Needle biopsy derived myofascial tissue samples are sufficient for quantification of myofibroblast density

Abstract

Introduction: Quantification of myofibroblasts is a promising method for assessing tissue properties in the field of fascia research. This is commonly performed by immunohistochemistry for α-smooth muscle actin. However, usually larger tissue samples sizes are required for quantification. The aim of this investigation was to explore whether a microscopic quantification of myofibroblasts can be conducted with fascial tissue samples derived via percutaneous needle biopsy.

Materials and Methods: Fascial tissues were derived via percutaneous needle biopsy from the fascia lata of 11 persons (aged 19 to 40 years). Following immunohistochemistry, selected fields for photomicroscopic analysis were chosen by a Monte Carlo method based randomization procedure. On these fields a digital quantification for the relative density of α-smooth muscle actin was attempted.

Results: The newly developed quantification method could successfully be applied in all tissue samples. The median α-smooth muscle actin density in the selected tissue samples ranged between 0% and 1.7% (median 0%, IQR 0%–0.001%).

Conclusions: The applied protocol proved to be workable for the purpose of an estimation of the α-smooth muscle actin density in fascial tissue samples derived via percutaneous needle biopsy. Since this type of biopsy is less invasive than the commonly performed open muscle biopsy, this offers a new and useful perspective for future histological investigations of fascial tissue properties in living patients. This article is protected by copyright. All rights reserved.

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Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas

http://ift.tt/2qkwHi3

Prevalence of Low Birth Weight before and after Policy Change to IPTp-SP in Two Selected Hospitals in Southern Nigeria: Eleven-Year Retrospective Analyses

Background. In 2005, Nigeria changed its policy on prevention of malaria in pregnancy to intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP). Indicators of impact of effective prevention and control of malaria on pregnancy (MIP) are low birth weight (LBW) and maternal anaemia by parity. This study determined the prevalence of LBW for different gravidity groups during periods of pre- and postpolicy change to IPTp-SP. Methods. Eleven-year data were abstracted from the delivery registers of two hospitals. Study outcomes calculated for both pre- (2000–2004) and post-IPTp-SP-policy (2005–2010) years were prevalence of LBW for different gravidity groups and risk of LBW in primigravidae compared to multigravidae. Results. Out of the 11,496 singleton deliveries recorded within the 11-year period, the prevalence of LBW was significantly higher in primigravidae than in multigravidae for both prepolicy (6.3% versus 4%) and postpolicy (8.6% versus 5.1%) years. The risk of LBW in primigravidae compared to multigravidae increased from 1.62 (1.17–2.23) in the prepolicy years to 1.74 (1.436–2.13) during the postpolicy years. Conclusion. The study demonstrated that both the prevalence and risk of LBW remained significantly higher in primigravidae even after the change in policy to IPTp-SP.

http://ift.tt/2lT5my9

Phenotype-based gene analysis allowed successful diagnosis of X-linked neutropenia associated with a novel WASp mutation

http://ift.tt/2CPK3Wi

Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study

Abstract

Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCAN™) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1 day to 20 years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤ 7 g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95–0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa.

http://ift.tt/2lSV9Cq

Complete response of age-related Epstein-Barr virus-associated polymorphic nodal lymphoproliferative disease of plasmacytic type to low-dose lenalidomide

http://ift.tt/2Cmeqmb

Liver fibrosis alleviation after co-transplantation of hematopoietic stem cells with mesenchymal stem cells in patients with thalassemia major

Abstract

The aims of this study are to determine the replacement rate of damaged hepatocytes by donor-derived cells in sex-mismatched recipient patients with thalassemia major and to determine whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells (HSCs) can alleviate liver fibrosis. Ten sex-mismatched donor-recipient pairs who received co-transplantation of HSCs with mesenchymal stem cells were included in our study. Liver biopsy was performed before transplantation. Two other liver biopsies were performed between 2 and 5 years after transplantation. The specimens were studied for the presence of donor-derived epithelial cells or hepatocytes using fluorescence in situ hybridization by X- and Y-centromeric probes and immunohistochemical staining for pancytokeratin, CD45, and a hepatocyte-specific antigen. All sex-mismatched tissue samples demonstrated donor-derived hepatocyte independent of donor gender. XY-positive epithelial cells or hepatocytes accounted for 11 to 25% of the cells in histologic sections of female recipients in the first follow-up. It rose to 47–95% in the second follow-up. Although not statistically significant, four out of ten patients showed signs of improvement in liver fibrosis. Our results showed that co-transplantation of HSC with mesenchymal stem cells increases the rate of replacement of recipient hepatocytes by donor-derived cells and may improve liver fibrosis.

http://ift.tt/2qoBa3q

Pooled analysis of the reports of carfilzomib/ixazomib combinations for relapsed/refractory multiple myeloma

Abstract

We sought to evaluate the activity and safety of carfilzomib-/ixazomib-containing combinations for patients with relapsed/refractory multiple myeloma (RRMM). We searched published reports including carfilzomib-/ixazomib-containing combinations for RRMM. Finally, we identified 11 prospective studies covering 2845 relapsed/refractory patients. Carfilzomib- and ixazomib-containing combinations respectively resulted in an impressive overall response rate (ORR 77 vs. 64%, P = 0.14), very good partial response or better (≥ VGPR 48 vs. 21%, P = 0.001), complete response or better (≥ CR 14 vs. 7%, P = 0.23), and clinical benefit rate (CBR 84 vs. 59%, P = 0.0002). Subgroup analysis showed that the carfilzomib (CFZ) +lenalidomide (LEN) + dexamethasone (DEX) triplet regimen resulted into similar response outcomes to those from CFZ + DEX doublet regimen in ORR (77 vs. 78%, P = 0.91), ≥VGPR (50 vs. 53%, P = 0.84), and ≥ CR (13 vs. 12%, P = 0.96) analysis in these previously heavily pretreated population. And, there were no statistically significant differences between IXA + LEN + DEX triplet regimen and CFZ + LEN + DEX triplet regimen in ORR (85 vs. 78%, P = 0.55), ≥ VGPR (37 vs. 53%, P = 0.19), and ≥ CR (18 vs. 12%, P = 0.70) analysis. There were favorable trend towards proteasome inhibitors (PIs) + IMiDs + DEX in comparison with PIs + alkylating agent + Dex in ORR (79 vs 49%, P < 0.00001), ≥ VGPR analysis (36 vs. 16%, P = 0.008), and ≥ CR (16 vs. 3%, P < 0.00001). Compared with current standard chemotherapy, carfilzomib containing combinations clearly improved overall survival (HR, 0.79; P = 0.01), progression free survival (HR, 0.61; P = 0.0001). Carfilzomib-/ixazomib-containing combinations produced clinical benefit for patients with R/RMM. PIs + IMiDs + DEX triplet regimens could be good options for such relapsed/refractory patients.

http://ift.tt/2lUbC9B

Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI—a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

Abstract

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.

http://ift.tt/2qp2IWu

The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes

Abstract

The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2–2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.

http://ift.tt/2lTbxmo

Inhaled Budesonide Does Not Affect Hypoxic Pulmonary Vasoconstriction at 4559 Meter of Altitude

High Altitude Medicine & Biology , Vol. 0, No. 0.


http://ift.tt/2Cn715W

Progesterone Receptor (PGR) Gene Variants Associated with Breast Cancer and Associated Features: a Case-Control Study

Abstract

Insofar as altered estrogen receptor-progesterone receptor (PR) expression contribute to breast cancer pathogenesis, previous studies examined the association of genetic variation in PR gene (PGR) with breast cancer, but with mixed outcome. We evaluated the association between PGR variants, and breast cancer and associated features. A retrospective case-control study involving 183 female breast cancer patients, and 222 control women. PGR genotyping was done by real-time PCR. Minor allele frequencies of rs1042838, rs590688, and rs10895068 PGR gene polymorphisms were significantly higher in breast cancer patients compared to controls. Patients carrying rs1042838 G/T, rs590688 C/C, and rs10895068 G/A genotypes had higher risk of breast cancer, while carriage of rs3740753 G/G genotype was associated with marginal reduction in breast cancer risk. In addition, carriage of rs1042839, rs3740753, and rs10895068 minor allele was associated with Her2 status, while rs3740753 and rs10895068 were associated with effective hormone replacement therapy. Furthermore, carriage of rs10895068 minor allele in breast cancer women were also associated with age at first pregnancy, hormone receptor (RH) status, and previous use of oral contraceptives. PGR haploview analysis documented moderate-strong linkage disequilibrium (non-random association of alleles at different loci) between 7 of the 8 tested PGR SNPs, thus allowing construction of 7-locus PGR haplotypes. Two haplotypes, ATGCCGA and GTGCCGA, both containing rs590688, were positively associated with breast cancer, thus assigning a breast cancer-susceptible nature to these haplotypes. PGR rs1042838, rs590688, and rs10895068, and ATGCCGA and GTGCCGA haplotypes are related with increased breast cancer susceptibility in Tunisian women.

http://ift.tt/2Cz1Djw

Differentiation of antemortem pulmonary thromboembolism and postmortem clot with unenhanced MRI: a case report

Abstract

We report a case of a 39-year-old woman who died of fulminant pulmonary thromboembolism (PE). Autopsy showed classical findings of fulminant PE with occlusion of the bilateral main stem pulmonary arteries. Ancillary testing revealed inherited thrombophilia (Prothrombin 20,210 G > A and MTHFR 677 C > T mutation). Pre-autopsy postmortem computed tomography was used to test whether virtual imaging studies alone (virtual autopsy) would be sufficient to detect PE. Our studies show that computed tomography (CT) can differentiate antemortem clots from a postmortem clot in certain cases, particularly when combined with magnetic resonance imaging (MRI), which is superior in the assessment of soft tissue. We show that postmortem CT and MRI can aid in the diagnosis of pulmonary embolism by virtual autopsy, especially when used in conjunction.

http://ift.tt/2CmpI9W

Stiripentol for the treatment of super-refractory status epilepticus with cross-sensitivity

Background

Cross-sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross-sensitivity in patients with super-refractory status epilepticus (SRSE).

