Medicine by Sfakianakis Alexandros: 07/09/18

Δευτέρα 9 Ιουλίου 2018

Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluoxetine

The SHANK2 gene codes for a protein involved in organising the postsynaptic density and disruptions have been associated with autism spectrum disorders (ASDs). ASDs are frequently comorbid with intellectual disability and anxiety disorders and emerging evidence suggests potentially common aetiologies. Here, we report the case of an 18-year-old man with ASD who presented with severe anorexia due to fear of food contamination, food avoidance and stereotypies attributable to underlying obsessive compulsive disorder (OCD). The patient was found to be heterozygous for c.2518C>T (p.Pro840Ser), a likely damaging coding variant in the proline rich region of SHANK2. Interestingly, the patient's disordered eating behaviour began to improve only after high-dose fluoxetine was initiated to target OCD symptoms. Overall, this case highlights the utility of molecular genetic testing in clinical psychiatry and provides an example of how genetic information can inform clinicians in the treatment of complex neuropsychiatric syndromes.

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Extremely common radiographic finding of cochlear nerve deficiency among infants with prelingual single-sided deafness and its clinical implications

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Woongsang Sunwoo, Won-Wook Lee, Byung Yoon Choi

Abstract

Objectives

To clarify the common radiographic findings of audiologically documented prelingual single-sided deafness (SSD) and identify the prevalence of cochlear nerve deficiency (CND) in SSD infants referred from the newborn hearing screening program.

Methods

Between March 2012 and March 2017, the records of all infants referred to our otology clinic after undergoing newborn hearing screening program were retrospectively reviewed. Twenty-four consecutive well infants without risk factors who had a confirmed diagnosis of prelingual SSD under the age of 1 year and who underwent internal auditory canal (IAC) magnetic resonance imaging (MRI) were included. The sizes of cochlear nerve (CN), IAC, and cochlear nerve canal (CNC) were measured on MRI. The presence of CND was visually determined by comparing the CN size to the ipsilateral facial nerve (FN) in the affected side via an oblique sagittal view of IAC MRI and defined when CN was absent or smaller than FN.

Results

CND was seen in all 24 deaf ears (100%) on MRI. There was one with incomplete partition type I, and another with combined cochleovestibular nerve absence. Twenty-four subjects demonstrated either an absent (20/24, 83.3%) or small (4/24, 16.7%) CN. When the absent and small CN groups were compared, the former group had a higher prevalence of narrow CNC and narrow IAC. Of the 20 infants without identifiable CN on the affected side, 17 (85%) had narrow IAC and 17 (85%) had narrow CNC. In the 20 ears with absent CN, only one had both normal-sized IAC and CNC.

Conclusion

The contribution of CND to prelingual SSD in Korean infants reached 100%, according to IAC MRI alone.

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Pediatric vestibular testing: Tolerability of test components in children

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Peter J. Ciolek, Elise Kang, Julie A. Honaker, Erika A. Woodson, Brandon S. Hopkins, Samantha Anne

Abstract

Introduction

Objective of the study is to define rates of successful completion of components of pediatric vestibular testing (VT).

Methods

Retrospective review of VT performed on patients less than 18 years of age from 2004 to 2015.

Results

188 pediatric patients (mean age: 13.9 ± 3.56 years old, range 2–17 years) underwent testing. Thirty-five (18.6%) had abnormal test results. Pediatric patients unable to complete all aspects of VT could still complete an average of 7.9 ± 4.0 of 12 test components. The optokinetic tracking test was the most commonly omitted component of the vestibular tests. In a multivariate analysis, failure to perform Nylen-Barany positional testing (χ² 27.5, p < 0.0001) or Dix-Hallpike (5.66, p = 0.0174) testing was associated with inability to obtain final diagnosis on VT.

Conclusions

Interpretable VT may be obtained in most children, even in those that do not tolerate the full testing protocol. Spontaneous and gaze-evoked nystagmus testing maybe considered as part of initial testing protocol before attempting less well-tolerated components such as bithermal calorics or components that require VNG goggles.

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Two novel homozygous missense mutations identified in the BSND gene in Moroccan patients with Bartter's syndrome

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Soukaina Elrharchi, Zied Riahi, Sara Salime, Halima Nahili, Hassan Rouba, Mostafa Kabine, Crystel Bonnet, Christine Petit, Abdelhamid Barakat

Abstract

Objectives

Hearing loss (HL) is one of the most common sensorineural disorders. In the present study, we identified two novel missense mutations in BSND gene causing Bartter syndrome type IV which is a genetic disease with an autosomal recessive transmission, characterized by hypokalaemia, metabolic alkalosis, an elevation in plasma renin activity and hyperaldosteronism as well as sensorineural deafness.

Methods

Whole-exome sequencing was performed to study the genetic causes of Hearing loss in two unrelated patients from two Moroccan families.

Results

The two novel homozygous mutations p.Arg8Gly (c.22C > G), p.Thr36Asn (c.107C > A) in exon 1 of BSND gene which encodes barttin were identified in 7 patients belonging to two unrelated families originated from central region of Morocco.

Conclusion

We identified two novel missense mutations p.Arg8Gly and p.Thr36Asn in exon 1 of BSND gene; both mutations were described for the first time in Moroccan patients with Bartter syndrome type IV.

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Decreased disulphide/thiol ratio in patients with autosomal recessive non-syndromic hearing loss

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Burhan Balta, Ramazan Gundogdu, Murat Erdogan, Murat Alisik, Aslihan Kiraz, Ibrahim Ozcan, Ozcan Erel

Abstract

Introduction

Oxidative stress plays a key role in the formation of age-related, noise-induced and drug-induced hearing loss. Thiols are organic compounds which can react with free radicals to protect against tissue and cell damage caused by reactive oxygen. There are no studies in literature on the association between autosomal recessive non-syndromic hearing loss(ARNSHL) including GJB2 and non-GJB2 mutations and thiol-disulphide balance. In this study, we aim to assess whether thiol-disulphide balance is disrupted in patients with ARNSHL.

Methods

Thirty-one ARNSHL patients and thirty-one healthy controls were included in this study. Patients whose parents were first degree cousins and who had at least two congenital hearing loss in the same family were included in the study. Audiological tests included air - bone pure tone audiometry and auditory brain stem response. GJB2 gene analysis was performed using sanger sequence method. Tests of thiol/disulphide homeostasis were conducted using the automated spectrophotometric method. We first investigated whether there was a significant difference between ARNSHL patients and healthy controls. Then, in order to determine the differential effect of the GJB2 gene mutations and non-GJB2 gene mutations on the thiol-disulphide balance, subjects were divided into three groups: Group 1 included patients with GJB2 mutations; Group 2 included patients with non-GJB2 mutations; Group 3 included healthy subjects.

Results

Patients with ARNSHL had significantly higher native thiol (411.6 ± 54.3 μmol/l vs. 368.0 ± 64.3 μmol/l, p = 0.006), total thiol levels (440.3 ± 56.2 μmol/l vs. 402.4 ± 65.9 μmol/l, p = 0.018), and lower disulphide levels (14.3 ± 5.7 μmol/l) vs. (17.1 ± 4.9 μmol/l), (p = 0.043) compared to the control group. Moreover, disulphide /native thiol (p < 0.001) and disulphide/total thiol (p < 0.001) were also detected lower in the ARNSHL group compared to the control group. Thiol-disulphide hemostasis parameters between all three groups showed that the native thiol and total thiol were increased in the Group 1 and Group 2. The disulphide levels decreased in Group 1 and 2, although not statistically significant.

Conclusion

It was shown that thiol levels increased and disulphide levels decreased in patients with autosomal recessive non-syndromic hearing loss. It also may suggest that there is a reverse association between ARNSHL and oxidative stress. Further studies are needed on whether or not ARNSHL cause oxidative stress limited to the inner ear and cochlea.

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Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases

Publication date: Available online 10 July 2018

Source: Clinical Immunology

Author(s): Eric Espinosa, Salvatore Valitutti, Michel Laroche, Camille Laurent, Pol André Apoil, Olivier Hermine, Michel Lavit, Carle Paul, Cristina Bulai Livideanu

Abstract

There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2).

We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

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Nasenseptumplastik und Nasenmuschelbehandlung – ambulant oder stationär?

Laryngo-Rhino-Otol 2018; 97: 450-452
DOI: 10.1055/a-0621-2108

Menezes AS et al. Septal and turbinate surgery: is overnight essential? Eur Arch Otorhinolaryngol 2018; 275: 131–138 Die ambulante Operation von Nasenscheidewand und Nasenmuschel ist zunehmende Praxis. Allerdings wird dieses Thema kontrovers diskutiert. Portugiesische Kopf- und Halschirurgen überprüften anhand eigener Daten, mit welchen unerwarteten Krankenhauswiederaufnahmen und Komplikationen zu rechnen ist.
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Welche Behandlung wirkt beim Hörsturz am besten?

