful – teaching kids that touches that fall within the area of your child's swimsuit are unsafe.

Trusting Their Instincts

Teach your children to trust their instincts, especially when they are in a situation and begin to feel scared, nervous, uncomfortable or icky. If they don't feel something is right – even if they are at school or around adults with authority (e.g., teachers, clergy, police officers, etc.) – they should stop, say "no," and go to a parent or someone they trust and tell them about the situation.

Avoid Secrets

Discourage "secrets." The notion of "keeping secrets" comes up in childhood, among friends and family members, and is usually harmless.  However, sexual perpetrators also often use this terminology to make children feel special and to prevent them from telling others about the abuse.  Instead of the term "secret" – which implies that someone is "left out" from knowing something (which doesn't feel good), encourage the term "surprise" – which implies that everyone will be informed/included in the end (who doesn't love a surprise party).  Teach your children the difference between the two.

Repetition is Key

Once is not enough. Bring this safety topic up again and again throughout childhood.  Once your child hits pre-adolescence/if you have a pre-teen, begin talking about sexual abuse in the context of dating.  Teens ages 16 to 19 are 3.5 times more likely than the general population to be victims of rape, attempted rape or sexual assault.  According to a 2013 national youth risk behavior survey, approximately 10% of high school students surveyed reported sexual victimization from a dating partner in the past 12 months.  Be direct in telling your teens that just because they are dating someone, it doesn't give that person a right to do anything that makes them feel uncomfortable.  It doesn't matter who initiated what or if there's a sexual attraction, it's their body – they have a right to say "no" at any time.

Social Media and Electronic Usage

Monitor your children's activity on electronics and social media. Electronic devices are a gateway for access to your children – good and bad.  About 13% of youth internet users received unwanted sexual solicitations, with the most common first encounter of a predator occurring in an online chat room.  About 15% of cell phone-owning teenagers ages 12-17 reported having received sexually suggestive nude/semi-nude images of someone they know via text.  Whether it be seemingly innocent photos shared on Snapchat or too much personal information shared through chats with internet "friends," young millennials who have grown up with digital technology likely do not have safety on the forefront of their minds when they are on their smartphones, tablets, and computers.

Understanding the Warning Signs

Know the warning signs. Children who have experienced sexual abuse often are too afraid or ashamed to tell someone.  They may fear that they will receive negative reactions from their parents or further harm from the perpetrator.  Only about 38% of child victims disclose their abuse, and disclosure is often delayed.  Some may attempt to disclose by providing hints or subtly implying something happened to them.

Some, but not all, children will exhibit symptoms, such as changes in behavior, mood, and sleep.  They may no longer want to go places they previously enjoyed, such as school, athletic events, or a friend's home.  They may begin acting out or exhibiting over-sexualized behavior.  Their grades might decline.  If you notice any concerning signs, contact your child's pediatrician.  Overall, children who have been sexually abused are at risk for a host of difficulties, including posttraumatic stress disorder, anxiety, depression and suicide, risky behavior, academic problems and dropping out of school, substance abuse, and involvement in crime.

Maintaining a Line of Open Communication

Keep communication open. Remind your children frequently that they can talk to you about anything, and that you are there for them even if things are hard to talk about. Remind them that safety trumps trouble. Let your children know that they will never get in trouble for informing you about something that is a matter of safety.

Using a Child Abuse Hotline

Call a child abuse hotline. Call at any point if you have reasonable cause to believe that a child you know may be a victim of abuse. The hotline worker will determine if the information given by the reporter meets the legal requirements to initiate an investigation.

  • Illinois Child Abuse Hotline: 1-800-252-2873
  • Missouri Child Abuse Hotline: 1-800-392-3738

The post Safe Touch Conversations and Sexual Abuse Prevention for Children appeared first on ChildrensMD.



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Anaphylaxis triggers in a large tertiary care hospital in Qatar: a retrospective study

Anaphylaxis is a serious allergic disease that may lead to death if not immediately recognized and treated. Triggers of anaphylaxis including food, drugs, and insect stings can vary widely. The incidence of an...