Aims of the study

To examine the optimal AED for treating SRSE with cross-sensitivity.

Methods

We performed a retrospective review of adult patients with SRSE treated at Nagoya City University Hospital, in which we investigated the frequency of cross-sensitivity among patients with SRSE and their clinical and medical profiles.

Results

We identified 10 adult patients with SRSE, 5 of whom had cross-sensitivity. Stiripentol (STP) was administered when previously used AEDs had demonstrated cross-sensitivity and failed to control seizures. After initiation of STP, the dose of general anaesthetics was reduced, and status epilepticus (SE) eventually ceased with co-administered AEDs without additional adverse effects. The mean time to SE cessation after initiation of STP was 30.8 days (range, 18-46 days), mean duration of general anaesthesia was 101.2 days (range, 74-128 days), and mean number of AEDs was 9.0 (range, 6-11).

Conclusions

This study suggests that cross-sensitivity between AEDs is common in adults with SRSE and that STP may be useful for treating SRSE with cross-sensitivity.

http://ift.tt/2E3YSDV

Mental disorder in children with physical conditions: a pilot study

Objectives

Methodologically, to assess the feasibility of participant recruitment and retention, as well as missing data in studying mental disorder among children newly diagnosed with chronic physical conditions (ie, multimorbidity). Substantively, to examine the prevalence of multimorbidity, identify sociodemographic correlates and model the influence of multimorbidity on changes in child quality of life and parental psychosocial outcomes over a 6-month follow-up.

Design

Prospective pilot study.

Setting

Two children's tertiary-care hospitals.

Participants

Children aged 6–16 years diagnosed in the past 6 months with one of the following: asthma, diabetes, epilepsy, food allergy or juvenile arthritis, and their parents.

Outcome measures

Response, participation and retention rates. Child mental disorder using the Mini International Neuropsychiatric Interview at baseline and 6 months. Child quality of life, parental symptoms of stress, anxiety and depression, and family functioning. All outcomes were parent reported.

Results

Response, participation and retention rates were 90%, 83% and 88%, respectively. Of the 50 children enrolled in the study, the prevalence of multimorbidity was 58% at baseline and 42% at 6 months. No sociodemographic characteristics were associated with multimorbidity. Multimorbidity at baseline was associated with declines over 6 months in the following quality of life domains: physical well-being, β=–4.82 (–8.47, –1.17); psychological well-being, β=–4.10 (–7.62, –0.58) and school environment, β=–4.17 (–8.18, –0.16). There was no association with parental psychosocial outcomes over time.

Conclusions

Preliminary evidence suggests that mental disorder in children with a physical condition is very common and has a negative impact on quality of life over time. Based on the strong response rate and minimal attrition, our approach to study child multimorbidity appears feasible and suggests that multimorbidity is an important concern for families. Methodological and substantive findings from this pilot study have been used to implement a larger, more definitive study of child multimorbidity, which should lead to important clinical implications.

http://ift.tt/2Cp6H6Y

Adverse events in patients in home healthcare: a retrospective record review using trigger tool methodology

Objective

Home healthcare is an increasingly common part of healthcare. The patients are often aged, frail and have multiple diseases, and multiple caregivers are involved in their treatment. This study explores the origin, incidence, types and preventability of adverse events (AEs) that occur in patients receiving home healthcare.

Design

A study using retrospective record review and trigger tool methodology.

Setting and methods

Ten teams with experience of home healthcare from nine regions across Sweden reviewed home healthcare records in a two-stage procedure using 38 predefined triggers in four modules. A random sample of records from 600 patients (aged 18 years or older) receiving home healthcare during 2015 were reviewed.

Primary and secondary outcome measures

The cumulative incidence of AEs found in patients receiving home healthcare; secondary measures were origin, types, severity of harm and preventability of the AEs.

Results

The patients were aged 20–79 years, 280 men and 320 women. The review teams identified 356 AEs in 226 (37.7%; 95% CI 33.0 to 42.8) of the home healthcare records. Of these, 255 (71.6%; 95% CI 63.2 to 80.8) were assessed as being preventable, and most (246, 69.1%; 95% CI 60.9 to 78.2) required extra healthcare visits or led to a prolonged period of healthcare. Most of the AEs (271, 76.1%; 95% CI 67.5 to 85.6) originated in home healthcare; the rest were detected during home healthcare but were related to care outside home healthcare. The most common AEs were healthcare-associated infections, falls and pressure ulcers.

Conclusions

AEs in patients receiving home healthcare are common, mostly preventable and often cause temporary harm requiring extra healthcare resources. The most frequent types of AEs must be addressed and reduced through improvements in interprofessional collaboration. This is an important area for future studies.

http://ift.tt/2CPT9Ct

Patient journey following lumbar spinal fusion surgery (LSFS): protocol for a multicentre qualitative analysis of the patient rehabilitation experience (FuJourn)

Introduction

There has been a 65% increase in lumbar spinal fusion surgery (LSFS) worldwide over the last 13 years, with costs of £26 million to the UK National Health Service annually. Patient dissatisfaction with outcome and persistent pain and disability incurs further costs. Three trials provide low-quality evidence for the role of physiotherapy. Our UK surveys investigating physiotherapy/surgeon practice concluded rehabilitation should be tailored to the individual patient owing to considerable clinical heterogeneity. This study will explore the perceptions of patients who undergo LSFS to inform precision rehabilitation.

Methods and analysis

A qualitative study, using interpretive phenomenological analysis, will recruit a purposive sample (n=40) to ensure patterns of similarity and difference in their journeys can be explored. In-depth semistructured interviews will be undertaken following discharge from hospital and at 12 months postsurgery. Patients' preoperative and postoperative experiences, underlying attitudes and beliefs towards the surgical intervention, facilitators and barriers to recovery, adherence to advice and physiotherapy, experiences of rehabilitation and return to normal function/activity/work will be explored. A 12-month patient diary will provide real time access to patient data, capturing a weekly record of life as lived, including symptoms, medication, experiences of stages of recovery, rehabilitation adherence, healthcare professional appointments, attitudes, their feelings and experiences throughout their journey. Data will be analysed in a number of stages in accordance with interpretive phenomenological analysis, supported using NVivo software. Analysis of the first interviews and patient diaries will afford a rich density of data to build an overall understanding of the patients' lived experiences, informing the 12-month interview. Strategies (eg, reflexivity) will ensure trustworthiness.

Ethics and dissemination

The study has ethical approval (IRAS 223283). Findings will ensure that patient-driven data inform precision rehabilitation by understanding the patient journey. Findings will be disseminated through peer-reviewed journals and conferences.

http://ift.tt/2Cnp245

Cochrane systematic review and meta-analysis of the impact of psychological treatments for people with epilepsy on health-related quality of life

Summary

Objective

Given the significant impact epilepsy can have on health-related quality of life (HRQoL) of individuals with this condition and their families, there is great clinical interest in evidence-based psychological treatments aimed at enhancing well-being in people with epilepsy (PWE). An evaluation of the current evidence is needed to assess the effects of psychological treatments for PWE on HRQoL outcomes to inform future therapeutic recommendations and research designs.

Methods

The operational definition of psychological treatments included a broad range of interventions that use psychological or behavioral techniques designed to improve HRQoL, psychiatric comorbidities, and seizure frequency and severity for adults and children with epilepsy. A systematic literature search was conducted in line with Cochrane criteria for randomized controlled trials (RCTs) and quasi-RCTs investigating psychological treatments and using HRQoL outcome measures as primary or secondary outcome measures. Standard methodological procedures required by the Cochrane Collaboration were used for data collection and analysis.

Results

Twenty-four completed RCTs were included in this review (2439 participants). Based on satisfactory methodological homogeneity, data from 9 studies (468 participants) providing Quality of Life in Epilepsy-31 (QOLIE-31) outcomes were pooled for meta-analyses, showing significant mean changes for QOLIE-31 total score and 6 subscales. The significant mean changes of QOLIE-31 total score (mean improvement of 5.68 points; 95% confidence interval = 3.11-8.24, P < .0001) and 3 subscales (emotional well-being, energy/fatigue, overall quality of life [QoL]) exceeded the threshold of minimally important change, indicating a clinically meaningful postintervention improvement of QoL. Overall, the meta-analysis quality of evidence was characterized as "moderate" due to the risk of bias present in 8 of the 9 included studies (Handbook for Systematic Reviews of Interventions, Version 5.1.0, 2011, Chapters 8 and 12). A narrative synthesis was conducted for all trials and outcomes that were not entered in the meta-analysis.