Laryngo-Rhino-Otol 2018; 97: 448-449
DOI: 10.1055/a-0621-2081

Ashtiani MK at al. Efficacy of systemic and intratympanic corticosteroid combination therapy versus intratympanic or systemic therapy in patients with idiopathic sudden sensorineural hearing loss: a randomized controlled trial. Eur Arch Otorhinolaryngol 2018; 275: 89–7 Iranische HNO-Ärzte verglichen die Heilungsraten einer Behandlung des idiopathischen Hörsturzes mit oralen und intratympanalen Kortikosteroidgaben in Mono- und Kombinationstherapien.
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Prävention von Stimmstörungen

Laryngo-Rhino-Otol 2018; 97: 453-454
DOI: 10.1055/a-0626-8754

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Schonende Operationstechnik beim Attikcholesteatom vielversprechend

Laryngo-Rhino-Otol 2018; 97: 449-450
DOI: 10.1055/a-0588-9272

Presutti L et al. The Impact of the Transcanal Endoscopic Approach and Mastoid Preservation on Recurrence of Primary Acquired Attic Cholesteatoma. Otol Neurotol 2018; 39: 445–450 Die chirurgische Behandlung eines Attikcholesteatoms ist anspruchsvoll und über eine optimale Strategie wird aktuell immer noch diskutiert. Wissenschaftler haben nun untersucht, welche Faktoren einen Einfluss auf postoperative Erkrankungen eines primär erworbenen Attikcholesteatoms haben. Die Autoren nahmen an, dass minimalinvasiv, schleimhautschonende Operationstechniken einen positiven Effekt auf die Ergebnisse in Bezug auf Rezidive haben.
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„Plastische Gesichtschirurgie – Hautdefekte und Wundversorgung“

Laryngo-Rhino-Otol 2018; 97: 453-453
DOI: 10.1055/a-0625-8508

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Akute Kehlkopfentzündung

Laryngo-Rhino-Otol 2018; 97: 455-456
DOI: 10.1055/a-0589-3229

Durch die akute Laryngitis wird die Stimme heiser und ist in ihrer Leistungsfähigkeit herabgesetzt. Stimmruhe ist die sicherste Methode, Folgeschäden durch weitere Belastung zu vermeiden.
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Aus der Gutachtenpraxis: Objektive Diagnostik mithilfe von Chirp-Stimuli bei stationären auditorischen Potenzialen (ASSR) in der Begutachtung von Hörstörungen

Laryngo-Rhino-Otol 2018; 97: 493-496
DOI: 10.1055/a-0589-3251

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Update Schwangerschaftsrhinitis

Laryngo-Rhino-Otol 2018; 97: 457-464
DOI: 10.1055/a-0589-3218

Als sog. Schwangerschaftsrhinitis (SSR) wird eine mehrwöchige, schwangerschaftsbegleitende nasale Obstruktion bezeichnet, die sich durch eine Schwellung der Mukosa sowie vermehrte Sekretion ohne Hinweis auf eine Entzündung, Infektion, Allergie oder Raumforderung auszeichnet und deren Symptome nach der Geburt rasch wieder verschwinden. Die SSR zählt zu den endokrinen nasalen Hyperreaktivitäten. Etwa ein Viertel aller Schwangeren ist von diesem Krankheitsbild betroffen, das zu jedem Zeitpunkt der Schwangerschaft auftreten kann. Pathophysiologisch werden vor allem hormonelle Einflüsse diskutiert, Rauchen sowie eine vorbestehende Hausstaubmilbenallergie gelten als Risikofaktoren. Nachfolgend stellen wir ein stufentherapeutisches Konzept für die Behandlung der SSR vor und diskutieren die aktuelle Literatur.
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Otitis media – Definition, Pathogenese, Klinik, Diagnose und Therapie

Laryngo-Rhino-Otol 2018; 97: 497-508
DOI: 10.1055/s-0044-101327

Unter dem Begriff Otitis media werden die akute Otitis media, die rezidivierende akute Otitis media, die Otitis media mit Erguss, die chronische Otitis media mesotympanalis und die chronische Otitis media epitympanalis, das Cholesteatom, zusammengefasst. Es handelt sich um vielfältige Krankheitsbilder, die teils ineinander übergehen können und eine individuell angepasste, zielgerichtete Therapie erfordern.
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Fragen für die Facharztprüfung

Laryngo-Rhino-Otol 2018; 97: 509-510
DOI: 10.1055/a-0589-3262

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Rhinoplastik

Laryngo-Rhino-Otol 2018; 97: 511-513
DOI: 10.1055/a-0589-3316

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Kommentar der Schriftleitung

Laryngo-Rhino-Otol 2018; 97: 444-445
DOI: 10.1055/a-0589-3196

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Contributors

SUJANA S. CHANDRASEKHAR, MD

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Sujana S. Chandrasekhar

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Forthcoming Issues

Nasal Obstruction

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Age-Related Deficits in Taste and Smell

Disturbances in both the ability to smell and to taste are common in older persons. Such disturbances influence nutrition, safety, quality of life, and psychological and physical health. The anatomic and physiologic causes of age-related disturbances are multiple and interacting, and depend on genetic and environmental factors. Frank losses of function, distortions, and hallucinations are common. Most distortions resolve over time, although this can take months or even years. Olfactory dysfunction occurs during the earliest stages of several neurologic disorders, most notably Alzheimer's disease and Parkinson's disease, likely heralding the onset of the underlying pathologies.

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ELSEVIER

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Geriatric Otolaryngology

According to the US census publications, the US population is expected to grow by 27% between 2012 and 2050, which would be an increase from 314 million to 400 million. About 80 million in the US are expected to be over 65 years old. The projection of increased elderly population is due to several factors: increase in life expectancy, decrease in mortality, and decrease in fertility. As such, the recognition of the geriatric patient with otolaryngologic problems will present some unique challenges.

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Geriatric Otolaryngology

OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA

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Effect of cumulative intravenous voriconazole dose on renal function in hematological patients [PublishAheadOfPrint]

The intravenous voriconazole (VRC) is formulated by the incorporation of sulfobutylether-β-cyclodextrin (SBECD), which may accumulate to adversely affect renal function. However, the effect of long-term use of intravenous VRC on renal function is unclear. Our retrospective data confirmed that worsening of renal function was significantly associated with cumulative dose of intravenous VRC (≥ 400mg/kg), suggesting that a higher cumulative dose of intravenous VRC was a risk factor for renal dysfunction.

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ROLE OF ASCORBIC ACID AS SUPPORTING IN THE THERAPEUTIC OF CHAGAS DISEASE: BENEFITS IN THE ASSOCIATION WITH LOW DOSE OF BENZNIDAZOLE [PublishAheadOfPrint]

The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen and nitrogen species (ROS and RNS, respectively). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds Benznidazole (BZ) and Nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of Trypanosoma cruzi, leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous and the use of BZ in low doses associated with antioxidants, as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our in vivo studies, mice receiving the combination AA(7.14mg/kg/day)+BZ10(10mg/kg/day) showed a reduction in parasitemia more effective than those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA associated with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.

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Echinocandin treatment of Candida albicans biofilms enhances neutrophil extracellular trap (NET) formation. [PublishAheadOfPrint]

The nosocomial pathogen Candida albicans forms biofilms on medical devices that persist in the face of antifungals and host defenses. Echinocandins, the most effective anti-biofilm drugs, have recently been shown to augment the activity of neutrophils against biofilms through an unknown mechanism. Here we show that treatment of C. albicans biofilms with sub-inhibitory concentrations of echinocandins promotes the formation of neutrophil extracellular traps (NETs), structures of DNA, histones, and antimicrobial proteins with antifungal activity.

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Synergy between circular bacteriocin AS-48 and ethambutol against Mycobacterium tuberculosis [PublishAheadOfPrint]

The increasing incidence of multi-drug resistant Mycobacterium tuberculosis and the very few drugs available for treatment is promoting the discovery and development of new molecules that could help in the control of this disease. Bacteriocin AS-48 is an antibacterial peptide produced by Enterococcus faecalis, active against several Gram-positive bacteria. We have found that AS-48 was active against Mycobacterium tuberculosis, including H37Rv and other reference and clinical strains, and also against some non-tuberculous clinical mycobacterial species. The combination of AS-48 with either lysozyme or with ethambutol (commonly used in the treatment of drug susceptible tuberculosis) increased the antituberculosis action of AS-48, showing a synergic interaction. Under these conditions, AS-48 exhibits a MIC close to some of the first-line antituberculosis agents. The inhibitory activity of AS-48 and its synergistic combination with ethambutol was also observed on M. tuberculosis infected macrophages.

