A Multi-Institutional Validation of Gleason Score Derived from Tissue Microarray Cores

Abstract

To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi-institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7–75.5) and 60.4% (95% CI:57.2–63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low-grade Gleason patients at RP.

https://ift.tt/2uRIJBJ

Outcome of Pancreaticoduodenectomy at Low-Volume Centre in Tier-II City of India

Abstract

Currently, pancreaticoduodenectomy (PD) is considered a common and feasibly performed surgery for periampullary tumours, but it is still a high-risk surgical procedure with potential morbidity and mortality rates. Previously, it was emphasised for the need of high-volume centres to perform specialised surgery such as PD. The authors have made an attempt to know the relation between low-volume centre and outcomes of PD. The study was conducted in a Tier-II city referral hospital located in Karnataka, India. A total of 37 patients with suspected periampullary neoplasms underwent surgical exploration with curative intent over a period of 4 years, i.e. from May 2012 to May 2016. Out of 37 patients, 26 underwent PD, either classic Whipple resection (n = 01) or pylorus-preserving modification (n = 25). In 11 patients, resection was not possible, where biliary and gastric drainage procedures were done. All patients were treated by standardised post-operative care protocols for pancreatic resection used at our centre. We recorded the perioperative outcome along with demographics, indications for surgery, and pre- and intra-operative factors of PD. Post-operative pancreatic fistulae were evident in 4 patients. Two patients had hepaticojejunostomy leak. One patient had chyle leak. Three patients had infection at the surgical site. One patient had post-operative pneumonia leading to mortality. None of the patients had post-op haemorrhage. The surgeon volume and surgeon experience may have minimal contributing factor in post-operative morbidity, especially if there is availability of well-equipped ICU and imaging facilities, along with well-experienced personnel like oncosurgeon, anaesthesiologist, intensivist, radiologist, and nursing staff. There is a need of a multicentre study from Tier-II city hospitals/low-volume centres and high-volume centres to come with perioperative surgical outcomes following PD.

https://ift.tt/2GDbnMJ

Managing Gait, Balance, and Posture in Parkinson’s Disease

Abstract

Purpose of Review

Postural instability and gait difficulties inexorably worsen with Parkinson's disease (PD) progression and become treatment resistant, with a severe impact on autonomy and quality of life. We review the main characteristics of balance instability, gait disabilities, and static postural alterations in advanced PD, and the available treatment strategies.

Recent Findings

It remains very difficult to satisfactorily alleviate gait and postural disturbances in advanced PD. Medical and surgical interventions often fail to provide satisfactory or durable alleviation of these axial symptoms, that may actually call for differential treatments. Exercise and adapted physical activity programs can contribute to improving the patients' condition.

Summary

Gait, balance, and postural disabilities are often lumped together under the Postural Instability and Gait Difficulties umbrella term. This may lead to sub-optimal patients' management as data suggest that postural, balance, and gait problems might depend on distinct underlying mechanisms. We advocate for a multidisciplinary approach from the day of diagnosis.

https://ift.tt/2GD9EqJ

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies

Abstract

Background

Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials.

Objectives

The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials.

Patient and Methods

This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017.

Results

Seventy-nine patients, median age 72 years (range 29–93), 71% men and 76% ECOG PS 0–1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8–3.6) and median PFS was 3.2 months (95%CI, 1.6–4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0–5.0) while 42% were referred to palliative care/hospice or died.

Conclusions

Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

https://ift.tt/2uOYAkG

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

Abstract

BACKGROUND

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors are driven by amplification or mutation of HER2.

MATERIALS AND METHODS

This paper reviews the role of HER2 as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type.

RESULTS

While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology.