Significance

These results provide moderate-quality evidence that psychological treatments for adults with epilepsy may enhance HRQoL in people with epilepsy.

http://ift.tt/2lQrp8u

Evaluation of the effects of curcumin in patients with metabolic syndrome

Abstract

Curcumin is a yellow pigment derived from rhizomes of turmeric (Curcuma longa L.) and can affect multiple components metabolic syndrome (MetS). In the current study, we aimed to evaluate the effects of curcumin on several CVD risk factors, including indices of depression and anxiety in individuals with MetS. This randomized clinical trial was undertaken in the Nutrition Clinic of the Ghaem Hospital. One hundred and twenty subjects (18–65 years old) were randomly assigned to one of three treatment groups: a group receiving phospholipidated curcumin (PC) capsules (1 g/day) for 6 weeks )n = 40), a group receiving unformulated curcumin (UC) capsules (1 g/day) for 6 weeks (n = 40), and a control group who received a placebo capsule (n = 40). Socio-demographic status of all participants was documented using a self-administered questionnaire. Blood samples were collected after a 12-h fasting. All biochemical factors and anthropometric indices were measured in all patients at baseline and after 6 weeks intervention. Complete blood count (CBC), serum levels of FBG, lipid profile, apolipoproteins, and hs-CRP were assessed. Physical activity level was measured using a standard questionnaire. At the beginning and end of study, Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were completed by all volunteers. According to the self-reported adverse effects, one subject in the PC-treated group reported hypersensitivity. Also, there were reports of cold sore (n = 1) and nausea (n = 1) in the UC group. Statistical analyses were performed using SPSS software. A total of 109 subjects completed the study. There were no significant differences between the three study groups for any of the variables at baseline, nor after the 6 weeks intervention, including anthropometric indices, serum biochemical factors, systolic and diastolic blood pressures, and CBC. However, subjects with severe anxiety appeared to be significantly improved by treatment with the PC and UC compared with the placebo group (p = 0.01). Curcumin supplementation did not improve any of the cardiovascular risk factors associated with MetS.

http://ift.tt/2CSr9OF

A network meta-analysis on the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus

Abstract

The aim of the present study is to assess the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus using a systematic review of the literature. Electronic and hand searches were performed until July 2017. The inclusion criteria were defined as follows: (1) randomized trial with a dietary approach; (2) adults with type 2 diabetes mellitus; (3) outcome either HbA1c (%) and/or fasting glucose (mmol/l); (4) minimum intervention period of 12 weeks. For each outcome measure, random effects network meta-analysis was performed in order to determine the pooled effect of each intervention relative to each of the other interventions. A total of 56 trials comparing nine dietary approaches (low-fat, Vegetarian, Mediterranean, high-protein, moderate-carbohydrate, low-carbohydrate, control, low GI/GL, Palaeolithic) enrolling 4937 participants were included. For reducing HbA1c, the low-carbohydrate diet was ranked as the best dietary approach (SUCRA: 84%), followed by the Mediterranean diet (80%) and Palaeolithic diet (76%) compared to a control diet. For reducing fasting glucose, the Mediterranean diet (88%) was ranked as the best approach, followed by Palaeolithic diet (71%) and Vegetarian diet (63%). The network analysis also revealed that all dietary approaches significantly reduce HbA1c (− 0.82 to − 0.47% reduction) and fasting glucose (− 1.61 to − 1.00 mmol/l reduction) compared to a control diet. According to the network meta-analysis the Mediterranean diet is the most effective and efficacious dietary approach to improve glycaemic control in type 2 diabetes patients.

http://ift.tt/2qmvVkG

Body–foot geometries as revealed by perturbed obstacle position with different time constraints

Abstract

This study examined the geometrical relationships between the feet, pelvis and an environmental obstruction when crossing an obstacle with unexpected changes to its position. Nine healthy young adults stepped over an obstacle 19 cm high with their right leg leading. The obstacle could be static or advanced at either lead (early detection) or trail (late detection) foot contact prior to clearance to force an adaptive reorganization of body–foot geometry and foot proximity to the obstacle. Stride length, minimum foot clearance over the obstacle, and foot-obstacle horizontal proximity before and after clearance were measured along with the relative position of the pelvis to each foot at eight points (four for each foot) during approach and clearance: heel contacts before and after crossing the obstacle, maximum foot heights and foot clearances. With early obstacle movement, trail limb stride length before crossing was lengthened, but foot proximity was still far from the final obstacle position. Clearance was less affected for the trail foot as compared to the lead foot. Proximity of the lead limb following clearance was the same for both early and late perturbations and closer than for the static obstacle condition. For relative body–foot positioning, significant differences were found only in the anterior-posterior direction. Following obstacle displacement, body–foot geometry was initially adapted, but then re-established to static obstacle values with an apparent focus on a balance geometry with the forward placed foot establishing new contact. These findings support an overall balance geometry that can be temporarily adjusted and coordinated with foot proximity to the obstruction to maintain continual gait and safe clearance.

http://ift.tt/2Cwz1aP

A clinical trial protocol paper discussing the BRIGHTER study

Future Oncology, Ahead of Print.


http://ift.tt/2ET8Yc4

Genome-Wide Characterisation of DNA Methylation in an Invasive Lepidopteran Pest, the Cotton Bollworm Helicoverpa armigera

The genes and genomes of insect pests are shaped by the wide array of selective forces encountered in their environments. While the molecular adaptations that evolve are beginning to be understood at the genomic and transcriptomic level they have been less well characterised at an epigenetic level. Here, we present a genome-wide map of DNA methylation, at single-nucleotide resolution for the cotton bollworm moth, Helicoverpa armigera; a globally invasive pest of agriculture. We show that methylation is almost identical in the larvae and adults of H. armigera and that, through whole genome bisulfite sequencing, at the most ~0.9% of CpG sites in this species are methylated. We find that DNA methylation occurs primarily in exons, is positively correlated with gene expression and methylated genes are enriched for cellular housekeeping roles. H. armigera has an exceptional capacity for long-range migration. To explore the role of methylation in influencing the migratory phenotype of H. armigera we performed targeted bisulfite sequencing on selected loci from sixteen genes that were differentially expressed between adult moths exhibiting distinct flight performance in behavioural assays. While most CpG sites in these genes were not methylated between flight phenotypes we identified hyper-methylation in a demethylase (KDM4) that targets lysine-specific histone modifications which are strongly associated with transcription and methylation. The H. armigera methylome provides new insights into the role of DNA methylation in a noctuid moth and is a valuable resource for further research into the epigenetic control of adaptive traits in this important pest.

http://ift.tt/2E3Wa1i

Vitamin C potentiates the killing of Mycobacterium tuberculosis by the first-line tuberculosis drugs isoniazid and rifampicin in mice [PublishAheadOfPrint]

The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We had previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis. Here, we tested sub-inhibitory concentration of vitamin C in combination with TB drugs against M. tuberculosis in vitro and in a mouse model of M. tuberculosis infection. In vivo, we showed that vitamin C level in mouse serum can be increased by intraperitoneal injection of vitamin C to reach vitamin C levels close to the concentrations required for activity in vitro. Although vitamin C had no activity by itself in M. tuberculosis-infected mice, the combination of vitamin C with the first-line TB drugs isoniazid and rifampicin reduced the bacterial burden in the lungs of M. tuberculosis-infected mice faster than isoniazid and rifampicin combined in two independent experiments. These experiments suggest that the addition of vitamin C to first-line TB drugs could shorten TB treatment. Vitamin C, an inexpensive and non-toxic compound, could be easily added to the TB pharmacopeia to substantially improve chemotherapy outcome, which would have a significant impact on the worldwide TB community.

http://ift.tt/2COS9hO

Hospice care in Medicare patients with primary liver cancer: the impact on resource utilisation and mortality

Summary

Background

Few studies have assessed the impact of hospice care in patients with primary liver cancer.

Aim

To examine the determinants of hospice care and its effects on resource utilisation and survival among Medicare beneficiaries with primary liver cancer.

Methods

We utilised the Surveillance, Epidemiology and End result Registry (SEER) database from 2002 to 2009 for this cross-sectional study. A total of 3385 patients with primary liver cancer were included. We used logistic regression to discern variables associated with hospice and Cox proportional hazards models to evaluate one-year mortality risk.

Results

Compared to patients who enrolled in a hospice, those patients who did not, were younger, non-White and sicker (P < .05 for all). Half of all patients with primary liver cancer died within six months of diagnosis, and one-year mortality was similar in both groups (P = .413). After adjusting for baseline characteristics [age at diagnosis, race, disease severity, tumour stage and treatment], shorter time to hospice care was associated with reduced mortality (HR per day: 0.99 [95% CI, 0.98-0.99]). Older age, decompensated cirrhosis and advanced tumours stage were associated with decreased time to hospice, while Asian/Pacific Islander race and history of radiosurgery were associated with increased time to hospice (all P < .05).

Hospitalisations were more costly for those who never enrolled in a hospice compared to hospice enrollees (median $31 607 [$18 394-$54 254] vs $22 316 [$13 741-$36 170], P < .0001).

Conclusions

Hospice enrolment of patients with primary liver cancer provides survival and resource utilisation benefits. Some clinical and demographic factors may represent barriers to hospice enrolment. Further studies are needed to fully understand these barriers in patients with primary liver cancer.

http://ift.tt/2lUnFTk

Sofosbuvir plus daclatasvir with or without ribavirin in 551 patients with hepatitis C-related cirrhosis, genotype 4

Summary

Background

The Daclatasvir and Sofosbuvir combination therapy (SOF/DCV) has shown efficacy in patients with chronic hepatitis C in clinical trials.

Aim

To investigate the efficacy and safety of SOF/DCV for treatment of patients with hepatitis C-related liver cirrhosis genotype 4.

Methods

Multicentre study involving 551 patients with liver cirrhosis genotype 4; 432 naïve patients and 119 treatment-experienced patients. All patients received SOF (400 mg) and DCV (60 mg) daily in addition to weight-based ribavirin (RBV) for 12 weeks and when RBV is contraindicated the treatment duration was extended to 24 weeks.

Results

Sustained virological response at 12 weeks after end of treatment (SVR12) rate was 92% in naïve cirrhotic patients and 87% in previous treated patients (by ITT analysis). Virological failure was infrequent, occurring in 42 patients (8%) overall. Thirty-two (6%) were non responders; and 10 (2%) cases were relapsers, 31 patients (7%) were CTP-A and 11 (13.3%) patients were CTP-B (by ITT analysis). The most common adverse events were anaemia, fatigue, headache, pruritus. Serious side effects were recorded mainly in CTP-B cirrhotic patients including HCC and hepatic encephalopathy.

