Reliability of histologic assessment in patients with eosinophilic oesophagitis

Summary

Background

The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist.

Aim

Formally assess the reliability of the EoEHSS and additional histologic features.

Methods

Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs).

Results

Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items.

Conclusion

The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

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Treatment selection for esophageal cancer: evaluation from a nationwide database

Abstract

Background

Most elderly patients poorly tolerate the standard treatment for esophageal cancer; however, little information is available regarding the appropriateness of non-standard esophageal cancer treatments for those patients. This study aims to analyze the treatment costs and completion rates of patients undergoing a real-world treatment for esophageal cancer to elucidate the treatment selection and its quality.

Materials and methods

We analyzed treatment costs and completion rates for patients with esophageal cancer and analyzed these data relative to patient age and center volumes. Patients with esophageal cancer [UICC, TMN, Clinical stage II/III (excluding T4)] who were diagnosed in 2013 were analyzed. Patients were classified into five groups defined as follows: surgical therapy, chemotherapy, concurrent chemoradiotherapy (CCRT), modified concurrent chemoradiotherapy (mCRT), and radiotherapy (RT).

Results

Mean and median age of patients who received surgery and CCRT were comparable; however, patients who underwent mCRT and RT tended to be older. Medical costs associated with surgery were higher than costs associated with other non-surgical treatments. Cost and completion rate of chemoradiotherapy did not differ between CCRT and mCRT; however, both had higher completion rates compared to that of RT. Surgical expenses tended to be the highest in low-volume centers and the lowest in high-volume centers.

Conclusion

Treatment of esophageal cancer at high-volume centers seems well balanced compared with medium- to low-volume centers. mCRT was widely performed and comparable in medical cost to CCRT, although additional clinical impacts were unclear.

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A 74-year-old woman with dyspnoea and a mass in the right atrium

A 74-year-old woman was admitted with pericardial effusion causing haemodynamic instability. On echographic and radiological examination, a mass was identified in the right atrium, extending into the epicardial layer. In the differential diagnosis of a cardiac mass, benign primary lesions like a myxoma must be distinguished from rare primary cardiac malignancies like sarcomas or more frequent secondary tumours. These include localisations of lymphomyeloproliferative disease and metastases of a melanoma or various subtypes of carcinoma. In this case, histopathological examination of a surgical biopsy showed findings consistent with a high-grade angiosarcoma. Because of the size and localisation, as well as the presence of a possible metastasis in the rib, surgical treatment was not possible. After diagnosis, the patient developed multiple additional metastasis. She received palliative radiotherapy to control the pain and died 10 months after the initial diagnosis was made. Median reported survival is 6 months.

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Tattoo-Paper Transfer as a Versatile Platform for All-Printed Organic Edible Electronics

Abstract

The use of natural or bioinspired materials to develop edible electronic devices is a potentially disruptive technology that can boost point-of-care testing. The technology exploits devices that can be safely ingested, along with pills or even food, and operated from within the gastrointestinal tract. Ingestible electronics can potentially target a significant number of biomedical applications, both as therapeutic and diagnostic tool, and this technology may also impact the food industry, by providing ingestible or food-compatible electronic tags that can "smart" track goods and monitor their quality along the distribution chain. Temporary tattoo-paper is hereby proposed as a simple and versatile platform for the integration of electronics onto food and pharmaceutical capsules. In particular, the fabrication of all-printed organic field-effect transistors on untreated commercial tattoo-paper, and their subsequent transfer and operation on edible substrates with a complex nonplanar geometry is demonstrated.

Temporary tattoo-paper is proposed as a simple and versatile platform for the integration of biocompatible organic electronics onto food and pharmaceutical capsules. The fabrication of all-printed biocompatible organic transistors and complementary logic on untreated commercial tattoo-paper, and their subsequent transfer to and operation on edible substrates is demonstrated, paving the way for novel point-of-care devices and smart food labels.

http://ift.tt/2Gu2ct4

Letter to the Editor concerning “Pilon fractures: A new classification system based on CT-scan” by Danilo Leonettia, *, Domenico Tiganib 2017. Injury. 2017 Oct;4810:2311-2317

Publication date: Available online 19 February 2018
Source:Injury
Author(s): Arvind Kumar, Vivek Trikha, Samarth Mittal




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New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

Abstract

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

http://ift.tt/2EEQYBy

Microvesicles in hepatic and peripheral vein can predict nonresponse to corticosteroid therapy in severe alcoholic hepatitis

Summary

Background

Severe alcoholic hepatitis patients have high mortality and limited response to corticosteroids. Microvesicles reflect cellular stress and disease conditions.

Aims

To investigate whether microvesicles are associated with severity, response to steroid therapy and inflammation in severe alcoholic hepatitis.

Methods

Microvesicles originating from different cells were studied pre-therapy in 101 patients; (71 responder to corticosteroid therapy and 30 nonresponders) and 20 healthy controls. Microvesicles and cells were determined in peripheral and hepatic vein samples using flow cytometry and correlated with outcomes. Inflammatory signalling pathways and functional alterations of immune cells after stimulation with microvesicles were also investigated.

Results

Microvesicles mean levels were higher in nonresponders for T cells (CD3⁺ CD4⁺; 10.1 MV/μL vs 5.4; P = 0.06), macrophages (CD68⁺ CD11b⁺; 136.5 vs 121.9 MV/μL; P = 0.01), haematopoietic stem-cells (CD45⁺ CD34⁺; 116.8 vs 13.4 MV/μL; P = 0.0001) and hepatocytes (ASGPR⁺; 470 vs 361 MV/μL; P = 0.01); the latter two predicting steroid nonresponse in 94% patients at baseline in peripheral plasma. Microvesicle levels correlated with histological and liver disease severity indices. Whereas, in non-responders hepatic vein CD34+ cells were lower (P = 0.02), the CD34+ microvesicles there from were higher (P = 0.04), thus suggesting impaired regeneration. Also, microvesicles of 0.2-0.4 μm size were higher in nonresponders (P < 0.03) at baseline. Microvesicles from patients trigger more (P = 0.04) ROS generation, TNF-α production (P = 0.04) and up-regulate pro-inflammatory cytokine related genes in neutrophils in vitro.

Conclusions

Pre-therapy peripheral plasma levels of CD34⁺ and ASGPR⁺ microvesicles are reliable non-invasive markers of steroid nonresponse and mortality in patients with severe alcoholic hepatitis.

http://ift.tt/2EER1xe

The inspired sinewave technique: A novel method to measure lung volume and ventilatory heterogeneity

Abstract

The Inspired Sinewave Technique (IST) is a novel method which can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal-breaths the concentration of a tracer gas (i.e. nitrous oxide, N₂O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sinewave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV₁₈₀/FRC_pleth, ELV₁₈₀/FRC_pred and ELV₆₀/ELV₁₈₀).

This investigation aimed to determine: the repeatability and agreement of ELV with FRC_pleth, and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent.

48 healthy never-smoker participants (20–86 years) underwent traditional pulmonary function testing: (e.g. spirometry, body plethysmography) and the IST test which consisted of 4 minutes of quiet breathing through a facemask while inspired N₂O concentrations are oscillated in a sinewave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 seconds or 60 seconds.

ELV₁₈₀/FRC_pleth and ELV₁₈₀/FRC_pred were age dependent (average decreases of 0.58% and 0.48% per year) suggesting an increase in VH with advancing age. ELV showed a mean bias of −1.09L vs. FRC_pleth, but when normalised for the effects of age this bias reduced to −0.35L. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be accounted for in clinical investigations.

This article is protected by copyright. All rights reserved

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Healthy interpretation is crucial [Letters]

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"Complainers, malingerers and drug-seekers" -- the stigma of living with chronic pain [News]

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Using frailty tools as prognostic markers in patients who are acutely ill [Commentary]

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Meat and dairy supporters seek industry-friendly changes to food guide [News]

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Impact of frailty on outcomes after discharge in older surgical patients: a prospective cohort study [Research]

BACKGROUND:

Frailty is a state of vulnerability to diverse stressors. We assessed the impact of frailty on outcomes after discharge in older surgical patients.

METHODS:

We prospectively followed patients 65 years of age or older who underwent emergency abdominal surgery at either of 2 tertiary care centres and who needed assistance with fewer than 3 activities of daily living. Preadmission frailty was defined according to the Canadian Study of Health and Aging Clinical Frailty Scale as "well" (score 1 or 2), "vulnerable" (score 3 or 4) or "frail" (score 5 or 6). We assessed composite end points of 30-day and 6-month all-cause readmission or death by multivariable logistic regression.

