Lithium (Li) is a chemical element used for treating and preventing bipolar disorder (BD) and exerts positive effects such as anti-inflammatory effects as well as undesirable side effects. These effects of Li can be influenced by interaction with some nutritional elements. Therefore, we investigated the potential effects of xanthine (caffeine and theobromine) and catechin molecules present in some food beverages broadly consumed worldwide, such as coffee and tea, on Li-induced anti-inflammatory effects. In the present study, we concomitantly exposed RAW 264.7 macrophages to Li, isolated xanthine and catechin molecules, and a xanthine-catechin mixture (XC mixture). We evaluated the effects of these treatments on cell proliferation, cell cycle progression, oxidative and antioxidant marker expression, cytokine levels, gene expression, and GSK-3β enzyme expression. Treatment with the XC mixture potentialized Li-induced anti-inflammatory effects by intensification of the following: GSK-3β inhibitory action, lowering effect on proinflammatory cytokines (IL-1β, IL-6, and TNFα), and increase in the levels of IL-10 that is an anti-inflammatory cytokine. Despite the controversial nature of caffeine consumption by BD patients, these results suggested that consumption of caffeine, in low concentrations, mixed with other bioactive molecules along with Li may be safe.
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Τρίτη 7 Νοεμβρίου 2017
Xanthine-Catechin Mixture Enhances Lithium-Induced Anti-Inflammatory Response in Activated Macrophages In Vitro
Efficacy and Mechanism of Preoperative Simvastatin Therapy on Myocardial Protection after Extracorporeal Circulation
Background. Cardiopulmonary bypass (CPB) causes systemic inflammatory response and ischemia-reperfusion (IR) injury. Objective. To investigate the effect and mechanism of simvastatin on myocardial injury in cardiac valve surgery with CPB. Methods. One hundred thirty patients were randomly assigned to the statin group () or control group (). Simvastatin was administered preoperatively and postoperatively. Duration of intensive care unit stay, duration of assisted ventilation, and left ventricular ejection fraction were recorded. Plasma was analysed for troponin T (cTnT), isoenzyme of creatine kinase (CK-MB), tumor necrosis factor alpha (TNF-), interleukin-6 (IL-6), and interleukin-8 (IL-8). Ultrastructure of the myocardium and autophagosomes were observed. Beclin-1, LC3-II/I, P62, AMPK, and the phosphorylation of AMPK in cardiomyocytes were detected. Results. Simvastatin significantly reduced the duration of assisted ventilation () and ejection fraction was significantly higher in the statin group (). Simvastatin significantly reduced the levels of cTnT, CK-MB, TNF-, IL-6, and IL-8 (), reduced the expression of LC3-II/LC3-I and Beclin 1, and increased the expression of phosphorylation of AMPK. Simvastatin reduced the generation of autophagosomes and the ultrastructural injuries to myocardium. Conclusion. Perioperative statin therapy reduced myocardial injury by regulating myocardial autophagy and activating the phosphorylation of AMPK. The registration number of this study is ChiCTR-TRC-14005164.
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Carcinoma showing thymus like elements: report of a case with EGFR T790M mutation
Abstract
Carcinoma showing thymus-like differentiation of the thyroid (CASTLE) is a rare tumor involving the thyroid and perithyroidal soft tissues. It shares morphological, immunohistochemical and molecular similarities with thymic carcinomas. Due to its relatively better prognosis, it needs differentiation from other primary and metastatic tumors of this region. A 40-year-old lady presented with a gradually progressive anterior neck swelling for one year. Imaging showed bulky right and left lobes of thyroid along with a solid soft tissue mass in the pretracheal region. Fine needle aspiration smears showed features of poorly differentiated carcinoma. Total thyroidectomy with excision of the mass revealed histopathological features characteristic of CASTLE, with evidence of thyroiditis in adjoining thyroid. Epidermal growth factor receptor (EGFR) assay revealed presence of EGFR T790M somatic mutation in exon 20. The same was not detectable on direct sequencing. We present a rare case of CASTLE, occurring in association with Hashimoto thyroiditis, with emphasis on cytological features and report for the first time the presence of a low level somatic mutation in EGFR (EGFR T790M mutation).
http://ift.tt/2j9uu5S
Telecytology: Is it possible with smartphone images?
Introduction
This study aimed to discuss smartphone usage in telecytology and determine intraobserver concordance between microscopic cytopathological diagnoses and diagnoses derived via static smartphone images.
Methods
The study was conducted with 172 cytologic material. A pathologist captured static images of the cytology slides from the ocular lens of a microscope using a smartphone. The images were transferred via WhatsApp® to a cytopathologist working in another center who made all the microscopic cytopathological diagnoses 5-27 months ago. The cytopathologist diagnosed images on a smartphone without knowledge of their previous microscopic diagnoses. The Kappa agreement between microscopic cytopathological diagnoses and smartphone image diagnoses was determined.
Results
The average image capturing, transfer, and remote cytopathological diagnostic time for one case was 6.20 minutes. The percentage of cases whose microscopic and smartphone image diagnoses were concordant was 84.30%, and the percentage of those whose diagnoses were discordant was 15.69%. The highest Kappa agreement was observed in endoscopic ultrasound-guided fine needle aspiration (1.000), and the lowest agreement was observed in urine cytology (0.665). Patient management changed with smart phone image diagnoses at 11.04%.
Conclusions
This study showed that easy, fast, and high-quality image capturing and transfer is possible from cytology slides using smartphones. The intraobserver Kappa agreement between the microscopic cytopathological diagnoses and remote smartphone image diagnoses was high. It was found that remote diagnosis due to difficulties in telecytology might change patient management. The developments in the smartphone camera technology and transfer software make them efficient telepathology and telecytology tools.
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Impact of variant microscopic interpretation of the uCyt+ immunocytological urine test for the detection of bladder cancer
Background
Urinary marker tests for bladder cancer (BC) detection and surveillance represent a desirable approach to diagnosis and follow-up. The SCIMEDX uCyt+ assay detects antigens expressed by BC cells (mucin glycoprotein and carcinoembryonic antigen) using green and red fluorescence and is interpreted according to specific manufacturer's recommendations. In the present study, we evaluated divergent approaches of numeric and morphological analysis of uCyt+ to generate a rationale for alternative test interpretation strategies.
Methods
A total of 444 patients with hematuria and without history of BC underwent uCyt+ analysis, cystoscopy and histological examination of tissue biopsies. Beside positive cells according to the manufacturer's definition (definitely positive cells, DPC), (i) cells showing borderline character (borderline cells, BLC), and (ii) cells with staining present below defined border (subliminal cells, SLC) were included into the analytical algorithm. Different cut-off levels for cell counts (>0, ≥3, ≥5) were evaluated separately with regard to their diagnostic accuracy. Moreover, the influence of clinical factors on test results were evaluated.
Results
Adding BLC at a cut-off of ≥3 cells resulted in Area Under the Curve (AUC) of 0.70 for green and 0.77 for red fluorescence, respectively. Adding SLC led to reduced AUC (0.62 and 0.73, respectively). Male gender was significantly associated with false positive results in the "best AUC" groups (P = .0101). No further correlations to clinical influencing factors were observed.