Conclusions

The SOF/DCV combination therapy has proven efficacy and safety in treating patients with hepatitis C-related liver cirrhosis genotype 4 in a large cohort of patients in the real world.

http://ift.tt/2CChwpw

Role of Basal Cells in Producing Persistent Lentivirus-Mediated Airway Gene Expression

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2CREBlO

Mogamulizumab Tops Standard of Care for CTCL [News in Brief]

Anti-CCR4 antibody significantly improves progression-free survival compared with vorinostat for type of non–Hodgkin lymphoma.

http://ift.tt/2lRLX0l

Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-{beta}, in advanced solid tumors

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap." Experimental DesignIn the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging and multiple expansion cohorts are ongoing in a range of tumors.

http://ift.tt/2E13r1V

Development and preclinical validation of a cysteine knottin peptide targeting Integrin {alpha}v{beta}6 for near-infrared fluorescent-guided surgery in pancreatic cancer

Purpose: Intraoperative near-infrared fluorescence (NIRF) imaging could help stratification for the proper primary treatment for patients with pancreatic ductal adenocarcinoma (PDAC), and achieve complete resection since it allows visualization of cancer in real time. Integrin αvβ6, a target specific for PDAC, is present in >90% of patients, and is able to differentiate between pancreatitis and PDAC. A clinically translatable αvβ6-targeting NIRF agent was developed, based on a previously developed cysteine knottin peptide for PET imaging, R01-MG, and validated in preclinical mouse models. Experimental Design: The applicability of the agent was tested for cell and tissue binding characteristics using cell-based plate assays, subcutaneous and orthotopic pancreatic models, and a transgenic mouse model of PDAC development (Pdx1-Cre tg/+;KRas LSL G12D/+;Ink4a/Arf). IRDye800CW was conjugated to R01-MG in a 1:1 ratio. R01-MG-IRDye800, was compared to a control peptide and IRDye800 alone. Results: In subcutaneous tumor models a significantly higher tumor-to-background ratio (TBR) was seen in BxPC-3 tumors (2.5±0.1) compared to MiaPaCa-2 (1.2±0.1) (p<0.001), and to the control peptide (1.6±0.4) (p<0.005). In an orthotopic tumor model tumor-specific uptake of R01-MG-IRDye800 was shown compared to IRDye800 alone (TBR 2.7 versus 0.86). The fluorescent signal in tumors of transgenic mice was significantly higher, TBR of 3.6±0.94, compared to the normal pancreas of wild type controls, TBR of 1.0±0.17 (p<0.001). Conclusion: R01-MG-IRDye800 shows specific targeting to αvβ6, and holds promise as a diagnostic and therapeutic tool to recognize PDAC for fluorescence-guided surgery. This agent can help improve the stratification of patients for a potentially curative, margin-negative resection.

http://ift.tt/2EQO3pV

Development and validation of a gene signature for patients with head and neck squamous cell carcinomas treated by postoperative radio(chemo)therapy

Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting loco-regional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C). Experimental Design: Gene expression analyses were performed using nanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed by genes with previously reported association to radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms. Results: We identified a 7-gene signature consisting of the 3 individual genes HILPDA, CD24,TCF3 and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, ACTN1. The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci=0.82), which was successfully validated (ci=0.71). The signature showed improved performance compared to clinical parameters alone (ci=0.66) and to a previously published model including hypoxia-associated genes and cancer stem cell markers (ci=0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (p<0.001). Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification.

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Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib

Purpose: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291).  Experimental Design:Three genetically modified mouse models (GEMMs) mimicking individual HER2 alterations in NSCLC were generated and osimertinib was tested for its efficacy against these HER2 aberrations in vivo. Results:Osimertinib treatment showed robust efficacy in HER2wt overexpression and EGFR del19/HER2 models but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2-mutant NSCLC while JQ1 single treatment did not show efficacy. Conclusions: Overall, our data indicated robust anti-tumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in NSCLC patients.

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Comparison between CT- and MRI-derived head and neck cancer target volumes using an integrated MRI-tri- 60 Co teletherapy device

Abstract

Purpose

Radiation treatment planning is typically based on the identification of a gross tumor volume (GTV) using computed tomography (CT). The clinical implementation of an integrated MRI-radiation therapy delivery unit allows for a strict comparison of CT- and MRI-derived GTVs for head and neck cancer.

Materials and methods

Twenty-six consecutive patients with squamous cell carcinoma of the head and neck were selected and planned for intensity-modulated radiotherapy (IMRT) on a novel tri-⁶⁰Co teletherapy system equipped with a 0.35 T MRI (ViewRay Incorporated, Oakwood Village, OH). All patients had measurable disease. Pre-treatment MRIs were imported into a contouring interface where the primary GTV were assessed and compared to those obtained from a registered CT with the patient in the identical position and immobilization apparatus.

Results

The median GTV as derived from the CT and MRI was 27.2 cm³ (range 3.8 to 155.0 cm³) and 34.9 cm³ (range, 5.0 to 189.5 cm³), respectively (p = 0.01). The MRI-derived GTV was larger than the CT-derived GTV in 21 of the 26 cases and was smaller in the remaining 5 cases. Among the 21 cases where the MRI-derived GTV was larger, the median difference in absolute GTV per individual patient was 6.9 cm³ (range 2.1 to 33.4 cm³), representing a 25% difference on average. The median concordance index for patients with de novo versus recurrent disease was 0.83 and 0.66, respectively (p = 0.03).

Conclusion

Significant differences in GTV extent were noted between MRI- and CT-derived ViewRay images. The implications for treatment planning are discussed.

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Depression and anxiety in caregivers of patients with celiac disease. Author's Reply

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Phosphorylation of P27 by AKT is required for inhibition of cell cycle progression in cholangiocarcinoma

P27 is a putative tumor suppressor when located in the nucleus and AKT is an inhibitor of P27 which promotes growth of cholangiocarcinoma. We hypothesized that AKT-dependent phosphorylation at the P27 nuclear localization sequence T157 leads to nuclear export of P27, and thus loss of its tumor suppressive function. This study investigated whether loss of cell cycle regulation in cholangiocarcinoma due to subcellular localization of P27.

http://ift.tt/2AiZ6ov

Randomized Trial Comparing the Franseen and Fork-tip needles for EUS-guided fine-needle biopsy of solid pancreatic mass lesions

Recently, 3-plane symmetric needle with Franseen geometry and Fork-tip biopsy needle have been developed for histological tissue procurement. We compared 22-gauge Franseen and 22-gauge Fork-tip needles in patients undergoing EUS-guided sampling of pancreatic masses.

http://ift.tt/2ERJdZI

Effect of BioZorb® surgical marker placement on post-operative radiation boost target volume

Abstract

Objective

BioZorb® is a tumor bed marker placed during partial mastectomy for targeted post-operative radiation. This study was designed to evaluate BioZorb® effect on radiation boost clinical target volume (CTV), planning target volume (PTV), median dose to ipsilateral lung (Gy), and heart irradiation in left-sided cancers.

Methods

Data was collected via a retrospective cohort study with two study arms: BioZorb® intra-operative placement versus no BioZorb® placement. Patients were stratified by BMI, age, tumor laterality and volume, and cancer stage. Mean, standard deviation, median, range of cubic centimeters of clinical and planning target volume, cardiac dose in left-sided cancers, ipsilateral lung dose, and volume of ipsilateral lung receiving 20 Gy were reported.

Results

Of 143 patients, median CTV (cm³) was 8.7 and 14.2 (P = 0.0048), median PTV (cm³) was 53.2 and 79.6 (P = 0.0010), median ipsilateral lung Gy was 7.53 and 6.74 (P = 0.0099) and volume (cc) of ipsilateral radiation lung at 20 Gy was 13.4 and 12 (P = 0.008), and median heart Gy in left-sided cancers was 2.01 and 2.21 (P = 0.9952) in BioZorb® and non-BioZorb® arms, respectively. Patients with BMIs of 25–30 had CTV medians of 7.8 and 11.1 in BioZorb® and non-BioZorb® arms, respectively (P = 0.0293).

Conclusion

The BioZorb® arm showed statistically significant reductions in CTV and PTV but not ipsilateral lung or heart irradiation.

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Non-severe form of severe fever with thrombocytopenia syndrome (SFTS)

http://ift.tt/2lQiqEk

EUS-FNB is superior to EUS-FNA in sampling pancreatic masses

http://ift.tt/2EPPXah

Here and Now: Clinical practice Hiatal and Paraesophageal Hernias

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Workup and Management of Bloating

http://ift.tt/2EOWhyO

EUS Fine Needle Biopsy Can Determine PD-L1 Immune Biomarker Status in Treatment Naïve Pancreatic Ductal Adenocarcinoma

http://ift.tt/2lSCRAn

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients with Genotype 1 Hepatitis C Virus Infection and Cirrhosis

We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET).