Finally, AS-48 did not show any cytotoxicity against THP-1, MHS and J774.2 macrophage cell lines, at concentrations close to its MIC. In summary, bacteriocin AS-48 has an interesting antimycobacterial activity in vitro and low cytotoxicity, so further studies in vivo will contribute to its development as a potential additional drug for antituberculosis therapy.

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Malaria Prophylaxis Using Naphthoquine-Azithromycin Combination: Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Protective Efficacy in Southeast Asia [PublishAheadOfPrint]

New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single-doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for two months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated without any serious adverse events. Four adverse events (transient and slight elevation of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale. These trials showed that NQAZ had a good safety profile and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

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Efficiency of Target Larvicides is Conditioned by ABC-Mediated Transport in the Zoonotic Nematode Anisakis pegreffii [PublishAheadOfPrint]

Anisakiasis is among the most significant emerging food-borne parasitoses contracted through consumption of thermally unprocessed seafood harbouring infective Anisakis spp. larvae. The efficacy of the currently applied anthelminthic therapy in humans and in model organisms has not proven sufficient, so alternative solutions employing natural compounds combined with chemical inhibitors should be explored. By testing toxicity of the natural monoterpenes nerolidol and farnesol, and conventional anthelminthics abamectin and levamisole, in the presence/absence of MK-571 and Valspodar that inhibit the ABC transporter proteins Multidrug Resistance Protein (MRP-like) and P-glycoprotein (P-gp), we determined the preliminary traits of Anisakis detoxifying mechanisms. We found that Anisakis P-gp and MRP-like transporters have a role in the efflux of the tested compounds, which could be useful in the design of novel anthelminthic strategies. Expectedly, transporter activation and efflux fluctuated over time; they were synchronously active very early post-exposure, while the activity of one transporter dominated over the other in a time-dependent manner. MRP-like transporters dominated in the efflux of farnesol and P-gp dominated in efflux of nerolidol, while both were active in effluxing levamisole. The highest toxicity was exerted by abamectin, a P-gp inhibitor per se, also eliciting the highest oxidative stress in treated Anisakis larvae. We suggest that ß-tubulin, observed for the first time as a core element in Anisakis cuticle, might represent an important target for the tested compounds.

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In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation [PublishAheadOfPrint]

Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the Odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead-optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against E. coli EN122 (ESBL) or E. coli ATCC BAA-2469 (NDM-1), achieving an ED₅₀ of 3.5 mg/kg and 1-, 2- and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a UTI model of E. coli UTI89, urine, bladder and kidney burdens were reduced by 2.39, 1.96, and 1.36 log₁₀ CFU/ml, respectively, after injecting 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or HRPT cells, no inhibition of hERG-CHO or Nav 1.5 -HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile.

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Repurposing strategy of atorvastatin against Trypanosoma cruzi: in vitro monotherapy and combined therapy with benznidazole exhibits synergistic trypanocidal activity [PublishAheadOfPrint]

Statins are inhibitors of cholesterol synthesis but other biological properties, like antimicrobial effects, have been assigned leading to the designation of their pleiotropic aspect. Our goal was investigate the activity and selectivity of atorvastatin (AVA) against T. cruzi using in vitro models aiming more effective and safer therapeutic options through drug repurposing proposals under monotherapy and in combination with benznidazole (BZ). Phenotypic screening used different strains (Tulahuen (DTU VI) and Y (DTU II)) and forms (intracellular forms, bloodstream and tissue-derived trypomastigotes) of the parasite. While assaying Tulahuen strain, AVA is more active against intracellular amastigotes (SI=3). Also, against another parasite DTU (Y strain), this statin was more active (2.1-fold) and selective (2.4-fold) against bloodstream trypomastigotes (SI=51) than upon the intracellular forms (SI=20). The cytomorphological approach using phalloidin–TRITC permitted to verify that AVA did not induced cell density reduction and CC maintained their typical cytoarchitecture. Combinatory approaches using fixed-ratio methods showed that AVA and BZ gave synergistic interactions against both trypomastigotes and intracellular forms (mean FICIs = 0.46 ± 0.12 and 0.48 ± 0.03 respectively). In this sense, the repurposing strategy of AVA, especially in combination with BZ leading to a synergic effect, encourages future studies in order to identify novel therapeutic protocols for Chagas disease treatment.

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Pharmacokinetics of ciprofloxacin in children with complicated urinary tract infection: results of a multicenter population pharmacokinetic study. [PublishAheadOfPrint]

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10-15 mg/kg body weight every 12 h) or per os (15-20 mg/kg every 12 h), were enrolled. 108 Serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range 0.31 – 15.51 years). A one-compartment model best described our data. Fat free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 – 0.43 L/h/kg of body weight, volume of distribution 0.06 – 2.88 L/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% for Pseudomonas aeruginosa, and 3% for Staphylococcus aureus, at the 15 mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat free mass and kidney function should be considered as they prove to be significant covariates for ciprofloxacin clearance and hence, exposure.

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Bioequivalence of a Fixed-Dose Combination Tablet of the Complete 2-Drug Regimen Dolutegravir and Rilpivirine for the Treatment of HIV-1 Infection [PublishAheadOfPrint]

Background: A complete 2-drug regimen of dolutegravir 50 mg and rilpivirine 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with separate tablets. Secondary endpoints were tolerability and safety of the fixed-dose combination tablet.

Methods: In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (test) and the combination of separate tablets (reference) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were area under the plasma concentration-time curve (AUC) and maximum concentration of drug (C_max). The study employed a prespecified sample-size re-estimation based on a blinded midpoint review of C_max variability to update the enrollment size to achieve statistical power.

Results: Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least squares means ratios for AUC_0-, AUC_0-t, and C_max (test vs reference) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n=5) and 3% (n=3) of participants reporting adverse events considered related to the test and reference treatments, respectively.

Conclusions: The dolutegravir/rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets and no new safety signals emerged.

https://ift.tt/2zo8SdE

Efficacy of short-course antibiotic treatments for community-acquired pneumonia in adults: A systematic review and meta-analysis [PublishAheadOfPrint]

Background: The duration of therapy for community-acquired pneumonia (CAP) remains undefined. We sought to investigate whether short-course antibiotic treatment for CAP is associated with favorable clinical outcomes in adult patients.

Methods: We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies comparing the effectiveness and safety between treatment regimens administered for ≤6 days and ≥7 days. We defined treatment for ≤6 days as "short-course" and treatment for ≥7 days as "long-course".

Results: Twenty-one clinical trials (4861 clinically evaluable patients) were included and 19 out of 21 trials were randomized. Clinical cure was similar between the compared groups [4069 patients, RR= 0.99 (95% CI, 0.97-1.01)], irrespective of patient setting (outpatient/inpatient) [RR= 0.98, (95% CI, 0.96-1.00)/RR= 1.00, (95% CI, 0.92-1.09), respectively] or severity of pneumonia [RR= 1.05, (95% CI, 0.96-1.14)]. Also, relapses were similar between short and long-course treatment groups [1923 patients, RR= 0.67 (95% CI, 0.30-1.46)]. Short-course treatment was associated with fewer serious adverse events [1923 patients, RR= 0.73 (95% CI, 0.55-0.97)] and, importantly, resulted in lower mortality compared to long-course treatment [2802 patients, RR= 0.52 (95% CI, 0.33-0.82)].

Conclusion: In CAP, short-course antibiotic treatment (≤6 days) is equally effective and potentially superior, in terms of mortality and serious adverse events, compared to longer-course treatment.

https://ift.tt/2uajTKA

HIV-1 integrase inhibitors that are broadly effective against drug-resistant mutants [PublishAheadOfPrint]

Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction, catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, Dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients.

Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had superior antiviral profiles against the mutants we tested compared to DTG.

The susceptibility profiles of 4c and 4d suggest that these compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that broadly effective in their ability to inhibit HIV-1 INs with mutations in the active site.

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Assessment of the additional value of verapamil to a moxifloxacin and linezolid combination regimen in a murine tuberculosis model. [PublishAheadOfPrint]

Favorable treatment outcome of multidrug resistant tuberculosis (MDR-TB) is only 54% and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the additional value of the efflux-pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 Log colony forming units, respectively), but sterilization was not achieved yet. The spleens of all mice were culture-negative after 12 weeks of treatment with both treatment modalities and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, p=0.017).

