Secondary amyloidosis can complicate chronic inflammatory autoimmune diseases. However, the clinical findings of primary amyloidosis may mimic those of primary rheumatologic disorders. We present the case of a 53-year-old woman who presented with dystrophic nail changes, dry eyes, bilateral carpal tunnel syndrome, Raynaud's phenomenon, and high titer positive nucleolar pattern antinuclear antibody. She was initially misdiagnosed as having Undifferentiated Connective Tissue Disease (UCTD). On further workup, she was eventually diagnosed with lambda light chain systemic amyloidosis by abdominal fat pad biopsy. Her symptoms completely resolved after autologous stem cell transplantation. With this case, we would like to highlight the similarities in the clinical features between light chain amyloidosis and rheumatological disorders. We would also like to emphasize the importance of the prompt recognition of the clinical features of amyloidosis which are crucial to triggering appropriate diagnostic procedures, since early diagnosis is a key to improving outcomes in this disease with an otherwise poor prognosis.
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 28 Νοεμβρίου 2016
Systemic Light Chain Amyloidosis Mimicking Rheumatic Disorders
The Influence of Timing and Frequency of Adipose-derived Mesenchymal Stem Cell Therapy on Immunomodulation Outcomes after Vascularized Composite Allotransplantation.
http://ift.tt/2gQZB3L
The Presence of Pretransplant HLA Antibodies Does Not Impact the Development of Chronic Lung Allograft Dysfunction or CLAD Related Death.
http://ift.tt/2gR0wBx
Differential role of B cells and IL-17 versus IFN-[gamma] during early and late rejection of pig islet xenografts in mice.
http://ift.tt/2gEibcA
Induction Therapy, Rejection and Graft Outcomes in Paediatric and Adolescent Kidney Transplant Recipients.
http://ift.tt/2gR0hWK
Necroptosis is Involved in CD4+ T cell Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection.
http://ift.tt/2gEe5kt
Absence of miR-182 Augments Cardiac Allograft Survival.
http://ift.tt/2gR10qX
Altered pharyngeal structure and dynamics among patients with cervical kyphosis
Objectives/Hypothesis
Deformities of the anterior cervical spine are an established cause of dysphagia. Whereas osteophytes and spinal fusion hardware have been reported to alter bolus flow and contribute to swallowing dysfunction, the relationship between abnormal spine curvature and swallowing dysfunction is not established. The purpose of this investigation was to evaluate the association between cervical kyphosis and objective measures of swallowing dysfunction on videofluoroscopy.
Study Design
Case-control study of patients presenting to tertiary dysphagia center.
Methods
All videofluoroscopic swallow studies (VFSS) performed at our institution, between August 1, 2014, and August 1, 2015, were retrospectively reviewed to identify patients with abnormal cervical kyphosis, according to Cobb and Jackson angle measurements. Patients with kyphosis were age- and gender-matched to persons without kyphosis. VFSS and demographic parameters were collected and compared between groups.
Results
Thirty-six patients with cervical kyphosis exceeding two standard deviations (SD) beyond established age-specific normal ranges were identified. The mean age of the entire cohort was 61.6 (SD ±19.1) years. Mean pharyngeal area was 3.34 cm2 greater in kyphosis patients compared to controls (95% confidence interval [CI]: 0.47-5.21 cm2; P = .0007). This was associated with increased hypopharyngeal transit time (0.57 seconds, 95% CI: 0.045-1.09 seconds, P = .034), and higher prevalence of penetration (P = .014). There was no significant difference in the pharyngeal constriction ratio (PCR), a surrogate measure of pharyngeal strength (P = .83).
Conclusions
Patients with cervical spine kyphosis have a significantly dilated pharynx (P = .0007), elongated hypopharyngeal transit time (P = .034), and worsened penetration aspiration scores (P = .021). Absence of a difference in PCR suggests adequate compensation as a group.
Level of Evidence
3b. Laryngoscope, 2016
http://ift.tt/2fwiBod
PPARγ targeted oral cancer treatment and additional utility of genomics analytic techniques
Objective
Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to have anti-proliferative, anti-angiogenic, and proapoptotic effects, leading to interest in their use as cancer therapeutics. Pioglitazone, a U.S. Food and Drug Administration-approved type II diabetes medication and PPARγ agonist, may have a role in adjuvant head-and-neck squamous cell carcinoma treatment or prevention. Therefore, the purpose of this study was: 1) to treat oral cavity cancer cells with the PPARγ activator, pioglitazone, to analyze gene expression changes; and 2) to compare those changes with our preexisting genomic data for development of hypothesis-driven additional basic and clinical studies.
Study Design
Prospective in vitro.
Methods
We utilized microarray technology, as well as OCPlus (Bioconductor open source software) and Ingenuity Pathway Analysis (Qiagen, Redwood City, CA), to analyze differential gene expression in tumor and pioglitazone-treated tumor cells on a genome-wide level to demonstrate the feasibility of such an approach and determine appropriate sample size for future investigations.
Results
We found that approximately 35 samples are required to adequately power future studies. We next discovered that pioglitazone significantly affects Inducible T-Cell Costimulator (iCOS)-Ligand for the T-cell-specific cell surface receptor ICOS (iCOSL) and type II diabetes mellitus pathways as a putative anti-cancer mechanism.
Conclusion
Genome-wide analysis is possible for the exploration of differential pathway modulation and rapid hypothesis generation. Both inflammation and type II diabetes pathways were significantly altered and therefore might provide unique hypothesis-driven pharmacodynamic parameters for future in vitro or in vivo studies utilizing thiazolidinediones. These techniques could be applied to microarray or other high throughput data from a variety of hypothesis-generating research scenarios in otolaryngology (e.g., middle ear proteomics, sinus microbiome studies).
Level of Evidence
NA. Laryngoscope, 2016
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Inhibition of Plasmodium liver infection by ivermectin [PublishAheadOfPrint]
Avermectins are powerful endectocides with an established potential to reduce the incidence of vector-borne diseases. Here, we show that several avermectins inhibit the hepatic stage of Plasmodium infection in vitro. Notably, ivermectin potently inhibits liver infection in vivo, by impairing parasite development inside hepatocytes. This impairment has a clear impact on the ensuing blood stage parasitemia, reducing disease severity and enhancing host survival. Ivermectin has been proposed as a tool to control malaria transmission due to its effects on the mosquito vector. Our study extends the effect of ivermectin to the early stages of mammalian host infection and supports the inclusion of this multipurpose drug in malaria control strategies.
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1. In Vitro and In Vivo Activity of Sulfur-Containing Linear Bisphosphonates against Apicomplexan Parasites [PublishAheadOfPrint]
We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (22, 1-[(n-decylsulfonyl)ethyl]-1,1-biphosphonic acid) is a sulfone-containing compound, which had an EC50 of 0.11 ± 0.02 μM against intracellular tachyzoites. The compound showed low toxicity when tested in tissue culture with a selectivity index of >2,000. 22 also showed high activity in vivo in a toxoplasmosis mouse model. The compound inhibited the Toxoplasma farnesyl diphosphate synthase (TgFPPS) but the concentration needed to inhibit 50% of the enzymatic activity (IC50) was higher than the concentration that inhibited 50% of growth. We tested 22 against two other Apicomplexan parasites, Plasmodium falciparum (EC50 of 0.6 ± 0.01 μM), the agent of malaria, and Cryptosporidium parvum (EC50 of ~65 μM), the agent of cryptosporidiosis. Our results suggest that 22 is an excellent novel compound that could lead to the development of potent agents against Apicomplexan parasites.
