http://sfaki.blogspot.gr/2017/04/nasal-ala-reconstruction-surgical.html
Skin tumours of the nasal ala are common and surgery is the treatment
of choice. Nasal ala reconstruction is challenging due to the reduced
mobility and unique features of its thick and sebaceous skin. The
natural arc of the ala and its boundary with the cheek are difficult
features to reproduce. One should bear in mind the functional and
cosmetic risks of nasal ala reconstruction. A distorted nasal contour
may impair the nasal valve; the alar rim may notch or elevate; facial
symmetry may be disrupted by blunting of the alar crease, trapdooring,
bridging of the nasofacial sulcus and poor colour and texture match.
Our aim is to review and compare the functional and cosmetic results
of different local flaps used to correct intermediate-thickness
defects on the nasal ala after surgical excision of cutaneous tumours.
We present representative patients who were treated at our
Dermatological Surgery Unit from June 2015 to September 2016.
The choice of the flap was adapted to the patients' physiognomy and
the defects' size: tunnelled island pedicle melolabial flap [Figure
1]; jigsaw puzzle advancement flap [Figure 2]; spiral flap [Figure 3];
dog-ear island pedicle flap [Figure 4] and banner melolabial
transposition flap [Figure 5]. Surgery was performed under
loco-regional anaesthesia, in an outpatient basis, followed by
prophylactic antibiotic therapy. There were neither immediate
complications nor subsequent flap necrosis. The tumours were
completely excised.
Figure 1: Female, 86-year-old, nodular ulcerated basal cell carcinoma
in the nasal ala: tunnelled island pedicle melolabial flap. (a)
Surgical plan, (b) primary defect, (c) secondary defect after
tunnelling of the flap, (d) immediate post-operative, (e and f) result
after healing (10 months after surgery).
Click here to view
Figure 2: Male, 76-year-old, nodular basal cell carcinoma on the nasal
ala: jigsaw puzzle advancement flap. (a) surgical plan, (b) primary
and secondary defects, (c) anchoring sutures secure the flap in place;
(d) immediate post-operative, (e) result after healing (3 months after
surgery).
Click here to view
Figure 3: Female, 76-year-old, nodular basal cell carcinoma on the
nasal ala: spiral flap, a combination of advancement and rotation. (a)
Surgical plan, (b) immediate post-operative, (c) result after healing
(2 months after surgery).
Click here to view
Figure 4: Female, 76-year-old, basal cell carcinoma on the nasal ala:
dog-ear island flap, combining two flaps: cheek advancement and
rotated island pedicle. (a) Surgical plan, (b) primary defect, (c)
immediate post-operative, (d) day 7 post-operative, (e) result after
healing (1 month after surgery).
Click here to view
Figure 5: Male, 83-year-old, two nodular basal cell carcinomas on the
nasal ala and dorsum: Banner's melolabial transposition flap. (a)
Surgical plan, (b) primary defect, (c) immediate post-operative, (d)
result after healing (7 months after surgery)
Click here to view
Facial symmetry was well preserved by the spiral and jigsaw puzzle
flaps [Figure 2] and [Figure 3]. The nasal sulcus was left intact by
the spiral flap as well as the tunnelled melolabial island flap
[Figure 1] and [Figure 3]. The melolabial flaps and the dog-ear island
flap allowed for the correction of larger defects on the nasal ala
[Figure 1], [Figure 4] and [Figure 5]. The dog-ear island flap [Figure
4] obtained a good result despite the large size of the primary
defect. Banner's melolabial transposition flap [Figure 5] was used to
correct a complex defect involving not only the nasal ala but also the
nasal dorsum and resulted in facial asymmetry due to trapdooring.
The small size of the defects that can be addressed by the spiral and
puzzle flaps may explain their superior cosmetic results.[1],[2] The
tunnelled melolabial island flap, although technically demanding, may
produce excellent results; compared to the cheek-to-nose interpolation
flap, the tunnelling technique offers the advantage of being one-stage
procedure. The dog-ear island flap is an adaptation of the cheek
advancement flap; despite its apparent complexity, it offers a viable
alternative to the melolabial flaps,[3] with a lower risk of trapdoor
effect and with proper preservation of the alar contour. The discussed
flaps are useful alternatives to the bilobed transposition flap and
the skin graft for the surgical reconstruction of the nasal ala.
When planning the surgery, it is important to assess the primary
defect on the nasal ala: size and location (medial or lateral), depth,
involvement of other cosmetic units/subunits and extension to the alar
rim, nasal tip or adjacent cheek. Several techniques have been
developed that are useful for the reconstruction of defects of the
nasal ala. Based on our experience and a review of the literature, we
present an algorithm [Table 1] to optimise the choices in the
reconstruction of intermediate-thickness defects in nasal ala. In
[Table 2], we review the main advantages and caveats of some of the
most useful surgical techniques for nasal ala
reconstruction.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]
Table 1: Nasal ala reconstruction: What is the optimal approach
according to the defects' size and location?
Click here to view
Table 2: Nasal ala reconstruction: major advantages and potential
caveats of different surgical techniques
Click here to view
In the nasal ala, given the paucity of surrounding skin and the
importance of minimising nasal ala distortion, flaps that recruit skin
from a distant site should be considered. Mastering different
techniques is essential for a surgeon to optimise treatment for each
patient. At the end of the day, the best choice depends on many
factors and should be adapted on a case-by-case basis and to the
surgeon's expertise.
--
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 17 Απριλίου 2017
Paediatric traumatic pneumomediastinum: the spinnaker sail sign
Description
A 20-month-old female infant was admitted to the emergency room after being run over by a car. She presented with pallor and signs of impaired peripheral perfusion, despite being conscious and alert. Signs of respiratory distress were recognised. There was a bilateral decrease of respiratory murmurs at pulmonary auscultation and her heart sounds were also diminished. Her peripheral oxygen saturation was 94% and her respiratory rate was 54 breaths per minute. A cervical and thoracic crepitus were present. There were no alterations at abdominal examination. Her blood pressure was 142/58 mmHg.
She presented with a Glasgow Coma Scale score of 15 and had normal reactive pupils. Facial oedema was observed and an epicranial haematoma was also detected. Haematological workup revealed a haemoglobin value of 12.9 g/dL.
A supine chest radiograph showed left hydropneumothorax, right pneumothorax and pulmonary contusion. This exam also showed significant pneumomediastinum revealing the spinnaker sail sign,...
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Serum Toll-Like Receptor-2, Toll-Like Receptor-4 Levels in Patients with HBeAg-Negative Chronic Viral Hepatitis B
Viral Immunology , Vol. 0, No. 0.
http://ift.tt/2ooc3qU
Detection of the Canine Parvovirus 2c Subtype in Australian Dogs
Viral Immunology , Vol. 0, No. 0.
http://ift.tt/2pbZZOH
Development and Validation of Monoclonal Antibody-Based Antigen Capture ELISA for Detection of Group A Porcine Rotavirus
Viral Immunology , Vol. 0, No. 0.
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Colistin-Resistant mcr-1-Positive Escherichia coli in Public Beaches, an Infectious Threat Emerging in Recreational Waters [PublishAheadOfPrint]
The emergence and rapid spread of colistin-resistant Escherichia coli carrying the mcr-1 gene has generated an urgent need to strengthen surveillance. We have performed a meticulous investigation of strains of this sort, resulting in the first identification of international clones of E. coli carrying IncX4 plasmid-mediated mcr-1 and blaCTX-M genes in recreational waters of public urban beaches in cities with high tourist turnover, highlighting a new environmental reservoir.
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In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia Coli in a Murine Thigh Infection Model [PublishAheadOfPrint]
Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug-resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six E. coli were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/L. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after administration of 2.5, 5, 10, 20, 40, and 80 mg/kg. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 0.34 to 2.58 mg/L, area under the concentration-time curve (AUC0-) values of 2.44 to 57.6 mg*h/L, and elimination half-lives of 3.9 to 17.6 h. Dose fractionation studies, were performed using total drug doses 6.25 mg/kg to 100 mg/kg fractionated into q6-, q8-, q12-, or q24-hourly regimens. Nonlinear regression analysis demonstrated 24h free drug AUC/MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy (R2 0.80). In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of eravacycline varied among pathogens. Mice were treated with two-fold increasing doses (range 3.125 to 50 mg/kg) of eravacycline every 12 hours. The mean fAUC/MIC magnitude associated with net stasis and 1-log kill endpoint were 27.97 ± 8.29 and 32.60 ± 10.85, respectively.
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Mycobacterium tuberculosis proteome response to anti-tuberculosis compounds reveals metabolic "escape" pathways that prolong bacterial survival [PublishAheadOfPrint]
Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of infecting organism, increasing the risk for the development of tolerance phenotype and drug-resistance. Studies indicate that M. tuberculosis (Mtb) takes several days to be killed upon treatment with lethal concentrations of antibiotics both in vitro and in vivo. To investigate how metabolic remodeling can enable transient bacterial survival during exposure with bactericidal concentrations of compounds, Mtb H37Rv strain was exposed to twice of the minimal inhibitory concentration of isoniazid, rifampicin, moxifloxacin, mefloquine or bedaquiline for 24h, 48h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using the quantitative shotgun mass spectrometry. Numerous sets of de novo bacterial proteins were identified over six-day treatment. Networking analysis and comparisons between each drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in non-pathogenic M. smegmatis extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in Mtb prevented the pathogen from escaping the fast killing in vitro and in macrophages as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.