Conclusions
Adding microscopic BLC as test-positive and adjusting cut-off level for the interpretation of uCyt+ may improve assay performance independent of clinical factors.
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Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials
Abstract
Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who initially were treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in nine phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDIs of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In the both groups, however, the decreasing relative dose intensity (RDI) over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.
This article is protected by copyright. All rights reserved.
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Savings from reducing low-value general surgical interventions
Background
Finding opportunities for improving efficiency is important, given the pressure on national health budgets. Identifying and reducing low-value interventions that deliver little benefit is key. A systematic literature evaluation was done to identify low-value interventions in general surgery, with further assessment of their cost.
Methods
A multiplatform method of identifying low value interventions was undertaken, including a broad literature search, a targeted database search, and opportunistic sampling. The results were then stratified by impact, assessing both frequency and cost.
Results
Seventy-one low-value general surgical procedures were identified, of which five were of high frequency and high cost (highest impact), 22 were of high cost and low frequency, 23 were of low cost and high frequency, and 21 were of low cost and low frequency (lowest impact). Highest impact interventions included inguinal hernia repair in minimally symptomatic patients, inappropriate gastroscopy, interval cholecystectomy, CT to diagnose appendicitis and routine endoscopy in those who had CT-confirmed diverticulitis. Their estimated cost was €153 383 953.
Conclusion
Low-value services place a burden on health budgets. Stopping only five high-volume, high-cost general surgical procedures could save the National Health Service €153 million per annum.
http://ift.tt/2Ajlyy0
Inorganic/Organic Double-Network Gels Containing Ionic Liquids
Abstract
Highly robust ion gels, termed double-network (DN) ion gels, composed of inorganic/organic interpenetrating networks and a large amount of ionic liquids (ILs), are fabricated. The DN ion gels with an 80 wt% IL content show extraordinarily high mechanical strength: more than 28 MPa of compressive fracture stress. In the DN ion gel preparation, a brittle inorganic network of physically bonded silica nanoparticles and a ductile organic network of polydimethylacrylamide (PDMAAm) are formed in the IL. Because of the different reaction mechanisms of the inorganic/organic networks, the DN ion gels can be formed by an easy and free-shapeable one-pot synthesis. They can be prepared in a controllable manner by manipulating the formation order of the inorganic and organic networks via not only multistep but also single-step processes. When silica particles form a network prior to the PDMAAm network formation, DN ion gels can be prepared. The brittle silica particle network in the DN ion gel, serving as sacrificial bonds, easily ruptures under loading to dissipate energy, while the ductile PDMAAm network maintains the shape of the material by the rubber elasticity. Given the reversible physical bonding between the silica particles, the DN ion gels exhibit a significant degree of self-recovery by annealing.
Robust ion gels with an inorganic/organic double-network (DN) are developed. The DN ion gels that can withstand more than 28 MPa of compressive stress are easily prepared by controlling the formation order of the inorganic and organic networks in a one-pot/one-step process. Recoverable physical bonding in the inorganic network lends to self-healing property of the DN ion gels.
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Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial
Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25–2.92)], genistein [1.51 (1.02–2.22), daidzein [1.80 (1.18–2.75) and glycitein [1.67 (1.15–2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93–2.25), 1.65 (1.07–2.54), 1.73 (1.13–2.66) and 1.80 (1.18–2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.
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A New Substitute for Formalin: Application to Embalming Cadavers
Abstract
The development of formalin-free fixatives is an urgent issue in gross anatomy because of the health hazard and the tissue-hardening actions of formalin. We recently identified the fixative, antimicrobial, and preservative effects of N-vinyl-2-pyrrolidone (NVP), a precursor of the water-soluble macromolecular polymer polyvinylpyrrolidone, in animal experiments. The aim of the present study is to investigate whether NVP solution can be used as an alternative to formalin in human cadaveric dissection. Twelve donated cadavers were infused with NVP via the femoral and common carotid arteries using a peristaltic pump. Experienced teaching staff members in our department dissected the cadavers and examined their macroanatomical properties. The NVP-embalmed corpses showed no sign of decomposition or fungal growth. The bodies remained soft and flexible. Notably, the shoulder, elbow, wrist, phalangeal, hip, knee, cervical spine, and temporomandibular joints were highly mobile, almost equivalent to those of living individuals. The range of motion of most joints was greater in the NVP-fixed than formalin-fixed cadavers. Under the dermis, the subcutaneous fat was markedly reduced and the connective tissues were transparent, so the ligaments, cutaneous nerves, and veins were easily discernible. The abdominal wall and the visceral organs remained pliable and elastic, resembling those of fresh cadavers. The lungs, liver, and gastrointestinal tract were moveable in the thoracic and abdominal cavities and were readily isolated. NVP can be used successfully as a fixative and preservative solution for human cadavers; furthermore, NVP-embalmed bodies could be valuable for learning clinical skills and for training, and for developing innovative medical devices. This article is protected by copyright. All rights reserved.
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Age-related microvascular dysfunction: novel insight from near-infrared spectroscopy
Abstract
Near-infrared spectroscopy (NIRS) has emerged as a promising tool to evaluate vascular reactivity in vivo. Whether this approach can be used to assess age-related impairments in microvascular function has not been tested. Tissue oxygen saturation (StO2) post-occlusion recovery kinetics were measured in two distinct age groups (<35 year and >65 years) using NIRS placed over the flexor digitorum profundus. Key end-points included: (1) the desaturation rate during cuff occlusion; (2) the lowest StO2 value obtained during ischemia (StO2min); (3) StO2 reperfusion rate; (4) the highest StO2 value reached after cuff release (StO2max); and (5) the reactive hyperemia area under the curve (AUC). First, using a conventional 5 minute cuff occlusion protocol, the elderly participants achieved a much slower rate of oxygen recovery (1.5 ± 0.2 vs. 2.5 ± 0.2%·s−1), lower StO2max (85.2 ± 2.9 vs. 92.3 ± 1.5%), and lower reactive hyperemia AUC (2651.8 ± 307.0 vs. 4940.0 ± 375.8%·s−1). However, due to a lower skeletal muscle resting metabolic rate, StO2min was also significantly attenuated in the elderly participants compared to the young controls (55.7 ± 3.5 vs. 41.0 ± 3.4%), resulting in a much lower ischemic stimulus. To account for this important group difference, we then matched the level of tissue ischemia in a subset of young healthy participants by reducing the cuff occlusion protocol to 3 minutes. Remarkably, when we controlled for tissue ischemia, we observed no differences in any of the hyperemic endpoints between the young and elderly participants. These data highlight the important role NIRS can serve in vascular biology, but also establishes the need for assessing tissue ischemia during cuff-occlusion protocols.