RESULTS:

Of 308 patients (median age 75 [range 65–94] yr, median Clinical Frailty Score 3 [range 1–6]), 168 (54.5%) were classified as vulnerable and 68 (22.1%) as frail. Ten (4.2%) of those classified as vulnerable or frail received a geriatric consultation. At 30 days after discharge, the proportions of patients who were readmitted or had died were greater among vulnerable patients (n = 27 [16.1%]; adjusted odds ratio [OR] 4.60, 95% confidence interval [CI] 1.29–16.45) and frail patients (n = 12 [17.6%]; adjusted OR 4.51, 95% CI 1.13–17.94) than among patients who were well (n = 3 [4.2%]). By 6 months, the degree of frailty independently and dose-dependently predicted readmission or death: 56 (33.3%) of the vulnerable patients (adjusted OR 2.15, 95% CI 1.01–4.55) and 37 (54.4%) of the frail patients (adjusted OR 3.27, 95% CI 1.32–8.12) were readmitted or had died, compared with 11 (15.3%) of the patients who were well.

INTERPRETATION:

Vulnerability and frailty were prevalent in older patients undergoing surgery and unlikely to trigger specialized geriatric assessment, yet remained independently associated with greater risk of readmission for as long as 6 months after discharge. Therefore, the degree of frailty has important prognostic value for readmission.

Trial registration for primary study

ClinicalTrials.gov, no. NCT02233153

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Physicians are not solely responsible for ensuring access to medical assistance in dying [Editorial]

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Severe coagulopathy after a massasauga rattlesnake bite [Practice]

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Time to change pain paradigms [Letters]

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Exercise-induced vasculitis [Practice]

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Incentivizing young doctors to practise in underserved areas [News]

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Educating Future Physicians for Ontario and the physicians strike of 1986: the roots of Canadian competency-based medical education [Humanities]

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Creating healthy cities and communities [Coda]

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Reply to ‘Comment on “Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study” by Muanda et al.’

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Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein–Taybi syndrome

In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein–Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.

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EMCrit RACC Podcast 218 – Physostigmine with Bryan Hayes

Physostigmine for Anticholinergic toxicity

EMCrit Project by Scott Weingart.

http://ift.tt/2FeJS84

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in OMIM genes and non-OMIM genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients, in order to identity novel MH-ID genes.

Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes PSD-95, a protein expressed in various tissues including the brain. In neurons, PSD-95 is localized at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one for a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients showed mild-to-moderate ID, similar marfanoid features, including a long face, high arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus).

Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Sixty-four probands presenting with at least intellectual disability with marfanoid habitus were analyzed by whole exome sequencing, 33 in a trio and 31 in a solo strategy in order to provide appropriate management, genetic counseling and to study diagnosis yield in this phenotype. After analyzing the data using classical approaches allowing to reach a molecular diagnosis in 53.2% of cases, a bioinformatic filtration procedure was applied on the cohort, consisting of searching for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. This strategy allowed to highlight DLG4 as a novel disease-causing gene responsible for intellectual disability and probably marfanoid features. mRNA studies on the blood of the 3 patients showed decreased gene expression in two patients and aberrant splicing leading to a premature stop codon in one patient confirming the likely pathogenic effect of the variants. DLG4 gene represent a good candidate gene as its PSD-95 protein product is localized at the post-synaptic density, is associated with glutamatergic receptor signaling and participates in dendritogenesis. Several mouse models support the pathogenicity of DLG4 expression deficiency.

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Systematic review: probiotics in the management of lower gastrointestinal symptoms – an updated evidence-based international consensus

Summary

Background

In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems.

Aim

To update the consensus with new evidence.

Methods

A systematic review identified randomised, placebo-controlled trials published between January 2012 and June 2017. Evidence was graded, previously developed statements were reassessed by an 8-expert panel, and agreement was reached via Delphi consensus.

Results

A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs placebo. Consensus statements with 100% agreement and "high" evidence level indicated that specific probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and have favourable safety. Statements with 70%-100% agreement and "moderate" evidence indicated that, in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel movement frequency/consistency.

Conclusions

This updated review indicates that specific probiotics are beneficial in certain lower GI problems, although many of the new publications did not report benefits of probiotics, possibly due to inclusion of new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This study will help clinicians recommend/prescribe probiotics for specific symptoms.

http://ift.tt/2ohLfL6

Evaluation of the benefit and use of the new terminology in endometrial cytology reporting system

Objective

The introduction and establishment of a new classification system for endometrial cytology, the "New Terminology in Endometrial Cytology (NTEMC) system," which is based on the Bethesda System for uterine cervical cytology, has recently been reported. However, the clinical management for new categories in the NTEMC system, particularly atypical endometrial cells (ATEC), has not been clarified. The objective of the present study is to determine how the ATEC category should be treated and whether the introduction of the system has decreased the number of unnecessary endometrial biopsies.

Methods

Fifty-nine cases were diagnosed as "suspicious positive" according to the three-tier reporting (TTR) system, which was adopted in Japan. The specimens were re-evaluated according to the NTEMC system. Thirty-seven of the 59 patients underwent endometrial biopsy. We correlated the pathological diagnosis with the NTEMC system category.

Results

The 59 cases were classified according to the NTEMC system as follows: 36 cases were classified as ATEC of undetermined significance (ATEC-US), 21 cases were classified as ATEC for which atypical endometrial hyperplasia or worse cannot be excluded (ATEC-A), and 2 cases were classified as endometrial hyperplasia. The ratio of atypical endometrial hyperplasia or malignancy in ATEC-US category was significantly lower than that in ATEC-A category. Fifteen cases in ATEC-US category did not show atypical endometrial hyperplasia lesions or malignancy after 3 months.

Conclusions

These data suggest that patients with ATEC-US results can be followed up for at least three months, and the introduction of the NTEMC system decreased the number of unnecessary endometrial biopsies.

http://ift.tt/2EGI5fa

Alcohol consumption and risk of hematological malignancies: A meta-analysis of prospective studies

Abstract

Current convincing evidence suggests that alcohol intake increases the risk of several carcinomas, which might subsequently lead to a recommendation towards limiting alcohol consumption. However, there are accumulating data worth meta-analyzing that show a different effect on the risk of hematological malignancies. Eligible cohort studies were sought in PubMed database up to August 31, 2016. Separate analyses were performed by subtype of hematological malignancy (non-Hodgkin lymphoma [NHL] and subtypes, Hodgkin lymphoma [HL], leukemia and subtypes), time status (ever, current, former), level of consumption (light, moderate, heavy), alcoholic beverage (total alcohol, beer, liquor, wine), and gender. Moderate and heavy alcohol consumption were significantly associated with reduced risk of NHL (relative risk [RR]=0.85, 95% confidence interval [CI]: 0.80-0.90 and RR=0.73, 95%CI: 0.60-0.89, respectively); a protective trend was also shown for light alcohol intake (RR=0.93, 95%CI:0.87-1.00). Specifically, beer consumption was associated with reduced NHL risk (RR=0.88, 95%CI: 0.81-0.95). However, the association regarding other alcoholic beverages seemed null. The beneficial effects of alcohol mainly pertained to Diffuse Large B-Cell Lymphoma (DLBCL) (RR=0.83, 95%CI:0.77-0.89) and Follicular Lymphoma (FL) (RR=0.85, 95%CI:0.78-0.93). There was also no association between alcohol consumption and risk of HL or leukemias. In contrast to most solid malignancies, alcohol seems to confer a protective effect on NHL risk, especially on DLBCL and FL subtypes, with beer being notably beneficial. This article is protected by copyright. All rights reserved.

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Immediate biopsy of cervical cytology-negative and non-HPV-16/18 oncogenic types positive patients

Background

According to the American Society of Colposcopy and Cervical Pathology (ASCCP), a co-test is recommended for patients one year after the detection of non-HPV 16/18 viral types in association with a negative cervical cytology. In this study, we used immediate colposcopy to evaluate the risks to the patient during the one year waiting period.

Methods

We included 544 Hpv-positive/cervical cytology-negative patients who underwent cervical cancer screening from June 2015 to June 2017. Cytological specimens were classified using the Bethesta method on a liquid based preparation. We used the Hybrid Capture 2 system to define HPV DNA. Biopsies were performed on all patients under colposcopy.

Results

Three hundred and seventy-five patients had HPV types 16/18 and 169 had non-HPV-16/18 oncogenic types. Of the 169 patients who had non-HPV-16/18 oncogenic types, 151 (89%) had no dysplasia, 16 (9.4%) had CIN 1, and 2 (1.1%) had CIN 2/CIN 3.