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Suboptimal IOA Alarming for Actions

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Lessons from Using Culture-Guided Treatment after Referral for Multiple Treatment Failures for Helicobacter pylori Infection

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Rubbery purple and red lesions in the GI tract: A Case of GI tract Kaposi Sarcoma

http://ift.tt/2lSCGoH

Associations Between Molecular Classifications of Colorectal Cancer and Patient Survival: a Systematic Review

In a systematic review, we found that systems for classifying colorectal tumors based on at least 3 molecular features do not accurately predict patient survival. Improvements to classification systems and validation are needed for them to have prognostic value and relevance to clinical practice.

http://ift.tt/2ERZHkw

Is HBV-associated intrahepatic cholangiocarcinoma preventable with antiviral treatment?

http://ift.tt/2lSCzcL

Heavy Consumption of Alcohol is Not Associated With Worse Outcomes in Patients With Idiosyncratic Drug-induced Liver Injury Compared to Non-Drinkers

The relationship between alcohol consumption and idiosyncratic drug induced liver injury (DILI) is not well understood. We investigated the relationship between heavy consumption of alcohol and characteristics and outcomes of patients with DILI enrolled in the Drug-induced Liver Injury Network (DILIN) prospective study.

http://ift.tt/2ERZKN0

Oxidative stress preconditioning of mouse perivascular myogenic progenitors selects a subpopulation of cells with a distinct survival advantage in vitro and in vivo

Oxidative stress preconditioning of mouse perivascular myogenic progenitors selects a subpopulation of cells with a distinct survival advantage in vitro and in vivo

Oxidative stress preconditioning of mouse perivascular myogenic progenitors selects a subpopulation of cells with a distinct survival advantage in vitro and in vivo, Published online: 03 January 2018; doi:10.1038/s41419-017-0012-9

Oxidative stress preconditioning of mouse perivascular myogenic progenitors selects a subpopulation of cells with a distinct survival advantage in vitro and in vivo

http://ift.tt/2qiKrd3

Follow-Up Recommendations after Diagnosis of Primary Cutaneous Melanoma: A Population-Based Study in New South Wales, Australia

Abstract

Background

Follow-up practices after diagnosis and treatment of primary cutaneous melanoma vary considerably. We aimed to determine factors associated with recommendations for follow-up setting, frequency, skin surveillance, and concordance with clinical guidelines.

Methods

The population-based Melanoma Patterns of Care study documented clinicians' recommendations for follow-up for 2148 patients diagnosed with primary cutaneous melanoma over a 12-month period (2006/2007) in New South Wales, Australia. Multivariate log binomial regression models adjusted for patient and lesion characteristics were used to examine factors associated with follow-up practices.

Results

Of 2158 melanomas, Breslow thickness was < 1 mm for 57% and ≥ 1 mm for 30%, while in situ melanomas accounted for 13%. Follow-up was recommended for 2063 patients (96%). On multivariate analysis, factors associated with a recommendation for follow-up at a specialist center were Breslow thickness ≥ 1 mm [prevalence ratio (PR) 1.05, 95% confidence interval (CI) 1.01–1.09] and initial treatment at a specialist center (PR 1.12, 95% CI 1.08–1.16). Longer follow-up intervals of > 3 months were more likely to be recommended for females, less likely for people living in rural compared with urban areas, and less likely for thicker (≥ 1 mm) melanomas compared with in situ melanomas. Skin self-examination was encouraged in 84% of consultations and was less likely to be recommended for patients ≥ 70 years (PR 0.88, 95% CI 0.84–0.93) and for those with thicker (≥ 1 mm) melanomas (PR 0.92, 95% CI 0.86–0.99). Only 1% of patients were referred for psychological care.

Conclusions

Follow-up recommendations were generally consistent with Australian national guidelines for management of melanoma, however some variations could be targeted to improve patient outcomes.

http://ift.tt/2lQpulo

Slit2/Robo1 signaling is involved in angiogenesis of glomerular endothelial cells exposed to a diabetic-like environment

Abstract

Abnormal angiogenesis plays a pathological role in diabetic nephropathy (DN), contributing to glomerular hypertrophy and microalbuminuria. Slit2/Robo1 signaling participates in angiogenesis in some pathological contexts, but whether it is involved in glomerular abnormal angiogenesis of early DN is unclear. The present study evaluated the effects of Slit2/Robo1 signaling pathway on angiogenesis of human renal glomerular endothelial cells (HRGECs) exposed to a diabetic-like environment or recombinant Slit2-N. To remove the effect of Slit2 derived from mesangial cells, human renal mesangial cells (HRMCs) grown in high glucose (HG) medium (33 mM) were transfected with Slit2 siRNA and then the HG-HRMCs-CM with Slit2 depletion was collected after 48 h. HRGECs were cultured in the HG-HRMCs-CM or recombinant Slit2-N for 0, 6, 12, 24, or 48 h. The mRNA and protein expressions of Slit2/Robo1, PI3K/Akt and HIF-1α/VEGF signaling pathways were detected by quantitative real-time PCR, western blotting, and ELISA, respectively. The CCK-8 cell proliferation assay, flow cytometry and the scratch wound-healing assay were used to assess cell proliferation, cycles, and migration, respectively. Matrigel was used to perform a tubule formation assay. Our results showed that the HG-HRMCs-CM with Slit2 depletion enhanced the activation of Slit2/Robo1, PI3K/Akt, and HIF-1α/VEGF signaling in HRGECs in time-dependent manner (0–24 h post-treatment). In addition, the HG-HRMCs-CM with Slit2 depletion significantly promoted HRGECs proliferation, migration, and tube formation. Pretreatment of HRGECs with Robo1 siRNA suppressed the activation of PI3K/Akt and HIF-1α/VEGF signaling and inhibited angiogenesis, whereas PI3K inhibitor suppressed HIF-1α/VEGF signaling, without influencing Robo1 expression. In the HRGECs treated with Slit2-N, Slit2-N time-dependently enhanced the activation of Robo1/PI3K/Akt/VEGF pathway but not HIF-1α activity, and promoted HRGECs proliferation, migration, and tube formation. The effects induced by Slit2 were also abolished by Robo1 siRNA and PI3K inhibitor. Taken together, our findings indicate that in a diabetic-like environment, in addition to mesangial cells, autocrine activation of Slit2/Robo1 signaling of HRGECs may contribute to angiogenesis of HRGECs through PI3K/Akt/VEGF pathway; therefore, Slit2/Robo1 signaling may be a potent therapeutic target for the treatment of abnormal angiogenesis in early DN and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.

http://ift.tt/2E1iCbf

Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an α5β1 integrin-mediated mechanism

Abstract

Spinal cord injury (SCI) leads to rapid destruction of neuronal tissue, resulting in devastating motor and sensory deficits. This is exacerbated by damage to spinal cord blood vessels and loss of vascular integrity. Thus, approaches that protect existing blood vessels or stimulate the growth of new blood vessels might present a novel approach to minimize loss or promote regeneration of spinal cord tissue following SCI. In light of the remarkable power of chronic mild hypoxia (CMH) to stimulate vascular remodeling in the brain, the goal of this study was to examine how CMH (8% O₂ for up to 7 days) affects blood vessel remodeling in the spinal cord. We found that CMH promoted the following: (1) endothelial proliferation and increased vascularity as a result of angiogenesis and arteriogenesis, (2) increased vascular expression of the angiogenic extracellular matrix protein fibronectin as well as concomitant increases in endothelial expression of the fibronectin receptor α5β1 integrin, (3) strongly upregulated endothelial expression of the tight junction proteins claudin-5, ZO-1 and occludin and (4) astrocyte activation. Of note, the vascular remodeling changes induced by CMH were more extensive in white matter. Interestingly, hypoxic-induced vascular remodeling in spinal cord blood vessels was markedly attenuated in mice lacking endothelial α5 integrin expression (α5-EC-KO mice). Taken together, these studies demonstrate the considerable remodeling potential of spinal cord blood vessels and highlight an important angiogenic role for the α5β1 integrin in promoting endothelial proliferation. They also imply that stimulation of the α5β1 integrin or controlled use of mild hypoxia might provide new approaches for promoting angiogenesis and improving vascular integrity in spinal cord blood vessels.

http://ift.tt/2ESHeUT

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials

Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed.

http://ift.tt/2E1Nvwc

Outcomes of Surgical Ligation after Unsuccessful Pharmacotherapy for Patent Ductus Arteriosus in Neonates Born Extremely Preterm

A retrospective cohort study of neonates born extremely preterm with persistent patent ductus arteriosus after unsuccessful pharmacologic closure compared outcomes between 166 surgically ligated and 142 nonligated neonates. After adjustment for confounders, ligation was not associated with the composite outcome of death or neurodevelopmental impairment, neurodevelopmental impairment alone, chronic lung disease, or retinopathy of prematurity among survivors.

http://ift.tt/2ET7Ghm

Delivery Room Resuscitation and Short-Term Outcomes in Moderately Preterm Infants

To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants.

http://ift.tt/2E2Lkc3

Neurodevelopmental Outcomes of Infants Born at <29 Weeks of Gestation Admitted to Canadian Neonatal Intensive Care Units Based on Location of Birth

To compare mortality and neurodevelopmental outcomes of outborn and inborn preterm infants born at <29 weeks of gestation admitted to Canadian neonatal intensive care units (NICUs).

http://ift.tt/2EOP9CL

Comparison of Different Maximal Oxygen Uptake Equations to Discriminate the Cardiometabolic Risk in Children and Adolescents

To determine the ability of 8 different maximal oxygen uptake (VO2max) equations to discriminate between low and high cardiometabolic risk, and to determine cardiorespiratory fitness (CRF) cutoffs associated with a more favorable cardiometabolic risk profile in Colombian children and adolescents.

http://ift.tt/2E2eXdv

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

Arteriovenous malformations of the brain are high-flow vascular malformations that occur in approximately 15 per 100,000 persons and cause hemorrhagic stroke in children. They are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary…

http://ift.tt/2Aiy0Of

Epidemiological characteristics and post-exposure prophylaxis of human rabies in Chongqing, China, 2007–2016

According to the global framework of eliminating human rabies, China is responding to achieve the target of zero human death from dog-mediated rabies by 2030. Chongqing is the largest municipality directly und...

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Erratum

Integrative and Comparative Biology; doi:10.1093/icb/icx073.