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Hyperglycemia induced by chronic i.p. and oral glucose loading leads to hypertension through increased Na+-retention in proximal tubule
Abstract
Feeding animals glucose, fructose, sucrose, and fat-enriched diets can lead to diet-induced hyperglycemia, severity of which largely depends on type and concentration of nutrients used and length of dietary intervention. As a strategy of dietary intervention, we adopted glucose-enriched diet, drinking water, and intraperitoneal (i.p.) glucose injection at the dose previously determined to be effective to establish a sustained hyperglycemia over a period of 2 weeks. In our current study, we used 4 groups of Sprague Dawley rats: control, glucose-treated, glucose+tempol, and glucose+captopril-treated groups. Our study demonstrated that glucose levels gradually started to increase from day 3, and reached to the highest levels (321 mg dl−1) at day 12 and maintained similar levels until the end of the study on day 14 in glucose treated-group compared to control. However, tempol- and captopril-treated groups showed significantly high glucose levels in only second week. Plasma insulin level has been significantly increased in glucose-treated animals but not in tempol- and captopril-treated groups when compared to control. We also observed elevated blood pressure (BP) in glucose-treated group compared to control, which can be attributed to increased Ang II production from 46.67 pg.ml−1 to 99 pg.ml−1 (control vs. glucose), increased oxidative stress in cortical proximal tubule (PT), decreased urine flow, and increased expression and activity of PT-specific α1-subunit of Na+-K+-ATPase in renal cortex, the latter is responsible for increased sodium reabsorption from epithelial cells of PT into peritubular capillaries, leading to increased blood volume and eventual blood pressure. All these events are reversed in captopril- and tempol-treated animals.
This article is protected by copyright. All rights reserved
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Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations
Abstract
Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer. However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and pancreatic cancer incidence in European populations.
We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident pancreatic cancer cases (EPIC n=626; HUNT2 n=112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI).
Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53); and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with pancreatic cancer risk (p for trend = 0.23).
Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of pancreatic cancer risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant. This article is protected by copyright. All rights reserved.
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Risk of skin cancer among patients with myotonic dystrophy type 1 based on Primary care physician data from the United Kingdom Clinical Practice Research Datalink
Abstract
Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1-free individuals matched on gender, birth year (±2 years), attending practice, and registration year (±1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow-up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow-up of 3.6 years, 35 DM1 patients and 108 matched DM1-free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR=5.44, 95% CI=3.33-8.89, p<.0001), and basal cell carcinoma (BCC) (HR=5.78, 95% CI=3.36-9.92, p<.0001). Risks did not differ by gender, or age at DM1 diagnosis (P-heterogeneity>0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions. This article is protected by copyright. All rights reserved.
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Midlife metabolic factors and prostate cancer risk in later life
Abstract
Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n=9,097, enrolled 1967-1987) were followed for incident (n=1,084 total; n=378 advanced; n=148 high-grade) and fatal (n=340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mmHg or taking anti-hypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides was associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs. 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p-trend=0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer. This article is protected by copyright. All rights reserved.
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Biweekly cisplatin and gemcitabine in patients advanced biliary tract cancer
Abstract
Treatment with cisplatin with gemcitabine (CG) demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1000mg/m2/min) and cisplatin 20mg/m2 on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%) and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%) and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies. This article is protected by copyright. All rights reserved.
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A comprehensive analysis of polymorphic variants in steroid hormone and IGF-1 metabolism and risk of in situ breast cancer: results from the Breast and Prostate Cancer Cohort (BPC3) Consortium
Abstract
We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and IGF-1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was done using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom=3.05, 95%CI = 1.72-5.44, Phom= 1.47 × 10−4), MAST2-rs12124649 (ORhom=1.73, 95% CI =1.18-2.54, Phom= 5.24 × 10−3), and INSR-rs10500204 (ORhom= 1.96, 95% CI =1.44-2.67, Phom=1.68 × 10−5) were associated with increased risk of BCIS; however only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom=1.78, 95% CI =1.30-2.44, Phom= 3.23 × 10−4).
The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further. This article is protected by copyright. All rights reserved.
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Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses
The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 1–11. ©2017 AACR.
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BAP1 is a novel target in HPV negative head and neck cancer.
Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC). Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV) -negative and HPV-positive, and examined the effects on radiosensitivity in vitro and in HNSCC mouse xenograft models. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients. Results. Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on -H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying homologous recombination. Finally, in patients with HNSCCC, overexpression of BAP1 was associated with higher failure rates after radiation therapy. Conclusions. BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC.
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Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial
Purpose: MPX, a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. Experimental Design: This was a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR PCa, powered to detect a prostate specific antigen doubling time (PSADT) difference of 6 months (low-dose) and 12 months (high-dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500mg MPX (low), 4000mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation and polyphenol pharmacokinetics. Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (p=0.81): control 0.9 months (n=20, range -6.7 to 83.1), low-dose 1.5 months (n=52, range: -10.3 to 87.2), high-dose 0.9 months (n=40, range: -27.3 to 88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms) (6.4 months, p=0.02), but not in control (1.8 months, p=0.25). Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study.
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Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
The incidence of cutaneous melanoma has continued to increase in recent years. For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis, with 5-year survival rates of 98% for stage I disease and 90% for stage II disease. However,…
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FDA Approves Second CAR T-cell Therapy [News in Brief]
Axicabtagene ciloleucel OK'd for the treatment of adults with certain non-Hodgkin lymphomas.
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Delayed Intraventricular Hemorrhage following a Ventriculoperitoneal Shunt Placement: Exploring the Surgical Anatomy of a Rare Complication
Ventriculoperitoneal shunt (VPS) placement is one of the commoner neurosurgical procedures worldwide. The purpose of this article is to report a case of delayed intraventricular hemorrhage (IVH) following a VPS and to review the literature regarding anatomic factors that could potentially explain this rare complication. A 78-year-old man with normal pressure hydrocephalus, who underwent an uneventful right VPS placement, suffered from a catastrophic isolated IVH five days later. The reported cases of delayed intracerebral hemorrhage (ICH) following VPS are rare and those with IVH are even rarer. Potential factors of surgical anatomy that could cause delayed ICH/IVH following a VPS procedure include erosion of vasculature by catheter cannulation, multiple attempts at perforation, puncture of the choroid plexus, improper placement of the tubing within the brain parenchyma, VPS system revision, venous infarction, vascular malformations, head trauma, and brain tumors. Other causes include generalized convulsion, VPS system malfunction, increased intracranial or blood pressure, sudden intracranial hypotension, and bleeding disorders. According to the current literature, our case is the first reported delayed isolated IVH after a VPS placement so far. Neurosurgeons should be aware of the delayed ICH/IVH as a rare, potentially fatal complication of VPS, as well as of its risk factors.
http://ift.tt/2AqpPk5
The suprachiasmatic nucleus drives day–night variations in postprandial triglyceride uptake into skeletal muscle and brown adipose tissue
New Findings
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What is the central question of this study?
What are the factors influencing day–night variations in postprandial triglycerides?
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What is the main finding and its importance?