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A Multicenter Observational Study of Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections [PublishAheadOfPrint]
Novel therapies for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are needed in the setting of reduced antibiotic susceptibilities and therapeutic failure. Ceftaroline is an advanced generation cephalosporin with MRSA activity. Although not FDA approved for MRSA BSI, ceftaroline has generated much interest as a potential treatment option. However, detailed description of its use in this setting remains limited. To address this, we conducted a retrospective, multicenter, observational study of adult patients with MRSA BSI treated with at least 72 hours of ceftaroline from 2011 to 2015. Safety outcomes were examined in the overall cohort while efficacy outcomes were examined among patients who had not cleared their BSI prior to ceftaroline initiation. Data were also stratified by ceftaroline monotherapy or combination therapy. Predictors of clinical failure on ceftaroline were also sought. Overall, 211 patients were included in the safety population; Clostridium difficile infection, rash, and neutropenia occurred in 6 (2.8%), 7 (3.3%), and 3 (1.4%) of patients, respectively. Clinical success was observed in 86 (68.3%) of the 126 patients included in efficacy population. The monotherapy and combination therapy subgroups had a similar proportion of patients experiencing success (69.7 and 64.9%, respectively). The median BSI duration post-ceftaroline was 2 (1 – 4) days among monotherapy and 3 (1.5 – 5) days for combination therapy. Higher APACHE II score and comorbid malignancy independently predicted treatment failure. Ceftaroline appears effective for MRSA BSI as both monotherapy and combination therapy. However, comparative studies are needed to further delineate the role of ceftaroline in MRSA BSI treatment.
http://ift.tt/2gQPITC
Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms: a case series from the compassionate-use program [PublishAheadOfPrint]
Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used Wilcoxon rank-sum and Fisher's exact tests to compare patients by treatment outcome. The sample included 36 patients with CRE and two with CRPa. The most common infections were intra-abdominal and respiratory. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was non-resistant in vitro. Twenty-eight patients (73.7%, 95% CI; 56.9-86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (p=0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.
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Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals on Failing First-Line Antiretroviral Therapy in South Africa [PublishAheadOfPrint]
Background: A vaginal ring containing dapivirine (DPV) has shown moderate protective efficacy against HIV-1 acquisition, but the activity of DPV against efavirenz (EFV)- and nevirapine (NVP)-resistant viruses that could be transmitted is not well-defined. We investigated DPV cross-resistance of subtype C HIV-1 from individuals on failing NVP- or EFV-containing antiretroviral therapy (ART) in South Africa (SA).
Methods: Plasma samples were obtained from individuals with >10,000 copies/mL HIV RNA and with HIV-1 containing at least one non-nucleoside reverse transcriptase (NNRTI) mutation. Susceptibility to NVP, EFV and DPV in TZM-bl cells was determined for recombinant HIV-1LAI containing bulk-amplified, plasma-derived, full-length reverse transcriptase sequences. Fold-change (FC) values were calculated compared with a composite IC50 value from 12 recombinant subtype C HIV-1LAI plasma-derived viruses from treatment-naïve individuals in SA.
Results: 25/100 (25%) samples showed >500-FC to DPV compared to treatment-naïve samples with IC50 values exceeding the maximum DPV concentration tested (132 ng/mL). 66/100 (66%) samples displayed 3 to 306-FC with median IC50 of 17.6 ng/mL. Only 9/100 (9%) samples were susceptible to DPV (FC <3). Mutations L100I and K103N were significantly more frequent in samples with >500-fold resistance to DPV compared to samples with ≤500-fold resistance.
Conclusions: 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in SA exhibit ≥3-fold cross-resistance to DPV. This level of resistance exceeds expected plasma concentrations, but very high genital tract DPV concentrations from DPV ring use could block viral replication. It is critically important to assess the frequency of transmitted and selected DPV resistance in individuals using the DPV ring.
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The occurrence of diverse AbGRI1-type genomic islands in Acinetobacter baumannii global clone 2 (GC2) isolates from Korea [PublishAheadOfPrint]
In this study, we analyzed the frequency of the AbGRI1-type genomic island (GI) and its association with genotypes. We obtained 130 A. baumannii isolates causing bloodstream infections from patients in Korea. Antimicrobial susceptibility testing and multilocus sequence typing were performed. The presence of AbGRI1-type GIs and their structure were determined by sequential PCR and sequencing. Ninety-eight isolates (75.3%) representing 14 sequence types (STs) belonged to CC208, corresponding to global clone 2 (GC2). AbGRI1-type GIs interrupted the comM gene in 107 isolates (82.4%). Four types of GIs were identified: Tn6022 (50 isolates, 46.7%), AbaR4 (23 isolates, 21.5%), Tn6166 (10 isolates, 9.3%), and Tn6166/Tn2006 (24 isolates, 22.4%). In the 50 isolates with Tn6022, Tn2006 or Tn2008B, both containing ISAba1-blaOXA-23, were present in sites other than GIs in three and 28 isolates, respectively. In the ten isolates with Tn6166, Tn2008B was identified in one isolate. AbGRI1-type GIs were identified nearly exclusively in CC208 isolates, with the exception of nine non-CC208 isolates (AbaR4 in eight ST229 isolates and Tn6022 in one ST1244 isolate). Within CC208 isolates, there was evidence of frequent recombination events, both in housekeeping genes and AbGRI1-type GIs, contributing to genotype diversification and the emergence of carbapenem resistance.
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Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime [PublishAheadOfPrint]
Background: Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in acute kidney injury (AKI) when combined with anti-pseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP).
Methods: This was a retrospective, matched cohort study at an academic medical center between September 2010 and September 2014 including adult patients receiving TZP-VAN or FEP-VAN for at least 48 hours and without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or hospital transfer. The primary outcome was difference in AKI incidence between TZP-VAN and FEP-VAN, evaluated using RIFLE criteria. Patients were matched based on: age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and IV contrast exposure.
Key Results: In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN compared to 12.6% in FEP-VAN(p<0.001). After matching, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN compared to FEP-VAN (21.4% vs. 12.5%, p<0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI compared to FEP-VAN (95% CI 1.64-2.94) in logistic regression.
Conclusions: AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than cefepime. This finding reinforces the need for judicious use of combination empiric antimicrobial therapy.
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Are Prophylactic and Therapeutic Target Concentrations Different? The Case of Lopinavir/ritonavir or Lamivudine Administered to Infants for the Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding [PublishAheadOfPrint]
The ANRS 12174 trial assessed the efficacy and tolerance of LPV/r versus 3TC prophylaxis administered to breastfed infants, whose HIV-infected mothers were not on ART. In this sub-study, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at week 6, 26 and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters based on previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered as missing doses and discarded from Bayesian analysis. The overall population analysis shows that 30 to 40% of infants did not reach therapeutic targets, regardless of treatment group. Median[IQR] LPV Ctrough at week 6, 26 and 38 were 2.8[1.7-4.4], 5.6[3.2-7.7] and 3.4[2.3–7.3] mg/L, respectively. Median[IQR] 3TC AUC0-12 were 5.6[4.1-7.8], 5.9[5.1-7.5] and 7.3[4.9-8.5] mg.h/Lat week 6, 26 and 38, respectively. The therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain most infants above therapeutic pharmacokinetic targets.
http://ift.tt/2gDZ6He
Mutations Associated with Decreased Susceptibility to Seven Antimicrobial Families in Field and Laboratory-Derived Mycoplasma bovis Strains [PublishAheadOfPrint]
The molecular mechanisms of resistance to fluoroquinolones, tetracyclines, an aminocyclitol, macrolides, a lincosamide, a phenicol and pleuromutilins were investigated in Mycoplasma bovis. For the identification of mutations responsible for the high minimal inhibitory concentrations (MICs) to certain antibiotics, whole genome sequencing of 35 M. bovis field isolates and 36 laboratory-derived antibiotic resistant mutants was performed. In vitro resistant mutants were selected by serial passages of M. bovis in broth medium containing subinhibitory concentrations of the antibiotics. Mutations associated with high MICs to fluoroquinolones were found at positions 244-260 and 232-250 (according to E. coli numbering) of quinolone resistance determining regions of gyrA and parC genes, respectively. Alterations related to elevated MICs to tetracyclines were described at positions 962-967, 1058, 1195, 1196 and 1199 of genes encoding the 16S rRNA and forming the primary tetracycline binding site. Single transversion at position 1192 of rrs1 gene resulted in 256 μg/ml MIC to spectinomycin. Mutations responsible for high MICs to macrolide, lincomycin, florfenicol and pleuromutilin antibiotics were identified in genes encoding the 23S rRNA.