Concluding, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.

https://ift.tt/2ugUL4j

Multiclonal expansion and high prevalence of {beta}-lactamase-negative high-level ampicillin-resistant Haemophilus influenzae in Japan, and susceptibility to quinolones [PublishAheadOfPrint]

β-lactam-resistant Haemophilus influenzae is a clinical concern. A high prevalence (>40%) of β-lactamase-negative high-level ampicillin-resistant H. influenzae (High-BLNAR) isolates has been reported in Japan. However, the reasons for the expansion are unknown. High-BLNAR possesses an amino acid substitution, either Asn526Lys (group III) or Arg517His (group III-like) in addition to Ser385Thr, in penicillin-binding protein 3 (PBP3). To determine the current prevalence of High-BLNAR and the mechanisms behind their expansion in Japan, their prevalence, PBP3 types, multilocus sequence types, and susceptibilities to quinolones approved in Japan as alternatives were determined.

Sixty percent of H. influenzae clinical isolates (n=62/104) were BLNAR. Among BLNAR, 92% (n=57/62) were High-BLNAR. Most were classified as belonging to group III, which contained many genotypes (11 PBP3 types and 25 sequence types). These results indicate that the expansion of High-BLNAR isolates was multiclonal and still dominant in Japanese clinical setting. One High-BLNAR harbored the novel amino acid substitution Asn526Met in addition to Ser385Thr in PBP3, suggesting a new group (group IV).

No quinolone-resistant H. influenzae isolates were identified. The minimum inhibitory concentrations (MICs) of the quinolones [lsqb]moxifloxacin, garenoxacin, and tosufloxacin[rsqb] were similar to that of levofloxacin, whereas sitafloxacin exhibited a lower MIC. However, we obtained four H. influenzae isolates showing decreased quinolone susceptibility with the amino acid substitution Ser84Leu in GyrA. Three of these were High-BLNAR.

In summary, this study shows that multiclonal High-BLNAR dominates in a Japanese university hospital. Isolates remain sensitive to quinolones, but vigilance is required to prevent the development of fluoroquinolone resistance in High-BLNAR strains.

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Insights into long-term catheter-related infections by multidrug-resistant bacteria: the role of lock-therapy [PublishAheadOfPrint]

Objectives: The management of long-term central venous catheters (LTCVCs) infections by multi-drug resistant (MDR) bacteria in cancer patient is a challenger. The objectives of this study were to analyse outcomes in cancer patients with LTCVC-associated infection, identify risks for unfavourable outcomes and determine the impact of MDR bacteria and antibiotic lock therapy (ALT) in managing such infections.

Methods: We evaluated all LTCVC-associated infections treated between January 2009 and December 2016. Infections were reported in accordance with international guidelines for catheter-related infections. The outcome measures were 30-day-mortality, and treatment failure. We analysed risk factors by Cox forward-stepwise regression.

Results: We identified 296 LTCVC-associated infections, 212 (71.6%) were classified as bloodstream infections (BSIs). The most common agent was Staphylococcus aureus.46 (21.7%) infections were due to multi-drug resistant (MDR) Gram-negative.ALT was used in 62 (29.2%) patients, with a 75.9% success rate. Risk factors identified for failure of the initial treatment were having a high Sequential Organ Failure Assessment (SOFA) score at diagnosis of infection and being in palliative care; introduction of ALT at the start of treatment was identified as a protective factor. Risk factors identified for 30-day-mortality after LTCVC-associated infection were a high SOFA score at diagnosis, infection with MDR bacteria, and palliative care; introduction of ALT at the start of treatment, haematological malignancies, and adherence to an institutional protocol for the management of LTCVC-associated infection were identified as protective factors.

Conclusions: Despite the high incidence of infection with MDR bacteria, ALT improves the outcome of LTCVC-associated infection in cancer patients.

https://ift.tt/2zvVrbA

The Fungal Cyp-51 Inhibitor VT-1129 is Efficacious in an Experimental Model of Cryptococcal Meningitis [PublishAheadOfPrint]

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with C. neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28 after which mice were monitored off-therapy until day 30 or day 60, respectively, to assess survival. Fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg once daily. VT-1129 at doses of ≥ 0.3 mg/kg/day and each dose of fluconazole significantly reduced brain tissue fungal burden compared to control after both 7 and 14 days of dosing. Fungal burden was also undetectable in most mice treated with dose of ≥ 3 mg/kg/day, even ≥ 20 days after dosing had stopped in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

https://ift.tt/2u6eHr5

Prevalence and molecular characterization of Escherichia coli clinical isolates carrying mcr-1 in a Chinese teaching hospital from 2002 to 2016 [PublishAheadOfPrint]

Colistin will be gradually banned from animal feeds in China and switched to clinical human therapy in the near future (1)....

https://ift.tt/2unxIoy

In Vivo Pharmacodynamic Characterization of a Novel Antibiotic Odilorhabdins, NOSO-502 against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model [PublishAheadOfPrint]

NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indice and magnitude best correlated with efficacy in the murine thigh infection model. Six E. coli and 6 K. pneumoniae were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/L. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125 and 500 mg/kg. Pharmacokinetic studies exhibited peak concentration (C_max) values of 1.49 to 84.6 mg/L, area under the concentration-time curve (AUC_0-) values of 1.94 to 352 mg*h/L, and beta-elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses 7.81 mg/kg to 2000 mg/kg fractionated into q3-, q6-, q12-, or q24-hourly regimens. Nonlinear regression analysis demonstrated AUC/MIC was the PK/PD parameter that best correlated with efficacy (R² 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with four-fold increasing doses (range 3.91 to 1000 mg/kg) of NOSO-502 every 6 hours. The mean fAUC/MIC magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

https://ift.tt/2u3dgtF

Molecular Insights into Functional Differences Between mcr-3- and mcr-1-Mediated Colistin Resistance [PublishAheadOfPrint]

The global emergence of plasmid-mediated colistin resistance genes mcr-1 and mcr-3 has threatened the role of the "last resort" drug colistin in the defense against infections caused by multidrug-resistant Gram-negative bacteria. However, functional differences between these two genes in mediating colistin resistance remains poorly understood. Protein sequence alignment of MCR-3 and MCR-1 was therefore conducted in Clustal Omega to identify sequence divergence. The molecular recognition of lipid A head group phosphatidylethanolamine and MCR-3 enzyme was studied by homology modeling and molecular docking, with the catalytic mechanism of MCR-3 also being explored. Thr277 in MCR-3 was validated as the key amino acid residue responsible for the catalytic reaction using site-directed mutagenesis and was shown to act as a nucleophile. Lipid A modification induced by the MCR-3 and MCR-1 enzymes was confirmed by electrospray ionization time-of-flight mass spectrometry. Far-UV circular dichroism spectra of the MCR-3 and MCR-1 enzymes suggested that MCR-3 was more thermostable than MCR-1, with a melting temperature of 66.19°C compared with 61.14°C for MCR-1. These data provided molecular insight into the functional differences between mcr-3 and mcr-1 in conferring colistin resistance.

https://ift.tt/2zoDbkn

{beta}-lactam dosage regimens in septic patients with augmented renal clearance [PublishAheadOfPrint]

Augmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance, and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients with a measured creatinine clearance ≥ 120 mL/min, and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic analysis of the data was performed using the Pmetrics software package for R. 55% of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due to Pseudomonas aeruginosa. There were significant, yet weak correlations between measured creatinine clearance and trough concentrations of meropenem (r= -0.21, p=0.01), trough concentrations of piperacillin (r= -0.28, p= 0.0071), concentrations at 50% of the dosage interval (r= -0.41, p <0.0001), and total body clearance of piperacillin (r= 0.39, p= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem, but not for piperacillin. Therefore, specific PK modelling can predict certain β-lactam concentrations based on renal function, but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

https://ift.tt/2u8Plc5

Severity strata for POEM, PO-SCORAD and DLQI in US adults with atopic dermatitis

Patient-Oriented Eczema Measure (POEM) is the preferred patient-reported outcome (PRO) for assessing symptoms of atopic dermatitis (AD). Dermatology Life Quality Index (DLQI) is commonly used to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing AD symptoms, yet severity strata are not established.

https://ift.tt/2L01Jlc

Effect of chitosan nanoparticles on the inhibition of Candida spp. biofilm on denture base surface

Publication date: Available online 9 July 2018

Source: Archives of Oral Biology

Author(s): Brenna Louise Cavalcanti Gondim, Lúcio Roberto Cançado Castellano, Ricardo Dias de Castro, Giovanna Machado, Hugo Lemes Carlo, Ana Maria Gondim Valença, Fabíola Galbiatti de Carvalho

Abstract

Objectives

Chitosan nanoparticles (ChNPs) have antifungal effects, however there is a lack of information about the effects of ChNPs against Candida biofilm on denture base surface. This study investigated the ChNPs effect against C. albicans biofilm adhesion and formation, and against Candida spp. biofilm on heat-cured acrylic resin.