CONCLUSION

HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

https://ift.tt/2Ix9i12

Major Determinants of Nucleosome Positioning

The compact structure of the nucleosome limits DNA accessibility and inhibits the binding of most sequence-specific proteins. Nucleosomes are not randomly located on the DNA but positioned with respect to the DNA sequence, suggesting models in which critical binding sites are either exposed in the linker, resulting in activation, or buried inside a nucleosome, resulting in repression. The mechanisms determining nucleosome positioning are therefore of paramount importance for understanding gene regulation and other events that occur in chromatin, such as transcription, replication, and repair.

https://ift.tt/2qdQ7lE

Routine histopathological examination after female‐to‐male gender‐confirming mastectomy

British Journal of Surgery, EarlyView.


https://ift.tt/2Hhy1Y0

Population‐based study of the sensitivity of axillary ultrasound imaging in the preoperative staging of node‐positive invasive lobular carcinoma of the breast

British Journal of Surgery, EarlyView.


https://ift.tt/2uUB45Y

Influence of Stem Cell Therapy on Thyroid Function and Reactive Oxygen Species Production in Diabetic Rats

Horm Metab Res 2018; 50: 331-339
DOI: 10.1055/a-0588-7944

Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2JkqKHg

The Effects of Injected Vitamin D on Prognosis of Patients with Urosepsis

Horm Metab Res
DOI: 10.1055/a-0595-7731

The aim of this study was to evaluate the effect of prescribing vitamin D on improving the symptoms of patients diagnosed with urosepsis. The participants were randomly divided into two equal groups (each consisting of 50 patients). The patients in the first group received standard treatment with 300 000 units of injected vitamin with a volume of 1 cc. As for the patients in the second group, they received standard treatment along with 1 cc normal saline injected to them as placebo. Vital signs of the patients were checked every 6 h, while their CBC, EXR, CRP, creatinine, urea, and uric acid were checked 0, 24, 48, and 72 h following the interventions. Calcium, phosphorus, and vitamin D levels were measured 72 h following injection of the medicine. A significant difference was observed between the two groups in terms of the number of WBC's in 24th, 48th, and 72nd hours. A similarly significant difference was reported between the case and control group in terms of the average BUN within 24th, 48th, and 72nd hours. The difference observed between the two groups in terms of average Cr within the 0th, 24th, 48th, and 72nd hours and in terms of days of hospitalization was also significant. Considering these results and keeping in mind the fact that no particular side effects were reported as a result of utilizing muscular injections of vitamin D and the easy and cheap use of this medicine, it can be used in auxiliary treatment of patients with urosepsis.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2IwYfoD

A Meta-Analysis of the Associations Between the ATP-Binding Cassette Transporter ABCA1 R219K (rs2230806) Polymorphism and the Risk of Type 2 Diabetes in Asians

Horm Metab Res 2018; 50: 308-316
DOI: 10.1055/a-0583-0201

Asians have relatively low insulin secretion capacity and readily develop type 2 diabetes mellitus (T2DM) when insulin resistant. For that reason, insufficient insulin secretion is critical factor for Asians at the early stage of T2DM. ATP-binding cassette transporter1 (ABCA1) is a membrane protein responsible for cholesterol efflux and its function is also important for secreting insulin in pancreatic β-cells. Given the importance of its role, different polymorphisms of ABCA1 gene might contribute differently to the development of T2DM. Here, we analyzed the association between a variant form of ABCA1 gene called ABCA1 rs2230806 and the prevalence of T2DM in a large sample size by pooling all of the case-control studies published. Relevant case-control studies were identified by searching PubMed, EMBASE, Cochrane Library, Korean scientific database, Chinese medical databases, and the Indian medical database. The association was evaluated using five genetic models such as the allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Heterogeneity of each genetic model was determined by the I2 test. A total of eight studies (7 published studies and one data set from the Korean Genetic Epidemiology Study) were eligible, satisfying Hardy–Weinberg equilibrium and included 2755 T2DM patients (case) and 16 635 nondiabetic subjects (control). All subjects in the studies were Asians. Each genetic model exhibited heterogeneity. In all genetic models, ABCA1 rs2230806 had a significant association with prevalence of T2DM: AG (OR=0.78, 95% CI: 0.61–0.98), RG (OR=0.72, 95% CI: 0.51–1.03), DG (OR=0.73, 95% CI: 0.55–0.97), HMG (OR=0.62, 95% CI: 0.41–0.96), and HTG (OR=0.78, 95% CI: 0.61–0.99). There was no single study that changed the overall effects in allelic genetic model with random effects. No publication bias existed in any models except the RG model. In conclusion, middle-aged and elderly adults with the minor allele of ABCA1 rs2230806 will have a lower risk of T2DM. This is the first meta-analysis to evaluate the association in Asians.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2Hc2XbU