Rats show low postprandial plasma triglyceride concentrations early in the active period that are attributable to a higher uptake by skeletal muscle and brown adipose tissue. We show that these day–night variations in uptake are driven by the suprachiasmatic nucleus, probably via a Rev-erbα-mediated mechanism and independent of locomotor activity. These findings highlight that the suprachiasmatic nucleus has a major role in day–night variations in plasma triglycerides and that disturbances in our biological clock might be an important risk factor contributing to development of postprandial hyperlipidaemia.
Energy metabolism follows a diurnal pattern, mainly driven by the suprachiasmatic nucleus (SCN), and disruption of circadian regulation has been linked to metabolic abnormalities. Indeed, epidemiological evidence shows that night work is a risk factor for cardiovascular disease, and postprandial hyperlipidaemia is an important contributor. Therefore, the aim of this work was to investigate the factors that drive day–night variations in postprandial triglycerides (TGs). Intact and SCN-lesioned male Wistar rats were subjected to an oral fat challenge during the beginning of the rest phase (day) or the beginning of the active phase (night). The plasma TG profile was evaluated and tissue TG uptake assayed. After the fat challenge, intact rats showed lower postprandial plasma TG concentrations early in the night when compared with the day. However, no differences were observed in the rate of intestinal TG secretion between day and night. Instead, there was a higher uptake of TG by skeletal muscle and brown adipose tissue early in the active phase (night) when compared with the rest phase (day), and these variations were abolished in rats bearing bilateral SCN lesions. Rev-erbα gene expression suggests this as a possible mediator of the mechanism linking the SCN and day–night variations in TG uptake. These findings show that the SCN has a major role in day–night variations in plasma TGs by promoting TG uptake into skeletal muscle and brown adipose tissue. Consequently, disturbance of the biological clock might be an important risk factor contributing to the development of hyperlipidaemia.
http://ift.tt/2hlHDsf
Targeting de novo lipogenesis as a novel approach in anti-cancer therapy
Targeting de novo lipogenesis as a novel approach in anti-cancer therapy
Targeting <i>de novo</i> lipogenesis as a novel approach in anti-cancer therapy, Published online: 07 November 2017; doi:10.1038/bjc.2017.374
http://ift.tt/2yGpdcX
CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma
CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma
CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma, Published online: 07 November 2017; doi:10.1038/bjc.2017.364
http://ift.tt/2m2rz03
Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer
Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer
Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer, Published online: 07 November 2017; doi:10.1038/bjc.2017.390
http://ift.tt/2yFBeQ5
Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing in a Patient with Varicella-Zoster Virus Encephalomyelitis
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing syndrome (SUNCT) is a type of trigeminal autonomic cephalalgia. Its etiology is generally idiopathic, though rarely it has been associated with viral infections. We describe the fourth case reported in the literature of SUNCT in association with viral meningoencephalitis.
http://ift.tt/2j7Xk6N
Survival Outcomes Following the Use of Extracorporeal Membrane Oxygenation as a Rescue Technology in Critically Ill Patients: Results From Pennsylvania 2007–2015
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Acute Physiologic Stress and Subsequent Anxiety Among Family Members of ICU Patients
http://ift.tt/2iDXYow
β-lactam Therapeutic Drug Management in the PICU
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Predictors, Prevalence, and Outcomes of Early Crystalloid Responsiveness Among Initially Hypotensive Patients With Sepsis and Septic Shock
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Technologic Distractions (Part 2): A Summary of Approaches to Manage Clinical Alarms With Intent to Reduce Alarm Fatigue
http://ift.tt/2iDey8e
Event-related neuronal responses to acoustic novelty in single-sided deaf cochlear implant users: Initial findings
Cochlear implants (CIs) restore hearing to deaf and severely hard of hearing individuals. They bypass a non-functional inner ear by direct electrical stimulation of auditory nerves (Zeng et al., 2011). Compared to normal acoustic hearing CI-transmitted sounds are degraded (Drennan and Rubinstein, 2008). This makes speech understanding difficult, particularly in background noise (Baskent et al., 2016; Wilson and Dorman, 2008). Speech intelligibility with the CI is typically assessed via word or sentences tests in quiet or noise (Hahlbrock, 1953; Haumann et al., 2010; Hey et al., 2014, 2016; Hochmair-Desoyer et al., 1997; Zeng and Fay, 2013).
http://ift.tt/2zrqJPy
Optimal use of EEG montages to identify inferior temporal epileptiform activity
The 10/20 EEG electrode position system recommended by Herbert Jasper at the 2nd International EEG Congress has remarkably stood the test of time (Klem et al., 1999). Image localization and studies of closely spaced electrode systems have generally confirmed that 10/20 electrode positions are located similarly, within 1 cm of major anatomic landmarks in individuals despite their varying head sizes and shapes (Homan et al., 1987). Silverman and other recognized, however, that interictal and ictal epileptiform discharges often originate in basal and anterior temporal regions that are poorly sampled by standard 10/20 leads and recommended T1/T2 electrodes for recording anterior inferior sources (Silverman, 1960).
http://ift.tt/2zE8DuB
Electromagnetic Source Imaging Using Simultaneous Scalp EEG and Intracranial EEG: An Emerging Tool for Interacting with Pathological Brain Networks
Functional brain imaging aims at studying the function and dysfunction of the brain by monitoring its functional dynamics over time. Such modalities include, for instance, functional magnetic resonance imaging (fMRI) (Bandettini et al., 1992; Kwong et al., 1992; Ogawa et al., 1992), positron emission tomography (PET) (Ter-Pogossian et al., 1975), electroencephalography (EEG) (He et al., 1987; Michel and He, 2011; Niedermeyer and da Silva, 2005), and magnetoencephalography (MEG) (Cohen, 1972; Hämäläinen et al., 1993).
http://ift.tt/2zr7GEM
Tumor-infiltrating T lymphocytes and morphogenesis of follicular lymphoma—reply
We thank Dr. Ree and colleagues for their interesting comment about our recent data about the favorable influence of CD3+ tumor-infiltrating lymphocytes (TILs) in follicular lymphoma (FL) patients [1]. They raised the question as to whether CD3+ TILs were free, directly in contact with tumor cells, or if they remain in and around vessels. In the latter case, they would suggest that postcapillary venules (PCVs), holding small lymphocytes in the endothelial wall and lumen could be involved in a putative T-zone attempt to contain B-cell neoplasm in a follicular and less aggressive state.
http://ift.tt/2hlwo31
BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers
The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in four digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry (IHC) on tissue microarrays. A total of 1546 samples of four types of cancer tissues, their matched adjacent non-tumor tissues, and corresponding benign tissues were studied respectively.
http://ift.tt/2zmoQE1
Low expression of NKD2 is associated with enhanced cell proliferation and poor prognosis in human hepatocellular carcinoma
NKD2 is a member of the Naked cuticle (Nkd) protein family and functions as a negative regulator of the Wnt signaling pathway. We investigated the prognostic value of NKD2 expression in hepatocellular carcinoma (HCC). Western blot and immunohistochemical analyses revealed that NKD2 was significantly downregulated in HCC specimens compared with adjacent non-tumorous tissues. Next, we found that NKD2 expression correlated significantly with several clinicopathologic features, such as tumor grade, tumor size, and Ki-67 expression.