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Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration [PublishAheadOfPrint]
Ceftazidime-avibactam 1.25 g every 8 hours was used to treat multi-drug resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Pre-filter plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 hours along with post-filter and ultrafiltrate concentrations at hours 2 and 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were Cmax 61.10 and 14.54 mg/L, Cmin 31.96 and 8.45 mg/L, t1/2 6.07 and 6.78 hours, Vss 27.23 and 30.81 liters, CLss 2.87 and 2.95 L/h, and AUC0-8 347.87 and 85.69 mg ⋅ h/L. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/L) throughout the 8 hour dosing interval. Mean CVVH extraction ratio % for ceftazidime and avibactam, respectively, were 14.44% and 11.53% and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 L/h and for avibactam it was 1.59 L/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data including multiple patients and dialysis modes are needed to verify the optimal dosing strategy of ceftazidime-avibactam during critical illness and CVVH.
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In-vitro study of ISApl1-mediated mobilization of the colistin resistance gene mcr-1 [PublishAheadOfPrint]
The plasmid-mediated mcr-1 gene encodes a phosphoethanolamine transferase conferring resistance to polymyxins. The mcr-1 gene is associated with insertion sequence ISApl1 (IS30 family). In-vitro mobilization assays demonstrated the functionality of the composite transposon structure ISApl1-mcr-1-ISApl1. Transposition generated a 2-bp duplication and occurred in AT-rich DNA regions. This is the first report demonstrating the mobility of the mcr-1 gene by transposition.
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In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-{beta}-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model [PublishAheadOfPrint]
The management of infections with New Delhi Metallo-beta-lactamase-1 (NDM) producing bacteria remains clinically challenging given the multi-drug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM+ Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against a MDR K. pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in > 2 log10CFU bacterial reduction, therefore, no in vivo synergy was observed.
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A Novel Non-Antibiotic Nitroglycerin Based Catheter Lock Solution for the Prevention of Intraluminal Central Venous Catheter Infections in Cancer Patients [PublishAheadOfPrint]
Background: For long-term central lines (CL), the lumen is the major source of central line associated bloodstream infections (CLABSI). Current standard of care for maintaining catheter patency includes flushing the CL with saline or heparin. Neither agent has any antimicrobial activity. Furthermore heparin may enhance staphylococcal biofilm formation. We evaluated the safety and efficacy of a novel non-antibiotic catheter lock solution for the prevention of CLABSI.
Patients and Methods: Between November 2015, and February 2016, we enrolled 60 patients with hematologic malignancies who had peripherally inserted central catheter (PICC) to receive the study lock solution. The study lock consisted of 15 or 30 micrograms/mL of nitroglycerin in combination with 4% sodium citrate and 22% ethanol. Each lumen was locked for at least 2 h once daily, prior to being flushed.
Results: After enrolling 10 patients at the lower nitroglycerin dose without evidence of toxicity, the dose was escalated to the higher dose (30 micrograms/ml). There was no serious related adverse events or episode of hypotension with lock administration. Two patients experienced mild transient adverse events (one headache and one rash) possibly related to the lock and that resolved without residual effect. CLABSI rate was 0 on lock days vs 1.6/1000 catheter-days (CD) off lock prophylaxis compared with a rate of 1.9/1000 CD at the institution in the same patient population.
Conclusions: The nitroglycerin-based lock prophylaxis is safe and well tolerated. It may prevent CLABSI when given daily to cancer patients. Large, prospective, randomized clinical trials are needed to validate these findings.
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Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene [PublishAheadOfPrint]
Terbinafine is one of the allylamine antifungal agents, whose target is squalene epoxidase (SQLE). This agent has been extensively used in the therapy of dermatophyte infections. The incidence of patients with tinea pedis or unguium tolerant to terbinafine treatment prompted us to screen terbinafine resistance of all Trichophyton clinical isolates from the laboratory of Centre Hospitalier Universitaire Vaudois collected over a three-year period, and to identify their mechanism of resistance. Among 2056 tested isolates, 17 ( 1%) showed reduced terbinafine susceptibility, all of which were found to harbor SQLE gene alleles with different single point mutations, leading to single amino acid substitutions at one of four positions (Leu393, Phe397, Phe415 and His440) of the SQLE protein. Point mutations leading to the corresponding amino acid substitutions were introduced into the endogenous SQLE gene of a terbinafine-sensitive Arthroderma vanbreuseghemii (formerly T. mentagrophytes) strain. All of the generated A. vanbreuseghemii transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the parent strain and to transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in A. vanbreuseghemii transformants expressing mutant forms of T. rubrum SQLE proteins. Considering that the genome size of dermatophytes is about 22 Mb, the frequency of terbinafine-resistant clinical isolates was strikingly high. Increased exposure to antifungal drugs could favor the generation of resistant strains.
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Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model [PublishAheadOfPrint]
The broadly neutralizing antibody (bNAb) VRC01, capable of neutralizing 91% of known HIV-1 isolates in vitro, is a promising candidate microbicide for preventing sexual HIV infection when administered topically to the vagina; however, accessibility to antibody-based prophylactic treatment by target populations in sub-Saharan Africa and other under-developed regions may be limited by the high cost and limited manufacturing capacity of conventionally produced antibodies. Intravaginal rings of the pod design (pod-IVRs) delivering Nicotiana-manufactured VRC01-N over a range of release rates have been developed. The pharmacokinetics and preliminary safety of VRC01-N pod-IVRs was evaluated in a rhesus macaque model. The devices sustained VRC01-N release for up to 21 days at controlled rates, with mean steady-state VRC01-N levels in vaginal fluids in the range 102 — 103 μg g-1 that were correlated with in vitro release rates. No adverse safety indications were observed. These findings indicate that VRC01-N pod-IVRs are a promising candidate topical microbicide against HIV-1 infection and merit further pre-clinical evaluation.
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Dissemination of mcr-1--Carrying Plasmids among Colistin-Resistant Salmonella Strains from Humans and Food-Producing Animals, Taiwan [PublishAheadOfPrint]
We detected the colistin-resistance gene mcr-1 in four Salmonella serovars isolated from humans and animals with diarrhea. The resistance gene was carried on different plasmids. One mcr-1—carrying conjugative plasmid, a variant of pHNSHP45, was disseminated among Salmonella isolates recovered from humans, pigs, and chickens.
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Simulating intestinal transporter and enzyme activity in a physiologically based pharmacokinetic model for tenofovir disoproxil fumarate [PublishAheadOfPrint]
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (p-glycoprotein), and intestinal degradation (carboxylesterase)....
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Deciphering heteroresistance to colistin in a Klebsiella pneumoniae isolate from Marseille, France [PublishAheadOfPrint]
Here, we report the description of a colistin-heteroresistant Klebsiella pneumoniae fortuitously isolated from the stool sample of a patient with suspicion of tuberculosis in public hospital of Marseille, France. In the colistin-resistant subpopulation, a mutation in the mgrB gene leading to a premature Stop-codon was found, and the hypermucoviscous phenotype was lost. Susceptibility to other antibiotics remained unchanged. To our knowledge, this is the first identification of such a colistin-heteroresistant Klebsiella pneumoniae isolate in France.
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Anti-influenza activity of Bacillus subtilis probiotic strain [PublishAheadOfPrint]
Among Bacillus bacteria, B. subtilis is the most productive species of antimicrobial compounds. In this study, we analyzed the activity of probiotic strain B. subtilis 3 against influenza virus. The antiviral effect of this strain has been demonstrated in vitro and in vivo. New peptide P18 produced by probiotic strain was isolated, purified, chemically synthesized, and characterized. Cytotoxicity studies demonstrated no toxic effect of P18 on Madin-Darby canine kidney (MDCK) cells, even in the highest tested concentration (100 μg/mL). Complete inhibition of influenza virus in vitro was observed at concentrations 12.5 — 100 μg/mL. Protective effect of P18 in mice was comparable with Tamiflu. Further study will assess the potential of peptide P18 as antiviral compound and as a promising candidate for the development of new antiviral vaccines.
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Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus [PublishAheadOfPrint]
The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four S. aureus strains were included. The telavancin MIC ranged from 0.06 — 0.25 mg/L and vancomycin MIC from 1 — 4 mg/L. Plasma pharmacokinetics of escalating doses (1.25, 5, 20 and 80 mg/kg) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed penetration into the ELF mirrored the percent free fraction (not protein bound) in plasma for each drug. Telavancin (0.3125 — 80 mg/kg/6h) and vancomycin (0.3125 — 1280 mg/kg/6h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity was observed in both models against all four strains. A sigmoid Emax model was used to determine the AUC/MIC exposure associated with net stasis and 1 log10 kill relative to the burden at the start of therapy. The 24 h plasma free drug AUC/MIC associated with stasis and 1 log kill were remarkably congruent. Net stasis for telavancin was noted at free drug AUC/MIC (fAUC/MIC) of 83 and 40.4 in the thigh and lung, respectively; and 1 log kill at 215 and 76.4, respectively. For vancomycin, the stasis fAUC/MIC was 77.9 and 45.3, respectively, and 1 log kill 282 and 113, respectively. Twenty-four h ELF total drug AUC/MIC targets in the lung model were very similar to 24 h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus.