Conclusion

For the patients who had cervical cytology negative/non-HPV-16/18 positive, we detected that 1.1% of these women had CIN 2-3. For this reason, by chasing the algorithm recommended by guidelines, gynecologists take risk missing a diagnosis of CIN 2 plus lesion in 1.1% of patients.

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The rs1024611 in the CCL2 gene and risk of gynecological cancer in Asians: a meta-analysis

Abstract

Background

The -2518A/G (rs1024611) polymorphism of the CCL2 (C-C motif chemokine ligand 2), also known as MCP-1 (monocyte chemotactic protein-1) gene, has been reported to be associated with increased gynecological cancer risk, but the results are conflicting.

Methods

In this analysis, 1089 cases and 1553 controls from six publications were used to investigate the association between CCL2-2518A/G (rs1024611) polymorphism and the risk of gynecological cancer with a meta-analytic approach. Studies published on EBSCO, EMBASE, Web of Science, PubMed, SpringerLink, ScienceDirect, Weipu, and CNKI databases were identified (last update was on November 3, 2015). Six articles focused on the association between CCL2-2518A/G (rs1024611) polymorphism, and gynecological cancer risk was selected and data were extracted. The cancer type included endometrial cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 2), and cervical cancer (n = 1). All statistical analyses were performed using the STATA version 12.0 software.

Results

The meta-analysis showed that CCL2-2518A/G (rs1024611) polymorphism is associated with risk of gynecological cancer (GG vs AG + AA, OR = 1.55, 95%CI = 1.07–2.24, P < 0.05; AA vs GG, OR = 0.59 95%CI = 0.38–0.92, P < 0.05). Notably, the subgroup analysis demonstrated that the genotype AA is associated with a reduced gynecological cancer risk in Asians, but an increased risk when compared to AG in Europeans.

Conclusions

Our data demonstrated the CCL2-2518A/G (rs1024611) polymorphism is significantly associated with risk of gynecological cancer, and the association differs by ethnicity.

http://ift.tt/2CwOfIG

Obesity and Cancer: Biological Links and Treatment Implications

Obesity is an epidemic disease and correlates with cardiovascular diseases increasing the overall mortality. However, it has been recently demonstrated that cancer is an unexpected consequence of obesity. In most of the studies, it is evaluated with body mass index (BMI): high BMI increases cancer risk and reduces survival of many solid tumors. The main biologic and clinic topics regarding obese cancer patients are here presented and discussed. Hyperinsulinemia and Insulin-like Growth Factors (IGFs) are among the most important links between cancer and obesity. However, adipose tissue (AT) also produces sex hormones, pro-inflammatory cytokines and hypoxia which in turn promote initiation and progression of tumors. One of the major clinic concern about obese cancer patients is the risk of chemotherapy-related toxicity. Previous studies showed that obese patients do not experience significant increased toxicity compared to non-obese patients. Thus, the increasing incidence and scientific knowledge of obesity should prompt the researchers to study for personalization of therapy in obese patients with cancer rather than for the simple chemotherapy "depotentiation". It has been demonstrated that weight loss reduces cancer risk and can ameliorate compliance to therapy. Thus, social politics as well as therapies against obesity may impact on cancer risk, treatment and survival.

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The Complexity of DEK Signaling in Cancer Progression

The DNA binding protein and chromatin structural regulator DEK regulate many cellular processes. These include proliferation, differentiation, apoptosis, senescence, DNA repairing and the maintenance of stem cell phenotype. DEK is increasingly recognized as a crucial player in many steps of cancer initiation and progression, and is precisely regulated by abundant promoting and inhibiting factors directly or indirectly. DEK may serve as an architectural modulating protein to regulate the expression and function of multiple human genes in cancer cells. In this article we have reviewed the specificities and complexities of DEK in the regulation of transcription factors and global chromatin, including its biologic roles in malignant cells, and summarized the current research. The possible use of DEK as a diagnostic marker and drug target in the prevention or treatment of tumors is also discussed.

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HIF1A is Overexpressed in Medulloblastoma and its Inhibition Reduces Proliferation and Increases EPAS1 and ATG16L1 Methylation

Background: Genetic and epigenetic modifications are closely related to tumor initiation and progression and can provide guidance for understanding tumor functioning, potentially leading to the discovery of new therapies. Studies have associated hypoxia-related genes to tumor progression and chemo/radioresistance in brain tumors. Information on the expression profile of hypoxiarelated genes in pediatric medulloblastoma, although scarce, may reveal relevant information that could support treatment decisions.

Objective: Our study focused on evaluation the of CA9, CA12, HIF1A, EPAS1, SCL2A1 and VEGF genes in 41 pediatric fresh-frozen medulloblastoma sample. Additionally, we analyzed the effect of hypoxia and normoxia in the pediatric medulloblastoma cell-line UW402. Furthermore, we assessed the effects of HIF1A knockdown in cell-proliferation and methylation levels of genes related to hypoxia, apoptosis and autophagy.

Method: qPCR was performed to evaluate mRNA levels, and Western blot to confirm HIF1A silencing in both patient samples and cell line. Pyrosequencing was performed to asses the methylation levels after HIF1A knockdown in the UW402 cell line.

Results: A higher HIF1A mRNA level was observed in MB patients when compared to the cerebellum (non-tumor match). In UW402 MB cell-line, chemically induced hypoxic resulted in an increase of mRNA levels of HIF1A, VEGF, SCL2A1 and CA9 genes. Additionally, HIF1A knockdown induced a decrease in the expression of hypoxia related genes and a decrease of 30% in cell proliferation was also observed. Also, a significant increase in the methylation of ATG16L1 promoter and decrease in the methylation of EPAS1 promoter were observed after HIF1A knockdown.

Conclusion: HIF1A knockdown in medulloblastoma cells lead to decreased cellular proliferation, suggesting that HIF1A can be a potential therapeutic target to be explored in the medulloblastoma. However, the mechanisms behind HIF1A protein stabilization and function are very complex and more data need to be generated to potentially use HIF1A as a therapeutical target.

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Elaborating the Role of Natural Products on the Regulation of Autophagy and their Potentials in Breast Cancer Therapy

Autophagy is an intracellular lysosomal/vacuolar degradation system, in which the inner cytoplasmic cell membrane is degraded by the lysosomal hydrolases, followed by the resulting products released back into the cytosol. It is involved in many physiological processes which are crucial for cell growth and survival. However, disturbance in the autophagic process is often associated with a variety of human diseases, such as cancer. Breast cancer is one of the most malignant tumors characterized by the imbalanced cell proliferation, apoptosis as well as disordered autophagy regulation. The alterations of autophagy related genes or protein levels in breast cancer cells also suggested a potential implication of autophagy in breast cancer development and progression. Many natural products had been reported as potential anti-cancer agents or being considered as direct or indirect sources of new chemotherapy adjuvants to enhance the efficacy or to ameliorate the side effects through the modulation of autophagy. Investigation of the underlying mechanism of these compounds could be crucial for the development of new therapeutic or chemopreventive options for breast cancer treatment. In this review, a summary of those natural products that can regulate autophagy in breast cancer is presented and the potential value of such autophagy modulators on the development of anti-cancer drugs is also discussed.

http://ift.tt/2Gt1dtb

Targeting STEAP1 Protein in Human Cancer: Current Trends and Future Challenges

Cancer is a global health issue that impairs the life quality of patients and origins thousands of deaths annually worldwide. Six-transmembrane epithelial antigen of the prostate (STEAP1) was identified to be overexpressed in several types of cancers, namely in prostate cancer (PCa). Considering its secondary structure, associated with its location in the cell membrane, has been suggested a role in intercellular communication between tumour cells. Taking into account its high specificity and overexpression in human cancers, STEAP1 is nowadays a promising candidate to be imposed as a therapeutic target. Several strategies have been developed during the last few years for targeting STEAP1, including antibody-drug conjugates, monoclonal antibodies (mAbs), DNA vaccines and small noncoding RNAs (ncRNAs). This review presents the current knowledge about STEAP1 protein expression in human tissues, its biochemical properties and targeting strategies with the purpose to evaluate its potential as therapeutic agent for cancer.

http://ift.tt/2GuC3L4

MicroRNA Key to Angiogenesis Regulation: MiRNA Biology and Therapy

Angiogenesis is involved in maintaining normal physiological processes like embryonic development, wound healing, inflammation and reproduction. Pathogenesis of various diseases like diabetic retinopathy, rheumatoid arthritis and cancer are associated with imbalanced angiogenesis. Angiogenic stimulators and inhibitors act together for keeping angiogenic switch in balance. Recently, miRNAs have been found to regulate various stages of angiogenesis. miRNAs are 21-23 nucleotides long, single stranded, noncoding RNA molecules generated endogenously. miRNA's ability to target multiple genes within a signaling pathway makes them promising target for the development of second generation anti-angiogenesis drugs. This review was conceived with the notion of availability of specific and comprehensive knowledge about AngiomiRs at one place. This will facilitate the research in basic understanding and in the development of new drugs.