http://ift.tt/2hklJWb
Restoration of A Healthy Intestinal Microbiota Normalizes Portal Hypertension In A Rat Model of Nonalcoholic Steatohepatitis
ABSTRACT
Portal hypertension (PH) drives most of the clinical complications in chronic liver diseases. However, its progression in nonalcoholic steatohepatitis (NASH) and its association with the intestinal microbiota (IM) has been scarcely studied. Our aim was to investigate the role of IM in the mechanisms leading to PH in early NASH. The experimental design was divided in two stages: Stage 1: Sprague-Dawley rats were fed for 8 weeks with high-fat diet and high-glucose/fructose syrup (HFGFD) or control diet/water (CD). Representative rats were selected as IM donors for Stage 2. Stage 2: additional HFGFD and CD rats underwent intestinal decontamination followed by IM transplantation with faeces from opposite diet donors (heterologous transplant, Tr) or autologous faecal transplant (Atr) ((as controls)), generating four groups: CD-Atr, CD-Tr, HFGFD-Atr, HFGFD-Tr. After IM transplantation, the original diet was maintained for 12-14 days until euthanasia.HFGFD rats developed obesity, insulin resistance, NASH without fibrosis but with PH, intrahepatic endothelial dysfunction and IM dysbiosis. In HFGFD rats, transplantation with faeces from CD donors caused a significant reduction of PH to levels comparable to CD without significant changes in NASH histology. The reduction in PH was due to a 31% decrease of intrahepatic vascular resistance compared to HFGFD-Atr (p<0.05). This effect occurs via the restoration of the sensitivity to insulin of the hepatic Akt-dependent eNOS signaling pathway. Conclusions The intestinal microbiota exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis. Portal hypertension, insulin resistance and endothelial dysfunction revert when a healthy intestinal microbiota is restored. This article is protected by copyright. All rights reserved.
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The Effect of Inspiratory Resistance on Exercise Performance and Perception in Moderate Normobaric Hypoxia
High Altitude Medicine & Biology , Vol. 0, No. 0.
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Pooled Analysis of Multiple Crossover Trials To Optimize Individual Therapy Response to Renin-Angiotensin-Aldosterone System Intervention
Background and objectives
In the treatment of CKD, individual patients show a wide variation in their response to many drugs, including renin-angiotensin-aldosterone system inhibitors (RAASi). To investigate whether therapy resistance to RAASi can be overcome by uptitrating the dose of drug, changing the mode of intervention (with drugs from similar or different classes), or lowering dietary sodium intake, we meta-analyzed individual responses to different modes of interventions.
Design, setting, participants, & measurementsRandomized crossover trials were analyzed to assess correlation of individual responses to RAASi and nonsteroidal anti-inflammatory drugs (NSAIDs; n=395 patients). Included studies compared the antialbuminuric effect of uptitrating the dose of RAASi (n=10 studies) and NSAIDs (n=1), changing within the same class of RAASi (e.g., angiotensin-converting enzyme inhibition to angiotensin receptor blockers; n=5) or NSAIDs (n=1), changing from RAASi to NSAIDs (n=2), and changing from high to low sodium intake (n=5). A two-stage meta-analysis was conducted: Deming regression was conducted in each study to assess correlations in response, and individual study results were then meta-analyzed.
ResultsThe albuminuria response to one dose of RAASi or NSAIDs positively correlated with the response to a higher dose of the same drug (r=0.72; 95% confidence interval [95% CI], 0.66 to 0.78), changes within the same class of RAASi or NSAIDs (r=0.54; 95% CI, 0.35 to 0.68), changes between RAASi and NSAIDs (r=0.44; 95% CI, 0.16 to 0.66), and changes from high to moderately low salt intake (r=0.36; 95% CI, 0.22 to 0.48). Results were similar when the individual systolic BP and potassium responses were analyzed, and were consistent in patients with and without diabetes.
ConclusionsIndividuals who show a poor response to one dose or type of RAASi also show a poor response to higher doses, other types of RAASi or NSAIDs, or a reduction in dietary salt intake. Whether other drugs or drug combinations targeting pathways beyond the renin-angiotensin-aldosterone system and prostaglandins would improve the individual poor response requires further study.
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Nephrology Provider Prognostic Perceptions and Care Delivered to Older Adults with Advanced Kidney Disease
Background and objectives
Prognostic uncertainty is one barrier that impedes providers in engaging patients with CKD in shared decision making and advance care planning. The surprise question has been shown to identify patients at increased risk of dying.
Design, setting, participants, & measurementsIn our prospective observational study, 488 patients ≥60 years of age with CKD stage 4 or 5 were enrolled. Binary surprise question (i.e., "Would you be surprised if this patient died in the next 12 months?") responses were recorded, and dialysis planning preferences, presence of advance care planning documentation, and care preceding death were abstracted.
ResultsThe median patient age was 71 (65–77) years old. Providers responded no and yes to the surprise question for 171 (35%) and 317 (65%) patients, respectively. Median follow-up was 1.9 (1.5–2.1) years, during which 18% of patients died (33% of surprise question no, 10% of surprise question yes; P<0.001). In patients with a known RRT preference (58%), 13% of surprise question no participants had a preference for conservative management (versus 2% of yes counterparts; P<0.001). A medical order (i.e., physician order for life-sustaining treatment) was documented in 13% of surprise question no patients versus 5% of yes patients (P=0.004). Among surprise question no decedents, 41% died at home or hospice, 38% used hospice services, and 54% were hospitalized in the month before death. In surprise question yes decedents, 39% died at home or hospice (P=0.90 versus no), 26% used hospice services (P=0.50 versus no), and 67% were hospitalized in the month before death (P=0.40 versus surprise question no).
ConclusionsNephrologists' prognostic perceptions were associated with modest changes in care, highlighting a critical gap in conservative management discussions, advance care planning, and end of life care among older adults with CKD stages 4 and 5 and high-risk clinical characteristics.
PodcastThis article contains a podcast at http://ift.tt/2yDWc1D
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Fibroblast Growth Factor 23 and Anemia in the Chronic Renal Insufficiency Cohort Study
Background and objectives
Anemia is an early complication of CKD that is associated with increased morbidity and mortality. Prior data show associations between abnormal mineral metabolism markers and decreased erythropoiesis. However, few studies have investigated elevated fibroblast growth factor 23 as a risk factor for the development of anemia in patients with CKD.
Design, setting, participants, & measurementsWe conducted a prospective cohort study of 3869 individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort Study between 2003 and 2008 and followed through 2013. We hypothesized that elevated baseline fibroblast growth factor 23 levels are associated with prevalent anemia, decline in hemoglobin over time, and development of incident anemia, defined as serum hemoglobin level <13 g/dl in men, serum hemoglobin level <12 g/dl in women, or use of erythropoietin stimulating agents.