Design

The ChNPs were synthetized (3,800 µg/mL) and characterized by infra-red spectrophotometry and transmission electron microscopy. The minimum inhibitory/fungicidal concentrations (MIC/MFC) against Candida spp. were determined. The time-kill assay and changes on C. albicans micromorphology were evaluated. The % inhibition of ChNPs on C. albicans biofilm formation and reduction were investigated using 1 min and 8 h exposure. Candida biofilm was developed on resin surfaces and ChNPs were applied every 8 h for 5 days. After, fungal cells were counted (CFU/mL) and the surface roughness (Ra) and vickers microhardness (HV) of resin were analysed. For all experiments, sodium hypochlorite (NaOCl) was used as control. Data were analyzed by ANOVA, Tukey and paired t-tests (α = 0.05).

Results

The MIC_80% of ChNPs was 30.1 µg/mL. ChNPs at 4 MIC showed complete inhibition in the time-kill assays. Blastoconidia cells were predominant after ChNPs application. The % inhibition ChNPs on C. albicans was proportional to its concentration, regardless of the exposure time. ChNPs decreased the CFU/mL of Candida spp. and showed lower alteration of HV and Ra values of resin surface compared to NaOCl.

Conclusions

The ChNPs inhibited C. albicans biofilm, reduced Candida biofilm on resin and caused small changes in roughness and hardness of acrylic resin surface.

Graphical abstract

Graphical abstract for this article

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Severity strata for POEM, PO-SCORAD and DLQI in US adults with atopic dermatitis

Publication date: Available online 9 July 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): JI Silverberg, JM Gelfand, D Margolis, L Fonacier, M Boguniewicz, LB Schwartz, EL Simpson, M Grayson, PY Ong, ZC Chiesa Fuxench

Abstract

Background

Objective

We sought to confirm previously developed strata for POEM and DLQI, and develop strata for the PO-SCORAD in a population-based cohort of adults with AD.

Methods

A cross-sectional, population-based study of 8,217 adults was performed using a structured questionnaire. A diagnosis of AD was determined using modified UK Diagnostic Criteria for AD (N=602). AD severity was assessed using self-reported global AD severity (anchoring question), POEM, PO-SCORAD, and DLQI. Strata were selected using an anchoring approach based on patient-reported disease severity.

Results

We confirmed the existing strata for DLQI (mild=0-5, moderate=6-10, severe=11-30) (kappa=0.446). However, the preferred strata for POEM was mild=0-7, moderate=8-19 and severe=20-28 (kappa=0.409) and PO-SCORAD was mild=1-27, moderate=28-56, severe=57-104 (kappa=0.444).

Conclusion

Existing strata for DLQI performed well in a population-based cohort of adult AD. The optimal severity strata for the POEM in our AD population varies slightly from those previously published for AD. This may suggest that different strata may be optimal in different study settings and cohorts. Finally, we proposed new strata for PO-SCORAD in adult AD.

https://ift.tt/2zqQGA8

Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa

Antiandrogen therapy has been reported as an effective treatment for hidradenitis suppurativa. This study evaluated both physician and patient reported hidradenitis suppurativa severity outcomes for patients treated with spironolactone. Antiandrogen therapy with spironolactone may be a useful treatment option for reducing inflammatory lesions and pain for female patients with HS.

https://ift.tt/2m8AhXI

Surgical Pearl: A Granny Sliding Knot for High Tension Closures

https://ift.tt/2zvqkgG

Topical Glycopyrronium Tosylate for the Treatment of Primary Axillary Hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 Phase 3 Randomized Controlled Trials

Current treatment options for hyperhidrosis are limited. The topical anticholinergic, glycopyrronium tosylate, results in significant reductions in sweating severity/production and favorable tolerability in two phase 3, randomized, vehicle-controlled trials in primary axillary hyperhidrosis. These results suggest glycopyrronium tosylate may provide a non-invasive, once-daily, topical treatment option for primary axillary hyperhidrosis.

https://ift.tt/2m4G0xC

Efficacy, Safety, and Comparison of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: A Systematic Review and Meta-Analysis

Sonic hedgehog inhibitors are systemic treatments for locally advanced and metastatic basal cell carcinomas. In locally advanced disease, overall response rate is similarly significant for sonidegib and vismodegib; complete response rate is significant for vismodegib only. Rates of major side effects do not differ between vismodegib and sonidegib. Patients should expect partial responses in locally advanced disease.

https://ift.tt/2uikclN

Ustekinumab treatment for neutrophilic dermatoses associated with Crohn’s disease: a multicenter-retrospective study

https://ift.tt/2m8A86C

Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-analysis

Although intralesional immunotherapy is commonly used for wart treatment, selection among existing immunotherapeutic modalities remains challenging. PPD and MMR are the most effective modalities for lesion clearance at primary and distant sites (along with autoinoculation), and also reduce recurrence. PPD and MMR may be considered as first-line treatments for warts.

https://ift.tt/2zvpXCO

Methotrexate for alopecia areata: a systematic review and meta-analysis

There is lack of synthesised data regarding methotrexate in AA, Good response was observed in 63% of patients and complete response in 36% of patients, Initial regrowth is observed after 3 months of treatment and takes 6-12 months to achieve complete regrowth, The pooled recurrence rate of AA was 47.7%

https://ift.tt/2m7BFda

The ALT-70 Predictive Model Outperforms Thermal Imaging for the Diagnosis of Lower Extremity Cellulitis: A Prospective Evaluation

Point-of-care diagnostic tools may decrease misdiagnosis rates and unnecessary care associated with lower extremity cellulitis. In our prospective study, the ALT-70 predictive model for lower extremity cellulitis outperformed thermal imaging in diagnostic accuracy. The high negative predictive value of ALT-70 effectively allows clinicians to rule out lower extremity cellulitis.

https://ift.tt/2zvpS1Y

Pigmentation of basal cell carcinoma is inversely associated with tumor aggressiveness in Asian patients

https://ift.tt/2m8zOoq

Drug-Induced Phototoxicity: A Systematic Review

Numerous oral drugs are implicated in phototoxicity; however, the level of evidence for most has not been assessed. Vemurafenib, NSAIDs, and antibiotics (fluoroquinolones, tetracyclines) have strongest evidence for phototoxicity. Most associations are not supported by robust evidence. Improved documentation of phototoxicity testing is required before labelling oral drugs as phototoxic.

https://ift.tt/2uj4K9g

“Comparing the eighth and the seventh editions of the ajcc staging system and the brigham and women’s hospital alternative staging system for cutaneous squamous cell carcinoma: implications for clinical practice”

The new 8th edition of the American Joint Committee on Cancer (AJCC) staging system incorporates changes regarding cutaneous squamous cell carcinoma (CSCC).

https://ift.tt/2m8zIgy

Mohs micrographic surgery (MMS) with MART-1 immunostaining for atypical intraepidermal melanocytic proliferation (AIMP)

Surgical outcomes for AIMP are unknown. Upstaging to unequivocal melanoma was identified in 18.8% of AIMP. No local recurrences occurred with a mean follow-up of 2.7 years. 23.8% of AIMP required greater than one stage of MMS. MMS may be an effective treatment option for AIMP.

https://ift.tt/2uihNrm

Beyond JAAD - October 2018

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Human Naive T Cells Express Functional CXCL8 and Promote Tumorigenesis [TUMOR IMMUNOLOGY]

Naive T cells are thought to be functionally quiescent. In this study, we studied and compared the phenotype, cytokine profile, and potential function of human naive CD4⁺ T cells in umbilical cord and peripheral blood. We found that naive CD4⁺ T cells, but not memory T cells, expressed high levels of chemokine CXCL8. CXCL8⁺ naive T cells were preferentially enriched CD31⁺ T cells and did not express T cell activation markers or typical Th effector cytokines, including IFN-, IL-4, IL-17, and IL-22. In addition, upon activation, naive T cells retained high levels of CXCL8 expression. Furthermore, we showed that naive T cell–derived CXCL8 mediated neutrophil migration in the in vitro migration assay, supported tumor sphere formation, and promoted tumor growth in an in vivo human xenograft model. Thus, human naive T cells are phenotypically and functionally heterogeneous and can carry out active functions in immune responses.

https://ift.tt/2uhLsAV

Early Generated B-1-Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma-like Neoplasia in Aged Mice [TUMOR IMMUNOLOGY]

In mice, fetal/neonatal B-1 cell development generates murine CD5⁺ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a V_H11/D/J_H knock-in mouse line (V_H11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity–deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eμ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgM^hiIgD^loCD5⁺CD23^–CD43⁺ cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma–like neoplasia in aged mice.

https://ift.tt/2m2NEZg

PD-1 Blockade Unleashes Effector Potential of Both High- and Low-Affinity Tumor-Infiltrating T Cells [TUMOR IMMUNOLOGY]