Understanding antibiotic resistance mechanisms is an important tool for future developments of genetic-based diagnostic assays for the rapid detection of resistant M. bovis strains.
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Evaluation of Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica serovar Typhimurium Using In Vitro Dynamic Models [PublishAheadOfPrint]
The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models, and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR) and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug- exposure were quantified. PK/PD indices associated with different levels of antibacterial activity were computed. Mechanisms of fluoroquinolone resistance were determined by analyzing target mutations in the quinolone resistance determining regions (QRDRs) and by analyzing overexpression of efflux pumps. Maximum losses in susceptibility of fluoroquinolone-exposed S. Typhimurium occurred at simulated AUC24h/MIC ratio of 47-71. Target mutations in gyrA (S83F) and overexpression of arcAB-tolC contributed to decreased susceptibility in fluoroquinolone-exposed S. Typhimurium. The current data suggest AUC24h/MIC (AUC24h/MPC)-dependent selection of resistant mutants of S. Typhimurium with AUC24h/MPC ratios of 69 (DIF), 62 (ENR) and 39 (MAR) being protective against selection of resistant mutants. These values could not be achieved in veterinary clinical area under the current recommended therapeutic doses of the fluoroquinolones, suggesting the need to reassess the current dosing regimen to include both clinical efficacy and minimization of emergence of resistant bacteria.
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A naturally occurring SNP in plasmid pB1000 produces a reversible increase in antibiotic resistance [PublishAheadOfPrint]
ColE1 plasmids are small mobilizable replicons that play an important role in the spread of antibiotic resistance in Pasteurellaceae. In this study we describe how a natural single nucleotide polymorphism (SNP) near the origin of replication of the ColE1-type plasmid pB1000 found in a Pasteurella multocida clinical isolate, generates two independent plasmid variants able to coexist in the same cell simultaneously. Using Haemophilus influenzae Rd strain as a model system, we combined antibiotic susceptibility tests, quantitative PCRs, competition assays and experimental evolution to characterize the consequences of the coexistence of the pB1000 plasmid variants. This coexistence produced an increase of the total plasmid copy number (PCN) in the host bacteria, leading to a rise in both the antibiotic resistance level and the metabolic burden produced by pB1000. Using experimental evolution we showed that in the presence of ampicillin the bacteria maintained both plasmid variants for 300 generations. In the absence of antibiotics, on the other hand, the bacteria are capable of reverting to the single-plasmid genotype via the loss of one of the plasmid variants. Our results revealed how a single mutation in plasmid pB1000 provides the bacterial host with a mechanism to increase PCN and consequently ampicillin resistance level. Crucially, this mechanism can be rapidly reversed to avoid the extra cost entailed by the increased PCN in the absence of antibiotics.
http://ift.tt/2gQJHGQ
An IncP plasmid carrying the colistin resistance gene mcr-1 in Klebsiella pneumoniae from hospital sewage [PublishAheadOfPrint]
A Klebsiella pneumoniae strain of ST313 recovered from hospital sewage was found to carry the plasmid-borne colistin resistance gene mcr-1, which was bracketed by two copies of the insertion sequence ISApl1 on a 57-kb self-transmissible IncP type plasmid of a new IncP-1 clade. The carriage of mcr-1 on a self-transmissible broad-host-range plasmid highlights that mcr-1 has the potential to be spread beyond the Enterobacteriaceae.
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Molecular investigation of resistance to second line injectable drugs in multidrug-resistant clinical isolates of Mycobacterium tuberculosis in France [PublishAheadOfPrint]
The second line injectable drugs (SLID, i.e. amikacin, kanamycin, capreomycin) are key drugs for the treatment of multidrug-resistant tuberculosis. Mutations in rrs region 1400, tlyA and eis promoter are associated with resistance to SLID, to capreomycin and to kanamycin respectively. In this study, the sequencing data of SLID resistance-associated genes were compared to the results of phenotypic drug susceptibility testing by the proportion method for the SLID in 206 multidrug-resistant clinical isolates of Mycobacterium tuberculosis collected in France. Among the 153 isolates susceptible to the 3 SLID, 145 showed no mutation, 1 harbored T1404C plus G1473A mutations in rrs and 7 had an eis promoter mutation. Among the 53 strains resistant to at least 1 of the SLID, mutations in rrs accounted for resistance to amikacin, capreomycin and kanamycin for 81%, 75% and 44% isolates, respectively, while mutations in eis promoter were detected in 44% of the isolates resistant to kanamycin. By contrast, no mutations in tlyA were observed in the isolates resistant to capreomycin. The discrepancies observed between the genotypic (on the primary culture) and phenotypic drug susceptibility testing were explained by i) resistance to SLID with MICs close to the critical concentration used for routine DST and not detected by phenotypic testing (n=8, 15% of SLID-resistant strains), ii) low-frequency heteroresistance not detected by sequencing of drug resistance-associated genes on the primary culture (n=8, 15% of SLID-resistant strains), and iii) to other resistance mechanisms not yet characterized (n=7, 13% of SLID-resistant strains).
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PROTECTIVE EFFECTS OF HUMAN AND MOUSE SOLUBLE SCAVENGER-LIKE CD6 LYMPHOCYTE RECEPTOR IN A LETHAL MODEL OF POLYMICROBIAL SEPSIS [PublishAheadOfPrint]
Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria, and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold-standard antibiotics, in a lethal model of polymicrobial sepsis. To this end, C57BL/6 mice undergoing high-grade septic shock induced by cecal ligation and puncture (CLP, ≥90% lethality) were infused via i.p. or i.v. with shCD6 at different doses and time-points, either alone or in combination with Imipenem/Cilastatin (I/C, 33 mg/Kg/8h). Significant reduced mortality, pro-inflammatory cytokine levels and bacterial load was observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1h pre- or post-CLP. When using the i.v. route, mice survival was significantly extended by starting shCD6 infusion at later time-points post-CLP (up to +6h). Significant adjunctive effects on mouse survival were observed by i.p or i.v. infusion of shCD6 in combination with i.p I/C post-CLP. Similar results were obtained in mice expressing high sustained serum levels (5-10 μg/mL) of mouse sCD6 by means of transduction with hepatotropic adeno-associated virus (AAV). Taken together, the data support the conserved antibacterial effects of human and mouse sCD6, and its use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis.
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De Novo Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells formed against Antituberculosis Drugs In Vitro [PublishAheadOfPrint]
Bacterial persisters are a subpopulation of cells that can tolerate lethal concentrations of antibiotics. However, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell population, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. In the present study, we found that Mycobacterium tuberculosis (Mtb) cells exposed continuously to lethal concentrations of rifampicin (RIF) or moxifloxacin (MXF) for prolonged durations showed killing, RIF/MXF persistence, and regrowth phases. RIF-resistant or MXF-resistant mutants carrying clinically relevant mutations in the rpoB or gyrA gene, respectively, were found to emerge at high frequency from the RIF persistence phase population. Luria-Delbruck fluctuation experiment using RIF-exposed Mtb cells showed that the rpoB mutants were not pre-existent in the population, but were formed de novo from the RIF persistence phase population. The RIF persistence phase Mtb cells carried elevated levels of hydroxyl radical that inflicted extensive genome-wide mutations, generating RIF-resistant mutants. Consistent with the elevated levels of hydroxyl radical mediated genome-wide random mutagenesis, MXF-resistant Mtb gyrA de novo mutants could be selected from the RIF persistence phase cells. Thus, unlike the previous studies, which showed emergence of genetically resistant mutants upon exposure of bacteria for short duration to sub-lethal concentrations of antibiotics, our study demonstrates that continuous prolonged exposure of Mtb cells to lethal concentrations of an antibiotic generates antibiotic persistence phase cells that form a reservoir for the generation of genetically resistant mutants to that antibiotic or another antibiotic. These findings may have clinical significance in the emergence of drug-resistant tubercle bacilli.