ResultsIn the 1872 of 3869 individuals who had prevalent anemia at baseline, mean age was 58 (11) years old, and mean eGFR was 39 (13) ml/min per 1.73 m2. Higher levels of fibroblast growth factor 23 were significantly associated with prevalent anemia (odds ratio per 1-SD increase in natural log–transformed fibroblast growth factor 23, 1.39; 95% confidence interval, 1.26 to 1.52), decline in hemoglobin over 4 years, and risk of incident anemia (hazard ratio per 1-SD increase in natural log–transformed fibroblast growth factor 23, 1.13; 95% confidence interval, 1.04 to 1.24; quartile 4 versus quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.19 to 2.11) independent of demographic characteristics, cardiovascular disease risk factors, CKD-specific factors, and other mineral metabolism markers. The results of our prospective analyses remained unchanged after additional adjustment for time-varying eGFR.
ConclusionsElevated fibroblast growth factor 23 is associated with prevalent anemia, change in hemoglobin over time, and development of anemia. Future studies are needed to elucidate the mechanisms for these associations.
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Patterns of NSAIDs Use and Their Association with Other Analgesic Use in CKD
Background and objectives
Avoiding nonsteroidal anti-inflammatory drugs is important for safe CKD care. This study examined nonsteroidal anti-inflammatory drug use patterns and their association with other analgesic use in CKD.
Design, setting, participants, & measurementsThe Chronic Renal Insufficiency Cohort Study is an observational cohort study that enrolled 3939 adults ages 21–74 years old with CKD between 2003 and 2008 using age-based eGFR inclusion criteria. Annual visits between June of 2003 and December of 2011 were organized into 15,917 visit-pairs (with an antecedent and subsequent visit) for 3872 participants with medication information. Demographics, kidney function, and clinical factors were ascertained along with report of nonsteroidal anti-inflammatory drug or other analgesic use in the prior 30 days.
ResultsIn our study, 24% of participants reported nonsteroidal anti-inflammatory drug use at baseline or at least one follow-up study visit. Having a 10 ml/min per 1.73 m2 higher eGFR level at an antecedent visit was associated with higher odds of starting nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 1.44; 95% confidence interval, 1.34 to 1.56). Seeing a nephrologist at the antecedent visit was associated with lower odds of starting or staying on nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87 and odds ratio, 0.61; 95% confidence interval, 0.46 to 0.81, respectively). Starting and stopping nonsteroidal anti-inflammatory drugs were both associated with higher odds of increasing the number of other analgesics (odds ratio, 1.52; 95% confidence interval, 1.25 to 1.85 and odds ratio, 1.78; 95% confidence interval, 1.39 to 2.28, respectively) and higher odds of increasing the number of opioid analgesics specifically (odds ratio, 1.92; 95% confidence interval, 1.48 to 2.48 and odds ratio, 1.46; 95% confidence interval, 1.04 to 2.03, respectively).
ConclusionsNonsteroidal anti-inflammatory drug use is common among patients with CKD but less so among those with worse kidney function or those who see a nephrologist. Initiation or discontinuation of nonsteroidal anti-inflammatory drugs is often associated with supplementation with or replacement by, respectively, other analgesics, including opioids, which introduces possible drug-related problems when taking these alternative analgesics.
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Disparity between Nephrologists Opinions and Contemporary Practices for Community Follow-Up after AKI Hospitalization
Background and objectives
Recent guidelines suggest that patients should be evaluated after AKI for resolution versus progression of CKD. There is uncertainty as to the role of nephrologists in this process. The objective of this study was to compare the follow-up recommendations from nephrologists with contemporary processes of care for varying scenarios of patients hospitalized with AKI.
Design, setting participants, & measurementsWe surveyed Canadian nephrologists using a series of clinical vignettes of patients hospitalized with severe AKI and asked them to rank their likelihood of recommending follow-up for each patient after hospital discharge. We compared these responses with administrative health data on rates of community follow-up with nephrologists for patients hospitalized with AKI in Alberta, Canada between 2005 and 2014.
ResultsOne hundred forty-five nephrologists participated in the survey (46% of the physician membership of the Canadian Society of Nephrology). Nephrologists surveyed indicated that they would definitely or probably re-evaluate patients in 87% of the scenarios provided, with a higher likelihood of follow-up for patients with a history of preexisting CKD (89%), heart failure (92%), receipt of acute dialysis (91%), and less complete recovery of kidney function (98%). In contrast, only 24% of patients with similar characteristics were seen by a nephrologist in Alberta within 1 year after a hospitalization with AKI, with a trend toward lower rates of follow-up over more recent years of the study. Follow-up with a nephrologist was significantly less common among patients over the age of 80 years old (20%) and more common among patients with preexisting CKD (43%) or a nephrology consultation before or during AKI hospitalization (78% and 41%, respectively).
ConclusionsThere is a substantial disparity between the opinions of nephrologists and actual processes of care for nephrology evaluation of patients after hospitalization with severe AKI.
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Health Care Costs Associated with AKI
Background and objectives
An understanding of the health care resource use associated with AKI is needed to frame the investment and cost-effectiveness of strategies to prevent AKI and promote kidney recovery.
Design, setting, participants, & measurementsWe assembled population-based cohort of adults hospitalized in Alberta between November of 2002 and March of 2009 without ESRD or an eGFR<15 ml/min per 1.73 m2. Outpatient serum creatinine measurements 6 months preceding admission defined baseline kidney function, and serum creatinine during the first 14 days of hospitalization defined Acute Kidney Injury Network stage; kidney recovery defined as serum creatinine within 25% of baseline and independence from dialysis was assessed at 90 days after AKI. Health care utilization and costs (in 2015 Canadian dollars) were determined from inpatient, outpatient, and physician claims datasets during the index hospitalization, recovery period (90 days post-AKI assessment), and 3–12 months post-AKI. A fully adjusted generalized linear model regression analysis was used to estimate costs associated with AKI.
ResultsOf 239,906 hospitalized subjects, 25,495 (10.6%), 4598 (1.9%), 2493 (1.0%), and 670 (0.3%) had Acute Kidney Injury Network stages 1, 2, 3 without dialysis, and 3 with dialysis, respectively. Greater severity of AKI was associated with incremental increases in length of stay (+2.8; 95% confidence interval, 1.4 to 4.3 to +7.4; 95% confidence interval, 7.2 to 7.5 days) and costs (+$3779; 95% confidence interval, $3555 to $4004 to +$18,291; 95% confidence interval, $15,573 to $21,009 Canadian dollars) from admission to recovery assessment (3 months). At months 3–12 postadmission, compared with subjects without AKI, AKI with kidney recovery and AKI without kidney recovery were associated with incremental costs of +$2912–$3231 and +$6035–$8563 Canadian dollars, respectively. The estimated incremental cost of AKI in Canada is estimated to be over $200 million Canadian dollars per year.
ConclusionsSeverity of AKI, need for dialysis, and lack of kidney recovery are associated with significant health care costs in hospitalized patients and persist a year after admission. Strategies to identify, prevent, and facilitate kidney recovery are needed.