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Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

http://ift.tt/2CBgavc

Spontaneous rhythms in a harbor seal pup calls

Timing and rhythm (i.e. temporal structure) are crucial, though historically neglected, dimensions of animal communication. When investigating these in non-human animals, it is often difficult to balance exper...

http://ift.tt/2CQGpeV

One consensual depression diagnosis tool to serve many countries: a challenge! A RAND/UCLA methodology

From a systematic literature review (SLR), it became clear that a consensually validated tool was needed by European General Practitioner (GP) researchers in order to allow multi-centred collaborative research...

http://ift.tt/2CiO1pd

Fabrication Procedures and Birefringence Measurements for Designing Magnetically Responsive Lanthanide Ion Chelating Phospholipid Assemblies

Fabrication procedures for highly magnetically responsive lanthanide ion chelating polymolecular assemblies are presented. The magnetic response is dictated by the assembly size, which is tailored by extrusion through nanopore membranes. The assemblies' magnetic alignability and temperature-induced structural changes are monitored by birefringence measurements, a complimentary technique to nuclear magnetic resonance and small angle neutron scattering.

http://ift.tt/2AhmQcN

Shuang-Huang-Lian prevents basophilic granulocyte activation to suppress Th2 immunity

Basophilic granulocytes (BGs) not only initiate the induction of Th2 cell differentiation, but also amplify the ongoing Th2 response. Shuang-Huang-Lian (SHL) is clinically used for relieving type I hypersensit...

http://ift.tt/2COHK5P

HPLC-DAD finger printing, antioxidant, cholinesterase, and α-glucosidase inhibitory potentials of a novel plant Olax nana

The medicinal importance of a novel plant Olax nana Wall. ex Benth. (family: Olacaceae) was revealed for the first time via HPLC-DAD finger printing, qualitative phytochemical analysis, antioxidant, cholinesteras...

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The Public and the Opioid-Abuse Epidemic

Over the past year, the U.S. opioid-abuse epidemic has gained enormous visibility. President Donald Trump has identified it as a "public health emergency," and a national commission and a commission of state governors have issued recommendations for action. This concern stems from the fact that in…

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Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

BACKGROUND

Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.

METHODS

Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi.

RESULTS

The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients.

CONCLUSIONS

The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018. © 2018 American Cancer Society.

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Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, because ICIs block coinhibitory molecules on T cells and other immune cells, unleashing them to mediate tumor cell killing, they also can disrupt the maintenance of immunological tolerance to self-antigens. Compared with chemotherapy, ICIs have a different toxicity profile, especially the occurrence of autoimmune-like manifestations against multiple organ systems, including endocrine glands, commonly referred to as immune-related adverse events. The aim of this review was to provide practical recommendations regarding the proper assessment and clinical management related to the new onset of endocrinopathies after the use of ICIs in patients with cancer. Cancer 2018. © 2018 American Cancer Society.

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Pediatric oncologist willingness to offer germline TP53 testing in osteosarcoma

BACKGROUND

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53. Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53. New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53.

METHODS

Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data.

RESULTS

One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P < .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing.

CONCLUSIONS

Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018. © 2018 American Cancer Society.

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Recipient Selection for Optimal Utilization of Discarded Grafts in Liver Transplantation

AbstractBackgroundIn France, liver grafts that have been refused by at least 5 teams are considered for rescue allocation, with the choice of the recipient being at the team's discretion. While this system permits the use of otherwise discarded grafts in a context of organ shortage, outcomes and potential benefits need to be assessed.MethodsBetween 2011 and 2015, outcomes of rescue allocation grafts (n=33) were compared to standard allocation grafts (n=321) at a single French center.ResultsLiver grafts in the rescue allocation group were older (63+/-17 vs. 54+/-18y, p=0.007) and had a higher donor risk index (1.86+/-0.45 vs. 1.61+/-0.47, p=0.010). Recipients in this group had a lower MELD score (14+/-5 vs. 22+/-10, p

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The Meaning of Being a Living Kidney, Liver or Stem Cell Donor - A Meta-Ethnography

ABSTRACTBackgroundStudies on living donors from the donors' perspective show that the donation process involves both positive and negative feelings involving vulnerability. Qualitative studies of living kidney, liver, and allogeneic hematopoietic stem cell donors have not previously been merged in the same analysis. Therefore, our aim was to synthesize current knowledge of these donors' experiences in order to deepen understanding of the meaning of being a living donor for the purpose of saving or extending someone's life.MethodsThe meta-ethnography steps presented by Noblit & Hare in 1988 were used.ResultsForty-one qualitative studies from 1968 to 2016 that fulfilled the inclusion criteria were analyzed. The studies comprised experiences of over 670 donors. The time since donation varied from 2 days to 29 years. A majority of the studies, 25 out of 41, were on living kidney donors. The synthesis revealed that the essential meaning of being a donor is doing what one feels one has to do, involving 6 themes; A sense of responsibility, Loneliness and abandonment, Suffering, Pride and gratitude, A sense of togetherness, and A life changing event.ConclusionThe main issue is that one donates irrespective of what one donates. The relationship to the recipient determines the motives for donation. The deeper insight into the donors' experiences provides implications for their psychological care. Background Studies on living donors from the donors' perspective show that the donation process involves both positive and negative feelings involving vulnerability. Qualitative studies of living kidney, liver, and allogeneic hematopoietic stem cell donors have not previously been merged in the same analysis. Therefore, our aim was to synthesize current knowledge of these donors' experiences in order to deepen understanding of the meaning of being a living donor for the purpose of saving or extending someone's life. Methods The meta-ethnography steps presented by Noblit & Hare in 1988 were used. Results Forty-one qualitative studies from 1968 to 2016 that fulfilled the inclusion criteria were analyzed. The studies comprised experiences of over 670 donors. The time since donation varied from 2 days to 29 years. A majority of the studies, 25 out of 41, were on living kidney donors. The synthesis revealed that the essential meaning of being a donor is doing what one feels one has to do, involving 6 themes; A sense of responsibility, Loneliness and abandonment, Suffering, Pride and gratitude, A sense of togetherness, and A life changing event. Conclusion The main issue is that one donates irrespective of what one donates. The relationship to the recipient determines the motives for donation. The deeper insight into the donors' experiences provides implications for their psychological care. Corresponding author: Annika M Kisch, Department of Haematology, Skåne University Hospital, S-221 85 Lund, Sweden, annika.m.kisch@skane.se AUTHORSHIP PAGE - Authorship statement Annika M Kisch, Anna Forsberg, Isabell Fridh, and Annette Lennerling were responsible for the research design. Annika M Kisch, Anna Forsberg, Isabell Fridh, and Annette Lennerling wrote the paper. Matilda Almgren, Martina Lundmark, Charlotte Lovén, Anne Flodén, Madeleine Nilsson, and Veronika Karlsson contributed with comments to the draft manuscript. All authors: Annika M Kisch, Anna Forsberg, Isabell Fridh, Matilda Almgren, Martina Lundmark, Charlotte Lovén, Anne Flodén, Madeleine Nilsson, Veronika Karlsson, and Annette Lennerling participated in conducting the research and data analysis. Annika M Kisch, Anna Forsberg, Isabell Fridh, and Annette Lennerling were primarily responsible for the synthesis. The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Elevated High-Sensitivity Troponin I During Living Donor Liver Transplantation is Associated With Postoperative Adverse Outcomes

ABSTRACTBackgroundThis study aimed to evaluate risk factors and postoperative clinical outcome associated with myocardial injury detected by an elevated high-sensitivity cardiac troponin I (hs-cTnI) immediately after living donor liver transplantation (LDLT).MethodsBetween January 2011 and December 2016, 313 adult recipients undergoing LDLT, with normal preoperative hs-cTnI were selected. Hs-cTnI level above 0.04 ng/mL according to 99th percentile reference limit was defined as myocardial injury. The recipients were divided into two groups according to postoperative hs-cTnI measured immediately after LDLT and postoperative clinical outcome was compared.ResultsThe primary outcome was composite of death or graft failure during hospital stay. Risk factors associated with myocardial injury during LDLT was also evaluated. Of the 313 recipients with normal preoperative hs-cTnI level, 159 (50.8%) had elevated hs-cTnI level and 154 (49.2%) had normal level after LDLT. The incidence of all-cause death or graft failure during hospital stay was significantly higher in recipients with myocardial injury (1.9% vs. 7.6% hazard ratio, 4.15; 95% confidence interval, 1.01-17.14; P = 0.049). The same result was shown in propensity-matched population (0.9% vs. 9.0% hazard ratio, 9.08; 95% confidence interval, 1.16-71.01; P = 0.04). The results during 1-year follow-up were not consistent. Female gender, ischemia time and presence of postreperfusion syndrome were independent predictors of myocardial injury during LDLT.ConclusionMyocardial injury detected by elevation of hs-cTnI level immediately after LDLT was independently associated with adverse outcome during hospital stay. Background This study aimed to evaluate risk factors and postoperative clinical outcome associated with myocardial injury detected by an elevated high-sensitivity cardiac troponin I (hs-cTnI) immediately after living donor liver transplantation (LDLT). Methods Between January 2011 and December 2016, 313 adult recipients undergoing LDLT, with normal preoperative hs-cTnI were selected. Hs-cTnI level above 0.04 ng/mL according to 99th percentile reference limit was defined as myocardial injury. The recipients were divided into two groups according to postoperative hs-cTnI measured immediately after LDLT and postoperative clinical outcome was compared. Results The primary outcome was composite of death or graft failure during hospital stay. Risk factors associated with myocardial injury during LDLT was also evaluated. Of the 313 recipients with normal preoperative hs-cTnI level, 159 (50.8%) had elevated hs-cTnI level and 154 (49.2%) had normal level after LDLT. The incidence of all-cause death or graft failure during hospital stay was significantly higher in recipients with myocardial injury (1.9% vs. 7.6% hazard ratio, 4.15; 95% confidence interval, 1.01-17.14; P = 0.049). The same result was shown in propensity-matched population (0.9% vs. 9.0% hazard ratio, 9.08; 95% confidence interval, 1.16-71.01; P = 0.04). The results during 1-year follow-up were not consistent. Female gender, ischemia time and presence of postreperfusion syndrome were independent predictors of myocardial injury during LDLT. Conclusion Myocardial injury detected by elevation of hs-cTnI level immediately after LDLT was independently associated with adverse outcome during hospital stay. J.C.P and S.H.L contributed equally to this work. Corresponding author at: Gaab Soo Kim, MD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; E-mail address: gskim@skku.edu Authorship • Participated in research design: Jungchan Park, Seung Hwa Lee, Myungsoo Park, Gaab Soo Kim • Participated in the writing of the paper: Jungchan Park, Seung Hwa Lee, Gaab Soo Kim • Participated in the performance of the research: Jungchan Park, Ki Yoon Kim, Go Eun Kim, • Contributed new reagents or analytic tools: Sangbin Han, Suk-Koo Lee, Gyu-Seong Cho • Participated in data analysis: Jungchan Park, Seung Hwa Lee, Soohyun Ahn, Hyeon Seon Ahn Disclosure: The authors declare no conflicts of interest Funding: none Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Desensitization and Prevention of Antibody-mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation

AbstractBackgroundCandidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection (AMR). Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent AMR in VCA.MethodsSkin transplants from Dark Agouti (DA) to Lewis rats were performed for sensitization. Orthotopic hind-limb transplants from DA donors were performed to sensitized and non-sensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation (TBI), fludarabine and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow-cytometry.ResultsSensitized recipients exhibited accelerated rejection by 5.5±1.2 days without immunosuppression and 10.2±3.6 days with daily tacrolimus, compared to 8.7±1.2 days and >30 days in non-sensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3±3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared to sensitized-controls (2.6±0.5-fold vs 6.0±1.2-fold, p30 days without evidence of C4d deposition (n=6).ConclusionsIn summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats. Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection (AMR). Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent AMR in VCA. Methods Skin transplants from Dark Agouti (DA) to Lewis rats were performed for sensitization. Orthotopic hind-limb transplants from DA donors were performed to sensitized and non-sensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation (TBI), fludarabine and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow-cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5±1.2 days without immunosuppression and 10.2±3.6 days with daily tacrolimus, compared to 8.7±1.2 days and >30 days in non-sensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3±3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared to sensitized-controls (2.6±0.5-fold vs 6.0±1.2-fold, p30 days without evidence of C4d deposition (n=6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats. These authors contributed equally to this work, Howard D. Wang, Samuel A.J. Fidder. Corresponding Author: Gerald Brandacher, MD, Associate Professor, Ross Research Building, Room 749A, 720 Rutland Avenue, Baltimore, MD 21205, Email: brandacher@jhmi.edu Authorship Contributions Howard D. Wang: Study design, data acquisition and analysis, manuscript composition and revision Samuel A.J. Fidder: Study design, data acquisition and analysis, manuscript composition and revision Devin T. Miller: Study design, data acquisition and analysis, manuscript composition Georg J. Furtmüller: Data acquisition and manuscript revision Ali Reza Ahmadi: Study design, data acquisition and analysis, manuscript revision Felix Nägele: Data acquisition and manuscript revision Joseph Lopez: Data acquisition and manuscript revision Amy Quan: Data acquisition and manuscript revision Joshua Budihardjo: Data acquisition and manuscript revision Denver M. Lough: Data acquisition and analysis, manuscript revision Burcu Akpinarli: Data acquisition Joanna Etra: Data acquisition Dalibor Vasilic: Study design, manuscript revision Giorgio Raimondi: Study conception and design, manuscript revision W.P. Andrew Lee: Study conception and design, manuscript revision Richard Montgomery: Study conception and design, manuscript revision Zhaoli Sun: Study conception and design, manuscript revision Gerald Brandacher: Study conception and design, manuscript revision Disclosure: The authors of this manuscript declare no conflicts of interest Funding: This work was partially supported by the Plastic Surgery Foundation and the Russel Scholarship from the Johns Hopkins Military and Veterans Health Institute. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A Protocol for Real-time 3D Single Particle Tracking

This protocol details the construction and operation of a real-time 3D single particle tracking microscope capable of tracking nanoscale fluorescent probes at high diffusive speeds and low photon count rates.

http://ift.tt/2Ci6Pot

Postoperative drug-induced priapism

Bartholomeus J G A Corten<br />May 31, 2017; 2017:bcr-2016-218060-bcr-2016-218060<br />research-article

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Severe hypophosphataemia after intravenous iron administration

Gurpreet Anand<br />Mar 13, 2017; 2017:bcr2016219160-bcr2016219160<br />case-report

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The Waterbirth Project: São Bernardo Hospital experience

Publication date: Available online 2 January 2018
Source:Women and Birth
Author(s): Joyce C.S. Camargo, Vitor Varela, Fernanda M. Ferreira, Lucila Pougy, Angela M. Ochiai, Maria Elisabete Santos, Maria Catarina L.R. Grande
IntroductionThe following quantitative observational study aimed to analyse the maternal and neonatal outcomes of 90 low-risk pregnant women who gave birth in water at São Bernardo Hospital.MethodsA form containing information on the obstetric history of the parturient, the type of immersion, and the labour and birth follow-up was used by midwives to collect the data.BackgroundThe Apgar score (at 1min after birth) used in this study, called Aqua Apgar, was adapted by Cornelia Enning.ResultsThe mean water immersion time was 1h and 46min and had an influence on the duration of labour (mean 5h and 37min), with a statistically significant difference (P=0.004). There was a decreased cervical dilatation time and a shorter duration of the expulsion phase. In the immersion scenario, 30% of the women did not undergo any examination to assess the length of the cervix, and 57.8% presented intact perennial areas or first-degree tears. As for neonatal outcomes, during maternal immersion, 97% maintained normal foetal heart rates (between 110 and 160 beats per minute) and Aqua Apgar was higher than 7, both in the first minute (mean of 9.4) and in the fifth minute of life (mean of 9.9).ConclusionThese safety outcomes, based on sound scientific evidence, should increasingly support and inform clinical decisions and increase the number of waterbirths in health facilities. The results of this study align with growing evidence that suggests waterbirth is a safe delivery option and therefore should be offered to women.



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Delayed relapse in pseudotumor cerebri due to new stenosis after transverse sinus stenting

Hugh Stephen Winters<br />Sep 8, 2015; 2015:bcr2015011896-bcr2015011896<br />case-report

http://ift.tt/2Cxdb74

Columella pressure necrosis: a method of surgical reconstruction and its long-term outcome

Yasas Shri Nalaka Jayaratne<br />Aug 5, 2014; 2014:bcr2013203132-bcr2013203132<br />case-report

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Missing the beat: arrhythmia as a presenting feature of eosinophilic granulomatosis with polyangiitis

Faye Amelia Sharpley<br />May 8, 2014; 2014:bcr2013203413-bcr2013203413<br />case-report

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Opposite Effects of Basolateral Amygdala Inactivation on Context-Induced Relapse to Cocaine Seeking after Extinction versus Punishment

Studies using the renewal procedure showed that basolateral amygdala (BLA) inactivation inhibits context-induced relapse to cocaine-seeking after extinction. Here, we determined whether BLA inactivation would also inhibit context-induced relapse after drug-reinforced responding is suppressed by punishment, an animal model of human relapse after self-imposed abstinence due to adverse consequences of drug use. We also determined the effect of central amygdala (CeA) inactivation on context-induced relapse.

We trained rats to self-administer cocaine for 12 d (6 h/d) in Context A and then exposed them to either extinction or punishment training for 8 d in Context B. During punishment, 50% of cocaine-reinforced lever-presses produced an aversive footshock of increasing intensity (0.1–0.5 or 0.7 mA). We then tested the rats for relapse to cocaine seeking in the absence of cocaine or shock in Contexts A and B after BLA or CeA injections of vehicle or GABA agonists (muscimol-baclofen). We then retrained the rats for cocaine self-administration in Context A, repunished or re-extinguished lever pressing in Context B, and retested for relapse after BLA or CeA inactivation.

BLA or CeA inactivation decreased context-induced relapse in Context A after extinction in Context B. BLA, but not CeA, inactivation increased context-induced relapse in Context A after punishment in Context B. BLA or CeA inactivation provoked relapse in Context B after punishment but not extinction. Results demonstrate that amygdala's role in relapse depends on the method used to achieve abstinence and highlights the importance of studying relapse under abstinence conditions that more closely mimic the human condition.

SIGNIFICANCE STATEMENT Relapse to drug use during abstinence is often provoked by re-exposure to the drug self-administration environment or context. Studies using the established extinction-reinstatement rodent model of drug relapse have shown that inactivation of the basolateral amygdala inhibits context-induced drug relapse after extinction of the drug-reinforced responding. Here, we determined whether basolateral amygdala inactivation would also inhibit relapse after drug-reinforced responding is suppressed by punishment, a model of human relapse after self-imposed abstinence. Unexpectedly, we found that basolateral amygdala inactivation had opposite effects on relapse provoked by re-exposure to the drug self-administration environment after extinction versus punishment. Our results demonstrate that depending on the historical conditions that lead to abstinence, amygdala activity can either promote or inhibit relapse.