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Successful Management of a Patient with Malignant Thyroid Teratoma
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Competency Education of Primary Care Physicians in Management of Thyroid Disorders: Implementation Experiences from a Pan India Certificate Course
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Differences in Brain Glucose Metabolism During Preparation for 131I Ablation in Thyroid Cancer Patients: Thyroid Hormone Withdrawal Versus Recombinant Human Thyrotropin
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Should Level V Be Routinely Dissected in N1b Papillary Thyroid Carcinoma?
Thyroid , Vol. 0, No. 0.
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Neural Correlates of the Binaural Masking Level Difference in Human Frequency-Following Responses
Abstract
The binaural masking level difference (BMLD) is an auditory phenomenon where binaural tone-in-noise detection is improved when the phase of either signal or noise is inverted in one of the ears (SπNo or SoNπ, respectively), relative to detection when signal and noise are in identical phase at each ear (SoNo). Processing related to BMLDs and interaural time differences has been confirmed in the auditory brainstem of non-human mammals; in the human auditory brainstem, phase-locked neural responses elicited by BMLD stimuli have not been systematically examined across signal-to-noise ratio. Behavioral and physiological testing was performed in three binaural stimulus conditions: SoNo, SπNo, and SoNπ. BMLDs at 500 Hz were obtained from 14 young, normal-hearing adults (ages 21–26). Physiological BMLDs used the frequency-following response (FFR), a scalp-recorded auditory evoked potential dependent on sustained phase-locked neural activity; FFR tone-in-noise detection thresholds were used to calculate physiological BMLDs. FFR BMLDs were significantly smaller (poorer) than behavioral BMLDs, and FFR BMLDs did not reflect a physiological release from masking, on average. Raw FFR amplitude showed substantial reductions in the SπNo condition relative to SoNo and SoNπ conditions, consistent with negative effects of phase summation from left and right ear FFRs. FFR amplitude differences between stimulus conditions (e.g., SoNo amplitude–SπNo amplitude) were significantly predictive of behavioral SπNo BMLDs; individuals with larger amplitude differences had larger (better) behavioral B MLDs and individuals with smaller amplitude differences had smaller (poorer) behavioral B MLDs. These data indicate a role for sustained phase-locked neural activity in BMLDs of humans and are the first to show predictive relationships between behavioral BMLDs and human brainstem responses.
http://ift.tt/2fYJM74
Natural Compounds as Occult Ototoxins? Ginkgo biloba Flavonoids Moderately Damage Lateral Line Hair Cells
Abstract
Several drugs, including aminoglycosides and platinum-based chemotherapy agents, are well known for their ototoxic properties. However, FDA-approved drugs are not routinely tested for ototoxicity, so their potential to affect hearing often goes unrecognized. This issue is further compounded for natural products, where there is a lack of FDA oversight and the manufacturer is solely responsible for ensuring the safety of their products. Natural products such as herbal supplements are easily accessible and commonly used in the practice of traditional eastern and alternative medicine. Using the zebrafish lateral line, we screened a natural products library to identify potential ototoxins. We found that the flavonoids quercetin and kaempferol, both from the Gingko biloba plant, demonstrated significant ototoxicity, killing up to 30 % of lateral line hair cells. We then examined a third Ginkgo flavonoid, isorhamnetin, and found similar levels of ototoxicity. After flavonoid treatment, surviving hair cells demonstrated reduced uptake of the vital dye FM 1-43FX, suggesting that the health of the remaining hair cells was compromised. We then asked if these flavonoids enter hair cells through the mechanotransduction channel, which is the site of entry for many known ototoxins. High extracellular calcium or the quinoline derivative E6 berbamine significantly protected hair cells from flavonoid damage, implicating the transduction channel as a site of flavonoid uptake. Since known ototoxins activate cellular stress responses, we asked if reactive oxygen species were necessary for flavonoid ototoxicity. Co-treatment with the antioxidant D-methionine significantly protected hair cells from each flavonoid, suggesting that antioxidant therapy could prevent hair cell loss. How these products affect mammalian hair cells is still an open question and will be the target of future experiments. However, this research demonstrates the potential for ototoxic damage caused by unregulated herbal supplements and suggests that further supplement characterization is warranted.
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Toward a Nonspeech Test of Auditory Cognition: Semantic Context Effects in Environmental Sound Identification in Adults of Varying Age and Hearing Abilities
by Valeriy Shafiro, Stanley Sheft, Molly Norris, George Spanos, Katherine Radasevich, Paige Formsma, Brian Gygi
ObjectiveSounds in everyday environments tend to follow one another as events unfold over time. The tacit knowledge of contextual relationships among environmental sounds can influence their perception. We examined the effect of semantic context on the identification of sequences of environmental sounds by adults of varying age and hearing abilities, with an aim to develop a nonspeech test of auditory cognition.
MethodThe familiar environmental sound test (FEST) consisted of 25 individual sounds arranged into ten five-sound sequences: five contextually coherent and five incoherent. After hearing each sequence, listeners identified each sound and arranged them in the presentation order. FEST was administered to young normal-hearing, middle-to-older normal-hearing, and middle-to-older hearing-impaired adults (Experiment 1), and to postlingual cochlear-implant users and young normal-hearing adults tested through vocoder-simulated implants (Experiment 2).
ResultsFEST scores revealed a strong positive effect of semantic context in all listener groups, with young normal-hearing listeners outperforming other groups. FEST scores also correlated with other measures of cognitive ability, and for CI users, with the intelligibility of speech-in-noise.
ConclusionsBeing sensitive to semantic context effects, FEST can serve as a nonspeech test of auditory cognition for diverse listener populations to assess and potentially improve everyday listening skills.
http://ift.tt/2gARRia
T H 9 cells in skin disorders
Abstract
Interleukin 9 secreting TH9 cells have been proposed as the latest addition to the family of T helper cell subsets. While a growing body of evidence from animal models points to important roles for these cells in allergic inflammation of the lung, autoinflammation of the gastrointestinal tract, and tumor immunity, their role in skin immunity and skin immunopathology remains poorly defined. Interestingly, studies of T helper cells from healthy humans suggest that TH9 cells are predominantly skin-homing and skin-resident and that they are involved in protection against extracellular pathogens. Thus, TH9 cells have entered the stage as potential mediators of cutaneous pathology. However, under which conditions and by which mechanisms these cells contribute to skin immunity and disease still has to be investigated. Here, we review our current understanding of TH9 cells as skin-tropic T helper cells and their involvement in skin pathology. Further, we discuss open questions with regard to the intricate nature of interleukin 9 producing T helper cells.
http://ift.tt/2fJy5n9
TNF superfamily cytokines in the promotion of Th9 differentiation and immunopathology
Abstract
The tumor necrosis factor (TNF) receptors and their corresponding cytokine ligands have been implicated in many aspects of the biology of immune functions. TNF receptors have key roles during various stages of T cell homeostasis. Many of them can co-stimulate lymphocyte proliferation and cytokine production. Additionally, several TNF cytokines can regulate T cell differentiation, including promoting Th1, Th2, Th17, and more recently the newly described Th9 subset. Four TNF family cytokines have been identified as regulators for IL-9 production by T cells. OX40L, TL1A, and GITRL can promote Th9 formation but can also divert iTreg into Th9, while 4-1BBL seems to inhibit IL-9 production from iTreg and has not been studied for its ability to promote Th9 generation. Regulation of IL-9 production by TNF family cytokines has repercussions in vivo, including enhancement of anti-tumor immunity and immunopathology in allergic lung and ocular inflammation. Regulating T cell production of IL-9 through blockade or agonism of TNF family cytokine receptors may be a therapeutic strategy for autoimmune and allergic diseases and in tumor.