Antitumor T cell responses involve CD8⁺ T cells with high affinity for mutated self-antigen and low affinity for nonmutated tumor-associated Ag. Because of the highly individual nature of nonsynonymous somatic mutations in tumors, however, immunotherapy relies often on an effective engagement of low-affinity T cells. In this study, we studied the role of T cell affinity during peripheral priming with single-peptide vaccines and during the effector phase in the tumor. To that end, we compared the antitumor responses after OVA_257–264 (N4) peptide vaccination of CD8⁺ T cells carrying TCRs with high (OT-1) and low (OT-3) avidity for the N4 peptide in B16.N4 tumor-bearing C57BL/6 mice. Additionally, we assessed the response of OT-1 cells to either high-affinity (B16.N4) or low-affinity (B16.T4) Ag-expressing tumors after high-affinity (N4) or low-affinity (T4) peptide vaccination. We noticed that although low-affinity tumor-specific T cells expand less than high-affinity T cells, they express lower levels of inhibitory receptors and produce more cytokines. Interestingly, tumor-infiltrating CD8⁺ T cells show similar in vivo re-expansion capacity to their counterparts in secondary lymphoid organs when transferred to tumor-free hosts, suggesting that T cells in tumors may be rekindled upon relief of tumor immunosuppression. Moreover, our results show that αPD-1 treatment enhances tumor control of high- and low-affinity ligand-expressing tumors, suggesting that combination of high-affinity peripheral priming by altered peptide ligands and checkpoint blockade may enable tumor control upon low-affinity Ag recognition in the tumor.

https://ift.tt/2uhLt7X

A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression [TUMOR IMMUNOLOGY]

Tumor hypoxia–driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A₂ adenosine receptors (A₂R) on tumor-reactive effector T cells, but there remains a need for careful evaluation of the limiting factors and properties of A₂R blockade–enabled antitumor immunity. In studies of A_2AR and/or A_2BR gene–deficient mice, we found that A_2AR deletion—but not A_2BR deletion—liberates endogenous CD8⁺ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A_2AR^–/–, A_2BR^–/–, or A_2AR^–/–/A_2BR^–/– tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A_2AR on CD8⁺ T cells. Treatment with A_2AR antagonist mimicked A_2AR gene deletion in adoptive T cell immunotherapy. This therapeutic benefit of targeting A_2AR was independent of the anatomical location of tumor growth. The enhanced antitumor reactivity also led to the eradication of established intracranial tumors, which was associated with mouse survival and the maintenance of long-lasting, tumor-specific immunological memory. The blockade of the A_2AR on adoptively transferred T cells by synthetic A_2AR antagonist led to higher levels of IFN- secretion by tumor-infiltrating CD8⁺ T cells. These data clarify the mechanism of hypoxia-driven immunosuppression in the tumor microenvironment by A_2AR on tumor-reactive CD8⁺ T cells and show that selective A_2AR antagonists can be effective in improving the outcomes of T cell–based immunotherapies. Demonstration of the T cell dose dependency of tumor rejection points to a major limitation of current cancer immunotherapies, in which the presence of sufficient numbers of tumor-reactive T cells in a patient is not known.

https://ift.tt/2m8ubGO

Leukocyte-Associated Ig-like Receptor 1 Inhibits Th1 Responses but Is Required for Natural and Induced Monocyte-Dependent Th17 Responses [TRANSPLANTATION]

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas T_h1 responses were enhanced as predicted, T_h17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal T_h17 responses to collagen type (Col)V. For pre-existing "natural" T_h17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive T_h17 and T_h1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased T_h1 responses in a dose-dependent manner, but it had no effect on T_h17 responses. In IL-17–dependent murine organ transplant models of chronic rejection, LAIR1^+/+ but not LAIR1^–/– littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human T_h17 cells as compared with T_h1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors T_h17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors T_h17 over T_h1 development, posing a risk to long-term graft survival.

https://ift.tt/2ujzuH0

Dual Roles for Ikaros in Regulation of Macrophage Chromatin State and Inflammatory Gene Expression [SYSTEMS IMMUNOLOGY]

Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. The transcription factor Ikaros has been shown to play a critical role in lymphoid cell development and differentiation; however, its function in myeloid cells and innate immune responses is less appreciated. Using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility, we describe unexpected dual repressor and activator functions for Ikaros in the LPS response of murine macrophages. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1^–/– macrophages showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of many delayed LPS response genes, and chromatin immunoprecipitation sequencing analyses support a key role for Ikaros in sustained NF-B chromatin binding. Decreased Ikaros expression in Ikzf1^+/– mice and human cells dampens these Ikaros-enhanced inflammatory responses, highlighting the importance of quantitative control of Ikaros protein level for its activator function. In the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin remodeling, gene expression, and cytokine responses. Together, our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.

https://ift.tt/2m7bdjW

Epithelial IL-15 Is a Critical Regulator of {gamma}{delta} Intraepithelial Lymphocyte Motility within the Intestinal Mucosa [MUCOSAL IMMUNOLOGY]

Intraepithelial lymphocytes (IELs) expressing the TCR ( IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates IEL migration into cultured epithelial monolayers, and inhibition of IL-2Rβ significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2Rβ signaling induced IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating T cell localization within the intestinal mucosa and regulating IEL motility and patrolling behavior as a critical component of host defense.

https://ift.tt/2uhLvg5

Mucosal Immunity in the Female Murine Mammary Gland [MUCOSAL IMMUNOLOGY]

The mammary gland is not classically considered a mucosal organ, although it exhibits some features common to mucosal tissues. Notably, the mammary epithelium is contiguous with the external environment, is exposed to bacteria during lactation, and displays antimicrobial features. Nonetheless, immunological hallmarks predictive of mucosal function have not been demonstrated in the mammary gland, including immune tolerance to foreign Ags under homeostasis. This inquiry is important, as mucosal immunity in the mammary gland may assure infant and women's health during lactation. Further, such mucosal immune programs may protect mammary function at the expense of breast cancer promotion via decreased immune surveillance. In this study, using murine models, we evaluated mammary specific mucosal attributes focusing on two reproductive states at increased risk for foreign and self-antigen exposure: lactation and weaning-induced involution. We find a baseline mucosal program of RORT⁺ CD4⁺ T cells that is elevated within lactating and involuting mammary glands and is extended during involution to include tolerogenic dendritic cell phenotypes, barrier-supportive antimicrobials, and immunosuppressive Foxp3⁺ CD4⁺ T cells. Further, we demonstrate suppression of Ag-dependent CD4⁺ T cell activation, data consistent with immune tolerance. We also find Ag-independent accumulation of memory RORT⁺ Foxp3⁺ CD4⁺ T cells specifically within the involution mammary gland consistent with an active immune process. Overall, these data elucidate strong mucosal immune programs within lactating and involuting mammary glands. Our findings support the classification of the mammary gland as a temporal mucosal organ and open new avenues for exploration into breast pathologic conditions, including compromised lactation and breast cancer.

https://ift.tt/2m4zvuI

Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities [MUCOSAL IMMUNOLOGY]

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4⁺ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4⁺ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4⁺ T cells from UC patients. Naive CD4⁺ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4⁺ T cells. CD4⁺ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.

https://ift.tt/2zqsA8K

Evidence for the Existence of a CXCL17 Receptor Distinct from GPR35 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The chemokine CXCL17 is associated with the innate response in mucosal tissues but is poorly characterized. Similarly, the G protein–coupled receptor GPR35, expressed by monocytes and mast cells, has been implicated in the immune response, although its precise role is ill-defined. A recent manuscript reported that GPR35 was able to signal in response to CXCL17, which we set out to confirm in this study. GPR35 was readily expressed using transfection systems but failed to signal in response to CXCL17 in assays of β-arrestin recruitment, inositol phosphate production, calcium flux, and receptor endocytosis. Similarly, in chemotaxis assays, GPR35 did not confirm sensitivity to a range of CXCL17 concentrations above that observed in the parental cell line. We subsequently employed a real time chemotaxis assay (TAXIScan) to investigate the migratory responses of human monocytes and the monocytic cell line THP-1 to a gradient of CXCL17. Freshly isolated human monocytes displayed no obvious migration to CXCL17. Resting THP-1 cells showed a trend toward directional migration along a CXCL17 gradient, which was significantly enhanced by overnight incubation with PGE₂. However, pretreatment of PGE₂-treated THP-1 cells with the well-characterized GPR35 antagonist ML145 did not significantly impair their migratory responses to CXCL17 gradient. CXCL17 was susceptible to cleavage with chymase, although this had little effect its ability to recruit THP-1 cells. We therefore conclude that GPR35 is unlikely to be a bona fide receptor for CXCL17 and that THP-1 cells express an as yet unidentified receptor for CXCL17.

https://ift.tt/2m6OeW9

C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca²⁺-dependent, the molecular identity of the Ca²⁺ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca²⁺ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca²⁺ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca²⁺-dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.