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Take me to the liver: adipose tissue macrophages coordinate hepatic neutrophil recruitment

In the lean, healthy state, adipose tissue (AT) has critical roles in maintaining organismal homeostasis. Paramount among the various roles of AT is the regulation of whole body metabolism. While adipocytes per se are key players in metabolic homeostasis, for example, by storing nutrients and releasing soluble factors, work over the last decade has revealed that AT-resident immune cells have a profound impact on AT function. Obesity is a risk factor for numerous conditions, including cardiovascular disease, type 2 diabetes, cancer, osteoarthritis, sleep apnoea and infertility. Obesity is also a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), an effect that is primarily attributable to increased hepatic lipid accumulation and inflammation. During the development of obesity, the AT expands and the AT-resident immune cell profile is dramatically altered,1 ultimately initiating AT inflammation and altered whole body metabolism. Most prominent among...

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Integrin a6 loss promotes colitis-associated colorectal cancer. Response to: "Integrin a6 variants and colorectal cancer" by Beaulieu JF

In a recently published letter,1 Dr Beaulieu questions our recent publication suggesting that α6 integrin acts as a tumour suppressor gene in colorectal cancer (CRC),2 given the apparent antagonistic role of α6A and α6B integrin isoforms in the intestine. We thank him for raising this important issue and welcome the opportunity of clarifying the topic. We showed that mice failing to express the α6 integrin (both α6A and α6B isoforms) specifically in intestinal epithelial cells (α6^IEC) spontaneously develop fully penetrant colitis and adenocarcinoma afterwards.2 These mice display epithelium detachment from the basement membrane, followed by oversecretion of interleukin (IL)-18 and IL-1β proinflammatory cytokines, infiltration of myeloid cells, and finally activation of the adaptive immunity, which mediates tumour progression. Thus, since α6^IEC mutant mice develop adenocarcinoma without any additional treatment, Itga6 behaves as a tumour suppressor gene (a gene that protects a cell from one step...

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Multicentre prospective evaluation of real-time optical diagnosis of T1 colorectal cancer in large non-pedunculated colorectal polyps using narrow band imaging (the OPTICAL study)

Objective

This study evaluated the preresection accuracy of optical diagnosis of T1 colorectal cancer (CRC) in large non-pedunculated colorectal polyps (LNPCPs).

Design

In this multicentre prospective study, endoscopists predicted the histology during colonoscopy in consecutive patients with LNPCPs using a standardised procedure for optical assessment. The presence of morphological features assessed with white light, and vascular and surface pattern with narrow-band imaging (NBI) were recorded, together with the optical diagnosis, the confidence level of prediction and the recommended treatment. A risk score chart was developed and validated using a multivariable mixed effects binary logistic least absolute shrinkage and selection (LASSO) model.

Results

Among 343 LNPCPs, 47 cancers were found (36 T1 CRCs and 11 ≥T2 CRCs), of which 11 T1 CRCs were superficial invasive T1 CRCs (23.4% of all malignant polyps). Sensitivity and specificity for optical diagnosis of T1 CRC were 78.7% (95% CI 64.3 to 89.3) and 94.2% (95% CI 90.9 to 96.6), and 63.3% (95% CI 43.9 to 80.1) and 99.0% (95% CI 97.1 to 100.0) for optical diagnosis of endoscopically unresectable lesions (ie, ≥T1 CRC with deep invasion), respectively. A LASSO-derived model using white light and NBI features discriminated T1 CRCs from non-invasive polyps with a cross-validation area under the curve (AUC) of 0.85 (95% CI 0.80 to 0.90). This model was validated in a temporal validation set of 100 LNPCPs (AUC of 0.81; 95% CI 0.66 to 0.96).

Conclusion

Our study provides insights in the preresection accuracy of optical diagnosis of T1 CRC. Sensitivity is still limited, so further studies will show how the risk score chart could be improved and finally used for clinical decision making with regard to the type of endoresection to be used and whether to proceed to surgery instead of endoscopy.

Trial registration number

NTR5561.

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Role of thiopurines as disease-modifying agents in Crohns disease

We agree with Danese et al1 that prospective studies to evaluate the disease-modifying action of antitumour necrosis factor (anti-TNF) drugs are overdue. As a counterpoint to this informative review, we would like to highlight some additional evidence for the role of thiopurines as disease-modifying agents in Crohn's disease. A cohort study by Magro et al2 supports a role for thiopurines in delaying phenotype progression from an inflammatory (B1) to a stricturing/penetrating (B2/B3) disease (HR 0.15, 95% CI 0.11 to 0.19). A meta-analysis of 10 population-based, multicentre, and referral centre studies comprising 12 586 patients found thiopurine use was associated with a 40% reduction in risk of first intestinal surgery (HR 0.59, 95 % CI 0.48 to 0.73).3 Furthermore several studies also support a role for early thiopurine use particularly in young patients who are at greater risk of disease progression.4–6 RAPID...

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Acute sedation-associated complications in GI endoscopy (ProSed 2 Study): results from the prospective multicentre electronic registry of sedation-associated complications

Objectives

Sedation has been established for GI endoscopic procedures in most countries, but it is also associated with an added risk of complications. Reported complication rates are variable due to different study methodologies and often limited sample size.

Designs

Acute sedation-associated complications were prospectively recorded in an electronic endoscopy documentation in 39 study centres between December 2011 and August 2014 (median inclusion period 24 months). The sedation regimen was decided by each study centre.

Results

A total of 368 206 endoscopies was recorded; 11% without sedation. Propofol was the dominant drug used (62% only, 22.5% in combination with midazolam). Of the sedated patients, 38 (0.01%) suffered a major complication, and overall mortality was 0.005% (n=15); minor complications occurred in 0.3%. Multivariate analysis showed the following independent risk factors for all complications: American Society of Anesthesiologists class >2 (OR 2.29) and type and duration of endoscopy. Of the sedation regimens, propofol monosedation had the lowest rate (OR 0.75) compared with midazolam (reference) and combinations (OR 1.0–1.5). Compared with primary care hospitals, tertiary referral centres had higher complication rates (OR 1.61). Notably, compared with sedation by a two-person endoscopy team (endoscopist/assistant; 53.5% of all procedures), adding another person for sedation (nurse, physician) was associated with higher complication rates (ORs 1.40–4.46), probably due to higher complexity of procedures not evident in the multivariate analysis.

Conclusions

This large multicentre registry study confirmed that severe acute sedation-related complications are rare during GI endoscopy with a very low mortality. The data are useful for planning risk factor-adapted sedation management to further prevent sedation-associated complications in selected patients.

Trial registration number

DRKS00007768; Pre-results.

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Proton-pump inhibitors and increased gastric cancer risk: time-related biases

We read with interest the cohort study by Cheung et al1 reporting that use of proton-pump inhibitors (PPIs) after Helicobacter pylori eradication is associated with an increased risk of gastric cancer (GC). We believe that the significantly elevated HR of GC with PPI use (HR 2.44; 95% CI 1.42 to 4.20) is a consequence of two time-related biases. Immortal time bias was introduced by misclassifying exposure,2–4 while latency bias was introduced by not incorporating latency in the exposure definition, a major issue for potential carcinogenic drug effects.5 6

Immortal time in a cohort study refers to a period of follow-up time when the outcome could not occur.3 It arises in this study from the definition of frequency of PPI use, 'calculated by dividing the total treatment duration by the duration of follow-up', namely the average use over the...

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A comparison of the prognosis between adenocarcinoma and squamous cell carcinoma in stage IB–IIA cervical cancer

Abstract

Objective

To explore differences in prognosis between adenocarcinoma (AC) and squamous cell carcinoma (SCC) and to explore feasibility of ovarian preservation in stage IB–IIA cervical cancer (CC).

Materials and methods

Medical records of 810 patients (682 SCC + 128 AC) with stage IB–IIA CC were reviewed. Clinical and pathological characters of the two groups were compared using the chi-squared test. Kaplan–Meier survival analysis was used in univariate analysis of prognostic factors. Multivariate analysis of prognostic factors was conducted by the Cox hazards regression model.

Results

The incidence of LVSI (lymphovascular space invasion) and poor cell differentiation in SCC patients was higher than that in AC patients (23.90% vs. 8.59%, P < 0.05; and 54.25% vs. 28.91%, P < 0.05). Results of univariate analysis showed that cell differentiation, clinical stage, lymph node metastasis (LNM), ovarian metastasis (OM), parametrial involvement (PI), LVSI, depth of stromal invasion, and tumor size were related to the prognosis of patients with stage IB–IIA CC (P < 0.05). Results of multivariate analysis showed that cell differentiation, clinical stage, and LNM were independent prognostic factors for patients with stage IB–IIA CC. There was no difference in 5-year survival rate between SCC patients and AC patients (87.3% vs. 82.4%; P > 0.05). In AC patients, there was no difference in the 5-year survival rate between patients with ovarian retention and patients with bilateral ovariectomy (75% vs. 86.6%; P > 0.05).

Conclusions

In stage IB–IIA CC, there is no difference in prognosis between AC and SCC. The ovaries of stage IB–IIA1 AC patients under age 45 might be preserved.

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Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma

Abstract

Background

Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC.

Methods

Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC.

Results

The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; P_{heterogeneity} = 0.08 I² = 41%). However, no association was found between the expression value of miR-34a and any clinicopathologic characteristics. In the NLP analysis of HCC, we obtained 25 significant HCC-associated signaling pathways. Besides, we explored 1000 miR-34a-related genes and 5 significant signaling pathways in which CCND1 and Bcl-2 served as necessary hub genes. In the integrative analysis, we found 61 hub genes and 5 significant pathways, including cell cycle, cytokine-cytokine receptor interaction, notching pathway, p53 pathway and focal adhesion, which proposed the relevant functions of miR-34a in HCC.

Conclusion

Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.

http://ift.tt/2EPRNYI