http://ift.tt/2gCIlMB
Discovery and initial characterization of Th9 cells: the early years
Abstract
The launch of the Th1/Th2 concept represented a decisive breakthrough concerning our understanding of how very diverse immune reactions can be regulated by functionally different T helper subpopulations via the secretion of different panels of cytokines. In this context, IL-9 was identified to be produced by T helper cell lines in addition to Th2 cytokines IL-4 and IL-5. Detailed analyses revealed that IL-9 production of mouse CD4+ T helper cells was dependent on a combination of IL-2, IL-4, and TGF-β. Roughly a decade later, it was found that TGF-β can also induce the development of CD4+ Treg cells. This finding engendered a series of studies on the central role of TGF-β for cytokine-mediated T helper cell differentiation which elucidated that IL-4 curbed the Treg cell-promoting effect of TGF-β while TGF-β impaired the Th2-promoting capacity of IL-4. Instead, TGF-β in combination with IL-4 induced the development of CD4+ T helper cells that preferentially produced IL-9 and that were different from Th2 cells which originally were thought to be the main source of IL-9. In addition, adoptive transfer of such IL-9-producing CD4+ T helper cells was shown to cause the development of colitis and peripheral neuritis. Hence, the unique cytokine expression pattern in combination with the inflammatory in vivo phenotype led to the designation of Th9 cells as a new CD4+ T helper subpopulation.
http://ift.tt/2gCLU5L
Community healthcare professionals overestimate the risk of fatal anaphylaxis for food allergic children
Summary
Background
Fatal food anaphylaxis is rare, but a major concern for people with food allergy and their carers. We evaluated whether community healthcare professionals accurately estimate risk of fatal anaphylaxis for food allergic children, and whether accurate risk estimation is related to competence in recognizing and managing anaphylaxis.
Methods
We enrolled 90 community healthcare professionals in a cross-sectional survey – 30 primary care nurses, 30 school first aiders, 30 community pharmacists. Participant risk estimates for fatal and non-fatal anaphylaxis, and all-cause fatalities, were measured using a risk ladder. Participant anaphylaxis knowledge was assessed by questionnaire, and practical skills using a simulated anaphylaxis scenario.
Results
In all three groups, participants significantly overestimated the risk of fatal anaphylaxis for food allergic children, by a mean factor of 13.5-fold (95% CI 5.0, 31.6), but did not overestimate non-fatal anaphylaxis risk or all-cause fatality risk. We found no evidence of a relationship between successful adrenaline administration and risk estimation.
Conclusions and Clinical Relevance
In conclusion, we have found evidence that community pharmacists, school first aiders and primary care nurses in the UK systematically overestimate the risk of fatal anaphylaxis for a food allergic child. This overestimation may result in increased patient and carer anxiety. Community practitioners who manage childhood food allergy and anaphylaxis need to be educated about the level of risk for fatal anaphylaxis in such children.
http://ift.tt/2ftnXAv
Dual Drug-Loaded Biofunctionalized Amphiphilic Chitosan Nanoparticles: Enhanced Synergy between Cisplatin and Demethoxycurcumin against Multidrug-Resistant Stem-Like Lung Cancer Cells
Huang, WT; Larsson, M; Lee, YC; Liu, DM; Chiou, GY; (2016) Dual Drug-Loaded Biofunctionalized Amphiphilic Chitosan Nanoparticles: Enhanced Synergy between Cisplatin and Demethoxycurcumin against Multidrug-Resistant Stem-Like Lung Cancer Cells. European Journal of Pharmaceutics and Biopharmaceutics , 109 pp. 165-173. 10.1016/j.ejpb.2016.10.014 .
http://ift.tt/2gykIHu
Disappearing spots, the global decline of cheetah and what it means for conservation
Durant, SM; Mitchell, N; Groom, R; Pettorelli, N; Ipavec, A; Jacobson, AJ; Woodroffe, R; Durant, SM; Mitchell, N; Groom, R; Pettorelli, N; Ipavec, A; Jacobson, AJ; Woodroffe, R; Bohm, M; Hunter, LTB; Becker, M; Broekhuis, F; Bashir, S; Andresen, L; Aschenborn, O; Beddiaf, M; Belbachir, F; Belbachir-Bazi, A; Berbash, A; Machado, I; Breitenmoser, C; Chege, M; Cilliers, D; Davies-Mostert, H; Dickman, AJ; Fabiano, E; Farhadinia, M; Funston, P; Henschel, P; Horgan, J; de Iongh, H; Jowkar, H; Klein, R; Lindsey, P; Marker, L; Marnewick, K; Melzheimer, J; Merkle, J; Msoka, J; Msuha, M; O'Neill, H; - view fewer (2016) Disappearing spots, the global decline of cheetah and what it means for conservation. Proceedings of the National Academy of Sciences of USA (In press).
http://ift.tt/2fEGe96
Critical Urban Cosmopolitanism and the Governance of Urban Diversity in European Cities
Raco, M; (2017) Critical Urban Cosmopolitanism and the Governance of Urban Diversity in European Cities. European Urban and Regional Studies (In press).
http://ift.tt/2gyroFK
Controllable pulse parameter TMS and TMS-EEG as novel approaches to improve neural targeting with rTMS in human cerebral cortex
Hannah, R; Rocchi, L; Tremblay, S; Rothwell, JC; (2016) Controllable pulse parameter TMS and TMS-EEG as novel approaches to improve neural targeting with rTMS in human cerebral cortex. Frontiers in Neural Circuits , 10 , Article 97. (In press). Green open access
http://ift.tt/2fEJAZU
Investigating nutrition and lifestyle factors as determinants of abdominal obesity: An environment-wide study
Wulaningsih, W; Van Hemelrijck, M; Tsilidis, KK; Tzoulaki, I; Patel, C; Rohrmann, S; (2016) Investigating nutrition and lifestyle factors as determinants of abdominal obesity: An environment-wide study. International Journal of Obesity 10.1038/ijo.2016.203 . (In press).
http://ift.tt/2gytTrr
No harm, no foul?: Expert views on the future direction of marine antibiofouling technologies
Larsson, LM; Vandeleur, HM; Nyden, M; Styan, CA; (2016) No harm, no foul?: Expert views on the future direction of marine antibiofouling technologies. In: Chemeca 2016: Chemical Engineering - Regeneration, Recovery and Reinvention. (pp. pp. 995-1006). Engineers Australia: Melbourne, Victoria, Australia.
http://ift.tt/2fEGVPz
Stochastic multi-scale models of competition within heterogeneous cellular populations: Simulation methods and mean-field analysis
Cruz, RDL; Guerrero, P; Spill, F; Alarcón, T; (2016) Stochastic multi-scale models of competition within heterogeneous cellular populations: Simulation methods and mean-field analysis. Journal of Theoretical Biology , 407 (C) pp. 161-183. 10.1016/j.jtbi.2016.07.028 . Gold open access
http://ift.tt/2gyrm0F
Targeting the muscle for the treatment and prevention of hepatic encephalopathy
Rombouts, K; Bemeur, C; Rose, CF; (2016) Targeting the muscle for the treatment and prevention of hepatic encephalopathy. Journal of Hepatology , 65 (5) pp. 876-878. 10.1016/j.jhep.2016.06.004 . Green open access
http://ift.tt/2fEJAsS
Bad air gets under your skin
Abstract
Air pollution is increasing beyond previous estimates and is viewed as the world's largest environmental health risk factor. Numerous clinical and epidemiological studies have highlighted the adverse effects of environmental pollutants on health. Although there is comparatively less research investigating the cutaneous effects of ambient pollution, there is growing recognition of the adverse effects on skin. In this article we provide an overview of the nature of environmental pollution and highlight the current evidence detailing the effects on cutaneous health. There is convincing evidence demonstrating that air pollution has a detrimental impact on skin and can exacerbate skin disease. Further epidemiological and experimental studies are required to assess the short and long term deleterious effects of ambient pollutant exposure on skin. The future challenge would be to use this evidence to develop specific strategies to protect against pollution-induced damage and prevent the effects of 'bad air getting under our skin'.