https://ift.tt/2uhLvN7

Opposing Effects of IL-1Ra and IL-36Ra on Innate Immune Response to Pseudomonas aeruginosa Infection in C57BL/6 Mouse Corneas [INNATE IMMUNITY AND INFLAMMATION]

Pseudomonas aeruginosa keratitis is characterized by severe corneal ulceration and may lead to blindness if not treated properly in a timely manner. Although the roles of the IL-1 subfamily of cytokines are well established, as a newly discovered subfamily, IL-36 cytokine regulation, immunological relevance, and relation with IL-1 cytokines in host defense remain largely unknown. In this study, we showed that P. aeruginosa infection induces the expression of IL-36α and IL-36, as well as IL-1β and secreted IL-1Ra (sIL-1Ra), but not IL-36Ra. Downregulation of IL-1Ra increases, whereas downregulation of IL-36Ra decreases the severity of P. aeruginosa keratitis. IL-1R and IL-36Ra downregulation have opposing effects on the expression of IL-1β, sIL-1Ra, IL-36, S100A8, and CXCL10 and on the infiltration of innate immune cells. Administration of recombinant IL-1Ra improved, whereas IL-36Ra worsened the outcome of P. aeruginosa keratitis. Local application of IL-36 stimulated the expression of innate defense molecules S100A9, mouse β-defensin 3, but suppressed IL-1β expression in B6 mouse corneas. IL-36 diminished the severity of P. aeruginosa keratitis, and its protective effects were abolished in the presence of S100A9 neutralizing Ab and partially affected by CXCL10 and CXCR3 neutralizations. Thus, our data reveal that IL-1Ra and IL-36Ra have opposing effects on the outcome of P. aeruginosa keratitis and suggest that IL-36 agonists may be used as an alternative therapeutic to IL-1β–neutralizing reagents in controlling microbial keratitis and other mucosal infections.

https://ift.tt/2m6uDWc

ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3 [INNATE IMMUNITY AND INFLAMMATION]

Ataxin-3 (ATXN3) belongs to the Josephin family of deubiquitinases. So far, ATXN3 is majorly linked to the neurodegenerative disease, Machado–Joseph disease. The role of ATXN3 in the antiviral function has not been explored, and the in vivo deubiquitinating activity of ATXN3 remains largely unknown. In this study, we report that ATXN3 is an important positive regulator of type I IFN (IFN-I)–mediated antiviral activity in murine primary lung cells and human epithelial and fibroblast cell lines. We clarify that ATXN3 does not promote IFN-I production, but enhances the IFN-I–mediated signaling pathway. Furthermore, ATXN3 physically interacts with histone deacetylase 3 (HDAC3) and upregulates the level of HDAC3 protein. Moreover, ATXN3 deubiquitinates HDAC3, thereby enhancing HDAC3 protein stability. Interestingly, the interaction between ATXN3 and HDAC3 increases during viral infection, which promotes IFN-I–induced signaling in murine primary lung cells. Finally, we reveal the ATXN3/HDAC3 axis–mediated regulation of IFN-I antiviral response. These findings reveal a novel biological function of ATXN3 and an important antiviral mechanism by which the deubiquitinase ATXN3 positively regulates IFN-I antiviral response, and they may provide a novel strategy for enhancing IFN-based antiviral therapy.

https://ift.tt/2zvvOYq

Myeloid Cell-Restricted STAT3 Signaling Controls a Cell-Autonomous Antifibrotic Repair Program [INNATE IMMUNITY AND INFLAMMATION]

Myeloid cells can be beneficial as well as harmful in tissue regenerative responses. The molecular mechanisms by which myeloid cells control this critical decision of the immune system are not well understood. Using two different models of physiological acute or pathological chronic skin damage, in this study we identified myeloid cell–restricted STAT3 signaling as important and an injury context–dependent regulator of skin fibrosis. Targeted disruption of STAT3 signaling in myeloid cells significantly accelerated development of pathological skin fibrosis in a model of chronic bleomycin-induced tissue injury, whereas the impact on wound closure dynamics and quality of healing after acute excision skin injury was minor. Chronic bleomycin-mediated tissue damage in control mice provoked an antifibrotic gene signature in macrophages that was characterized by upregulated expression of IL-10, SOCS3, and decorin. In contrast, in STAT3-deficient macrophages this antifibrotic repair program was abolished whereas TGF-β1 expression was increased. Notably, TGF-β1 synthesis in cultured control bone marrow–derived macrophages (BMDMs) was suppressed after IL-10 exposure, and this suppressive effect was alleviated by STAT3 deficiency. Accordingly, coculture of IL-10–stimulated control BMDMs with fibroblasts suppressed expression of the TGF-β1 downstream target connective tissue growth factor in fibroblasts, whereas this suppressive effect was lost by STAT3 deficiency in BMDMs. Our findings highlight a previously unrecognized protective role of myeloid cell–specific STAT3 signaling in immune cell–mediated skin fibrosis, and its regulatory pathway could be a potential target for therapy.

https://ift.tt/2m8ubXk

Down Syndrome as an Indicator for Pediatric Otolaryngologic Procedures

Publication date: Available online 9 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Terral A. Patel, Shaun A. Nguyen, David R. White

Abstract

Objective

Down Syndrome (DS) is the most common chromosome abnormality in humans. Due to the phenotype associated with DS, there are many disease states that require otolaryngologic procedures. Our goal is to use national data to study otolaryngologic procedures, their association with DS, and the degree of difference in risk profiles encountered with DS.

Methods

Data was obtained from the 2012-2015 American College of Surgeons' National Surgical Quality Improvement Program-Pediatric public use files. ENT procedure CPT codes were used to query the database and DS patients were identified using ICD-9 code 758.0. The ENT procedures were grouped into 18 categories and their frequency in DS patients as well as outcomes were analyzed. Postoperative outcomes were measured by complication rates, readmission rates, operation time, anesthesia time, and total length of stay.

Results

Results showed that DS patients are significantly (p<0.05) over-represented in the following categories: Tracheostomy, Endoscopy, Laryngoscopy, Tracheoplasty, Myringoplasty, Tympanoplasty with Mastoidectomy, and Tympanoplasty without Mastoidectomy. DS patients are under-represented in the following categories: Abscess, Palatoplasty, Excision of Congenital Neck Cyst, and Cochlear Implantation. Logistic regression analysis showed that DS patients were significantly (p<0.05) more likely to undergo procedures in the over-represented categories and were significantly (p<0.05) less likely to undergo procedures in the under-represented categories as listed above. Outcomes analysis yielded no pattern of significance.

Conclusion

Our data showed that DS may predispose patients to require certain procedures over others.

https://ift.tt/2una77s

SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages [INNATE IMMUNITY AND INFLAMMATION]

There is increasing evidence that proton-coupled oligopeptide transporters (POTs) can transport bacterially derived chemotactic peptides and therefore reside at the critical interface of innate immune responses and regulation. However, there is substantial contention regarding how these bacterial peptides access the cytosol to exert their effects and which POTs are involved in facilitating this process. Thus, the current study proposed to determine the (sub)cellular expression and functional activity of POTs in macrophages derived from mouse bone marrow and to evaluate the effect of specific POT deletion on the production of inflammatory cytokines in wild-type, Pept2 knockout and Pht1 knockout mice. We found that PEPT2 and PHT1 were highly expressed and functionally active in mouse macrophages, but PEPT1 was absent. The fluorescent imaging of muramyl dipeptide–rhodamine clearly demonstrated that PEPT2 was expressed on the plasma membrane of macrophages, whereas PHT1 was expressed on endosomal membranes. Moreover, both transporters could significantly influence the effect of bacterially derived peptide ligands on cytokine stimulation, as shown by the reduced responses in Pept2 knockout and Pht1 knockout mice as compared with wild-type animals. Taken as a whole, our results point to PEPT2 (at plasma membranes) and PHT1 (at endosomal membranes) working in concert to optimize the uptake of bacterial ligands into the cytosol of macrophages, thereby enhancing the production of proinflammatory cytokines. This new paradigm offers significant insight into potential drug development strategies along with transporter-targeted therapies for endocrine, inflammatory, and autoimmune diseases.

https://ift.tt/2zqEm34

Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169⁺ macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169⁺ macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2–related factor 2–dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

https://ift.tt/2m3uKS5

IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms [INFECTIOUS DISEASE AND HOST RESPONSE]

Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. Candida albicans is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to C. albicans are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate Type-17 immune responses to clear C. albicans infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. In this study, we identify IL-36 cytokines as a new player in these responses. We show that C. albicans infection of the oral mucosa induces the production of IL-36. As with IL-1α/β, induction of epithelial IL-36 depends on the hypha-associated peptide toxin Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-B, and PI3K signaling and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R^–/– mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17–dependent genes, indicating that this protection occurs via an alternative pathway to IL-1–driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell–driven protective pathways in immunity to oral C. albicans infection.