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Identification and optimization of thienopyridine carboxamides as inhibitors of HIV regulatory complexes [PublishAheadOfPrint]
Viral regulatory complexes perform critical functions during virus replication and are important targets for therapeutic intervention. In HIV, the Tat and Rev proteins form complexes with multiple viral and cellular factors to direct transcription and export of the viral RNA. These complexes are composed of many proteins and are dynamic, making them difficult to fully recapitulate in vitro. Therefore we developed a cell-based reporter assay to monitor the assembly of viral complexes for inhibitor screening. We screened a small molecule library and identified multiple hits that inhibit the activity of the viral complexes. A subsequent chemistry effort was focused on a thieno[2,3-b]pyridine scaffold, examples of which inhibited HIV replication and the emergence from viral latency. Notable aspects of the SAR effort include migration to the regioisomeric thieno[2,3-c]pyridine ring system and the identification of analogs with single-digit nanomolar activity in both reporter and HIV infectivity assays, an improvement of >100-fold in potency over the original hits. These results validate the screening strategy employed and reveal a promising lead series for the development of a new class of HIV therapeutics.
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Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons [PublishAheadOfPrint]
Although genotype (GT) 4-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents: grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor, in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For grazoprevir, the EC50 value against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC50 value for grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range 0.11-0.33 nM; N=5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced grazoprevir antiviral activity by 137- and 47-fold, respectively in the background of the G162R replicon. For elbasvir, the EC50 value against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC50 value for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range 0.0002-34 nM; N=14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F/S, M31V and Y93H) indicated they conferred 15-, 4-, 2.5- and 7.5-fold potency losses respectively to elbasvir. The activity profiles of grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.
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In vivo efficacy of liposomal amphotericin B against wild type and azole-resistant Aspergillus fumigatus isolates in two different immunosuppressed models of invasive aspergillosis [PublishAheadOfPrint]
Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported (AAC, 2013, 57, 4, 1866–1871) that the efficacy of liposomal amphotericin B (L-AmB) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus. We here investigated the role of immune suppression, i.e. neutropenic and steroid-treated, on L-AmB efficacy in mice infected with a wild type (WT) and azole-resistant Aspergillus fumigatus harboring TR34/L98H mutation in cyp-51A gene.
Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of non-treated controls. A dose-response relationship was observed independent of the azole-resistant mechanism and immunosuppression used. In the neutropenic model, 100% survival was reached at a L-AmB dose of 16 mg/kg for the WT and the TR34/L98H isolate. In the steroid-treated group, 90.9 % and 100% survival was achieved for the WT and TR34/L98H isolate with a L-AmB dose of 16 mg/kg, respectively. In the neutropenic model, the 50% effective dose (ED50) was 1.40 (95% CI, 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate, and 2.40 (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group.
Overall, there were no significant differences in efficacy of L-AmB against wild type and azole-resistant isolates between the two different immunosuppressed conditions (P > 0.9). However, the required L-AmB exposure was significantly higher than immunocompetent model.
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High Resolution Melting Analysis for the Rapid Detection of Sequence Type 131 Escherichia coli [PublishAheadOfPrint]
Introduction E. coli belonging to sequence type 131 clonal complex (ST131) have been associated with the global distribution of fluoroquinolone and β-lactam resistance. Whole genome sequencing and multi-locus sequence typing identify sequence type but are expensive when evaluating large numbers of samples. This study was designed to develop a cost-effective screening tool using high resolution melting (HRM) analysis to differentiate ST131 from non-ST-131 E. coli in large sample populations in the absence of sequence analysis.
Methods The method was optimized using DNA from twelve E. coli isolates. Singleplex PCR was performed using 10 ng of DNA, Type-it HRM buffer and Multi-Locus Sequence Typing primers followed by multiplex PCR. Amplicon sizes ranged from 630-737 bp. Melt temperature peaks were determined by performing HRM analysis at 0.1°C resolution from 50-95°C on a Rotor-Gene Q 5-Plex HRM system. Derivative melt curves were compared between sequence types and analyzed by principal component analysis. A blinded study of 191 E. coli of ST131 and unknown sequence types validated this methodology.
Results This methodology returned 99.2% specificity (True Negative=124, False Positive=1) and 100% sensitivity (True Positive=66, False Negative=0).
Conclusion This HRM methodology distinguishes ST131 from non-ST131 E. coli without sequence analysis. The analysis can be accomplished in about 3 hours in any laboratory with a HRM-capable instrument and principal component analysis software. Therefore, this assay is a fast and cost-effective alternative to sequencing-based ST131 identification.
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Efflux attenuates the anti-bacterial activity of Q203 in Mycobacterium tuberculosis [PublishAheadOfPrint]
New and improved treatments for tuberculosis (TB) are urgently needed. Recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available anti-tuberculosis agents. The aim of this study was to evaluate the effectiveness of verapamil in combination with the anti-tuberculosis drug candidate Q203, which has recently been developed and is currently under clinical trials as a potential anti-tuberculosis agent. We evaluated changes of Q203 activity in the presence and absence of verapamil in vitro using the resazurin microplate assay and ex vivo using a microscopy-based phenotypic assay for the quantification of intracellular replicating mycobacteria. Verapamil increased the potency of Q203 against Mycobacterium tuberculosis both in vitro and ex vivo, indicating that efflux pumps are associated with the activity of Q203. Other efflux pump inhibitors also displayed an increase in Q203 potency, strengthening this hypothesis. Therefore, verapamil and Q203 may be a promising combinatorial strategy for anti-TB treatment to accelerate the elimination of M. tuberculosis.
http://ift.tt/2pc0Vmf
Potential toxicity of polymyxins in human lung epithelial cells [PublishAheadOfPrint]
Inhaled polymyxins are of considerable utility to achieve optimal exposure in the respiratory tract for the treatment of lung infections caused by multidrug-resistant Gram-negative pathogens. Current inhaled polymyxin therapy is empirical and often high doses are used which may lead to potential pulmonary adverse effects. This study aimed to investigate the effect of polymyxins on human lung epithelial cells (A549). Viability of A549 cells was examined after treatment with polymyxins using flow cytometry. Activation of caspase-3, -8, -9, expression of Fas ligand (FasL), loss of mitochondrial membrane potential and mitochondrial oxidative stress induced by polymyxin B was evaluated. The EC50 (95% CI) value of polymyxin B induced cell death was 1.74 mM (1.60 to 1.90 mM). Colistin was at least two-fold less toxic than polymyxin B while colistimethate (CMS) was non-toxic. With 2.0 mM polymyxin B, apoptotic cells were 30.6 ± 11.5% (mean ± SD) at 8 h and increased to 71.3 ± 3.72% at 24 h. Concentration- and time-dependent activation of caspase-3, -8 and -9 were evident while the activation of caspase-9 was more dramatic. Furthermore, polymyxin B caused concentration- and time-dependent FasL expression, production of mitochondrial reactive oxygen species and changes in mitochondrial membrane potential. This is the first study to demonstrate that both extrinsic death receptor pathway and intrinsic mitochondrial pathway are involved in polymyxin-induced toxicity in A549 cells. This knowledge base is critical for the development of novel strategies for the safe and effective inhalation therapy of polymyxins against Gram-negative 'superbugs'.
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Metabolic reprograming of anti-tumor immunity
Madhusudhanan Sukumar | Rigel J Kishton | Nicholas P Restifo
http://ift.tt/2oQlELl
How Should Physicians Respond to Latest Alopecia Research?
Dr Lipper discusses evidence and strategy for treating patients with alopecia areata.
Medscape Dermatology
http://ift.tt/2nWZisk
Movie Villains With Scars May Haunt Those With Skin Conditions
The scars and facial features of some of cinema's most terrifying villains may end up haunting people who share those traits, suggests a new study.
Reuters Health Information
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Nasal ala reconstruction: Surgical conundrum
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):55-58
http://ift.tt/2nWO3jw
Should advertising by aesthetic surgeons be permitted?