Cushing’s Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century

Horm Metab Res 2018; 50: 280-289
DOI: 10.1055/a-0580-0460

Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients – the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2GFG7bT

ACA Marketplaces Expand Coverage for Chronically Ill

THURSDAY, April 5, 2018 -- The Affordable Care Act's Marketplaces covered a disproportionate share of non-elderly adults with high health care risks in the 2014 to 2015 time period, according to a study published in the April issue of Health...

https://ift.tt/2JomvL0

Sex Differences Persist in Academic Rank for Neurologists

THURSDAY, April 5, 2018 -- Sex differences persist in academic rank among neurologists, with men more likely to be full professors, according to a study published online April 2 in JAMA Neurology. Mollie McDermott, M.D., from the University of...

https://ift.tt/2Jomuqq

Large Drop Seen in Infection-Related Post-Transplant Deaths

THURSDAY, April 5, 2018 -- There has been a large drop in infection-related deaths following kidney transplantation since the 1990s, according to a study published online April 5 in the Clinical Journal of the American Society of Nephrology. Susanna...

https://ift.tt/2qakrgP

Preserved Neurogenesis in Hippocampus of Healthy Seniors

THURSDAY, April 5, 2018 -- Healthy older subjects display preserved neurogenesis, according to a study published in the April 5 issue of Cell Stem Cell. Noting that aging humans are thought to exhibit waning neurogenesis and exercise-induced...

https://ift.tt/2qbfLr5

Online Doc Reviews Don't Reflect Patient Satisfaction Surveys

THURSDAY, April 5, 2018 -- Online physician reviews do not reflect patient satisfaction surveys (PSSs), according to a study published in the April issue of the Mayo Clinic Proceedings. R. Jay Widmer, M.D., Ph.D., from the Mayo Clinic Center for...

https://ift.tt/2JomrLg

Enhanced Vascular Biocompatibility and Remodeling of Decellularized and Secured Xenogeneic/Allogeneic Matrices in a Porcine Model

Background/Purpose: Calcifications and absence of growth potential are the major drawbacks of glutaraldehyde-treated prosthesis. Decellularized and secured xeno-/allogeneic matrices were assessed in a preclinical porcine model for biocompatibility and vascular remodeling in comparison to glutaraldehyde-fixed bovine pericardium (GBP; control). Methods: Native human (fascia lata, pericardium) and porcine tissues (peritoneum) were used and treated. In vitro, biopsies were performed before and after treatment to assess decellularization (hematoxylin and eosin/DAPI). In vivo, each decellularized and control tissue sample was implanted subcutaneously in 4 mini-pigs. In addition, 9 mini-pigs received a patch or a tubularized prosthesis interposition on the carotid artery or abdominal aorta of decellularized (D) human fascia lata (DHFL; n = 4), human pericardium (DHP; n = 9), porcine peritoneum (DPPt; n = 7), and control tissue (GBP: n = 3). Arteries were harvested after 1 month and subcutaneous samples after 15–30 days. Tissues were processed for hematoxylin and eosin/von Kossa staining and immunohistochemistry for CD31, alpha-smooth muscle actin, CD3, and CD68. Histomorphometry was achieved by point counting. Results: A 95% decellularization was confirmed for DHP and DPPt, and to a lower degree for DHFL. In the subcutaneous protocol, CD3 infiltration was significantly higher at day 30 in GBP and DHFL, and CD68 infiltration was significantly higher for GBP (p #x3c; 0.05). In intravascular study, no deaths, aneurysms, or pseudoaneurysms were observed. Inflammatory reaction was significantly higher for DHFL and GBP (p #x3c; 0.05), while it was lower and comparable for DHP/DPPt. DHP and DPPt showed deeper recellularization, and a new arterial wall was characterized. Conclusions: In a preclinical model, DPPt and DHP offered better results than conventional commercialized GBP for biocompatibility and vascular remodeling.
Eur Surg Res 2018;59:58–71