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Correction to: Effect of Stimulus Polarity on Detection Thresholds in Cochlear Implant Users: Relationships with Average Threshold, Gap Detection, and Rate Discrimination

The middle initial of Julie G. Arenberg's name was incorrect in the original publication; it is correct as displayed here.



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Reply to Li et al: Late 20th-century drought in northern China reflects influence of global warming, aerosols, and natural variability [Physical Sciences]

Day et al. (1) present a lens for understanding the rainfall climatology of eastern China. Frontal rainfall occurs year-round due to a unique juxtaposition of continental configuration and orography. By creating an algorithm to identify frontal rain events (FREs), we are able to identify changes in properties, such as their...

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Reply to Roberts et al.: Faith in no fishery impact on New Zealand sea lions based on misunderstandings and unsubstantiated claims [Biological Sciences]

In Meyer et al. (1), we fitted a Bayesian state-space Gompertz population model to assess whether the implementation of sea lion exclusion devices (SLEDs) in trawl fisheries has served to protect New Zealand sea lions (NZSLs) or obscured ongoing mortality. We found strong evidence of obscured ongoing mortality. Roberts et...

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Suppression of convective precipitation by elevated man-made aerosols is responsible for large-scale droughts in north China [Physical Sciences]

It has been proposed that the summer "South Flood–North Drought" (SFND) pattern observed in China over recent decades is caused by the relative impacts of global warming, aerosol loading, and natural variability on regional rainfall (1–3). This conclusion is supported by a recent study by Day et al. (4) in...

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No evidence of cryptic bycatch causing New Zealand sea lion population decline [Biological Sciences]

In PNAS, Meyer et al. (1) analyze whether exclusion devices in trawl nets contributed to New Zealand sea lion (NZSL; Phocarctos hookeri) population decline at the Auckland Islands. We refute the primary conclusion from their correlative assessment: that annual pup production changes (as a measure of population size) were primarily...

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Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson’s disease [Neuroscience]

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the...

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Correction for Mitchell et al., Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation [Correction]

SYSTEMS BIOLOGY Correction for "Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation," by Simon Mitchell, Koushik Roy, Thomas A. Zangle, and Alexander Hoffmann, which was first published March 7, 2018; 10.1073/pnas.1715639115 (Proc Natl Acad Sci USA 115:E2888–E2897). The authors wish to note the following: "We have become aware that...

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Correction for Negron-Oyarzo et al., Coordinated prefrontal-hippocampal activity and navigation strategy-related prefrontal firing during spatial memory formation [Correction]

NEUROSCIENCE Correction for "Coordinated prefrontal–hippocampal activity and navigation strategy-related prefrontal firing during spatial memory formation," by Ignacio Negrón-Oyarzo, Nelson Espinosa, Marcelo Aguilar, Marco Fuenzalida, Francisco Aboitiz, and Pablo Fuentealba, which was first published June 18, 2018; 10.1073/pnas.1720117115 (Proc Natl Acad Sci USA 115:7123–7128). The authors note that the author name...

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Correction to Supporting Information for Potting et al., Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy [SI Correction]

CELL BIOLOGY Correction to Supporting Information for "Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy," by Christoph Potting, Christophe Crochemore, Francesca Moretti, Florian Nigsch, Isabel Schmidt, Carole Manneville, Walter Carbone, Judith Knehr, Rowena DeJesus, Alicia Lindeman, Rob Maher, Carsten Russ, Gregory McAllister, John S....

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Circadian clock protein BMAL1 regulates IL-1{beta} in macrophages via NRF2 [Immunology and Inflammation]

A variety of innate immune responses and functions are dependent on time of day, and many inflammatory conditions are associated with dysfunctional molecular clocks within immune cells. However, the functional importance of these innate immune clocks has yet to be fully characterized. NRF2 plays a critical role in the innate...

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Bistable emergence of oscillations in growing Bacillus subtilis biofilms [Biophysics and Computational Biology]

Biofilm communities of Bacillus subtilis bacteria have recently been shown to exhibit collective growth-rate oscillations mediated by electrochemical signaling to cope with nutrient starvation. These oscillations emerge once the colony reaches a large enough number of cells. However, it remains unclear whether the amplitude of the oscillations, and thus their...