This article is protected by copyright. All rights reserved.
http://ift.tt/2gymWGW
Dihydroavenanthramide D inhibits mast cell degranulation and exhibits anti-inflammatory effects through the activation of neurokinin 1 receptor
Abstract
Chronic pruritus is difficult to treat. Current treatment options are frequently ineffective and new therapeutic approaches are urgently needed. Avenanthramides are active substances in oats that exhibit anti-inflammatory effects. Their potential to interrupt pruritus mechanisms was investigated in this study. It was found that the synthetic analog dihydroavenanthramide D (DHAvD) can interact with the neurokinin-1 receptor (NK1R) and inhibit mast cell degranulation. DHAvD also affects inflammatory processes and reduces secretion of the cytokine interleukin-6. Our findings indicate that DHAvD may act as a NK1R inhibitor and could be a promising candidate for topical treatments of chronic pruritus.
This article is protected by copyright. All rights reserved.
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Polyinosinic-polycytidylic acid (poly(I:C)) attenuates imiquimod-induced skin inflammation in mice by increasing cutaneous PD-L1 expression
Abstract
While the keratinocyte isivation in controlling skin inflammation.
This article is protected by copyright. All rights reserved.
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Low baseline levels of NK cells may predict a positive response to ipilimumab in melanoma therapy
Abstract
The introduction of immune checkpoint blockade (ICB) has been a breakthrough in the therapy of metastatic melanoma. The influence of ICB on T cell populations has been studied extensively but little is known about the effect on NK cells.
In this study, we analysed the relative and absolute amounts of NK cells and of the subpopulations of CD56dim and CD56bright NK cells among the peripheral blood mononuclear cells (PBMCs) of 32 patients with metastatic melanoma before and under treatment with ipilimumab or pembrolizumab by flow cytometry.
In 15 (47%) patients an abnormal low amount of NK cells was found at baseline. Analysis of the subpopulations showed also low or normal baseline levels for CD56dim NK cells, whereas the baseline levels of CD56bright NK cells were either normal or abnormally high.
The relative and absolute amounts of NK cells and of CD56dim and CD56bright NK cell subpopulations in patients with a normal baseline did not change under treatment. However, patients with a low baseline of NK cells and CD56dim NK cells showed a significant increase in these immune cell subsets, but the amounts remained to be lower than the normal baseline. The amount of CD56bright NK cells was unaffected by treatment.
The baseline levels of NK cells were correlated to the number of metastatic organs. Their proportion increased whereas the expression of NKG2D decreased significantly when more than one organ was affected my metastases.
Low baseline levels of NK cells and CD56dim NK cells as well as normal baseline levels of CD56bright NK cells correlated significantly with a positive response to ipilimumab but not to pembrolizumab.
Survival curves of patients with low amounts of CD56dim NK cells treated with ipilimumab showed a trend to longer survival. Normal baseline levels of CD56bright NK cells were significantly correlated with longer survival as compared to patients with high baseline levels.
In conclusion, analysis of the amounts of total NK cells and of CD56dim and CD56bright NK cells subpopulations at baseline may help to predict the outcome of treatment with ipilimumab.
This article is protected by copyright. All rights reserved.
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Endothelial cell-derived endothelin-1 is involved in abnormal scar formation by dermal fibroblasts through RhoA/Rho-kinase pathway
Abstract
Hypertrophic scars and keloids are characterized by excessive dermal deposition of extracellular matrix due to fibroblast-to-myofibroblast differentiation. Endothelin-1 (ET-1) is primarily produced by vascular endothelial cells, and plays multiple roles in the wound-healing response and organ fibrogenesis. In this study, we investigated the pathophysiological significance of ET-1 and involvement of RhoA, a member of the Rho GTPases, in hypertrophic scar/keloid formation. We found that ET-1 expression on dermal microvascular endothelial cells (ECs) in hypertrophic scars and keloids was higher than that in normal skin and mature scars. We also confirmed that ET-1 induced myofibroblast differentiation and collagen synthesis in cultured human dermal fibroblasts through the RhoA/Rho-kinase pathway. Finally, since hypertrophic scar/keloid formation was most prominent in areas exposed to mechanical stretch, we examined how mechanical stretch affected ET-1 secretion in human dermal microvascular ECs, and found that mechanical stretch increased ET-1 gene expression and secretion from ECs. Taken together, these results suggest that dermal microvascular ECs release ET-1 in response to mechanical stretch, and thereby contribute to the formation of hypertrophic scars and keloids through the RhoA/Rho-kinase pathway.
This article is protected by copyright. All rights reserved.
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The biomarker landscape in mycosis fungoides and sézary syndrome
Abstract
The practice of preemptive individualized medicine is predicated on the discovery, development, and application of biomarkers in specific clinical settings. Mycosis fungoides and Sézary syndrome are the two most common type of cutaneous T-cell lymphoma, yet diagnosis, prognosis, and disease monitoring remain a challenge. In this review, we discuss the current state of biomarker discovery in mycosis fungoides and Sézary syndrome, highlighting the most promising molecules in different compartments. Further, we emphasize the need for continued multicenter efforts to validate available and new biomarkers and to develop prospective combinatorial panels of already discovered molecules.
This article is protected by copyright. All rights reserved.
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EMILIN3, an extracellular matrix molecule with restricted distribution in skin
Abstract
EMILIN3 is an extracellular matrix glycoprotein that displays a dynamic and restricted expression pattern in connective tissues during post-natal life. In this study, we report the characterization of EMILIN3 deposition in the skin. In addition, to unravel the functions of this protein in skin homeostasis, we generated Emilin3 null mice and provide evidence that EMILIN3 is dispensable for hair follicle growth and maintenance throughout adult life.
This article is protected by copyright. All rights reserved.
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Interleukin (IL)-6 modulates transforming growth factor -β receptor I and II (TGF-βRI and II) function in epidermal keratinocytes
Abstract
It been shown that IL-6 modulates TGF-β1 expression in fibroblasts, however; what role IL-6 plays concerning TGF-βR expression and function in skin is unknown. Therefore, the aim of this study was to investigate the mechanism by which IL-6 might modulates TGF-β receptors in skin.
Skin from WT, IL-6 overexpressing mice, and IL-6 treated keratinocyte cultures were analyzed for TGF-βRI and TGF-βRII expression via histology, PCR, and flow cytometry. Receptor function was assessed by cell migration, bromodeoxyuridine (BrdU) proliferation assays, and Smad7 expression and Smad2/3 phosphorylation. Receptor localization within the membrane was determined by co-immunoprecipitation.
IL-6 overexpression and treatment increased TGF-βRII expression in the epidermis. IL-6 treatment of keratinocytes induced TGF-βRI and II expression, and augmented TGF-β1-induced function as demonstrated through increased migration and decreased proliferation. Additionally, IL-6 treatment of keratinocytes altered receptor activity as indicated by altered Smad2/3 phosphorylation and increased Smad7 and membrane localization.
These results suggest that IL-6 regulates keratinocyte function by modulating TGF-βRI and II expression and signal transduction via trafficking of the receptor to lipid raft pools.
This article is protected by copyright. All rights reserved.
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Towards a bacterial treatment for armpit malodour
Abstract
Axillary malodour is a frustrating condition for many people. It can lead to significant discomforts and various psychological effects. The underarm microbiome generally plays a major role in axillary malodour formation. Not only the bacteria on the armpit epidermis, but especially those living in the sweat glands, sweat pores and hair follicles play a pivotal role in malodour development.
In order to treat underarm malodour, this viewpoint paper envisions a bacterial treatment. Replacing the autochthonous malodour causing microbiome with a non-odour causing microbiome, through an armpit bacterial transplantation or direct application of probiotics/non-odour causing bacteria could resolve the condition. Selective steering of the microbiome with prebiotics, biochemicals or plant extracts could likewise greatly help in improving the underarm odour. Elimination/inhibition of the 'bad bugs' and application/stimulation of the 'good bugs' should be part of the future treatment for axillary body odour.
This article is protected by copyright. All rights reserved.
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An Advanced Mouse Model for Human Skin Wound Healing
Abstract
Here we report a model for studying wound repair based on skin regenerated from human tissue culture-expanded cells. The reconstituted skin (hRSK) responds to injury similar to that of intact human skin, and its constituent cells contribute to the healing process. As we have demonstrrated that hRSK composed of GFP-labelled cells also heals "normally", we believe this model will be useful in analyzing the wound repair process using genetically modified human cells.