In this review, we have summarized the biology and therapeutic potential of the miRNAs, which are involved in controlling angiogenesis process. In miRNA biology, we have provided the updated summary of miRNAs in the regulation of endothelial cells, showed role of miRNAs in the signaling pathways of angiogenesis and, discussed the gaps in complete knowledge of mechanism. We have also provided exclusive insights regarding therapeutic potential of these miRNAs, in angiogenesis related disorders. Additionally, we have discussed the challenges in miRNA based drug delivery and updated the current efforts in the development of miRNA delivery methods. Though much research is needed to discover the complete miRNA network regulating angiogenesis but once it is done, targeting miRNA may be considered as a potential candidate for therapeutic invention against angiogenesis related disorders.

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Meet Our Editorial Board Member

http://ift.tt/2Ff8ugP

Effects of PHA-665752 and Cetuximab Combination Treatment on In Vitro and Murine Xenograft Growth of Human Colorectal Cancer Cells with KRAS or BRAF Mutations

Background: It remains unknown whether blockade of c-Met signaling and epidermal growth factor receptor signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. In this study, we investigated the effects of the c-Met inhibitor PHA-665752 alone and in combination with cetuximab on the growth of human CRC cells in vitro and in mouse xenografts.

Methods: Human CRC cell lines (Caco2, HCT-116, and HT-29) and mice bearing HCT-116 xenografts were treated with cetuximab in the absence or presence of PHA-665752. Cell viability and apoptosis were examined using the MTT and TUNEL assays, respectively. Vimentin was measured by immunohistochemistry as a marker for epithelial-to-mesenchymal transition. Western blotting was used to determine signaling protein expression levels.

Results: The MTT assay showed that the growth of Caco2, HCT-116, and HT-29 cells was inhibited by PHA-665752 in a dose-dependent manner, but only Caco2 cell growth was suppressed by cetuximab. Combination treatment with PHA-665752 and cetuximab inhibited the proliferation of Caco2 cells and RAS mutant CRC cell lines. However, relative to the PHA-665752-alone treatment group, HT-29 cells with a BRAF mutation showed no noticeable effect. The mean tumor volume in mice treated with cetuximab in combination with PHA-665752 was significantly smaller than that in the mice treated with only cetuximab (P = 0.033) or PHA-665752 (P

Conclusion: Combination treatment with PHA-665752 and cetuximab suppressed in vitro and in vivo CRC cell growth more than treatment with either agent alone did.

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Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance

Background: Autophagy is a physiological pathway characterized by lysosomedependent self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However, during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma (Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma is largely uninvestigated.

Objective: This study is to investigate the change of autophagy level in nephroblastoma, and whether autophagy could be a therapeutic target in anaplastic nephroblastoma.

Method: In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure. Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was studied both in vivo and in vitro.

Results: In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes, suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics including vincristine and cisplatin. In G401 tumor model established in nude mice, combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor mass compared with single use of the chemotherapeutics vindesine, although no statistical significance was achieved.

Conclusion: Our results suggest that autophagy deregulation is involved in nephroblastoma, and targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases.

http://ift.tt/2Hx3QLZ

CrosstalkNet: A visualization tool for differential co-expression networks and communities

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and obtain insights into the biological processes that govern crosstalk between different tumor compartments.

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Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicentre study including postmenopausal women with an oestrogen-receptor (ER)-positive breast cancer receiving first line tamoxifen, 20mg daily in the neo-adjuvant or metastatic setting recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS) and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%) of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, the odds ratio of ORR was 1.008 per µg/l increase in endoxifen (95% CI 0.971-1.046, p=0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the pre-specified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neo-adjuvant or metastatic setting.

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Pediatric Eating Behaviors as the Intersection of Biology and Parenting: Lessons from the Birds and the Bees

Abstract

Purpose of Review

Current feeding advice to prevent pediatric obesity focuses on caregiver feeding behaviors. This review integrates newer data showing that child appetitive traits also have a genetic component.

Recent Findings

Caregiver feeding behaviors robustly correlate with child eating behaviors; however, there is also a strong heritable component.

Summary

The satiety cascade delineates the biological drive underlying hunger, satiation, and satiety. Innate individual differences exist for the components of the satiety cascade, which may explain the heritability of child eating behaviors. However, given the correlation of caregiver feeding behaviors with child eating behaviors, any etiological model should include both genetic/biological components and environmental. Integrating the biological etiology of child eating behaviors into the current environmental model has implications for tailoring feeding advice which needs to move from a "one size fits all" approach to one that is tailored to individual differences in children's biological drives to appetite.

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Apalutamide Approved for Certain Prostate Cancers [News in Brief]

Along with its relative enzalutamide, antiandrogen prolongs metastasis-free survival in patients with few treatment options, studies show.

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Pancreaticoduodenectomy for an Ampullary Region Carcinoma Occurred in Annular Pancreas Coexistent with Replaced Common Hepatic Artery

Introduction. Annular pancreas is a rare congenital abnormality characterized by a ring of pancreatic tissue surrounding the descending portion of the duodenum. Annular pancreas coexisting with replaced common hepatic artery which is also a rare anatomical variation has not been reported previously. Case Presentation. A 53-year-old man visited our hospital complaining of epigastric pain. Based on radiological examinations, he was diagnosed as having pancreatitis, annular pancreas, and hepatomesenteric trunk. One month later, obstructive jaundice developed. Endoscopic examination revealed ampullary region carcinoma. We performed pancreaticoduodenectomy using the "artery-first" approach. Discussion. Both annular pancreas and common hepatic artery anomaly are rare. High-quality preoperative imaging and awareness of such rare conditions are necessary for operative safety. Although the embryological relationship between these anomalies is uncertain, the present case may suggest some relevance between the two. Conclusion. The "artery-first" approach may be a useful method for pancreaticoduodenectomy in patients who have an anatomical abnormality.

http://ift.tt/2ECzohC

PTX3: A Potential Biomarker in Thyroid Associated Ophthalmopathy

Background. Thyroid associated ophthalmopathy (TAO) is an autoimmune disease, which involves inflammation and tissue remodeling. Pentraxin-3 (PTX3) is a component of innate immune system and recently implicated in autoimmunity. This observation may indicate that PTX3 participates in the inflammatory process of TAO. Methods. All studies were performed on TAO patients and healthy controls (45: 28 in total). RNA-seq was used to detect differential gene expression of orbital adipose-connective tissue. Quantitative PCR was performed to verify the results. PTX3 protein in orbital adipose-connective tissues was visualized by immunohistochemistry (IHC). PTX3 concentration in serum was determined by enzyme-linked immunosorbent assay (ELISA). Results. RNA-seq showed 1.86- higher PTX3 expression in the orbital adipose-connective tissues from TAO group than controls (FDR = 0.0059). qPCR confirmed the difference (5.59-fold increase, ). The presence of PTX3 protein was demonstrated. Orbital adipose tissue from healthy controls showed weak staining for PTX3 while tissue from TAO group was strongly positive. Serum PTX3 concentration was significantly elevated in patients when compared to the control group (1.9-fold increase; ). Conclusions. Patients with TAO showed increased presence of PTX3 in orbital tissue and serum, which may suggest a potential relationship of PTX3 and TAO.

http://ift.tt/2FfDtt7

Differences of the Morphology of Subaxial Cervical Spine Endplates between Chinese and White Men and Women

Objective. The aim of this comparative anatomical study was to specifically investigate endplate morphology differences between Chinese and White men and women. Materials and Methods. Three-dimensional cervical endplate models were constructed using computed tomography imaging of 41 healthy Chinese and 24 White subjects. The morphologic measurements of cervical endplate included linear parameters (EPWu: upper endplate width; EPDu: upper endplate depth; EPWl: lower endplate width; and EPDl: lower endplate depth) and area parameters with a digital measuring system. Results. All linear parameters showed a constant increase from C3 to C7 except for EPDl in both the Chinese and the White subjects. An increase trend was observed on area parameters in both Chinese and White subjects. The ratio of EPWl/EPDl was smaller in Chinese females than in White females at C3, C4, and C6 levels . The ratio of EPWl/EPDl was significantly different between the Chinese and White men at C4-5 levels . Conclusions. Our data indicates that the morphology of subaxial cervical spine endplates between Chinese and White men and women is different in most of the linear and area parameters. This information could provide guidelines for the design of CDA implants and the improvement of surgical techniques.