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Chance, long tails, and inference in a non-Gaussian, Bayesian theory of vocal learning in songbirds [Neuroscience]

Traditional theories of sensorimotor learning posit that animals use sensory error signals to find the optimal motor command in the face of Gaussian sensory and motor noise. However, most such theories cannot explain common behavioral observations, for example, that smaller sensory errors are more readily corrected than larger errors and...

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Closely packed, low reorganization energy {pi}-extended postfullerene acceptors for efficient polymer solar cells [Chemistry]

New organic semiconductors are essential for developing inexpensive, high-efficiency, solution-processable polymer solar cells (PSCs). PSC photoactive layers are typically fabricated by film-casting a donor polymer and a fullerene acceptor blend, with ensuing solvent evaporation and phase separation creating discrete conduits for photogenerated holes and electrons. Until recently, n-type fullerene acceptors...

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Macrophages release plasma membrane-derived particles rich in accessible cholesterol [Medical Sciences]

Macrophages are generally assumed to unload surplus cholesterol through direct interactions between ABC transporters on the plasma membrane and HDLs, but they have also been reported to release cholesterol-containing particles. How macrophage-derived particles are formed and released has not been clear. To understand the genesis of macrophage-derived particles, we imaged...

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Decreasing fire season precipitation increased recent western US forest wildfire activity [Earth, Atmospheric, and Planetary Sciences]

Western United States wildfire increases have been generally attributed to warming temperatures, either through effects on winter snowpack or summer evaporation. However, near-surface air temperature and evaporative demand are strongly influenced by moisture availability and these interactions and their role in regulating fire activity have never been fully explored. Here...

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Rapid diffusion-state switching underlies stable cytoplasmic gradients in the Caenorhabditis elegans zygote [Developmental Biology]

Protein concentration gradients organize cells and tissues and commonly form through diffusion away from a local source of protein. Interestingly, during the asymmetric division of the Caenorhabditis elegans zygote, the RNA-binding proteins MEX-5 and PIE-1 form opposing concentration gradients in the absence of a local source. In this study, we...

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Morphological intelligence counters foot slipping in the desert locust and dynamic robots [Engineering]

During dynamic terrestrial locomotion, animals use complex multifunctional feet to extract friction from the environment. However, whether roboticists assume sufficient surface friction for locomotion or actively compensate for slipping, they use relatively simple point-contact feet. We seek to understand and extract the morphological adaptations of animal feet that contribute to...

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Metastatic cells are preferentially vulnerable to lysosomal inhibition [Medical Sciences]

Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A1, which are inhibitors...

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Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells [Applied Biological Sciences]

Variations in a multitude of material microenvironmental properties have been observed across tissues in vivo, and these have profound effects on cell phenotype. Phenomenological experiments have suggested that certain of these features of the physical microenvironment, such as stiffness, could sensitize cells to other features; meanwhile, mechanistic studies have detailed...

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Phospholipid retention in the absence of asymmetry strengthens the outer membrane permeability barrier to last-resort antibiotics [Microbiology]

The outer membrane of Gram-negative bacteria is a critical barrier that prevents entry of noxious compounds. Integral to this functionality is the presence of lipopolysaccharide (LPS) or lipooligosaccharide (LOS), a molecule that is located exclusively in the outer leaflet of the outer membrane. Its lipid anchor, lipid A, is a...

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Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials [Applied Biological Sciences]

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2−14 y (CYD14) and 9−16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence...

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The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells

Abstract

Epithelial tissues cover most of the external and internal surfaces of the body and its organs. Inevitably, these tissues serve as first line of defence against inorganic, organic, and microbial intruders. Epithelial cells are the main cell type of these tissues. Besides their function as cellular barrier, there is growing evidence that epithelial cells are of particular relevance as initial sensors of danger and also as executers of adequate defence responses. These cells feature various essential functions to maintain tissue integrity in health and disease. In this review, we survey some of the different innate immune functions of epithelial cells in mucosal tissues being constantly exposed to a plethora of harmless contaminants but also of pathogens. We discuss how epithelial cells avoid inadequate immune responses in such conditions. In particular, we will focus on the diverse types and mechanisms of phagocytosis used by epithelial cells to not only maintain homeostasis but to also harness the host response against invading pathogens.