This article is protected by copyright. All rights reserved.
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SVEP1 plays a crucial role in epidermal differentiation
Abstract
SVEP1 is a recently identified multi-domain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell-cell adhesion in an integrin dependent-manner in osteogenic cells. In the present study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT-PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Down-regulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 down-regulation was associated with disturbed differentiation and marked epidermal acanthosis in three-dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs. low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homeostasis in vivo, we down regulated SVEP1 in zebra fish embryos with a Svep1-specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the center of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell-cell adhesion with disadhesion between cells in Svep1-deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.
This article is protected by copyright. All rights reserved.
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Beside to bench: JAK-inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus
Abstract
This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2-kinase inhibitor ruxolitinib. We investigated the in-vivo expression of phospho-JAK2 in CLE skin samples as well as the immunomodulatory in-vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE-typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases.
This article is protected by copyright. All rights reserved.
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Anterior chamber exudation in chronic myeloid leukaemia
Anterior chamber leukaemic hypopyon is a rare occurrence in chronic myeloid leukaemia. We discuss two cases marked by rapid exudation inside the anterior chamber, which were subsequently diagnosed as chronic myeloid leukaemia. The hypopyon in both the cases resolved on induction of chemotherapy.
http://ift.tt/2gzdX4S
Malignant melanoma of cervix
A 68-year-old woman presented with symptoms of bleeding per vaginum. On examination, a growth was seen in the cervix, clinically considered to be squamous cell carcinoma. The growth was confined to the cervix and did not involve the parametria. However, on biopsy it was diagnosed as malignant melanoma. She underwent surgery elsewhere and was advised chemotherapy as these tumours are aggressive; however, she refused chemotherapy. She has been on regular follow-up and has an ongoing survival and disease-free period of more than 5 years. Primary cervical malignant melanomas are very rare as compared with vulval and vaginal counterparts and should be considered in the histological differential diagnosis of poorly differentiated malignant neoplasms involving cervix. Moreover, it is important to rule out metastasis from common primary sites such as skin, oesophagus, uveal tract and anorectal region before considering diagnosis of primary cervical melanoma.
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Why so blue? A case of neonatal cyanosis due to congenital methaemoglobinaemia (HbM Iwate)
Description
A 2.18 kg male baby was born by elective caesarean section at 34+3 weeks to a primiparous mother with autosomal dominant congenital methaemoglobinaemia (HbM Iwate) and gestational diabetes. Having been asymptomatic throughout her life, she developed significant respiratory symptoms in the third trimester, possibly due to a superimposed acquired methaemoglobinaemia, which necessitated hospitalisation, red cell exchange and early delivery of her infant.
At birth, the baby remained cyanosed despite good respiratory effort, and congenital methaemoglobinaemia was presumed. However, he quickly developed moderate respiratory distress (presumably unrelated) and was managed with facial continuous positive airway pressure (CPAP) in the delivery room, demonstrating maximal preductal saturations of 73% in 100% oxygen.
In the neonatal unit, he was started on nasal high-flow therapy. Urgent echocardiography excluded heart disease, and chest X-ray was unremarkable. Saturation monitoring was deemed unreliable; therefore, respiratory support was weaned (and stopped within 48 hours) based on regular normal capillary...
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Unusual cause of pleuritic chest pain in a child
We present the case of a 5-year-old boy with hereditary multiple exostoses who presented with left-sided pleuritic chest pain. A CT scan of the chest revealed an intrathoracic exostosis in close association with the heart.
http://ift.tt/2gzd3Fh
VURD syndrome in an infant presenting with potentially fatal staphylococcal urinary tract infection and septicaemia
Description
A newborn (NB) boy was delivered at 39 weeks of gestation with 4160 g weight and an APGAR score of 8/9. The pregnancy was uneventful, with normal first and second trimester ultrasound. The third trimester ultrasound revealed an isolated right kidney hydronephrosis, a normal sized bladder without thickening of wall as well a normal amniotic fluid volume. Kidney and bladder ultrasound (KBU) scan performed 48 hours after birth showed persistence of right kidney hydronephrosis as well dilation of right ureter. The left kidney and ureter were normal and alteration in bladder volume, bladder wall thickness and posterior urethra were observed. Trimethoprim prophylaxis was started, and the NB was discharged home in good condition. At 1 month age he was revaluated and remained asymptomatic, with an appropriate weight gain. The parents reported normal micturition with good urinary stream, without straining or dribbling. No changes were found on physical examination and the bladder...
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Locking plate external fixation and negative pressure wound therapy for treatment of a primary infection in a closed clavicle fracture
Infection in a clavicle fracture is uncommon, but remains a challenging problem. A paucity of soft tissue coverage often combined with significant displacement and interfragmentary movement add complexity to an already difficult situation for effective infection treatment. External fixation in principle offers a means of achieving fracture stability, while the infection is being eradicated. We present the case of a closed clavicle fracture, initially treated conservatively, that presented 5 weeks later with infection. The fracture was definitively treated with external fixation using a locking plate positioned superficially to the skin, plus negative pressure wound therapy and subsequent secondary closure and antibiotic therapy. This case illustrates a novel method of treatment in this unusual presentation that was well tolerated by the patient and resulted in a good clinical outcome.
http://ift.tt/2gzcaNd
Acquired male urethral diverticulum: a rare entity treated in a one-stage procedure
Acquired male urethral diverticulum is a rare entity with most of the literature revolving around case reports or small case series. Up to two-thirds of cases are acquired, mostly as a result of trauma, stricture or infection. Infrequently, some cases develop as a complication of urological procedures, or even penile clamping. We present the case of an adult male with lower urinary tract symptoms, recurrent urinary infections and a history of multiple surgeries to treat a complicated perineal fistulae disease. With the help of imaging techniques, a bulbar urethral diverticulum was discovered. Owing to the symptomatic nature of the diverticulum, an open procedure was performed with excision and primary urethral anastomosis. No urinary symptoms were reported and follow-up imaging and flowmetry demonstrated very good functional outcome.
http://ift.tt/2fstE1w
Anterior Hypopituitarism and Treatment Response in Hunter Syndrome: A Comparison of Two Patients
Hypopituitarism is a clinically important diagnosis and has not previously been reported in Hunter syndrome. We contrast two cases with anatomic pituitary anomalies: one with anterior panhypopituitarism and the other with intact pituitary function. Patient 1, a 10-year-old boy with Hunter syndrome, was evaluated for poor growth and an ectopic posterior pituitary gland. Endocrine testing revealed growth hormone (GH) deficiency, secondary adrenal insufficiency, and tertiary hypothyroidism. An improvement in growth velocity with hormone replacement (GH, thyroxine, and corticosteroid) was seen; however, final adult height remained compromised. Patient 2, a 13-year-old male with Hunter syndrome, was evaluated for growth failure. He had a large empty sella turcica with posteriorly displaced pituitary. Functional endocrine testing was normal and a trial of GH-treatment yielded no significant effect. Panhypopituitarism associated with pituitary anomalies has not been previously reported in Hunter syndrome and was an incidental finding of significant clinical importance. In the setting of documented anterior hypopituitarism, while hormone replacement improved growth velocity, final height remained impaired. In patient 2 with equivocal GH-testing results, treatment had no effect on linear growth. These cases highlight the importance of careful clinical assessment in Hunter syndrome and that judicious hormone replacement may be indicated in individual cases.