https://ift.tt/2qbdo7F

Editorial introductions

No abstract available

https://ift.tt/2GV46qP

Evolving criteria for the diagnosis of antibody-mediated rejection in renal allografts

Purpose of review To review changes in the Banff schema for antibody-mediated renal allograft rejection over the past decade, including key revisions agreed upon during and immediately subsequent to the 2017 Banff Conference on Allograft Pathology. Recent findings The original Banff schema for diagnosis of acute and chronic active antibody-mediated rejection (ABMR) in renal allografts was formulated at the 2001 and 2007 Banff Conferences, and required histologic (primarily microvascular inflammation and transplant glomerulopathy), immunohistologic (C4d in peritubular capillaries), and serologic [circulating donor-specific antibodies (DSA)] evidence for a definitive diagnosis of ABMR. This schema was updated at the 2013 Banff Conference, recognizing C4d-negative ABMR, intimal arteritis as a potential manifestation of ABMR, and revising definitions and thresholds for glomerulitis and transplant glomerulopathy to improve interobserver agreement and correlation with clinical, molecular, and serologic data. Compared with the 2007 criteria, Banff 2013 improved the sensitivity of the classification for diagnosing ABMR and the correlation of ABMR diagnosis with graft outcomes. At the 2017 Banff Conference, new modifications to the classification were discussed and have subsequently been agreed upon, accepting C4d and thoroughly validated molecular classifiers as surrogate markers for DSA. Summary From a consensus reached at the 2017 Banff Conference, updated criteria for diagnosis of active and chronic active ABMR have been developed that recognize C4d and molecular classifiers as surrogate markers for DSA. In addition, specific recommendations for the use of molecular diagnostics in the diagnosis of ABMR were developed.

https://ift.tt/2EnpoYH

Novel oral anticoagulants in chronic kidney disease: ready for prime time?

Purpose of review Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD. Recent findings Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs. Summary The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.

https://ift.tt/2Jo1BvE

Changing concepts of HIV infection and renal disease

Purpose of review Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) was identified as the major renal manifestation of HIV infection early in the HIV epidemic. However, HIV infection now is associated with a different spectrum of renal lesions leading to chronic kidney disease. This review examines the changes in kidney injury occurring in the current HIV era and the factors involved in this transformation of disease expression. Recent findings The incidence of HIVAN and opportunistic infections in HIV-infected individuals has declined in concert with the use of effective combination antiretroviral agents. Chronic kidney disease has become more prevalent as patients infected with HIV are living longer and developing non-HIV-associated diseases such as hypertension and diabetes. Additionally, noncollapsing focal and segmental glomerulosclerosis, co-infection with hepatitis C, HIV-associated immune complex kidney disease, HIV-related accelerated aging, and antiretroviral therapies contribute to progressive loss of renal function. Summary HIV infection is now associated with a variety of renal lesions causing chronic kidney disease, not all of which are virally induced. It is important to determine the cause of renal functional decline in an HIV-infected patient, as this will impact patient management and prognosis.

https://ift.tt/2EnpgZd

Fluid status assessment in hemodialysis patients and the association with outcome: review of recent literature