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Correction to: Effect of Stimulus Polarity on Detection Thresholds in Cochlear Implant Users: Relationships with Average Threshold, Gap Detection, and Rate Discrimination

The middle initial of Julie G. Arenberg's name was incorrect in the original publication; it is correct as displayed here.



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Congenital Syphilis—Still a Shadow on the Land

The US Surgeon General, Thomas Parran, chose an ominous phrase—Shadow on the Land—as the title of his best-selling book about syphilis, published in 1937. It was not without reason. At the time, according to Parran, nearly 700 000 Americans were being treated for syphilis, constituting only a fraction of the approximately 1.7 million that he estimated needed treatment. At least 500 000 new infections occurred in the United States each year, Parran stated, including 60 000 cases of congenital syphilis. Cardiovascular syphilis claimed 40 000 lives each year. The arsenic-containing compound salvarsan, supplemented with mercury or bismuth, was the most effective treatment. Syphilis, Parran wrote, was "the most urgent public health problem in this country today."(p52)

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Druckdolenter, subkutaner Tumor an der Handinnenfläche



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Effects of double‐dose intranasal corticosteroid for allergic rhinitis: a systematic review and meta‐analysis

International Forum of Allergy &Rhinology, EarlyView.


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Ultrasonographic assessment of the lens

Description 

B scan ultrasonography is the most commonly used modality for the assessment of posterior segment pathologies.1–3 On placing the probe along the lateral longitudinal axis, the nasal aspect of the retina, ciliary body, the lens in its entirety, iris, angle and peripheral cornea can be appreciated easily. Using this technique, the anatomy of the lens can be studied in terms of its width along the horizontal and anteroposterior extent; similarly, by placing the probe along the inferior longitudinal axis, the vertical width of the lens can be defined, along with the anteroposterior thickness. This technique helps in the assessment of lens in its entirety, from the anterior capsule to the posterior capsule. Herein few pathologies of the lens and its capsule are illustrated using B scan ultrasound (Sonomed, New York, USA).

After making the patient lie down in a comfortable supine...



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First report of concomitant pheochromocytoma and duodenal neuroendocrine tumour in a sporadic multiple endocrine neoplasia type 1

A 77-year-old woman was diagnosed with pheochromocytoma followed by adrenalectomy at age 57. Hyperparathyroidism without osteoprosis was diagnosed at age 58. At age 75, Dual Energy X-ray Absoptiometry (DEXA) revealed osteoporosis and sestamibi scan showed a left parathyroid adenoma. Criteria for parathyroidectomy were met, and she underwent parathyroidectomy. Furthermore, she presented with haematochezia at age 75. An abdominal CT demonstrated a mass in the second portion of the duodenum. Additionally, octreoscan revealed somatostatin receptor positive tissue in the duodenum and Gallium 68 dotatate scan also showed a well-differentiated duodenal neuroendocrine tumour (NET). Genetic testing for MEN1, MEN2 and MEN4 was negative. Diagnosis of sporadic MEN1 syndrome was made. The patient underwent resection of the duodenal NET at age 76. She is in good health 21 years after her first presentation of MEN1. In summary, we present the first sporadic case of MEN1 with concomitant pheochromocytoma and duodenal NET which occurred 20 years apart.



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Mumps presenting with unilateral, synchronous parotid and submandibular gland swelling

A previously healthy 22-year-old woman presented with acute, unilateral facial and neck swelling, associated with fever and malaise. She was initially treated with intravenous antibiotics; however, CT imaging showed unilateral, synchronous swelling and inflammation of the parotid and submandibular glands, and a PCR swab from the parotid duct was positive for mumps. She was fully immunised and had no contact in the preceding period with anyone diagnosed with mumps. She responded to supportive management and her symptoms resolved over the course of her admission. Unilateral, synchronous swelling and severe inflammation of both the parotid and submandibular glands in mumps is a very unusual presentation, and not one previously reported in the literature.