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):48-48
http://ift.tt/2nWK2LK
Autologous platelet-rich fibrin matrix in non-healing trophic ulcers in patients with Hansen's disease
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):3-7
Background: Non-healing trophic ulcers in Hansen's disease patients is one of the major causes for disability. It has been shown that autologous platelet-rich fibrin matrix (PRFM) is effective in healing chronic non-healing leg ulcers. Aim: The objective of this study is to demonstrate the efficacy of autologous platelet-rich fibrin matrix (PRFM) in non-healing trophic ulcers in patients treated for Hansen's disease. Design: A prospective study. Setting: An institution-based clinic. Participants: Seven treated patients with Hansen's disease, with a mean age of 38.33 years, with nine non-healing trophic ulcer of more than 6 weeks duration. Measurements: Photographs were taken before treatment and at every subsequent sitting. Area and volume were calculated at baseline and every subsequent sitting till the closure was achieved. Materials and Methods: The healthy ulcers were treated with PRFM at weekly intervals, repeated once a week for a maximum of five sittings as per requirement. Results: The mean percentage improvement in the area was 93.52%, and volume was 97.74% at the end of the second sitting. All ulcers closed by a maximum of five sittings. No adverse events were noted. Conclusion: PRFM for the treatment of trophic ulcers in treated patients with Hansen's disease is a feasible, safe, simple and inexpensive method.
http://ift.tt/2nWK2ve
Accelerated wound healing: Harnessing the power of platelets, biomaterials, stem cells and gene therapy
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):1-2
http://ift.tt/2pLl26R
Comparison of efficacy of autologous platelet-rich fibrin versus saline dressing in chronic venous leg ulcers: A randomised controlled trial
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):8-12
Background: Venous leg ulcer is a chronic condition, and various treatment modalities are available. Platelet-rich fibrin (PRF) is one of the newer modalities and it contains fibroblast growth factor (GF), vascular endothelial GF, angiopoitin and platelet-derived GF which enhances the wound healing. Hence, we conducted a randomised controlled trial to compare the efficacy of PRF versus saline dressing in chronic venous leg ulcers. Aim: This study aims to compare the efficacy of autologous PRF with saline dressing in patients with chronic venous leg ulcer and to compare the mean reduction in ulcer area at the end of 4 weeks. Materials and Methods: Fifteen patients with chronic venous leg ulcers of >6 months duration having an ulcer area of 1 cm × 1 cm to 5 cm × 5 cm were taken into the study and were randomly divided into two groups. Group 1: Patients received PRF dressing. Ten millilitres of patient's blood was taken and centrifuged at 3000 rpm for 15 min. A fibrin clot obtained in the middle of the tube was removed and used for dressing over the wound surface. It was repeated every week for 4 weeks. Group 2: Patients received saline dressings once a week for 4 weeks. The assessment of the ulcer size was done with the help of photographs, and ulcer area was measured. Results: The mean reduction in the area of the ulcer size in PRF group was 85.51%, and the mean reduction in the area of the ulcer size in Saline group was 42.74% which was statistically significant with a P< 0.001 and t = 4.11. Conclusion: We conclude that PRF dressing can be used as it is effective, inexpensive, safe and an outpatient procedure.
http://ift.tt/2nWNOoJ
Plaque like giant dermatofibroma: A case report
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):51-53
Dermatofibroma, also known as benign fibrous histiocytoma, is a soft-tissue tumour that usually occurs in the mid-adult life and shows a slight female predominance. Giant dermatofibroma, a very rare clinical variant, is characterised by its unusually large size, benign biological behaviour despite its large size and same histopathological characteristics as conventional dermatofibroma. We report a 63-year-old woman who presented with a large tumour on the scapular region which showed histopathological features of benign dermatofibroma.
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Using amniotic membrane as a novel method to reduce post-burn hypertrophic scar formation: A prospective follow-up study
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):13-17
Background: Several studies have shown that the application of amniotic membrane as a biological dressing in the management of burns is accompanied by rapid re-epithelialisation. In this follow-up study, we aimed to evaluate the possible role of amniotic membrane as an adjunct to split thickness skin grafting on reducing itching and severity of hypertrophic scar formation. Materials and Methods: From October 2013 to January 2015, in a prospective follow-up study, 54 patients (108 limbs) with second and third degree burns, covering 4%–15% of total body surface area (TBSA), were included in the study. All patients needed split-thickness skin grafts for burn-wound coverage. Selected patients had symmetric burns on two (upper or lower) extremities. Then, in every patient, the extremities were randomly divided into two groups: In one limb, the skin graft was traditionally fixed with skin staples (control group) and in the other limb, the skin graft was covered with an amniotic membrane (amnion group). Therefore, in every patient, the graft was covered with an amniotic membrane in one extremity and fixed with skin staples in the other extremity. Finally, after 6 months, the degree of itching and hypertrophic scar formation was compared between the two groups. Results: The study group was composed of 108 limbs in 54 patients (27 males and 27 females) with a mean age of 23.54 % 4.9 years and burn 9.03 % 2.69% TBSA. The patients were divided into two groups: 54 limbs in amnion group and 54 limbs in control group. In 59.25% of the cases, patient had less itching in the extremity covered with amniotic membrane. Furthermore, in 64.81% of the cases, patients had less hypertrophic scar formation in the extremity covered with amniotic membrane. These differences were statistically significant (P < 0.001). Conclusions: Amniotic membrane used as an adjunct in split thickness skin grafting is a novel modality which significantly reduces scar formation and itching that can be greatly distressing to burn patients. However, still more prospective well designed studies are needed to prove it.
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Successful management of dowling-degos disease with combination of Q-switched Nd: YAG and fractional carbon dioxide laser
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):60-62
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A comparative study of collagen dressing versus petrolatum gauze dressing in reducing pain at the donor area
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):18-21
Background: Skin graft is one of the commonly done procedures by plastic surgeons, dermato surgeons and general surgeons. Pain at the donor area is a common complaint by the patient. The skin graft donor site area is usually covered with petrolatum dressing dermatosurgeons. Aim: This study was done to compare collagen dressing with petroleum gauze dressing in control of post-operative pain on skin graft donor area. Materials and Methods: The study was done on forty patients, twenty as study group who received collagen dressing and twenty as control group who received petroleum gauze dressing. The procedure was randomly selected by permutated block size of four. The post-operative pain was assessed with numerical pain rating scale 0 to 10. Nursing staff did the recording of pain scale. The nursing staff was not aware whether patient had collagen or petroleum gauze dressing. Statistics: Statistical analysis used was independent 't'-test (two-sample test) and Levene's test. Results: Statistics proved that study group (collagen dressing) had lesser pain than control group (petroleum gauze dressing). Conclusion: The collagen sheet dressing on skin graft donor area reduces pain in post-operative period.
http://ift.tt/2pLelBz
Should advertising by aesthetic surgeons be permitted?
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):45-47
Cosmetic, aesthetic and cutaneous surgical procedures require qualified specialists trained in the various procedures and competent to handle complications. However, it also requires huge investments in terms of infrastructure, trained staff and equipment. To be viable advertising is essential to any establishment which provides cosmetic and aesthetic procedures. Business men with deep pockets establish beauty chains which also provide these services and advertise heavily to sway public opinion in their favour. However, these saloons and spas lack basic medical facilities in terms of staff or equipment to handle any complication or medical emergency. To have a level playing field ethical advertising should be permitted to qualified aesthetic surgeons as is permitted in the US and UK by their respective organisations.
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Nasolabial perforator flap for one-stage reconstruction of nasal defects
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):22-27
Background: The excellent freedom of movement and range of this flap when based on a the nasolabial perforator flap have not been sufficiently explored. In this study, along with demonstrating the other key advantages of this flap over its traditional counterpart, we will endeavour to fill these lacunae in the available literature. Materials and Methods: From February 2009 to February 2012, twenty patients with nasal defects were repaired with a nasolabial perforator flap in the Department of Plastic and Cosmetic Surgery at Sir Ganga Ram Hospital, New Delhi. Of these, two patients (10%) underwent the procedure bilaterally. Thus, a total of 22 nasolabial perforator flap procedures were carried out. Prospectively, collected clinical records and data of each patient were retrospectively retrieved and reviewed to study the nasal defect and surgery done. Results: All the twenty (100%) patients had good functional and aesthetic outcome. All patients who had nasal stenosis preoperatively had very good improvement in the patency of the nasal passages, breathing and nasal blockage with complete recovery of symptoms. The patients were entirely satisfied with the functional recovery. Conclusions: The reliability and versatility of the nasolabial perforator flap exceed its recognised application in reconstruction of nasal defects and it must form a part of every plastic surgeon's armamentarium.
http://ift.tt/2pL9OiS
Spring-loaded syringe for multiple rapid injections
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):49-50
Mesotherapy refers to multiple injections of small quantity of the drug over a large area. The mesoguns available are expensive and the motor-driven models tends to waste the expensive material to be injected since the plunger stops after injecting without recoil. We searched for a less expensive device which would inject like the mesogun and still not waste the solution. On searching the web, we identified a spring-loaded syringe. We describe the assembly and use of this inexpensive syringe for delivering multiple injections with minimal wastage.