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APOL1 Risk Variants, Incident Proteinuria, and Subsequent eGFR Decline in Blacks with Hypertension-Attributed CKD
Background and objectives
The natural history of kidney disease among blacks who carry the APOL1 high-risk variants varies, with only a subgroup progressing to ESRD. We aimed to determine whether the APOL1 risk variants are associated with incident proteinuria in the context of hypertension-attributed CKD, and whether subsequent kidney function decline after the onset of proteinuria differs by APOL1 risk status.
Design, setting, participants, & measurementsUsing Cox models, we studied the association between APOL1 risk status and incident proteinuria (defined as a doubling of urine protein-to-creatinine ratio to a level ≥0.22 g/g creatinine) among African-American Study of Kidney Disease and Hypertension (AASK) trial participants with APOL1 genotyping and without proteinuria at baseline.
ResultsOf the 480 participants in our study, 82 (17%) had the high-risk genotypes (2 alleles), and 254 (53%) developed proteinuria over a median follow-up of 6.8 years. At baseline, mean eGFR was lower in the APOL1 high-risk group compared with the low-risk group (0 or 1 allele; 49.6 versus 53.2 ml/min per 1.73 m2, respectively; P=0.02), but median proteinuria was similar (0.04 g/g creatinine for both groups; P=0.43). Individuals with the high-risk genotypes were 1.72-fold more likely to develop incident proteinuria compared with those with the low-risk genotypes (95% confidence interval, 1.27 to 2.32), independent of age, sex, ancestry, baseline eGFR, baseline systolic BP, and randomized treatment groups. Although eGFR declined faster after the onset of proteinuria, this rate did not differ significantly by APOL1 risk status.
ConclusionsAmong blacks with established moderate CKD, the APOL1 high-risk variants are associated with greater risk of incident proteinuria. After proteinuria onset, kidney function declines more rapidly but does not differ by APOL1 risk status. This suggests that factors that lead to proteinuria, beyond APOL1, may additionally drive CKD progression.
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Infrequent Provision of Palliative Care to Patients with Dialysis-Requiring AKI
Background and objectives
The use of palliative care in AKI is not well described. We sought to better understand palliative care practice patterns for hospitalized patients with AKI requiring dialysis in the United States.
Design, setting, participants, & measurementsUsing the 2012 National Inpatient Sample, we identified patients with AKI and palliative care encounters using validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. We compared palliative care encounters in patients with AKI requiring dialysis, patients with AKI not requiring dialysis, and patients without AKI. We described the provision of palliative care in patients with AKI requiring dialysis and compared the frequency of palliative care encounters for patients with AKI requiring dialysis with that for patients with other illnesses with similarly poor prognoses. We used logistic regression to determine factors associated with the provision of palliative care, adjusting for demographics, hospital-level variables, and patient comorbidities.
ResultsWe identified 3,031,036 patients with AKI, of whom 91,850 (3%) received dialysis. We observed significant patient- and hospital-level differences in the provision of palliative care for patients with AKI requiring dialysis; adjusted odds were 26% (95% confidence interval, 12% to 38%) lower in blacks and 23% (95% confidence interval, 3% to 39%) lower in Hispanics relative to whites. Lower provision of palliative care was observed for rural and urban nonteaching hospitals relative to urban teaching hospitals, small and medium hospitals relative to large hospitals, and hospitals in the Northeast compared with the South. After adjusting for age and sex, there was low utilization of palliative care services for patients with AKI requiring dialysis (8%)—comparable with rates of utilization by patients with other illnesses with poor prognosis, including cardiogenic shock (9%), intracranial hemorrhage (10%), and acute respiratory distress syndrome (10%).
ConclusionsThe provision of palliative care varied widely by patient and facility characteristics. Palliative care was infrequently used in hospitalized patients with AKI requiring dialysis, despite its poor prognosis and the regular application of life-sustaining therapy.
http://ift.tt/2m3QkZs
Metabolomic Alterations Associated with Cause of CKD
Background and objectives
Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression.
Design, setting, participants & measurementsMetabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (n=687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (n=166), and replication was performed in Study A, a substudy of MDRD with higher GFR (n=423).
ResultsOverall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrulline, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (P<0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, and hippurate) were replicated in Study A (P<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes.
ConclusionsMetabolomic profiling identified several metabolites strongly associated with cause of CKD.
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Risk of Infective Endocarditis in Patients with End Stage Renal Disease
Background and objectives
Endocarditis is a serious complication in patients treated with RRT. The study aimed to examine incidence and risk factors of endocarditis in patients with ESRD.
Design, setting, participants, & measurementsThe Danish National Registry on Regular Dialysis and Transplantation contains data on all Danish patients receiving renal replacement (hemodialysis, peritoneal dialysis, or kidney transplantation) for ESRD. Incidence of endocarditis was estimated for each RRT modality. Independent risk factors of endocarditis were identified in multivariable Cox regression models.
ResultsFrom January 1st, 1996 to December 31st, 2012, 10,612 patients (mean age 63 years, 36% female) initiated RRT (7233 hemodialysis, 3056 peritoneal dialysis, 323 pre-emptive kidney transplantation). Endocarditis developed in 267 (2.5%); of these 31 (12%) underwent valve surgery. The overall incidence of endocarditis was 627 per 100,000 person-years in patients receiving RRT. Incidence was higher in patients receiving hemodialysis compared with those receiving peritoneal dialysis or kidney transplantation (1092 per 100,000 person-years, 212 per 100,000 person-years, and 85 per 100,000 person-years, respectively). Adjusted hazard ratios for endocarditis in patients receiving hemodialysis were 5.46 (95% confidence interval [95% CI], 3.28 to 9.10) and 0.41 (95% CI, 0.18 to 0.91) for kidney-transplanted recipients, respectively, as compared with patients in peritoneal dialysis. The incidence of endocarditis in hemodialysis recipients with central venous catheters was more than two-fold higher as compared with those with arteriovenous fistulas. Overall mortality, subsequent to endocarditis, was 22% in-hospital and 51% at 1 year. The first 6 months in RRT, aortic valve disease, and previous endocarditis were identified as significant risk factors of endocarditis.
ConclusionsPatients receiving RRT have a high incidence of endocarditis, in particular during hemodialysis treatment using central venous catheters. The first 6 months in RRT, aortic valve disease, and previous endocarditis are significant risk factors for developing endocarditis.
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Perspectives from the Kidney Health Initiative on Advancing Technologies to Facilitate Remote Monitoring of Patient Self-Care in RRT
Telehealth and remote monitoring of a patient's health status has become more commonplace in the last decade and has been applied to conditions such as heart failure, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease. Conversely, uptake of these technologies to help engender and support home RRTs has lagged. Although studies have looked at the role of telehealth in RRT, they are small and single-centered, and both outcome and cost-effectiveness data are needed to inform future decision making. Furthermore, alignment of payer and government (federal and state) regulations with telehealth procedures is needed along with a better understanding of the viewpoints of the various stakeholders in this process (patients, caregivers, clinicians, payers, dialysis organizations, and government regulators). Despite these barriers, telehealth has great potential to increase the acceptance of home dialysis, and improve outcomes and patient satisfaction while potentially decreasing costs. The Kidney Health Initiative convened a multidisciplinary workgroup to examine the current state of telehealth use in home RRTs as well as outline potential benefits and drawbacks, impediments to implementation, and key unanswered questions.