Purpose of review In this review, we will discuss the most recent literature regarding fluids status assessment in hemodialysis patients, and the associations with outcome. Recent findings Research toward technique-assisted assessment of fluid status in hemodialysis patients has been going on for many years. However, there is no absolute agreement between techniques, such as bioimpedance, lung ultrasound, biochemical markers or vena caval diameter, likely because they reflect different fluid compartments with potentially altered distribution in hemodialysis patients. Recent studies, mostly based on bioimpedance, have shown not only an association of severe, but also of moderate predialysis fluid overload with overall survival. Also predialysis fluid depletion has been found to associate with and increased mortality risk. Interventional studies with fluid-guided management are scarce and outline the difficulties of achieving dry weight is the dialysis population. Summary Optimal estimation of predialysis fluid status remains challenging and may require a combination of clinical and technical derived parameters. There appears to be a narrow window of optimal predialysis fluid status. Further clinical studies are necessary to identify strategies to improve survival in hemodialysis patients with abnormalities in fluid status.

https://ift.tt/2H2g5Tp

Apolipoprotein L1 nephropathies: 2017 in review

Purpose of review To review publications relating to apolipoprotein L1 (APOL1) renal risk variants published 2017. Recent findings The study of APOL1 variants continues to be highly active; 24 articles published in 2017 were selected to highlight. These include clinical studies of kidney disease, kidney transplantation, hypertension, cardiovascular disease, and genetic diversity. Laboratory studies included APOL1 association with vesicle-associated membrane soluble N-ethylmaleimide-sensitive factor activating protein receptor protein and with soluble urokinase-type plasminogen activator receptor, mitochondrial dysfunction, endolysosomal dysfunction, and inflammasome activation. Summary Our understanding of the role of APOL1 genetic variants and the mechanisms for renal toxicity continues to deepen. It is not yet clear which pathways are most relevant to human disease, and so, the most relevant drug targets remain to be defined.

https://ift.tt/2EnpaRl

An update on predicting renal progression in IgA nephropathy

Purpose of review Immunoglobulin A (IgA) nephropathy (IgAN) is a heterogeneous disease, and predicting individual patient risk of renal progression is challenging. Recent studies provide new evidence regarding the use of clinical, histologic, and biomarker predictors of renal outcome in IgAN. Recent findings A meta-analysis of clinical trials demonstrated that early change in proteinuria is a valid surrogate outcome measure for longer term decline in renal function, which supports the use of proteinuria to dynamically re-evaluate patient prognosis over time. The MEST histologic classification has been further validated in a large European cohort. An international multiethnic observational study demonstrated that crescents are independently associated with renal outcome, and as a result a crescent score (25% of glomeruli) has been added to MEST. Proteinuria, estimated glomerular filtration rate (GFR), and blood pressure at the time of biopsy can be used to accurately predict prognosis when combined with MEST, instead of using 2 years of follow-up data. Currently, no available risk prediction model that combines clinical and histologic predictors has been sufficiently validated for routine use. There are multiple biomarkers that have been studied in IgAN, however none have been externally validated and shown to improve prediction beyond clinical and histologic risk factors. Summary Proteinuria, estimated GFR, blood pressure, and the MEST-C score are the most readily available risk factors to predict renal prognosis in IgAN. Future research is required to develop and validate methods of integrating these risk factors together to accurately risk stratify individual patients, and provide the framework for evaluating biomarkers capable of further improving risk prediction.