http://ift.tt/2GryDZi

Stimulus dependent neural oscillatory patterns show reliable statistical identification of Autism Spectrum Disorder in a face perceptual decision task

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication as well as by repetitive and restrictive behaviors and interests (American Psychiatric Association, 2013). Given the heterogeneity of this spectrum (Walsh et al., 2011) it is of paramount importance to identify experimental paradigms that are able to target cognitive processes that can be translated into the development of disease related biomarkers. Impaired attentional allocation to social features (including joint attention) (Amaral et al., 2015) or face processing deficits (Tavares et al., 2016) include the type of cognitive processes that might be targeted.

http://ift.tt/2C9lhTF

Occurrence of Thalamic High Frequency Oscillations in Patients with Different Tremor Syndromes

Abnormal oscillatory activity in the basal ganglia plays a pivotal role in the pathophysiology of movement disorders. In particular, an increase of beta activity (15-30Hz) in the subthalamic nucleus (STN) has been suggested to underlie slowing of movement in Parkinson's disease (PD) (Kühn et al., 2009; Ray et al., 2008). Beta oscillations are modulated by dopaminergic medication (Brown et al., 2001; Levy et al., 2002; Priori et al., 2004) and voluntary movement (Cassidy et al., 2002; Levy et al., 2002).

http://ift.tt/2BG2GgU

Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that involves both upper and lower motor neurons and eventually leads to muscle weakness, muscle atrophy, bulbar palsy, and respiratory failure. Creatine kinase (CK) is an enzyme that catalyzes the reversible conversion of creatine and utilizes adenosine triphosphate (ATP) to generate phosphocreatine and adenosine diphosphate. This enzyme is important in tissues and cells that rapidly consume ATP, particularly skeletal muscle.

http://ift.tt/2C7DvEK

Long-term neurophysiological and clinical response in patients with chronic inflammatory demyelinating polyradiculoneuropathy treated with subcutaneous immunoglobulin

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated disorder presenting with sub-acute onset and progressive symmetrical weakness over at least 2 months, involving proximal and distal limb muscles, associated with hypo/areflexia and impaired sensory functions (Latov, 2014; Koller et al., 2005).

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Impact of dietary patterns and the main food groups on mortality and recurrence in cancer survivors: a systematic review of current epidemiological literature

Objective

To determine whether there is an association between dietary patterns/indices and foods from the main food groups (highest vs lowest intakes) prior to or after cancer diagnosis and mortality and cancer recurrence in cancer survivors.

Participants

Survivors of common cancers with a 10-year survival rate of ≥50%: bladder, bowel, breast, cervical, kidney, laryngeal, prostate, testicular, uterine cancer, malignant melanoma and (non-)Hodgkin's lymphoma.

Outcome measures

Mortality (overall, cancer-specific, from other causes) and cancer recurrence.

Information sources

PubMed, Embase and the Cochrane Library were searched from inception to April 2017. Additional studies were identified by searching reference lists. Two authors independently screened titles and abstracts, assessed study quality and extracted the data.

Results

A total of 38 studies were included. The risk of bias was rated low for the included randomised controlled trials (RCTs) and moderate for the cohort studies. The quality of evidence was assessed with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach and was rated moderate (RCTs), and (very)low (cohort studies). Reducing the amount of fat after diagnosis appears to decrease the risk of breast cancer recurrence. Adherence to a high-quality diet and prudent diet after diagnosis appears to decrease the risk of death from other causes (and overall mortality for high-quality diet) in breast cancer survivors. Adherence to a Western diet, before and after diagnosis, appears to increase the risk of overall mortality and death from other causes among breast cancer survivors. Evidence from studies among other cancer survivors was too limited or could not be identified.

Conclusion

For many cancer survivors, there is little evidence to date to indicate that particular dietary behaviours influence outcomes with regard to recurrence and mortality. Notwithstanding, limited evidence suggests that a low-fat diet, a high-quality diet and a prudent diet are beneficial for breast cancer survivors, while a Western diet is detrimental for breast cancer survivors.

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Clinical, Endocrine and Imaging Characteristics of Patients with Primary Hypophysitis

Horm Metab Res
DOI: 10.1055/s-0044-101036

Primary hypophysitis (PH) is a rare disease with a poorly-defined natural history. Our aim was to characterise patients with PH at presentation and during prolonged follow-up. Observational retrospective study of 22 patients was conducted from 3 centres. In 14 patients, PH was confirmed histologically and in the remaining 8 clinically, after excluding secondary causes of hypophysitis. All patients had hormonal and imaging investigations before any treatment. Median follow up was 48 months (25–75%: 3–60). There was a female predominance with a female/male ratio: 3.4:1. Eight out of 22 patients had another autoimmune disease. Headaches and gonadal dysfunction were the most common symptoms. Five patients presented with panhypopituitarism; 17 patients had anterior pituitary deficiency, and 7 had diabetes insipidus. At presentation, 9 patients were treated surgically, 5 received replacement hormonal treatment, and 8 high-dose glucocorticoids from whom 5 in association with other immunosuppressive agents. Six patients showed complete recovery of pituitary hormonal deficiencies while 6 showed a partial recovery during a 5-year follow-up period. No difference was found between patients treated with surgery and those treated medically. The overall relapse rate was 18%. PH can be manifested with a broad spectrum of clinical and hormonal disturbances. Long-term follow-up is required to define the natural history of the disease and response to treatment, since pituitary hormonal recovery or relapse may appear many years after initial diagnosis. We suggest that surgery and immunosuppressive therapy be reserved for exceptional cases.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children

Horm Metab Res
DOI: 10.1055/s-0044-101144

Glucocorticoids are widely used for immunosuppression in autoimmune diseases. After the resolution of hypercortisolemia, the immune system recovers allowing for autoimmune diseases to manifest. Here we investigated the presence of autoimmune and related diseases that developed after cure of endogenous Cushing syndrome (CS) in children. We identified 129 children who were diagnosed and successfully treated for endogenous CS at the National Institutes of Health from 1997 until 2017, and who were followed for at least 6 months after treatment. We performed a retrospective chart review analysis to identify the presence of autoimmune or related diseases after cure. Ten children were diagnosed with a new autoimmune or related disorder after resolution of hypercortisolemia. This results in a frequency of 7.8% of our pediatric CS population. The identified patients had a shorter duration of hypercortisolemia prior to diagnosis, but did not otherwise differ from the remaining patients. The various identified diseases were: celiac disease (n=1), psoriasis (n=1), Hashimoto thyroiditis (n=1), Graves disease (n=1), optic neuritis (n=2), skin hypopigmented lesions/vitiligo (n=2), allergic rhinitis/asthma (n=1), and neuropathy responding to glucocorticoid treatment (n=1). The reported time between the treatment of CS and diagnosis of autoimmune disorder ranged from 6 to 19 months. The presence of autoimmune or related diseases might be masked by the hypercortisolemic state in endogenous CS. After resolution of hypercortisolemia, the presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Thyroid-Stimulating Hormone-Stimulated Human Adipocytes Express Thymic Stromal Lymphopoietin

Horm Metab Res
DOI: 10.1055/s-0044-101834

When recombinant human (rh) thyroid-stimulating hormone (TSH) is administered to thyroid cancer survivors, an acute extra-thyroidal effect raises pro-inflammatory cytokines and activates platelets. Thymic stromal lymphopoietin (TSLP) is a cytokine recently implicated in platelet activation. Our aim was to measure platelet microparticle levels after rhTSH stimulation in vivo, and to investigate TSLP expression in TSH-stimulated human adipocytes in culture. Blood samples for total and platelet microparticle analysis were obtained from thyroid cancer survivors before (day 1) and after rhTSH administration (day 5). Adipocytes, differentiated from stromal preadipocytes isolated from adipose tissue from surgical patients, were stimulated with TSH. TSLP mRNA expression, protein expression, and protein release into the adipocyte medium were measured. The level of platelet microparticles in thyroid cancer patients rose 5-fold after rhTSH stimulation. TSH upregulated TSLP mRNA expression in adipocytes in culture through a pathway that was inhibited by 66% by H89, a protein kinase A inhibitor. TSLP protein expression rose in response to TSH, and TSH-stimulated TSLP release into the medium was completely blocked by dexamethasone. In conclusion, TSLP is a novel TSH-responsive adipokine. Future studies will be needed to address the potential role of adipocyte-derived TSLP and whether it is linked to TSH-dependent platelet activation.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2GuXbRl

Evidence Underpinning the U.S. Government–Mandated Hemodynamic Interventions for Sepsis A Systematic Review

Background:

The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1), the sepsis performance measure introduced by the Centers for Medicare & Medicaid Services (CMS), requires up to 5 hemodynamic interventions, as many as 141 tasks, and 3 hours to document for a single patient.