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Vascular Access Type and Clinical Outcomes among Elderly Patients on Hemodialysis
Background and objectives
The optimal type of initial permanent access for hemodialysis among the elderly is controversial. Duration of central venous catheter dependence, patient comorbidities, and life expectancy are important considerations in whether to place an arteriovenous fistula or graft. We used an observational study design to compare clinical outcomes in elderly patients who initiated hemodialysis with a central venous catheter and subsequently had an arteriovenous fistula or graft placed.
Design, setting, participants, & measurementsWe identified 9458 United States patients ages ≥67 years old who initiated hemodialysis from July 1, 2010 to June 30, 2011 with a central venous catheter and no secondary vascular access and then received an arteriovenous fistula (n=7433) or graft (n=2025) within 6 months. We evaluated key clinical outcomes during the 6 months after vascular access placement coincident with high rates of catheter use and used a matched propensity score analysis to examine patient survival.
ResultsCentral venous catheter dependence was greater in every month during the 6-month period after arteriovenous fistula versus graft placement (P<0.001). However, rates of all-cause infection-related hospitalization (adjusted relative risk, 0.93; 95% confidence interval, 0.87 to 0.99; P=0.01) and bacteremia/septicemia-related hospitalization (adjusted relative risk, 0.90; 95% confidence interval, 0.82 to 0.98; P=0.02) were lower in the arteriovenous fistula versus graft group as was the adjusted risk of death (hazard ratio, 0.76; 95% confidence interval, 0.73 to 0.80; P<0.001).
ConclusionsDespite extended central venous catheter dependence, elderly patients initiating hemodialysis with a central venous catheter who underwent arteriovenous fistula placement within 6 months had fewer hospitalizations due to infections and a lower likelihood of death than those receiving an arteriovenous graft.
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Randomized Crossover Trial of Blood Volume Monitoring-Guided Ultrafiltration Biofeedback to Reduce Intradialytic Hypotensive Episodes with Hemodialysis
Background and objectives
Intradialytic hypotension (IDH) is associated with morbidity. The effect of blood volume–guided ultrafiltration biofeedback, which automatically adjusts fluid removal rate on the basis of blood volume parameters, on the reduction of IDH was tested in a randomized crossover trial.
Design, setting, participants, & measurementsWe performed a 22-week, single blind, randomized crossover trial in patients receiving maintenance hemodialysis who had >30% of sessions complicated by symptomatic IDH in five centers in Calgary, Alberta, Canada. Participants underwent a 4-week run-in period to standardize dialysis prescription and dry weight on the basis of clinical examination. Those meeting inclusion criteria were randomized to best clinical practice hemodialysis (control) or best clinical practice plus blood volume–guided ultrafiltration biofeedback (intervention) for 8 weeks, followed by a 2-week washout and subsequent crossover for a second 8-week phase. The primary outcome was rate of symptomatic IDH.
ResultsThirty-five participants entered, 32 were randomized, and 26 completed the study. The rate of symptomatic IDH with biofeedback was 0.10/h (95% confidence interval, 0.06 to 0.14) and 0.07/h (95% confidence interval, 0.05 to 0.10) during control (P=0.29). There were no differences in the rate or proportion of sessions with asymptomatic IDH or symptoms alone. Results remained consistent when adjusted for randomization order and study week. There were no differences between intervention and control in the last study week in interdialytic weight gain (difference [SD], –0.02 [0.8] kg), brain natriuretic peptide (1460 [19,052] ng/L), cardiac troponins (3 [86] ng/L), extracellular water–to–intracellular water ratio (0.05 [0.33]), ultrafiltration rate (1.1 [7.0] ml/kg per hour), and dialysis recovery time (0.43 [19.25] hours).
ConclusionThe use of blood volume monitoring–guided ultrafiltration biofeedback in patients prone to IDH did not reduce the rate of symptomatic IDH events.
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Statistical Methods for Modeling Time-Updated Exposures in Cohort Studies of Chronic Kidney Disease
When estimating the effect of an exposure on a time-to-event type of outcome, one can focus on the baseline exposure or the time-updated exposures. Cox regression models can be used in both situations. When time-dependent confounding exists, the Cox model with time-updated covariates may produce biased effect estimates. Marginal structural models, estimated through inverse-probability weighting, were developed to appropriately adjust for time-dependent confounding. We review the concept of time-dependent confounding and illustrate the process of inverse-probability weighting. We fit a marginal structural model to estimate the effect of time-updated systolic BP on the time to renal events such as ESRD in the Chronic Renal Insufficiency Cohort. We compare the Cox regression model and the marginal structural model on several attributes (effects estimated, result interpretation, and assumptions) and give recommendations for when to use each method.
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Optimized Setup and Protocol for Magnetic Domain Imaging with In Situ Hysteresis Measurement
This paper elaborates the sample and sensor preparation procedures and the protocols for using the test rig particularly for dynamic domain imaging with in situ BH measurements in order to achieve optimal domain pattern quality and accurate BH measurements.
http://ift.tt/2m1dfou
Capturing Flow-weighted Water and Suspended Particulates from Agricultural Canals During Drainage Events
Nutrients present in particulate form can contribute significantly to the overall loads in agricultural drainage waters. This study describes a novel method to capture flow-weighted water and suspended particulates from farm canal drainage over the entire duration of the drainage event.
http://ift.tt/2hQZuUR
A Wireless, Bidirectional Interface for In Vivo Recording and Stimulation of Neural Activity in Freely Behaving Rats
http://ift.tt/2yFcZl3
New variant identified in major susceptibility locus to tuberculosis on chromosomal region 8q12-q13 in Moroccan population: a case control study
Tuberculosis (TB) remains a global health problem. Several studies have implicated genetic host factors in predisposing populations to TB disease. In this study, we have selected NSMAF (Neutral Sphingomyelinase A...
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Correction to: The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study
After publication of the original article [1] the authors noted that the following errors had occurred:
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Visionaries define top 7 current health care challenges
Health care spending, the silver tsunami, technology and epidemiology issues require innovative solutions
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SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer
Objective
To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6.
DesignWe performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo.
ResultsSRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity.
ConclusionsSRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6.
Accession numbersThe accession numbers for sequencing data are SRP111763 and SRP111797.
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Variants in CIB2 cause DFNB48 and not USH1J
The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher Syndrome (USH). Variants in the CIB2 gene have been previously reported to cause of hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function variants, 2 families segregated missense variants (one novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic loss of function variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here we provide evidence disqualifying CIB2 as an USH-causing gene.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