http://ift.tt/2nWKxG0
Intra-individual right-left comparative study of medium depth peels in superficial nail abnormalities
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):28-32
Background: Superficial nail abnormalities include conditions which produce nail surface changes such as trachyonychia, pitting and ridging. Mostly, this is a neglected area due to the dearth of treatment options. Glycolic acid peeling has been reported to be effective in such cases. Aim: This study aims to assess the safety and efficacy of medium depth peels (70% glycolic acid versus phenol combination peel [8% phenol with 15% trichloroacetic acid]) in patients with superficial nail abnormalities. Materials and Methods: A right-left comparative study in patients with superficial nail abnormalities was done. On the right finger or toenails phenol combination peels and on the left side 70% glycolic acid was used in a predefined protocol over 12 weeks. The severity was assessed objectively by a new devised index (Nail Surface abnormality Index (NSI]). Patient's subjective perception of severity was assessed by Visual Analogue Scale (VAS), and that of the physician was assessed by Physician's Global Assessment (PGA) scores. Results: A total of 17 patients were enrolled, two dropped out and 15 patients were included in the final analysis (mean age 19.2 years, total 120 nails treated). The mean NSI score declined from 7.88 % 0.45 to 4.02 % 0.45 on the right side; and from 8.0 % 0.45 to 4.32 % 0.44 on left side, at the end of 12 weeks. The VAS declined from 6.57 % 0.26 to 3.87 % 0.33 on right side and from 6.32 % 0.28 to 3.78 % 0.32 on left side. According to PGA score, five patients showed good improvement, seven showed moderate improvement and three responded poorly. Conclusion: Both the medium depth peels were found to be safe and equally efficacious modalities for treatment of superficial nail abnormalities.
http://ift.tt/2pLfvgD
Reconstruction with dorsal nasal flap after excision of basal cell carcinoma of the nose
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):54-55
http://ift.tt/2nWI5PP
Comparative study of efficacy and safety of botulinum toxin a injections and subcutaneous curettage in the treatment of axillary hyperhidrosis
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):33-39
Background: Primary focal axillary hyperhidrosis is a chronic distressing disorder affecting both the sexes. When the condition is refractory to conservative management, we should go for more promising therapies like intradermal botulinum toxin A (BtxA) injections in the axilla, and surgical therapies like subcutaneous curettage of sweat glands. Aims and Objectives: The aim of this study is to compare the efficacy, safety and duration of action of intradermal BtxA injections in one axilla and subcutaneous curettage of sweat glands in the other axilla of the same patient with axillary hyperhidrosis. Materials and Methods: Twenty patients (40 axillae) received intradermal BtxA injections on the right side (20 axillae) and underwent tumescent subcutaneous curettage of sweat glands on the left side (20 axillae). Sweat production rate was measured using gravimetry analyses at baseline and at 3 months after the procedure. Subjective analyses were done using hyperhidrosis disease severity scale (HDSS) score at baseline, at 3rd and 6th month after the procedure. Results: At 3 months post-treatment, the resting sweat rate in the toxin group improved by 80.32% versus 79.79% in the subcutaneous curettage method (P = 0.21). Exercise-induced sweat rate in the toxin group improved by 88.76% versus 88.8% in the subcutaneous curettage group (P = 0.9). There was a significant difference in the HDSS score after treatment with both the modalities. There were no adverse events with BtxA treatment compared to very minor adverse events with the surgical method. Conclusion: Both intradermal BtxA injections and tumescent subcutaneous curettage of sweat glands had a significant decrease in the sweat rates with no significant difference between the two modalities. Hence, in resource poor settings where affordability of BtxA injection is a constraint, subcutaneous curettage of sweat glands can be preferred which has been found equally effective with no or minimal adverse events.
http://ift.tt/2nWRQgC
Squamous cell carcinoma of the nail bed: The great mimicker
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):59-60
http://ift.tt/2pLkVIt
Long-pulsed Nd: YAG laser and intense pulse light-755 nm for idiopathic facial hirsutism: A comparative study
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):40-44
Background: Hirsutism means excessive terminal hair growth in a female in male pattern distribution. Perception of hirsutism is subjective. Permanent laser hair reduction is a slow process taking many sessions and tracking of improvement parameters is tedious. Hence, a lot of confusion still exists regarding the type of laser most beneficial for treatment. Aim: The aim of this study was to compare the effectiveness and safety profile of long-pulsed Nd: YAG laser (1064 nm) and intense pulse light (IPL)-755 nm in management of idiopathic facial hirsutism. Settings and Design: Open-labelled, randomly allocated experimental study. Subjects and Methods: The study included 33 cases of idiopathic facial hirsutism. Patients were randomly divided into Group A, treated with long-pulsed Nd: YAG laser and Group B, treated with IPL-755 for a total of six sessions at 1 month interval. Statistical Analysis: Chi-square test was used in Medcalc® version 9.0 and the test of significance was taken to be P< 0.05. Results: Average percentage of improvement in Group A, according to patients at each sessions were 46.33%, 70.66%, 81.66%, 84.67%, 85.33%, 87.33% and that in Group B were 28.06%, 39.72%, 52.22%, 64.72%, 67.78%, 71.11%, respectively. Excellent response (>75% reduction in hair) after six sessions in Group A was seen in fourteen (93.33%) out of fifteen patients, whereas in Group B, it was seen only in three (16.66%) out of eighteen patients. In Group A, erythema was seen in 26.67%, perifollicular edema and hyperpigmentation in 13.33% each. In Group B, erythema was seen in 50% patients, perifollicular edema in 16.67% and hyperpigmentation in 38.89% patients. Conclusions: Long-pulsed Nd: YAG Laser (1064 nm) is better than IPL-755 nm in terms of safety and effectiveness in the management of idiopathic facial hirsutism.
http://ift.tt/2pLkXQB
Erratum: Recurrent adult nasal dermoid cyst
Journal of Cutaneous and Aesthetic Surgery 2017 10(1):63-63
http://ift.tt/2pLjObR
The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis
Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses.
http://ift.tt/2psee1f
The effect of handedness and laterality in a microlaryngeal surgery simulator
There are no controlled prospective studies evaluating the effect of dominant handedness in left- and right-sided surgery in otolaryngology. Endoscopic microlaryngeal phonosurgery is an ideal procedure to assess technical aspects of handedness and laterality, due to anatomic symmetry. In this study, we analyzed (1) choice of surgical approach and (2) outcomes based on handedness and laterality in a microlaryngeal simulator.
http://ift.tt/2pscOUD
Prevalence and Descriptive Epidemiology of Atopic Dermatitis and Its Impact on Quality of Life in Singapore
Abstract
Atopic dermatitis (AD) is a common, chronic, pruritic skin condition that is known to negatively impact the quality of life (QOL) of patients1,2. Due to its increasing prevalence, AD can impose a substantial economic burden on a country's healthcare system.3 A study in 2002 found a prevalence of 20.8% of AD in Singapore schoolchildren aged between 7 and 12 years4.
This article is protected by copyright. All rights reserved.
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Serum Endocan Levels in Children with Community-Acquired Pneumonia
Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.
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Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo [TRANSPLANTATION]
Azacitidine (AzaC) mitigates graft-versus-host disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust graft-versus-leukemia effect. Previous studies have failed to investigate the role of natural regulatory T cells (nTregs) on the mitigation of GvHD by AzaC, instead focusing on the generation of suppressive Tregs (CD4+CD25+FOXP3+) through the in vivo conversion of alloreactive donor T effectors (Teffs; CD4+CD25–FOXP3–) and the direct antiproliferative effects of AzaC on allogeneic T cells. Using B6.Foxp3DTR/GFP mice in which Tregs can be specifically ablated through administration of diphtheria toxin, we demonstrate that natural Tregs are required in the donor graft for AzaC to optimally protect against GvHD and that nTregs, unlike Teffs (CD3+FOXP3–), are resistant to the antiproliferative effects of AzaC. Gene expression analysis identified the potent cell cycle inhibitor, p21, was significantly upregulated in Teffs but not nTregs after treatment with AzaC. Furthermore, we demonstrate that Teffs deficient in p21 are less sensitive to the antiproliferative effects of AzaC. These results demonstrate that nTregs are essential for AzaC to fully protect against GvHD and have important clinical implications for future clinical trials testing AzaC as a novel method of GvHD prophylaxis in man.
http://ift.tt/2onyCMC
Identification of Novel STAT6-Regulated Proteins in Mouse B Cells by Comparative Transcriptome and Proteome Analysis [SYSTEMS IMMUNOLOGY]
The transcription factor STAT6 plays a key role in mediating signaling downstream of the receptors for IL-4 and IL-13. In B cells, STAT6 is required for class switch recombination to IgE and for germinal center formation during type 2 immune responses directed against allergens or helminths. In this study, we compared the transcriptomes and proteomes of primary mouse B cells from wild-type and STAT6-deficient mice cultured for 4 d in the presence or absence of IL-4. Microarray analysis revealed that 214 mRNAs were upregulated and 149 were downregulated >3-fold by IL-4 in a STAT6-dependent manner. Across all samples, ~5000 proteins were identified by label-free quantitative liquid chromatography/mass spectrometry. A total of 149 proteins was found to be differentially expressed >3-fold between IL-4–stimulated wild-type and STAT6–/– B cells (75 upregulated and 74 downregulated). Comparative analysis of the proteome and transcriptome revealed that expression of these proteins was mainly regulated at the transcriptional level, which argues against a major role for posttranscriptional mechanisms that modulate the STAT6-dependent proteome. Nine proteins were selected for confirmation by flow cytometry or Western blot. We show that CD30, CD79b, SLP-76, DEC205, IL-5Rα, STAT5, and Thy1 are induced by IL-4 in a STAT6-dependent manner. In contrast, Syk and Fc receptor–like 1 were downregulated. This dataset provides a framework for further functional analysis of newly identified IL-4–regulated proteins in B cells that may contribute to germinal center formation and IgE switching in type 2 immunity.