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Management of a giant uterine leiomyoma

Uterine leiomyomas are the most common tumours arising from the female reproductive tract. However, giant myomas, which are greater than 11.4 kg in weight, are exceedingly rare. They may cause a pressure effect on surrounding organs, heart and lungs, which can be potentially life threatening. We present a case of a 53-year-old woman with a massive uterine mass complicated by restrictive lung disease. She underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy with frozen section and reconstruction of the abdominal wall by the gynaecologists and plastic surgeons. The excised specimen weighed 27.8 kg, which included a benign subserosal leiomyoma measuring 64 by 50.5 by 15 cm. Intraoperative blood loss was 7 L and her postoperative recovery was complicated by coagulopathy and haemorrhagic shock. This case illustrates the pivotal role of multidisciplinary care in the management of complicated surgical patients and the need for careful perioperative care.



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Vacuum-assisted right atrial infected clot extraction due to persistent bacteraemia: a percutaneous approach for the management of right-sided endocarditis

A 56-year-old woman with non-ischaemic cardiomyopathy with implantable cardioverter defibrillator (ICD) presented to the hospital with progressive dyspnoea of 4 weeks' duration. She soon spiralled down to develop septic shock with methicillin-sensitive Staphylococcus aureus bacteraemia. A transoesophageal echocardiogram revealed a 2.4x2.1 cm large mobile echodensity in the right atrium likely attached to the ICD lead and to the interatrial septum. Although the ICD along with its leads was extracted, bacteraemia persisted despite appropriate antibiotic therapy. Because of her worsening condition, she underwent a right atrial infected clot extraction by the AngioVac system. Her clinical condition noticeably improved soon after evacuation of the infected clot.



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Laryngopyocoele with contralateral laryngocoele: a rare cause of respiratory distress

We present the case of a 76-year-old patient who attended our emergency department with signs of sepsis and severe respiratory distress. She had stridor, type 1 respiratory failure and a left-sided neck swelling. On CT, it was initially misdiagnosed as parapharyngeal abscess. When the imaging was reviewed, it was found to be a left-sided mixed laryngopyocoele obstructing the larynx with an asymptomatic contralateral laryngocoele. The internal component of the left laryngopyocoele was excised through a microlaryngoscopy approach while the external component was approached through a transcervical incision. The patient recovered well despite a postoperative myocardial infarction. Both laryngocoeles and laryngopyocoeles are rare, with the latter being the rarer of the two, however, extensive literature review could not identify any previous cases where both have coexisted in the same patient.



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Hereditary sensory and autonomic neuropathy in a male child: 'The other side of not feeling pain

Description 

A 1-year-old boy was brought to our outpatient department with complaints of whitish opacity in both eyes noticed 3 months ago. The mother also gave a history of self-mutilating behaviour in the child. There was a history of absence of crying during vaccination. There was no history of consanguinity and a similar disease in the family. The child was following light binocularly. On anterior segment examination, bilateral corneal scarring secondary to keratitis was seen (figure 1A). Corneal sensations were absent. An ocular ultrasonography was done for posterior segment evaluation, which revealed no abnormalities. There were signs of self-mutilation in the perioral area in form of damage to both upper and lower lips that caused as a result of repeated insults in form of tooth bite (figure 1B). Apart from this, similar injuries were present in fingers of hands (figure 1C) as...



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Atypical presentation of acute aortic dissection in a young competitive rower

A 27-year-old man (who is also the lead author) presented with dull pain deep to the suprasternal notch, following a period of intense exercise (rowing). He was initially sent home with no diagnosis, but 24 hours later returned to a different Accident & Emergency (A&E), due to continued discomfort and an increasingly altered mental state, and was diagnosed with an extensive type A aortic dissection extending from the aortic root to the iliac bifurcation of the aorta, with an ~8 cm aneurysm on the ascending aorta and a diseased aortic valve. Following emergency surgery to replace the aortic valve and the aorta from the aortic root to the middle of the aortic arch (hemiarch), the patient recovered well.