https://ift.tt/2GZaLAc

Glomerulogenesis and the role of endothelium

Purpose of review Earlier works of the glomerulogenesis described morphological steps and protein expression during in-vivo and in-vitro kidney development. Recent technologies using cell-specific or conditional knock-out mice for several factors provide important knowledge about cross-talk signaling among resident cells as local events. Based on the recent advancement, this review revisits comprehensive morphological development of the glomerulus. Recent findings Interactions of presumptive podocyte vascular endothelial growth factor with vascular endothelial growth factor-2 on angioblasts initiate glomerular vascularization. In induced pluripotent stem cells or organoid-derived nephron formation, the lack of endothelium and mesangial cells under differentiated podocytes suggests the presence of another unknown mechanism for glomerular neovascularization. Mesangial cell migration is prerequisite for glomerular looping by interaction of endothelial platelet-derived grothe factor beta and mesangial platelet-derived growth factor receptor beta and requires the coreceptor neuropilin1. Development of the filtration barrier is promoted by cross-talk among resident cells and may need shear stress. The components of the glomerular basement membrane change during glomerulogenesis, and endothelium and podocytes produce laminin and type IV collagen α1 and α2, whereas type IV collagen α3, α4, α5 is derived only from podocytes. Summary Glomerulogenesis progresses by dynamic cellular migration/differentiation induced by cross-talk signaling in resident cells. Glomerular vasculogenesis and subsequent capillary development provide insight into glomerular regeneration and remodeling for medical application.

https://ift.tt/2GGKx1R

The association of proton pump inhibitors and chronic kidney disease: cause or confounding?

Purpose of review To discuss whether the recently described relationship between proton pump inhibitor (PPI) use and the risk of adverse kidney outcomes represents a causal relationship or is merely the result of confounding. Recent findings A wave of observational studies has described an association between PPI use and the risk of development of chronic kidney disease and its progression to end-stage renal disease. The results are generally robust and remarkably consistent across different studies. The application of modern pharmacoepidemiologic methods to estimate the effect of a putative unmeasured or unknown confounder or set of confounders on the relationship of PPI use and risk of adverse renal outcomes suggests that confounding is unlikely to explain away the reported association. Summary The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted.

https://ift.tt/2GYP1Ew

Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome

Purpose of review The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). Recent findings C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease. Summary Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade.

https://ift.tt/2EoxwIu

Advances in molecular diagnosis and therapeutics in nephrotic syndrome and focal and segmental glomerulosclerosis

Purpose of review The widespread adoption of next-generation sequencing by research and clinical laboratories has begun to uncover the previously unknown genetic basis of many diseases. In nephrology, one of the best examples of this is seen in focal and segmental glomerulosclerosis (FSGS) and nephrotic syndrome. We review advances made in 2017 as a result of human and molecular genetic studies as it relates to FSGS and nephrotic syndrome. Recent findings There are more than 50 monogenic genes described in steroid-resistant nephrotic syndrome and FSGS, with seven reported in 2017. In individuals presenting with FSGS or nephrotic syndrome before or at the age of 18 years, the commonest genes in which a mutation is found continues to be limited to only a few including NPHS1 and NPHS2 based on multiple studies. For FSGS or nephrotic syndrome that presents after 18 years, mutations in COl4A3/4/5, traditionally associated with Alport syndrome, are increasingly being reported. Despite the extensive genetic heterogeneity in FSGS, there is evidence that some of these genes converge onto common pathways. There are also reports of in-vivo models exploring apolipoprotein 1 biology, variants in which account for part of the increased risk of nondiabetic kidney disease in African-Americans. Finally, genetic testing has several clinical uses including clarification of diagnosis and treatment; identification of suitable young biologic relatives for kidney donation; and preimplantation genetic diagnosis. CRISPR gene editing is currently an experimental tool only, but the recent reports of excising mutations in embryos could be a therapeutic option for individuals with any monogenic disorder in the future. Summary Sequencing efforts are bringing novel variants into investigation and directing the efforts to understand how these lead to disease phenotypes. Expanding our understanding of the genetic basis of health and disease processes is the necessary first step to elaborate the repertoire of therapeutic agents available for patients with FSGS and nephrotic syndrome.