Purpose:

To evaluate whether moderate- or high-level evidence shows that use of SEP-1 or its hemodynamic interventions improves survival in adults with sepsis.

Data Sources:

PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov from inception to 28 November 2017 with no language restrictions.

Study Selection:

Randomized and observational studies of death among adults with sepsis who received versus those who did not receive either the entire SEP-1 bundle or 1 or more SEP-1 hemodynamic interventions, including serial lactate measurements; a fluid infusion of 30 mL/kg of body weight; and assessment of volume status and tissue perfusion with a focused examination, bedside cardiovascular ultrasonography, or fluid responsiveness testing.

Data Extraction:

Two investigators independently extracted study data and assessed each study's risk of bias; 4 authors rated level of evidence by consensus using CMS criteria. High- or moderate-level evidence required studies to have no confounders and low risk of bias.

Data Synthesis:

Of 56 563 references, 20 studies (18 reports) met inclusion criteria. One single-center observational study reported lower in-hospital mortality after implementation of the SEP-1 bundle. Sixteen studies (2 randomized and 14 observational) reported increased survival with serial lactate measurements or 30-mL/kg fluid infusions. None of the 17 studies were free of confounders or at low risk of bias. In 3 randomized trials, fluid responsiveness testing did not alter survival.

Limitation:

Few trials, poor-quality and confounded studies, and no studies (with survival outcomes) of the focused examination or bedside cardiovascular ultrasonography.

Conclusion:

No high- or moderate-level evidence shows that SEP-1 or its hemodynamic interventions improve survival in adults with sepsis.

Primary Funding Source:

National Institutes of Health. (PROSPERO: CRD42016052716)

http://ift.tt/2sGEW9j

Hydroxychloroquine to Reduce Symptoms of Hand Osteoarthritis

http://ift.tt/2ERhDOT

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update

Description:

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD) is a selective update of the prior CKD–MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis.

Methods:

Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations.

Recommendations:

The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD–MBD and treatment of CKD–MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

http://ift.tt/2sFWimS

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis A Randomized Trial

Background:

Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse.

Objective:

To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis.

Design:

Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104)

Setting:

13 primary and secondary care centers in England.

Participants:

Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point.

Intervention:

Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care.

Measurements:

The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done.

Results:

At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of −0.16 point (95% CI, −0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group).

Limitation:

Hydroxychloroquine dosage restrictions may have reduced efficacy.

Conclusion:

Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.

Primary Funding Source:

Arthritis Research UK.

http://ift.tt/2EUntiu

The Health Consequences of Natural Disasters in the United States: Progress, Perils, and Opportunity

After Hurricane Katrina devastated New Orleans in 2005, the United States responded by revamping its approach to preparedness, hardening the medical infrastructure, leveraging technology, and building community resilience. These changes resulted in a health infrastructure that performed significantly better during the 2017 hurricane season. The author emphasizes that the nation must continue to strengthen its planning and response infrastructure so that the tragedy of Katrina is never repeated.

http://ift.tt/2sApyLy

Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase Results From a Single-Group, Phase 2, Open-Label Study

Background:

Treatment-free remission (TFR)—that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response—is an emerging treatment goal in chronic myeloid leukemia (CML).

Objective:

To evaluate TFR after discontinuation of second-line nilotinib therapy.

Design:

Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905)

Setting:

63 centers in 18 countries.

Patients:

Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR^4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1^IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR^4.5 during consolidation were eligible to enter TFR.

Interventions:

Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1^IS ≤0.1%) or confirmed loss of MR⁴ (BCR-ABL1^IS ≤0.01%) during TFR reinitiated nilotinib treatment.

Measurements:

Proportion of patients without loss of MMR, confirmed loss of MR⁴, or treatment reinitiation within 48 weeks of stopping treatment (primary end point).

Results:

163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR^4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation.

Limitation:

The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment.

Conclusion:

TFR seems achievable in patients with sustained MR^4.5 after switching to nilotinib.

Primary Funding Source:

Novartis Pharmaceuticals Corporation.

http://ift.tt/2ERP18g

Hydroxychloroquine: Another Battle Lost in the Campaign to Find Effective Therapies for Hand Osteoarthritis

The findings from the HERO (Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis) trial are reported in this issue. The editorialists discuss the observation of no benefit of hydroxychloroquine compared with placebo in light of the hypothesized role of inflammation in nodal hand osteoarthritis.

http://ift.tt/2sEuvTE

Immune-Mediated Necrotizing Myopathy and Dietary Sources of Statins

http://ift.tt/2CarRJe

Treating Sepsis Is Complicated: Are Governmental Regulations for Sepsis Care Too Simplistic?

Regulatory agencies evaluate hospitals' care of patients with sepsis according to their completion of the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) performance measure. Pepper and colleagues found that evidence is lacking to support a survival benefit of SEP-1 or its hemodynamic interventions. The editorialists discuss this study's importance in light of the many hours it may require for clinicians to comply with SEP-1's documentation requirements.

http://ift.tt/2sBMhao

Ibuprofen + acetaminophen did not differ from opioids + acetaminophen for reducing acute extremity pain at 2 h

http://ift.tt/2ETRteC

Shouldering

http://ift.tt/2EGskjW

Low Prevalence of Hepatitis B Vaccination Among Patients Receiving Medical Care for HIV Infection in the United States, 2009 to 2012

Background:

Persons with HIV infection are at increased risk for hepatitis B virus infection. In 2016, the World Health Organization resolved to eliminate hepatitis B as a public health threat by 2030.

Objective:

To estimate the prevalence of hepatitis B vaccination among U.S. patients receiving medical care for HIV infection ("HIV patients").

Design:

Nationally representative cross-sectional survey.

Setting:

United States.

Participants:

18 089 adults receiving HIV medical care who participated in the Medical Monitoring Project during 2009 to 2012.

Measurements:

Primary outcomes were prevalence of 1) no documentation of hepatitis B vaccination or laboratory evidence of immunity or infection (candidates to initiate vaccination), and 2) initiation of vaccination among candidates, defined as documentation of at least 1 vaccine dose in a 1-year surveillance period during which patients received ongoing HIV medical care.

Results:

At the beginning of the surveillance period, 44.2% (95% CI, 42.2% to 46.2%) of U.S. HIV patients were candidates to initiate vaccination. By the end of the surveillance period, 9.6% (CI, 8.4% to 10.8%) of candidates were vaccinated, 7.5% (CI, 6.4% to 8.6%) had no documented vaccination but had documented infection or immunity, and 82.9% (CI, 81.1% to 84.7%) remained candidates. Among patients at facilities funded by the Ryan White HIV/AIDS Program (RWHAP), 12.5% (CI, 11.1% to 13.9%) were vaccinated during the surveillance period versus 3.7% (CI, 2.6% to 4.7%) at facilities not funded by RWHAP. At the end of surveillance, 36.7% (CI, 34.4% to 38.9%) of HIV patients were candidates to initiate vaccination.

Limitation:

The study was not designed to describe vaccine series completion or actual prevalence of immunity.

Conclusion:

More than one third of U.S. HIV patients had missed opportunities to initiate hepatitis B vaccination. Meeting goals for hepatitis B elimination will require increased vaccination of HIV patients in all practice settings, particularly at facilities not funded by RWHAP.

Primary Funding Source:

Centers for Disease Control and Prevention.

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Aspirin in Patients With Previous Percutaneous Coronary Intervention Undergoing Noncardiac Surgery

Background:

Uncertainty remains about the effects of aspirin in patients with prior percutaneous coronary intervention (PCI) having noncardiac surgery.

Objective:

To evaluate benefits and harms of perioperative aspirin in patients with prior PCI.

Design:

Nonprespecified subgroup analysis of a multicenter factorial trial. Computerized Internet randomization was done between 2010 and 2013. Patients, clinicians, data collectors, and outcome adjudicators were blinded to treatment assignment. (ClinicalTrials.gov: NCT01082874)

Setting:

135 centers in 23 countries.

Patients:

Adults aged 45 years or older who had or were at risk for atherosclerotic disease and were having noncardiac surgery. Exclusions were placement of a bare-metal stent within 6 weeks, placement of a drug-eluting stent within 1 year, or receipt of nonstudy aspirin within 72 hours before surgery.

Intervention:

Aspirin therapy (overall trial, n = 4998; subgroup, n = 234) or placebo (overall trial, n = 5012; subgroup, n = 236) initiated within 4 hours before surgery and continued throughout the perioperative period. Of the 470 subgroup patients, 99.9% completed follow-up.

Measurements:

The 30-day primary outcome was death or nonfatal myocardial infarction; bleeding was a secondary outcome.