http://ift.tt/2oGqASA
Rip2 Is Required for Nod2-Mediated Lysozyme Sorting in Paneth Cells [MUCOSAL IMMUNOLOGY]
Paneth cells play an important role in maintaining intestinal homeostasis by secreting a large number of antimicrobial peptides into the intestinal lumen. In this study, we found that Rip2 is required for lysozyme sorting in Paneth cells in a manner that is dependent on Nod2, LRRK2, and Rab2a. Rip2 deficiency in mouse led to lysosomal degradation of lysozyme in Paneth cells and prevented the recruitment of Rab2a onto dense core vesicles (DCVs). Like Nod2 and LRRK2, Rip2 localizes to DCVs in Paneth cells, and its DCV localization depends on Nod2 and LRRK2. Thus, we delineated a genetic pathway, consisting of Nod2–LRRK2–Rip2–Rab2a, which is required for lysozyme sorting. Taken together, our results indicate that the lysozyme-sorting process in Paneth cells is orchestrated by a number of host factors and highlight the importance of Paneth cell function in intestinal homeostasis.
http://ift.tt/2oGxZBf
Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma [MUCOSAL IMMUNOLOGY]
The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.
http://ift.tt/2onbHRE
Inducible TAP1 Negatively Regulates the Antiviral Innate Immune Response by Targeting the TAK1 Complex [INNATE IMMUNITY AND INFLAMMATION]
The innate immune response is critical for host defense and must be tightly controlled, but the molecular mechanisms responsible for its negative regulation are not yet completely understood. In this study, we report that transporter 1, ATP-binding cassette, subfamily B (TAP1), a virus-inducible endoplasmic reticulum–associated protein, negatively regulated the virus-triggered immune response. In this study, we observed upregulated expression of TAP1 following virus infection in human lung epithelial cells (A549), THP-1 monocytes, HeLa cells, and Vero cells. The overexpression of TAP1 enhanced virus replication by inhibiting the virus-triggered activation of NF-B signaling and the production of IFNs, IFN-stimulated genes, and proinflammatory cytokines. TAP1 depletion had the opposite effect. In response to virus infection, TAP1 interacted with the TGF-β–activated kinase (TAK)1 complex and impaired the phosphorylation of TAK1, subsequently suppressing the phosphorylation of the IB kinase complex and NF-B inhibitor α (IBα) as well as NF-B nuclear translocation. Our findings collectively suggest that TAP1 plays a novel role in the negative regulation of virus-triggered NF-B signaling and the innate immune response by targeting the TAK1 complex.
http://ift.tt/2onBKrF
Hydrogen Peroxide Triggers a Dual Signaling Axis To Selectively Suppress Activated Human T Lymphocyte Migration [INNATE IMMUNITY AND INFLAMMATION]
H2O2 is an early danger cue required for innate immune cell recruitment to wounds. To date, little is known about whether H2O2 is required for the migration of human adaptive immune cells to sites of inflammation. However, oxidative stress is known to impair T cell activity, induce actin stiffness, and inhibit cell polarization. In this study, we show that low oxidative concentrations of H2O2 also impede chemokinesis and chemotaxis of previously activated human T cells to CXCL11, but not CXCL10 or CXCL12. We show that this deficiency in migration is due to a reduction in inflammatory chemokine receptor CXCR3 surface expression and cellular activation of lipid phosphatase SHIP-1. We demonstrate that H2O2 acts through an Src kinase to activate a negative regulator of PI3K signaling, SHIP-1 via phosphorylation, providing a molecular mechanism for H2O2-induced chemotaxis deficiency. We hypothesize that although H2O2 serves as an early recruitment trigger for innate immune cells, it appears to operate as an inhibitor of T lymphocyte immune adaptive responses that are not required until later in the repair process.
http://ift.tt/2oGuN8G
Identification of C3b-Binding Small-Molecule Complement Inhibitors Using Cheminformatics [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions. Despite several potential advantages of modulating complement with small-molecule inhibitors, small-molecule drugs are highly underrepresented in the current complement-directed therapeutics pipeline. In this study, we have employed a cheminformatics drug discovery approach based on the extensive structural and functional knowledge available for the central proteolytic fragment of the cascade, C3b. Using parallel in silico screening methodologies, we identified 45 small molecules that putatively bind C3b near ligand-guided functional hot spots. Surface plasmon resonance experiments resulted in the validation of seven dose-dependent C3b-binding compounds. Competition-based biochemical assays demonstrated the ability of several C3b-binding compounds to interfere with binding of the original C3b ligand that guided their discovery. In vitro assays of complement function identified a single complement inhibitory compound, termed cmp-5, and mechanistic studies of the cmp-5 inhibitory mode revealed it acts at the level of C5 activation. This study has led to the identification of a promising new class of C3b-binding small-molecule complement inhibitors and, to our knowledge, provides the first demonstration of cheminformatics-based, complement-directed drug discovery.
http://ift.tt/2onwtRc
Vigilin Regulates the Expression of the Stress-Induced Ligand MICB by Interacting with Its 5' Untranslated Region [INNATE IMMUNITY AND INFLAMMATION]
NK cells are part of the innate immune system, and are able to identify and kill hazardous cells. The discrimination between normal and hazardous cells is possible due to an array of inhibitory and activating receptors. NKG2D is one of the prominent activating receptors expressed by all human NK cells. This receptor binds stress-induced ligands, including human MICA, MICB, and UL16-binding proteins 1-6. The interaction between NKG2D and its ligands facilitates the elimination of cells under cellular stress, such as tumor transformation. However, the mechanisms regulating the expression of these ligands are still not well understood. Under normal conditions, the NKG2D ligands were shown to be posttranscriptionally regulated by cellular microRNAs and RNA-binding proteins (RBPs). Thus far, only the 3' untranslated regions (UTRs) of MICA, MICB, and UL16-binding protein 2 were shown to be regulated by RBPs and microRNAs, usually resulting in their downregulation. In this study we investigated whether MICB expression is controlled by RBPs through its 5'UTR. We used an RNA pull-down assay followed by mass spectrometry and identified vigilin, a ubiquitously expressed multifunctional RNA-binding protein. We demonstrated that vigilin binds and negatively regulates MICB expression through its 5'UTR. Additionally, vigilin downregulation in target cells led to a significant increase in NK cell activation against said target cells. Taken together, we have discovered a novel mode of MICB regulation.
http://ift.tt/2oGpSVf
IL-26 Confers Proinflammatory Properties to Extracellular DNA [INNATE IMMUNITY AND INFLAMMATION]
In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10–based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26–DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation.
http://ift.tt/2onmew2
Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation [INNATE IMMUNITY AND INFLAMMATION]
Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency (Il22ra2–/–) displayed exacerbated disease that associated with enhanced expression of IL-22–inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti–IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22–inducible molecules (IL-20, IL-24, IL-36, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis.
http://ift.tt/2oGonX0
Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation [INNATE IMMUNITY AND INFLAMMATION]
The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B–form DNA, cGAS synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized. In this study we used a single-molecule technique combined with traditional biochemical and cellular assays to demonstrate that binding of nonspecific dsDNA by the N-terminal domain of cGAS promotes its activation. We have observed that the N terminus of human cGAS (hcGAS-N160) undergoes secondary structural change upon dsDNA binding in solution. Furthermore, we showed that the hcGAS-N160 helps full length hcGAS to expand the binding range on DNA and facilitates its binding efficiency to dsDNA compared with hcGAS without the 160 N-terminal residues (hcGAS-d160). More importantly, hcGAS-N160 endows full length hcGAS relatively higher enzyme activity and stronger activation of STING/IRF3-mediated cytosolic DNA signaling. These findings strongly indicate that the N-terminal domain of cGAS plays an important role in enhancing its function.
http://ift.tt/2onEMfB
Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury [INNATE IMMUNITY AND INFLAMMATION]
Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (TH1/TH17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and TH1/TH17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.
http://ift.tt/2oGOInZ
IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide [INNATE IMMUNITY AND INFLAMMATION]
Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-B, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3–/– male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3–/– mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3–/– mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-–inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3–/– neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.
http://ift.tt/2ony3m0
The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages [INNATE IMMUNITY AND INFLAMMATION]
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun–deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
http://ift.tt/2oGvDSM
Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery [INNATE IMMUNITY AND INFLAMMATION]
Neutrophils are key effector cells in inflammation and play an important role in neutralizing invading pathogens. During inflammation resolution, neutrophils undergo apoptosis before they are removed by macrophages, but if apoptosis is delayed, neutrophils can cause extensive tissue damage and chronic disease. Promotion of neutrophil apoptosis is a potential therapeutic approach for treating persistent inflammation, yet neutrophils have proven difficult cells to manipulate experimentally. In this study, we deliver therapeutic compounds to neutrophils using biocompatible, nanometer-sized synthetic vesicles, or polymersomes, which are internalized by binding to scavenger receptors and subsequently escape the early endosome through a pH-triggered disassembly mechanism. This allows polymersomes to deliver molecules into the cell cytosol of neutrophils without causing cellular activation. After optimizing polymersome size, we show that polymersomes can deliver the cyclin-dependent kinase inhibitor (R)-roscovitine into human neutrophils to promote apoptosis in vitro. Finally, using a transgenic zebrafish model, we show that encapsulated (R)-roscovitine can speed up inflammation resolution in vivo more efficiently than the free drug. These results show that polymersomes are effective intracellular carriers for drug delivery into neutrophils. This has important consequences for the study of neutrophil biology and the development of neutrophil-targeted therapeutics.
http://ift.tt/2onjIWQ
Serum Endocan Levels in Children with Community-Acquired Pneumonia
Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.
http://ift.tt/2oPT4JZ
Folic Acid – Who does what with Methotrexate?