http://ift.tt/2fIkpbW
Pembrolizumab and Lenvatinib in Treating Metastatic or Recurrent Differentiated Thyroid Cancer That Cannot Be Removed by Surgery
Interventions: Other: Laboratory Biomarker Analysis; Drug: Lenvatinib; Biological: Pembrolizumab
Sponsors: Academic and Community Cancer Research United; National Cancer Institute (NCI)
Not yet recruiting - verified November 2016
http://ift.tt/2fsuqLP
Comparison of Concomitant Cisplatin Versus Carboplatin and 5-fluorouracil With Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma
Interventions: Drug: cisplatin; Drug: carboplatin; Drug: 5-FU
Sponsors: University Medical Center Groningen; VU University Medical Center
Recruiting - verified November 2016
http://ift.tt/2gzaKlM
Targeting of the WT1 91–138 fragment to human dendritic cells improves leukemia-specific T-cell responses providing an alternative approach to WT1-based vaccination
Abstract
Due to its immunogenicity and overexpression concomitant with leukemia progression, Wilms tumor protein 1 (WT1) is of particular interest for immunotherapy of AML relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, WT1-specific T-cell responses have mainly been induced by vaccination with peptides presented by certain HLA alleles. However, this approach is still not widely applicable in clinical practice due to common limitations of HLA restriction. Dendritic cell (DC) vaccines electroporated with mRNA encoding full-length protein have also been tested for generating WT1-derived peptides for presentation to T-cells. Alternatively, an efficient and broad WT1 peptide presentation could be elicited by triggering receptor-mediated protein endocytosis of DCs. Therefore, we developed antibody fusion proteins consisting of an antibody specific for the DEC205 endocytic receptor on human DCs and various fragments of WT1 as DC-targeting recombinant WT1 vaccines (anti-hDEC205-WT1). Of all anti-hDEC205-WT1 fusion proteins designed for overcoming insufficient expression, anti-hDEC205-WT110–35, anti-hDEC205-WT191–138, anti-hDEC205-WT1223–273, and anti-hDEC205-WT1324–371 were identified in good yields. The anti-hDEC205-WT191–138 was capable of directly inducing ex vivo T-cell responses by co-incubation of the fusion protein-loaded monocyte-derived mature DCs and autologous T-cells of either healthy or HSCT individuals. Furthermore, the DC-targeted WT191–138-induced specific T-cells showed a strong cytotoxic activity by lysing WT1-overexpressing THP-1 leukemia cells in vitro while sparing WT1-negative hematopoietic cells. In conclusion, our approach identifies four WT1 peptide-antibody fusion proteins with sufficient production and introduces an alternative vaccine that could be easily translated into clinical practice to improve WT1-directed antileukemia immune responses after allo-HSCT.
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When the Patient Believes That the Organs Are Destroyed: Manifestation of Cotard’s Syndrome
Cotard's Syndrome (CS) is a rare clinical event described for the first time in 1880 by the neurologist and psychiatrist Jules Cotard and characterized by negation delusions (or nihilists). Immortality and hypochondriac delusions are also typical. Nowadays, it is known that CS can be associated with many neuropsychiatric conditions. In this article, we describe the case of a patient that believed not having more organs and having the body deformed and whose CS was associated with a bigger depressive disorder. Although the electroconvulsive therapy is the most described treatment modality in the literature, the reported case had therapeutic success with association of imipramine and risperidone.
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Volar Locking Plate Breakage after Nonunion of a Distal Radius Osteotomy
We report a 38-year-old male with a nonunion followed by plate breakage after volar plating of a distal radius osteotomy. Volar locking plates have added a new approach to the treatment of distal radius malunions, due to a lower morbidity of the surgical approach and the strength of the final construction, allowing early mobilization and return to function. Conclusion. Plate breakage is an uncommon complication of volar locking plate fixation. To our knowledge, few cases have been described after a distal radius fracture and no case has been described after a distal radius corrective osteotomy. In the present case, plate breakage appears to have occurred as a result of a combination of multiple factors as the large corrective lengthening osteotomy, the use of demineralized bone matrix instead of bone graft, and the inappropriate fixation technique as an unfilled screw on the osteotomy site, rather than the choice of plate.
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Enzyme’s ‘Editing’ Preferences Have Implications for Infertility and Cancer
To "turn off" particular regions of genes or protect them from damage, DNA strands can wrap around small proteins, called histones, keeping out all but the most specialized molecular machinery. Now, new research shows how an enzyme called KDM4B "reads" one and "erases" another so-called epigenetic mark on a single histone protein during the generation of sex cells in mice. The researchers say the finding may one day shed light on some cases of infertility and cancer.
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A Multi-Center Study on Anaphylaxis caused by Peanut, Tree Nuts and Seeds in Children and Adolescents
Abstract
Peanut (PN) and tree nuts (TNs) are common causes of anaphylaxis in Western countries but no information is available in Korea. To feature clinical characteristics of anaphylaxis caused by PN, TNs, and seeds, a retrospective medical record review was performed in 14 university hospitals in Korea (2009-2013).One hundred and twenty-six cases were identified, with the mean age of 4.9 years. PN, walnut (WN), and pine nut accounted for 32.5%, 41.3%, and 7.1%, respectively. The median values of specific IgE (sIgE) to PN, WN and pine nut were 10.50 kUA/L, 8.74 kUA/Land 4.61 kUA/L, respectively. Among 50 cases managed in the emergency department, 52.0% were treated with epinephrine, 66.0% with steroid, 94.0% with antihistamines, 36.0% with oxygen, and 48.0% with bronchodilator. In conclusion, WN, PN and pine nut were the 3 most common triggers of anaphylaxis in Korean children and anaphylaxis could occur at remarkably low levels of sIgE.
This article is protected by copyright. All rights reserved.
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From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis
An urgent need exists in the United States to establish treatment goals in psoriasis.
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Intra-Attack Vestibuloocular Reflex Changes in Ménière’s Disease
Ménière's attack has been shown to temporarily alter the vestibuloocular reflex (VOR). A patient with unilateral Ménière's disease was serially evaluated with the video Head Impulse Test during single, untreated episodes of acute vertigo. Spontaneous nystagmus activity was concurrently recorded in order to establish the three typical phases of Ménière's attack (irritative, paralytic, and recovery) and correlate them with VOR performance. The onset of attack was associated with a quick change in VOR gain on the side of the affected ear. While a rapidly progressive reduction of the VOR was evident at the paralytic nystagmus phase, in the recovery phase the VOR gain returned to normal and the direction of the previous nystagmus reversed. The membrane rupture potassium intoxication theory provides a good foundation with which to explain these dynamic VOR changes and the observed triphasic direction behavior of the spontaneous nystagmus. We additionally postulated that endolymphatic fluid displacement could have a synergic effect during the earliest phase of attack.
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Human papillomavirus–induced oropharyngeal cancer in Hispanics in the United States
Objectives/Hypothesis
Determine disparities in survival outcome and clinical presentation between Hispanic and non-Hispanic white patients with human papillomavirus–positive oropharyngeal squamous cell carcinoma.
Study Design
Retrospective clinical research.
Methods
Clinical data on Hispanics and non-Hispanic white patients with diagnosis of human papillomavirus/p16–positive oropharyngeal squamous cell carcinoma were drawn from a tumor registry from the University of Miami Hospitals and Clinics from 2008 to 2014.
Of 436 patients with oropharyngeal squamous cell carcinoma, 237 patents met inclusion criteria. Patient's age, gender, smoking history, alcohol history, race/ethnicity, tumor T stage, nodal N stage, and composite TNM stage were included in the analysis. Associations between race and other categorical variables were explored with χ2 test or Fisher exact test where appropriate. Survival curves were generated using the Kaplan-Meier method.
Results
Significant differences in clinical presentation was detected between Hispanic (N = 70) and non-Hispanic white (N = 167) patients. Hispanic human papillomavirus–positive oropharyngeal squamous cell carcinoma patients showed a higher proportion of women with disease, a higher proportion of patients presenting with tonsil rather than tongue base primary subsite cancer, and a higher proportion of patients who do not consume alcohol compared to non-Hispanic white human papillomavirus–positive oropharyngeal squamous cell carcinoma patients. A statistically significant survival difference between these two ethnic groups was not detected in the current dataset.
Conclusions
Unique differences in clinical presentations between Hispanic patients and non-Hispanic whites with human papillomavirus–positive oropharyngeal squamous cell carcinoma were detected. This may be the first study to report novel clinical presentation in Hispanic human papillomavirus–positive patients with oropharyngeal squamous cell carcinoma living in the United States.
Level of Evidence
4. Laryngoscope, 2016
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