Results:

In patients with prior PCI, aspirin reduced the risk for the primary outcome (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, −2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50).

Limitation:

Nonprespecified subgroup analysis with small sample.

Conclusion:

Perioperative aspirin may be more likely to benefit rather than harm patients with prior PCI.

Primary Funding Source:

Canadian Institutes of Health Research.

http://ift.tt/2EzkgS7

The Value-Based Payment Modifier: Program Outcomes and Implications for Disparities

Background:

When risk adjustment is inadequate and incentives are weak, pay-for-performance programs, such as the Value-Based Payment Modifier (Value Modifier [VM]) implemented by the Centers for Medicare & Medicaid Services, may contribute to health care disparities without improving performance on average.

Objective:

To estimate the association between VM exposure and performance on quality and spending measures and to assess the effects of adjusting for additional patient characteristics on performance differences between practices serving higher-risk and those serving lower-risk patients.

Design:

Exploiting the phase-in of the VM on the basis of practice size, regression discontinuity analysis and 2014 Medicare claims were used to estimate differences in practice performance associated with exposure of practices with 100 or more clinicians to full VM incentives (bonuses and penalties) and exposure of practices with 10 or more clinicians to partial incentives (bonuses only). Analyses were repeated with 2015 claims to estimate performance differences associated with a second year of exposure above the threshold of 100 or more clinicians. Performance differences were assessed between practices serving higher- and those serving lower-risk patients after standard Medicare adjustments versus adjustment for additional patient characteristics.

Setting:

Fee-for-service Medicare.

Patients:

Random 20% sample of beneficiaries.

Measurements:

Hospitalization for ambulatory care–sensitive conditions, all-cause 30-day readmissions, Medicare spending, and mortality.

Results:

No statistically significant discontinuities were found at the threshold of 10 or more or 100 or more clinicians in the relationship between practice size and performance on quality or spending measures in either year. Adjustment for additional patient characteristics narrowed performance differences by 9.2% to 67.9% between practices in the highest and those in the lowest quartile of Medicaid patients and Hierarchical Condition Category scores.

Limitation:

Observational design and administrative data.

Conclusion:

The VM was not associated with differences in performance on program measures. Performance differences between practices serving higher- and those serving lower-risk patients were affected considerably by additional adjustments, suggesting a potential for Medicare's pay-for-performance programs to exacerbate health care disparities.

Primary Funding Source:

The Laura and John Arnold Foundation and National Institute on Aging.

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Late thrombectomy reduced disability in acute stroke with mismatched clinical deficit and infarction volume

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Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection A Systematic Review and Meta-analysis

Background:

The quick Sequential Organ Failure Assessment (qSOFA) has been proposed for prediction of mortality in patients with suspected infection.

Purpose:

To summarize and compare the prognostic accuracy of qSOFA and the systemic inflammatory response syndrome (SIRS) criteria for prediction of mortality in adult patients with suspected infection.

Data Sources:

Four databases from inception through November 2017.

Study Selection:

English-language studies using qSOFA for prediction of mortality (in-hospital, 28-day, or 30-day) in adult patients with suspected infection in the intensive care unit (ICU), emergency department (ED), or hospital wards.

Data Extraction:

Two investigators independently extracted data and assessed study quality using standard criteria.

Data Synthesis:

Thirty-eight studies were included (n = 385 333). qSOFA was associated with a pooled sensitivity of 60.8% (95% CI, 51.4% to 69.4%) and a pooled specificity of 72.0% (CI, 63.4% to 79.2%) for mortality. The SIRS criteria were associated with a pooled sensitivity of 88.1% (CI, 82.3% to 92.1%) and a pooled specificity of 25.8% (CI, 17.1% to 36.9%). The pooled sensitivity of qSOFA was higher in the ICU population (87.2% [CI, 75.8% to 93.7%]) than the non-ICU population (51.2% [CI, 43.6% to 58.7%]). The pooled specificity of qSOFA was higher in the non-ICU population (79.6% [CI, 73.3% to 84.7%]) than the ICU population (33.3% [CI, 23.8% to 44.4%]).

Limitation:

Potential risk of bias in included studies due to qSOFA interpretation and patient selection.

Conclusion:

qSOFA had poor sensitivity and moderate specificity for short-term mortality. The SIRS criteria had sensitivity superior to that of qSOFA, supporting their use for screening of patients and as a prompt for treatment initiation.

Primary Funding Source:

Canadian Association of Emergency Physicians. (PROSPERO: CRD42017075964)

http://ift.tt/2E3Iq72

Annals for Hospitalists - 20 February 2018

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Mid- and Long-Term Health Risks in Living Kidney Donors A Systematic Review and Meta-analysis

Background:

Long-term health risks for adults who donate kidneys are unclear.

Purpose:

To summarize evidence about mid- and long-term health risks associated with living kidney donation in adults.

Data Sources:

PubMed, Embase, Scopus, and PsycINFO without language restriction from April 1964 to July 2017.

Study Selection:

Observational studies with at least 1 year of follow-up that compared health outcomes in adult living kidney donors versus nondonor populations.

Data Extraction:

Two investigators independently extracted study data and assessed study quality.

Data Synthesis:

52 studies, comprising 118 426 living kidney donors and 117 656 nondonors, were included. Average follow-up was 1 to 24 years. No evidence suggested higher risk for all-cause mortality, cardiovascular disease, hypertension, type 2 diabetes, or adverse psychosocial health outcomes in living kidney donors than in nondonor populations. Donors had higher diastolic blood pressure, lower estimated glomerular filtration rates, and higher risk for end-stage renal disease (ESRD) (relative risk [RR], 8.83 [95% CI, 1.02 to 20.93]) and preeclampsia in female donors (RR, 2.12 [CI, 1.06 to 4.27]). Despite the increased RR, donors had low absolute risk for ESRD (incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1000 person-years) and preeclampsia (incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies).

Limitation:

Generalizability was limited by selected control populations, few studies reported pregnancy-related outcomes, and few studies were from low- and middle-income countries.

Conclusion:

Although living kidney donation is associated with higher RRs for ESRD and preeclampsia, the absolute risk for these outcomes remains low. Compared with nondonor populations, living kidney donors have no increased risk for other major chronic diseases, such as type 2 diabetes, or for adverse psychosocial outcomes.

Primary Funding Source:

National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284)

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Increasing Incidence of Multiply Recurrent Clostridium difficile Infection

http://ift.tt/2ECtDk3

Chief Concern: “I'm Worried I Have Chronic Traumatic Encephalopathy”

Chronic traumatic encephalopathy has recently been the focus of extensive attention. This commentary addresses diagnosis, prevention, treatment, and financial compensation for patients with a history of head trauma and their families.

http://ift.tt/2CThgDs

Review: In primary prevention, BP-lowering treatment reduces major CV events in patients with SBP ≥ 140 mm Hg

http://ift.tt/2EF1gBI

The ACC/AHA 2017 Hypertension Guidelines: Both Too Much and Not Enough of a Good Thing?

The most notable recommendation in the 2017 American College of Cardiology and American Heart Association hypertension guidelines is the reduced threshold for the diagnosis of hypertension, from ≥140/90 mm Hg to ≥130/80 mm Hg in the general population. This commentary discusses the guidelines and why they create as many questions as they answer.

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Review: Procalcitonin-guided starting and stopping of antibiotics in acute respiratory infections reduces mortality

http://ift.tt/2ED7nGV

Low-Dose Aspirin to Reduce the Risk for Myocardial Infarction Among Patients With Coronary Stents Undergoing Noncardiac Surgery

Graham and colleagues' post hoc analysis of the POISE-2 trial compared outcomes when aspirin was continued in the subgroup of patients with a history of previous PCI who had noncardiac surgery. The editorialists discuss the implications of the findings for perioperative care of patients with prior PCI.

http://ift.tt/2ETRtLE

In patients with rheumatoid arthritis, bDMARD therapy was not associated with malignant neoplasms

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Face the Facts: We Need to Change the Way We Do Pay for Performance

Roberts and colleagues found that the Medicare Value-Based Payment Modifier, which measures quality and costs among physician group practices and provides bonuses or levies penalties accordingly, had no beneficial effect on the quality or cost of care. The editorialists discuss why these findings show us that it is time to abandon stand-alone pay-for-performance programs as an approach to improve care.