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Missed ureteral injury in a young man with stab injury

Description 

An 18-year-old man was referred to us from the department of emergency surgery for management of his ureteric injury. The patient underwent exploratory laparotomy for bowel injury that he had sustained due to a stab wound to his left flank 1 month ago. At that time his ureteric injury was missed. Two weeks after being discharged he developed fever and his ultrasonogram was suggestive of a large left retroperitoneal collection with mild left hydronephrosis. A contrast-enhanced CT (CECT) scan was done that demonstrated leak of contrast from left ureter into the collection (figure 1A). The patient then underwent insertion of a percutaneous nephrostomy tube into the left kidney along with placement of a drain into the retroperitoneal collection. The drain placed into the collection had purulent output suggesting an infected urinoma. Two weeks later another CECT scan was done, which showed persistent retroperitoneal urinoma, and ureter...



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Typhoid fever with isolated left lateral rectus palsy

A 17-year-old young woman presented to Patan Hospital, Kathmandu, Nepal, with high-grade fever and headache for 4 days and non-projectile vomiting for 1 day. She also had blurred vision with dizziness on and off. There was no abnormal physical finding. Enteric fever was suspected, and she was empirically started on azithromycin (20 mg/kg) for 7 days. She became afebrile after 2 days and was followed up in 7 days with diplopia since 5 days. At this time, the blood culture was positive for Salmonella serovar typhi. On examination, there was isolated left lateral rectus palsy which accounted for her diplopia. Methylprednisolone (1 mg/kg) was prescribed which was tapered over 1 month and gradually her diplopia subsided. We hypothesise that vasculitic change in the blood vessel supplying the left abducens nerve could be causing the diplopia.



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Clear cell chondrosarcoma of the larynx

Chondrosarcomas represent a group of malignant tumours composed of cells producing cartilage, and clear cell chondrosarcomas (CCC) represent a variant of these. A rare case of a laryngeal CCC is presented. The patient was a 70-year-old man who presented with a 6-week history of throat pain, worsening dysphonia and a lump in the neck. Examination revealed a level 3 neck mass and positron emission tomography imaging revealed a metabolically active right laryngeal mass. Biopsies revealed a cartilaginous neoplasm. The patient underwent total laryngectomy, and the pathology confirmed CCC of the larynx. Chondrosarcomas are the most common type of sarcoma in the larynx but the CCC variant is rare. CCC are usually low-grade tumours affecting long bones, with a male predominance. Less than six cases have been described in the literature affecting the larynx. Management of these malignancies is complete surgical excision given the high risk of local recurrence.



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Double pylorus

Description 

A 69-year-old man with a past medical history of asthma, chronic back pain and hypertension presented with symptoms of light headedness, epigastric pain and blood-mixed bowel movement of 2 days duration. Since the past 9 months the patient had been taking two to three pills of ibuprofen almost on a daily basis for his back pain. He had also received short courses of prednisone tablets frequently in the last 6 months for his poorly controlled asthma. On arrival in the emergency room, his blood pressure was 84/48 mm Hg, heart rate 121/min, respiratory rate 18/min, temperature 36°C and oxygen saturation was 94% on room air. His haemoglobin (Hb) was 7.2 mg/dL. The patient was given proton pump inhibitor (PPI) therapy, volume resuscitated and was admitted to the intensive care unit. After 2 units of packed red blood cell transfusion his Hb was 9.1 mg/dL. He underwent upper gastrointestinal (GI) endoscopy which showed two openings into...



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Incidentally detected adrenocortical carcinoma in familial adenomatous polyposis: an unusual presentation of a hereditary cancer syndrome

Description 

A 30-year-old woman presented to us with complaints of intermittent bleeding per rectum, vague abdominal pain and altered bowel habits for last 3 months. There was no history of headache, palpitations, diarrhoea, weight loss, skin lesions, haematuria and hypertension. Her grandmother had history of colostomy for acute intestinal obstruction and died of unexplained cause at age of 55 years. Her laboratory investigations were normal. On digital rectal examination, multiple polypoidal firm masses were felt approximately 1–5 cm from anal verge. On colonoscopy, number of polyps were seen in the colon around 40–50 in number, ranging from few millimetres to largest measuring around 3 cm. These polyps spread over ascending to sigmoid colon and rectum in increasing number. The biopsy from these polyps was suggestive of tubular adenomas. A definitive diagnosis of familial adenomatous polyposis (FAP) was made. FAP is associated with a myriad of presentations, and hence, a thorough work...



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