Abstract
Methotrexate is a folic acid derivative that inhibits dihydrofolate reductase which has effects on DNA synthesis and cellular replication. In Dermatology, it is licensed for use in recalcitrant psoriasis but is also used off-label in many other conditions.1
It is given either orally or by subcutaneous injection. Folic acid is usually prescribed alongside methotrexate but there is often variation in prescribing practice.
This article is protected by copyright. All rights reserved.
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Oral Lichenoid Reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings
Abstract
Immune checkpoint inhibitors targeting the programmed cell death receptor-1 (PD-1) or its ligand (PD-L1) show broad activity across different tumor types and currently represent one of the keystones of cancer management. Dermatologic toxicities are one of the most frequent immune-related adverse events (irAEs) induced by these new monoclonal antibodies. Maculopapular rash, pruritus, exacerbation of psoriasis or more specific autoimmune disorders (e.g. vitiligo, alopecia areata, and bullous pemphigoid) are amongst the most commonly reported AEs.1-4 In addition, cutaneous lichenoid reaction has also emerged as one of the most prevalent dermatological toxicities in treated patients.
This article is protected by copyright. All rights reserved.
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Do outdoor workers know their risk of NMSC? Perceptions, beliefs and preventive behaviour among farmers, roofers and gardeners
Abstract
Background
Non-melanoma skin cancer (NMSC) was officially recognized in 2015 as an occupational disease for outdoor workers in Germany. Together with the enormous socioeconomic impact of NMSC, this has led to the continuous demand of evidence-based prevention. However, studies assessing the perceptions and beliefs along with risk behavior of outdoor workers as an essential prerequisite for prevention are rare.
Objective
To assess perceptions, beliefs, barriers, risk and preventive behavior towards non-melanoma skin cancer among different outdoor groups as a basis for the development of sustainable prevention programs.
Patients and Methods
Cross-sectional study among outdoor workers of three different occupational groups (farmer, gardener, roofer) using a 20-question online survey on NMSC awareness, risk and preventive behavior.
Results
Between March and April 2016, 353 outdoor workers participated in the study. Of these, 153 (43.4%) reported never to use sunscreen during work. Wearing headgear and long pants were the most common sun protection measures. Poor use of sunscreen was more likely in males and farmers. A low perceived skin cancer risk was significantly associated with poor use of sunscreen, long-sleeved shirts, sunglasses and headgear.
Conclusions
Despite great evidence on NMSC risk in outdoor professions throughout the literature, high risk groups in fact are not yet aware of the topic. Sustainable target group oriented awareness prevention programs are needed to lower the immense burden of NMSC.
This article is protected by copyright. All rights reserved.
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Prepubertal vulvar fibroma, a rare entity little-known to dermatologists: Report of two cases
Abstract
Prepubertal vulvar tumors are rare and may represent mesenchymal tumors, hamartomas, or vascular malformations. Their presentation may be similar but they do not have the same prognosis and management. We report 2 cases of labium majus hypertrophy corresponding to prepubertal vulvar fibromas.
This article is protected by copyright. All rights reserved.
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Lava lake structure and cloud-like structureless area: new clues for diagnosing extramammary Paget disease
Abstract
Extramammary Paget disease (EMPD) is a rare malignant skin neoplasm mostly found in the genital area. Its clinical and histopathological features are similar to mammary Paget disease. The clinical differential diagnosis includes various skin diseases. The dermoscopic findings of EMPD have been described in the literature.
This article is protected by copyright. All rights reserved.
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Genome-wide differential expression profiling of long non-coding RNAs in androgenetic alopecia in a Chinese male population
Abstract
Background
Androgenetic alopecia (AGA), or male pattern baldness (MPB), is the most common form of hair loss in males. A combination of genetic and androgen causes have been suggested as factors that contribute to the development of AGA. However, the specific molecular mechanisms that underly AGA remain largely unknown. Long noncoding RNAs (lncRNAs), a new class of regulatory noncoding RNAs that are longer than 200 nucleotides, have been shown to play important roles in a number of cellular processes, including transcription, chromosome remodelling, and posttranscriptional processing. The dysregulation of lncRNAs is associated with many forms of diseases, but it remains unknown whether lncRNAs are associated with AGA.
Objective
The aim of this study was to identify AGA-associated lncRNAs and predict the potential roles of these lncRNAs in AGA.
Methods
A genome-wide microarray was used to identify lncRNAs that are differentially expressed between AGA and adjacent normal tissues. Real-time qRT-PCR was used to validate the microarray data.
Results
A large number of lncRNAs were differentially expressed (fold change >2.4) between AGA and adjacent normal tissues. Of these, 770 were up-regulated, and 1,373 were down-regulated. Moreover, pathway analysis revealed that 53 functional pathways were associated with the up-regulated transcripts, while 11 pathways were associated with the down-regulated transcripts.
Conclusion
To our knowledge, this is the first study to investigate AGA-associated lncRNAs. LncRNA profiles are altered in AGA, and these lncRNAs and their target genes may serve as novel candidates for preventing and treating AGA.
This article is protected by copyright. All rights reserved.
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Prognostic risk factors of first recurrence in patients with primary stage I-II cutaneous malignant melanoma -from the population-based Swedish melanoma register
Abstract
Background
Prognostic factors in patients with localised primary cutaneous malignant melanoma (CMM) are well described. However, prognostic factors for recurrence are less documented.
Objectives
The aim of this study was to identify prognostic risk factors for first recurrence in patients with localised stage I-II CMM using population-based data.
Methods
This study included 1 437 CMM patients registered in one region of Sweden during 1999-2012 followed-up through December 31, 2012. To identify first recurrence of CMM disease, data from a care data warehouse, the pathology and radiology department registries were used. Patients were also followed through a census register and the national Cause of Death Register.
Results
The 5- and 10-year RFS were 85.7% and 81.2%, respectively. The most common site of first recurrence was regional lymph node metastasis closely followed by distant metastasis. After adjusting for all prognostic factors, women had 50% lower risk of recurrence than men (HR = 0.5, 95% CI 0.4 - 0.7) and patients ≥75 had higher risk compared to patients 55-69 years (HR = 1.7, 95% CI 1.2 - 2.5). Other significant prognostic factors for risk of recurrence were tumour thickness, presence of ulceration, Clark's level of invasion and histogenetic type.
Conclusion
Tumour thickness was found to be the predominant risk factor for recurrence. The prognostic factors for recurrence coincided with prognostic factors for CMM-death. The most common site of first recurrence in stage I-II CMM is regional lymph node (42.8%) closely followed by distant metastases (37.6%), a fact which has to be taken into consideration when choosing follow-up strategies.
This article is protected by copyright. All rights reserved.
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Reformulations of well-known active ingredients in the topical treatment of psoriasis vulgaris can improve clinical outcomes for patients
Abstract
Background
Although the majority of patients with psoriasis vulgaris are treated exclusively with topical therapies, research to develop more effective topical therapies that are associated with higher patient satisfaction has lagged behind the development of systemic agents.
Objective
The aim of this literature review was to determine whether there is documented evidence that applying an innovative approach to improving the formulation of active ingredients commonly used in the topical treatment of psoriasis can have a positive effect on clinical outcomes and patient-reported outcomes (PROs).
Methods
The Embase and PubMed databases were searched for articles published between 2001 and 2016 that made direct head-to-head comparisons of different formulations of an active pharmaceutical ingredient (API), focusing on clinical outcomes and PROs.
Results
In total, 22 publications on APIs or API combinations met the eligibility criteria (19 head-to-head clinical trials, one pooled analysis, one health-economic modelling study, and one systematic review). Significant clinical benefit associated with the use of a reformulated API over an older formulation was reported in three trials of clobetasol propionate, one trial of calcipotriol, three trials of betamethasone, and five trials/pooled analyses of calcipotriol/calcipotriene + betamethasone dipropionate (Cal/BD) formulations. Significantly improved PRO associated with the use of a reformulated API over an older formulation was reported in three trials of clobetasol propionate, one trial of betamethasone valerate, and two trials of Cal/BD formulations.
Conclusion
These results demonstrate that the innovative reformulation of APIs used in the treatment of psoriasis can produce therapies that attain significantly improved clinical outcomes and PROs. This suggests that improvement in topical therapy for psoriasis need not only to be achieved by the identification of new targets and the development of new APIs, but that improvement in the vehicle used to deliver existing APIs has the potential to result in significant clinical and patient benefits.