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Epizootic Outbreak of Yellow Fever Virus and Risk for Human Disease in Salvador, Brazil

http://ift.tt/2EDTkkd

qSOFA, Cue Confusion

Fernando and colleagues' review compared the prognostic accuracy of the quick Sequential Organ Failure Assessment (qSOFA) and the systemic inflammatory response syndrome (SIRS) criteria for identifying patients with sepsis. The editorialists discuss the confusion surrounding sepsis scores and note that neither qSOFA nor the SIRS criteria are diagnostic for infection or sepsis, but they do offer information on the host's inflammatory reaction to an insult and the degree of physiologic perturbation.

http://ift.tt/2ELFfSQ

Increasing Incidence of Multiply Recurrent Clostridium difficile Infection

http://ift.tt/2EzkeJZ

A biocompatible sol–gel derived titania coating for medical implants with antibacterial modification by copper integration

Implant-associated infections are dangerous complications and may cause dramatic illness with hematogeneous spread of bacteria and secondary infections. Since treatment of these infections remains most challen...

http://ift.tt/2Ffu6tL

Chemical Precipitation Method for the Synthesis of Nb2O5 Modified Bulk Nickel Catalysts with High Specific Surface Area

A protocol for the synthesis of sponge-like and fold-like Ni1-xNbxO nanoparticles by chemical precipitation is presented.

http://ift.tt/2obPQPE

Combustion Chemistry of Fuels: Quantitative Speciation Data Obtained from an Atmospheric High-temperature Flow Reactor with Coupled Molecular-beam Mass Spectrometer

An investigation of the oxidative combustion chemistry of novel biofuels, fuel components, or jet fuels by comparison of quantitative speciation data is presented. The data can be used for kinetic model validation and enables fuel assessment strategies.This manuscript describes the atmospheric high-temperature flow reactor and demonstrates its capabilities.

http://ift.tt/2BASTsl

Monitoring the Effect of Osmotic Stress on Secretory Vesicles and Exocytosis

Osmotic stress affects exocytosis and the amount of neurotransmitter released during this process. We demonstrate how combining electrochemical methods together with transmission electron microscopy can be used to study the effect of extracellular osmotic pressure on exocytosis activity, vesicle quantal size, and the amount of neurotransmitter released during exocytosis.

http://ift.tt/2EFciuQ

Erythrocyte glutathione transferase in kidney transplantation: a probe for kidney detoxification efficiency

Erythrocyte glutathione transferase in kidney transplantation: a probe for kidney detoxification efficiency

Erythrocyte glutathione transferase in kidney transplantation: a probe for kidney detoxification efficiency, Published online: 19 February 2018; doi:10.1038/s41419-018-0289-3

Erythrocyte glutathione transferase in kidney transplantation: a probe for kidney detoxification efficiency

http://ift.tt/2oiQmL7

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg), Published online: 19 February 2018; doi:10.1038/s41419-018-0298-2

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

http://ift.tt/2ocTxVh

Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10

Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10

Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10, Published online: 19 February 2018; doi:10.1038/s41419-018-0317-3

Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10

http://ift.tt/2oiQlXz

Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p

Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p

Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p, Published online: 19 February 2018; doi:10.1038/s41419-018-0321-7

Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p

http://ift.tt/2o9YNZU

The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane

The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane

The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane, Published online: 19 February 2018; doi:10.1038/s41419-018-0312-8

The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane

http://ift.tt/2oi1dF3

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes, Published online: 19 February 2018; doi:10.1038/s41419-017-0171-8

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes

http://ift.tt/2oaxyya

Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells

Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells

Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells, Published online: 19 February 2018; doi:10.1038/s41419-018-0331-5

Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells

http://ift.tt/2oiQcU1

Using a Microfluidics Device for Mechanical Stimulation and High Resolution Imaging of C. elegans

New tools for mechanobiology research are needed to understand how mechanical stress activates biochemical pathways and elicits biological responses. Here, we showcase a new method for selective mechanical stimulation of immobilized animals with a microfluidic trap allowing high-resolution imaging of cellular responses.

http://ift.tt/2sGbeRS

The (Spatial) Memory Game: Testing the Relationship Between Spatial Language, Object Knowledge, and Spatial Cognition

We present a protocol to explore the relationship between spatial language production, spatial memory, and object knowledge. The procedure allows experimental manipulation of, and control over, conditions of object knowledge, language at instruction, and physical location, thus teasing apart cognitive and linguistic models describing interactions between these variables.

http://ift.tt/2EP3Wjx

German Value Set for the EQ-5D-5L

Abstract

Objectives

The objective of this study was to develop a value set for EQ-5D-5L based on the societal preferences of the German population. As the first country to do so, the study design used the improved EQ-5D-5L valuation protocol 2.0 developed by the EuroQol Group, including a feedback module as internal validation and a quality control process that was missing in the first wave of EQ-5D-5L valuation studies.

Methods

A representative sample of the general German population (n = 1158) was interviewed using a composite time trade-off and a discrete choice experiment under close quality control. Econometric modeling was used to estimate values for all 3125 possible health states described by EQ-5D-5L. The value set was based on a hybrid model including all available information from the composite time trade-off and discrete choice experiment valuations without any exclusions due to data issues.

Results

The final German value set was constructed from a combination of a conditional logit model for the discrete choice experiment data and a censored at −1 Tobit model for the composite time trade-off data, correcting for heteroskedasticity. The value set had logically consistent parameter estimates (p < 0.001 for all coefficients). The predicted EQ-5D-5L index values ranged from −0.661 to 1.

Conclusions

This study provided values for the health states of the German version of EQ-5D-5L representing the preferences of the German population. The study successfully employed for the first time worldwide the improved protocol 2.0. The value set enables the use of the EQ-5D-5L instrument in economic evaluations and in clinical studies.

http://ift.tt/2EF2GQW

miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis

Abstract

Glioblastoma Multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM is still lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In this study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. Firstly, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3'UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124–3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFκB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124–3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFκB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future. This article is protected by copyright. All rights reserved.

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Tobacco-attributable burden of cancer according to socioeconomic position in France

Abstract

Smoking is a major preventable cause of cancers and is increasingly concentrated among the most deprived individuals leading to increasing socioeconomic inequalities in the incidence of cancers linked to smoking. We aimed to estimate the tobacco-attributable cancer burden according to socioeconomic position in France. The analysis was restricted to cancer sites for which tobacco smoking was recognized as a risk factor. Cancer cases by sex, age group and European Deprivation Index (EDI) among people aged 30–74 between 2006 and 2009 were obtained from cancer registries covering approximately 20% of the French population. The tobacco-attributable burden of cancer according to EDI was estimated applying the population attributable fraction (PAF) computed with the Peto-Lopez method. The PAF increased from 56% in the least deprived EDI quintile to 70% in the most deprived EDI quintile among men and from 26% to 38% among women. In total, 28% of the excess cancer cases in the four most deprived EDI quintiles in men and 43% in women could be prevented if smoking in these 4 EDI quintiles was similar to that of the least deprived EDI quintile. A substantial smoking-attributable burden of cancer by socioeconomic position was observed in France. The results highlight the need for policies reducing tobacco consumption. More comprehensive interventions integrating the various dimensions of health determinants and proportionate according to socioeconomic position may essentially contribute to the reduction of socioeconomic inequalities in cancer. This article is protected by copyright. All rights reserved.

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Low T3 syndrome as a predictor of poor prognosis in chronic lymphocytic leukemia

Abstract

Low triiodothyronine (T3) state is associated with poor prognosis in critical acute and prolonged illness. However, the information on thyroid dysfunction and cancer is limited. The aim of our study was to evaluate the prognostic value of low T3 syndrome in chronic lymphocytic leukemia (CLL). Two hundred and fifty-eight patients with detailed thyroid hormone profile at CLL diagnosis were enrolled. Low T3 syndrome was defined by low free T3 (FT3) level accompanied by normal-to-low free tetraiodothyronine (FT4) and thyroid-stimulating hormone (TSH) levels. A propensity score-matched method was performed to balance the baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors related to time-to-first-treatment (TTFT) and cancer-specific survival (CSS). Area under the curve (AUC) assessed the predictive accuracy of CLL-International Prognostic Index (IPI) together with low T3 syndrome. The results showed that 37 (14.34%) patients had low T3 syndrome, which was significantly associated with unfavorable TTFT and CSS in the propensity-matched cohort, and it was an independent prognostic indicator for both TTFT and CSS. Serum FT3 level was positively related to protein metabolism and anemia, and inversely related to inflammatory state. Patients with only low FT3 demonstrated better survival than those with synchronously low FT3 and FT4, while those with synchronously low FT3, FT4 and TSH had the worst clinical outcome. Low T3 syndrome together with CLL-IPI had larger AUCs compared with CLL-IPI alone in TTFT and CSS prediction. In conclusion, low T3 syndrome may be a good candidate for predicting prognosis in future clinical practice of CLL. This article is protected by copyright. All rights reserved.

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