https://ift.tt/2uhLB7r

Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniae [INFECTIOUS DISEASE AND HOST RESPONSE]

Chitinases and chitinase-like proteins are an evolutionary conserved group of proteins. In the absence of chitin synthesis in mammals, the conserved presence of chitinases suggests their roles in physiology and immunity, but experimental evidence to prove these roles is scarce. Chitotriosidase (chit1) is one of the two true chitinases present in mammals and the most prevalent chitinase in humans. In this study, we investigated the regulation and the role of chit1 in a mouse model of Klebsiella pneumoniae lung infection. We show that chitinase activity in bronchoalveolar lavage fluid is significantly reduced during K. pneumoniae lung infection. This reduced activity is inversely correlated with the number of neutrophils. Further, instilling neutrophil lysates in lungs decreased chitinase activity. We observed degradation of chit1 by neutrophil proteases. In a mouse model, chit1 deficiency provided a significant advantage to the host during K. pneumoniae lung infection by limiting bacterial dissemination. This phenotype was independent of inflammatory changes in chit1^–/– mice as they exerted a similar inflammatory response. The decreased dissemination resulted in improved survival in chit1^–/– mice infected with K. pneumoniae in the presence or absence of antibiotic therapy. The beneficial effects of chit1 deficiency were associated with altered Akt activation in the lungs. Chit1^–/– mice induced a more robust Akt activation postinfection. The role of the Akt pathway in K. pneumoniae lung infection was confirmed by using an Akt inhibitor, which impaired health and survival. These data suggest a detrimental role of chit1 in K. pneumoniae lung infections.

https://ift.tt/2m2r8zY

Cysteine-Reactive Free ISG15 Generates IL-1{beta}-Producing CD8{alpha}+ Dendritic Cells at the Site of Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

IFN-stimulated gene (ISG) 15 is a ubiquitin-like protein induced after type I IFN stimulation. There is a dearth of in vivo models to study free unconjugated ISG15 function. We found that free ISG15 enhances the production of IFN- and IL-1β during murine infection with Toxoplasma gondii. In our model, ISG15 is induced in a type I IFN–dependent fashion and released into the serum. Increased ISG15 levels are dependent on an actively invading and replicating parasite. Two cysteine residues in the hinge domain are necessary determinants for ISG15 to induce increased cytokine levels during infection. Increased ISG15 is concurrent with an influx of IL-1β–producing CD8α⁺ dendritic cells to the site of infection. In this article, we present Toxoplasma infection as a novel in vivo murine model to study the immunomodulatory properties of free ISG15 and uniquely link it to IL-1β production by CD8α⁺ dendritic cells driven by two cysteines in the hinge region of the protein.

https://ift.tt/2ujzBSW

The Outcome of the Cryptococcus neoformans-Macrophage Interaction Depends on Phagolysosomal Membrane Integrity [INFECTIOUS DISEASE AND HOST RESPONSE]

Cryptococcus neoformans is a fungal pathogen with worldwide distribution. C. neoformans resides within mature phagolysosomes where it often evades killing and replicates. C. neoformans induces phagolysosomal membrane permeabilization (PMP), but the mechanism for this phenomenon and its consequences for macrophage viability are unknown. In this study, we used flow cytometry methodology in combination with cell viability markers and LysoTracker to measure PMP in J774.16 and murine bone marrow–derived macrophages infected with C. neoformans. Our results showed that cells manifesting PMP were positive for apoptotic markers, indicating an association between PMP and apoptosis. We investigated the role of phospholipase B1 in C. neoformans induction of PMP. Macrophages infected with a C. neoformans plb1 mutant had reduced PMP compared with those infected with wild-type and phospholipase B1–complemented strains, suggesting a mechanism of action for this virulence factor. Capsular enlargement inside macrophages was identified as an additional likely mechanism for phagolysosomal membrane damage. Macrophages undergoing apoptosis did not maintain an acidic phagolysosomal pH. Induction of PMP with ciprofloxacin enhanced macrophages to trigger lytic exocytosis whereas nonlytic exocytosis was common in those without PMP. Our results suggest that modulation of PMP is a critical event in determining the outcome of C. neoformans–macrophage interaction.

https://ift.tt/2m6uGks

Association of medullary sponge kidney and hyperparathyroidism with RET G691S/S904S polymorphism: a case report

Medullary sponge kidney is a rare renal malformation, which usually manifests as nephrocalcinosis, renal tubular acidosis, and recurrent urinary tract infections. Medullary sponge kidney is often associated wi...

https://ift.tt/2KJzmMa

Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies

Bjorefeldt, A; Illes, S; Zetterberg, H; Hanse, E; (2018) Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies. Frontiers in Neural Circuits , 12 , Article 5. 10.3389/fncir.2018.00005 . Green open access

https://ift.tt/2KGpWAQ

The Addition Of The MTORr Inhibitor, Everolimus, To Consolidation Therapy In Acute Myeloid Leukaemia: Experience From The UK NCRI AML17 Trial

Burnett, AK; Das Gupta, E; Knapper, S; Khwaja, A; Sweeney, M; Kjeldsen, L; Hawkins, T; ... Russell, NH; + view all Burnett, AK; Das Gupta, E; Knapper, S; Khwaja, A; Sweeney, M; Kjeldsen, L; Hawkins, T; Betteridge, SE; Cahalin, P; Clark, RE; Hills, RK; Russell, NH; - view fewer (2018) The Addition Of The MTORr Inhibitor, Everolimus, To Consolidation Therapy In Acute Myeloid Leukaemia: Experience From The UK NCRI AML17 Trial. Haematologica 10.3324/haematol.2018.189514 . (In press). Green open access

https://ift.tt/2N3xJWn

Silaindacenodithiophene-Based Low Band Gap Polymers - The Effect of Fluorine Substitution on Device Performances and Film Morphologies

Schroeder, BC; Huang, Z; Ashraf, RS; Smith, J; D'Angelo, P; Watkins, SE; Anthopoulos, TD; ... McCulloch, I; + view all Schroeder, BC; Huang, Z; Ashraf, RS; Smith, J; D'Angelo, P; Watkins, SE; Anthopoulos, TD; Durrant, JR; McCulloch, I; - view fewer (2012) Silaindacenodithiophene-Based Low Band Gap Polymers - The Effect of Fluorine Substitution on Device Performances and Film Morphologies. Advanced Functional Materials , 22 (8) pp. 1663-1670. 10.1002/adfm.201102941 . Green open access

https://ift.tt/2NDAkXV

Optimal echo time for functional MRI of the infant brain identified in response to noxious stimulation

Goksan, S; Hartley, C; Hurley, SA; Winkler, AM; Duff, EP; Jenkinson, M; Rogers, R; ... Slater, R; + view all Goksan, S; Hartley, C; Hurley, SA; Winkler, AM; Duff, EP; Jenkinson, M; Rogers, R; Clare, S; Slater, R; - view fewer (2017) Optimal echo time for functional MRI of the infant brain identified in response to noxious stimulation. Magnetic Resonance in Medicine , 78 (2) pp. 625-631. 10.1002/mrm.26455 . Green open access

https://ift.tt/2N1GIaq

Choreographies of the protest: The body, the city and their ephemeral transformations

Vergara Perucich, JF; (2012) Choreographies of the protest: The body, the city and their ephemeral transformations. Revista De Diseño Urbano Y Paisaje - Du&p , 9 (23) pp. 121-130. Green open access

https://ift.tt/2KHPhL0

Strategies to improve epithelialisation of tissue engineered airway constructs

Butler, Colin R; (2018) Strategies to improve epithelialisation of tissue engineered airway constructs. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2N15449

Oral health and performance impacts in elite and professional athletes

Gallagher, J; Ashley, P; Petrie, A; Needleman, I; (2018) Oral health and performance impacts in elite and professional athletes. Community Dentistry and Oral Epidemiology 10.1111/cdoe.12392 . (In press).

https://ift.tt/2NEiqEv

Socio-economic gradients in prevalent tuberculosis in Zambia and the Western Cape of South Africa

Yates, TA; Ayles, H; Leacy, FP; Schaap, A; Boccia, D; Beyers, N; Godfrey-Faussett, P; Yates, TA; Ayles, H; Leacy, FP; Schaap, A; Boccia, D; Beyers, N; Godfrey-Faussett, P; Floyd, S; - view fewer (2018) Socio-economic gradients in prevalent tuberculosis in Zambia and the Western Cape of South Africa. Tropical Medicine & International Health , 23 (4) pp. 375-390. 10.1111/tmi.13038 . Green open access

https://ift.tt/2N1Gq3k

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Δευτέρα 9 Ιουλίου 2018

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