This article is protected by copyright. All rights reserved.
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Regulation of Th2 responses by different cell types expressing the interleukin-31 receptor
Interleukin-31 (IL-31) is a recently identified cytokine produced by Th2 cells that is involved in the development of atopic dermatitis-induced skin inflammation and pruritus. Its receptor, IL-31RA, is express...
http://ift.tt/2oEGw5W
Preconception allergen sensitization can induce B10 cells in offspring: a potential main role for maternal IgG
The mechanisms through which allergies can be inhibited after preconception immunization with allergens are not fully understood. We aimed to evaluate whether maternal immunization can induce a regulatory B (B...
http://ift.tt/2oEKPhL
Factors associated with lingual tonsil hypertrophy in Canadian adults
Hypertrophy of the lingual tonsil tissue in the adult patient is thought to contribute to the pathophysiology of obstructive sleep apnea. The underlying etiology of lingual tonsil hypertrophy (LTH) in the adul...
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Factors associated with lingual tonsil hypertrophy in Canadian adults
Abstract
Background
Hypertrophy of the lingual tonsil tissue in the adult patient is thought to contribute to the pathophysiology of obstructive sleep apnea. The underlying etiology of lingual tonsil hypertrophy (LTH) in the adult patient is unclear and likely multifactorial. Previous studies have suggested that the lingual tonsils may undergo compensatory hyperplasia post-tonsillectomy in children, although it is unknown if this occurs or persists into adulthood. The purpose of this study was to determine what factors are associated with LTH in a population of Canadian adults.
Methods
Adult patients presenting for consultation to an academic Rhinology/General Otolaryngology practice were eligible for enrollment. Demographic data including age, body mass index (BMI), Reflux Symptom Index (RSI), history of allergy, and history of tonsillectomy was collected via questionnaire. Endoscopic photographs of the base of tongue and larynx were captured. These were graded for LTH and Reflux Finding Scale (RFS) by blinded examiners. Statistical analysis was performed by comparing the mean LTH value to the variables of interest using two-tailed T-test. P < .05 was considered significant.
Results
One hundred two subjects were enrolled. Age ranged from 18 to 78. 28 patients had previous tonsillectomy. This was not associated with a significant increase in lingual tonsil tissue (r = −0.05, p = 0.61). RFS >7 or RSI >13 was considered positive for laryngopharyngeal reflux. There was no difference in LTH based on RSI positivity (p = 0.44). RFS positivity correlated with increased lingual tonsil tissue (p < 0.05). BMI >30 was associated with increased lingual tonsil hypertrophy (p < 0.05).
Conclusions
An elevated body mass index and positive Reflux Finding Score are associated with lingual tonsil hypertrophy in adults. Reflux symptom index, history of allergy and history of childhood tonsillectomy are not associated with LTH.
http://ift.tt/2oPeUx8
The Blood Brain Barrier and Neuropsychiatric Lupus: New perspectives in light of advances in understanding the neuroimmune interface
Source:Autoimmunity Reviews
Author(s): Ariel D. Stock, Sivan Gelb, Ofer Pasternak, Ayal Ben-Zvi, Chaim Putterman
Experts have previously postulated a linkage between lupus associated vascular pathology and abnormal brain barriers in the immunopathogenesis of neuropsychiatric lupus. Nevertheless, there are some discrepancies between the experimental evidence, or its interpretation, and the working hypotheses prevalent in this field; specifically, that a primary contributor to neuropsychiatric disease in lupus is permeabilization of the blood brain barrier. In this commonly held view, any contribution of the other known brain barriers, including the blood-cerebrospinal fluid and meningeal barriers, is mostly excluded from the discussion. In this review we will shed light on some of the blood brain barrier hypotheses and try to trace their roots. In addition, we will suggest new research directions to allow for confirmation of alternative interpretations of the experimental evidence linking the pathology of intra-cerebral vasculature to the pathogenesis of neuropsychiatric lupus.
http://ift.tt/2pqbdi8
Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: A systematic review
Source:Autoimmunity Reviews
Author(s): Bernd Merkel, Helmut Butzkueven, Anthony L. Traboulsee, Eva Havrdova, Tomas Kalincik
BackgroundImmunotherapy initiated early after first presentation of relapsing-remitting multiple sclerosis is associated with improved long-term outcomes. One can therefore speculate that early initiation of highly effective immunotherapies, with an average efficacy that is superior to the typical first-line therapies, could further improve relapse and disability outcomes. However, the most common treatment strategy is to commence first-line therapies, followed by treatment escalation in patients who continue to experience on-treatment disease activity. While this monitoring approach is logical, the current lack of effective regenerative or remyelinating therapies behoves us to consider high-efficacy treatment strategies from disease onset (including induction therapy) in order to prevent irreversible disability.ObjectiveIn this systematic review, we evaluate the effect of high-efficacy immunotherapies at different stages of MS.MethodsA systematic review of literature reporting outcomes of treatment with fingolimod, natalizumab or alemtuzumab at different stages of MS was carried out.Results and conclusionsTwelve publications reporting relevant information were included in the systematic review. The literature suggests that treatment with high-efficacy immunotherapies is more potent in suppressing relapse activity when initiated early vs. with a delay after the MS diagnosis. The evidence reported for disability and MRI outcomes is inconclusive.
http://ift.tt/2ppX3xG
For Keeping X Chromosomes Active, Chromosome 19 Marks The Spot
After nearly 40 years of searching, Johns Hopkins researchers report they have identified a part of the human genome that appears to block an RNA responsible for keeping only a single X chromosome active when new female embryos are formed, effectively allowing for the generally lethal activation of more than one X chromosome during development. Because so-called X-inactivation is essential for normal female embryo development in humans and other mammals, and two activated X chromosomes create an inherently fatal condition, the research may help explain the worldwide human sex ratio that has slightly favored males over females for as long as science has been able to measure it. The results appear online in the April 12 issue of the journal PLOS ONE.
http://ift.tt/2pJ7TLG
Testosterone Reduces Promiscuity of Female Blue Tits (Cyanistes caeruleus): An Experimental Study
In many animal species, extra-pair copulations (EPCs) are common and can increase fitness in both sexes. In males, EPCs can increase total reproductive output, whereas in females benefits of EPCs can be indirect through improving the genetic quality of their offspring. Males and females of many vertebrates show an increase in levels of the hormone testosterone (T) during the mating period. In males, T plays an important role in regulating mating behaviour including increasing their EPC rate. While much is known about the role of T in male mating behaviour, the role of T in female reproduction remains unclear. To study the influence of T on extra-pair paternity rates in females in a field setting, we created three experimental groups of female blue tits (Cyanistes caeruleus): treated with either T, flutamide (Flu; an androgen receptor blocker) or empty implants before egg laying. Subsequently, we scored the number of extra-pair offspring (EPO) in their broods. We also assessed the attractiveness of females treated with either T or Flu to males in mate choice trials in the laboratory. The overall proportion of EPO was lower for the T-implanted group compared with the control group, whereas Flu had no effect. Given that males did not show a preference for Flu- vs. T-treated females in the mate choice trials, it appears less likely that the reduction in EPO in the T-implanted females was due to a reduction in their attractiveness. T levels may have negatively influenced EPO rate by affecting female within-pair and/or extra-pair mating behaviour. Future behavioural studies should investigate how elevated T levels reduce the number of EPO.
http://ift.tt/2oDHKOM
Predictable food supplies induce plastic shifts in avian scaled body mass
Urbanization constitutes one of the most profound forms of land-use change and strongly affects global biodiversity and ecosystem functioning. Expansion of urban areas typically leads to species loss but may also induce more subtle changes in species dynamics through selection or plasticity. Using a dual correlative (field) and experimental (aviary) approach, we here show that free-ranging urban house sparrows in southern France were smaller and lighter than their rural counterparts after allometric scaling, whereas 2 independent indices of nutritional (feather growth rates) and developmental (feather asymmetry) stress did not vary with urbanization. When subjecting these individuals to urban or rural diets in a highly predictable, controlled setting, rural but not urban sparrows decreased their body mass, independent of diet type, to the extent that initial scaled mass differences between urban and rural birds disappeared by the end of the captive period. By integrating field-and aviary measurements of body size and mass with indices of nutritional and developmental stress, we conclude that the lower scaled body masses of urban birds likely reflect a plastic response to predictable food supplies, possibly mediated through predation. Urban environments therefore do not necessarily constitute nutritionally stressful environments for species that typically cohabit with humans, such as house sparrows.
http://ift.tt/2oDSOf2
Docetaxel and Loplatin Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Locally Advanced SCCHN
Condition: Locally Advanced Head and Neck Squamous Cell Carcinoma
Interventions: Drug: Lobaplatin; Drug: Cisplatin
Sponsor: Guiyang Medical University
Recruiting - verified April 2017
http://ift.tt/2omJLgR
Interventions: Drug: Lobaplatin; Drug: Cisplatin
Sponsor: Guiyang Medical University
Recruiting - verified April 2017
http://ift.tt/2omJLgR
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