https://ift.tt/2JpzRXh

Halogens are key cofactors in building of collagen IV scaffolds outside the cell

Purpose of review The purpose of this review is to highlight recent advances in understanding the molecular assembly of basement membranes, as exemplified by the glomerular basement membrane (GBM) of the kidney filtration apparatus. In particular, an essential role of halogens in the basement membrane formation has been discovered. Recent findings Extracellular chloride triggers a molecular switch within non collagenous domains of collagen IV that induces protomer oligomerization and scaffold assembly outside the cell. Moreover, bromide is an essential cofactor in enzymatic cross-linking that reinforces the stability of scaffolds. Halogenation and halogen-induced oxidation of the collagen IV scaffold in disease states damage scaffold function. Summary Halogens play an essential role in the formation of collagen IV scaffolds of basement membranes. Pathogenic damage of these scaffolds by halogenation and halogen-induced oxidation is a potential target for therapeutic interventions.

https://ift.tt/2GEPTef

Controversies in vascular access

Purpose of review There is renewed interest in vascular access research, fueled by new perspectives and a critical re-examination of traditional thinking. This review summarizes important developments in vascular access from the past year, highlight areas of controversy, and makes recommendations for future research. Recent findings Recent studies provide an innovative and critical look at the assumptions underlying the promotion of fistulas as the preferred form of vascular access and highlight the need for a randomized comparison of different forms of access. Promising work that will help determine predictors of fistula maturation and potentially improve patient selection is ongoing. The role of early cannulation grafts continues to generate interest, and new approaches to reducing the risk of catheter-related bacteremia show promise. Summary The scientific community should capitalize on this opportunity to critically re-examine fundamental questions that have gone unanswered to date. High-quality randomized trials are needed to quantify the magnitude of benefit of different vascular access strategies, gather information about the risks, benefits, and cost-effectiveness of different approaches, and to get a clear view of the patient experience and how it is impacted by choice of vascular access.

https://ift.tt/2H2w0kR

Gender differences in hypertension

Purpose of review The review is a short discussion of sex/gender differences in blood pressure control with a focus on gender differences in hypertension awareness, prevalence, and treatment, the new American College of Cardiology/American Heart Association Guidelines, and recent discoveries in animal models and humans on mechanisms responsible for sex/gender differences in hypertension. Recent findings Hypertension awareness is greater in women than men, the prevalence of hypertension is higher in men than women until after menopause, and although the American College of Cardiology/American Heart Association Guidelines recommend similar treatment for men and women, this is not currently the case in practice. New studies into mechanisms responsible for sex/gender differences in hypertension include the role of the kidneys, the renin–angiotensin system, relaxin, and developmental programming. Summary Specific guidelines for hypertension treatment in women and men have yet to be developed. However, numerous animal and human studies have shown differences in the mechanisms responsible for blood pressure control between the sexes. Thus more research into the sex/gender differences in mechanisms responsible for hypertension are needed to determine the best treatment options that will reduce the risk of hypertension and subsequent cardiovascular diseases in both genders.

https://ift.tt/2EnjXZY

Fracture risk and treatment in chronic kidney disease

Purpose of review Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. The purpose of this review is to provide an update on recent findings in the diagnosis and treatment of osteoporosis in patients with CKD. Recent findings Multiple observational studies have shown that bone mineral density measurement using DEXA is equally predictive in CKD stages 1–3, as in the general population. Post hoc analyses from randomized trials of bisphosphonates, SERM, RANKL inhibitors and PTH agonists all suggest equal efficacy in mild–moderate CKD. A recent systematic review also found evidence for efficacy of bisphosphonates in patients with a kidney transplant. Summary Bone mineral density measurement using DEXA is accurate in patients with CKD stages 1–3 and should be considered to guide treatment of osteoporosis. Current treatments are unaffected by mild-to-moderate decline in kidney function, and physicians should use bisphosphonates and other osteoporosis treatments in this population, whenever indicated. Studies evaluating the optimal diagnostic and management strategy in patients with CKD stages (G4-5D) are needed.

https://ift.tt/2JpzEmX

Clinical and Endoscopic Remission in a Patient With Cronkhite-Canada Syndrome

A 60-year-old man presented with chronic diarrhea for 9 months, anorexia, a 6-kg weight loss, and dysgeusia. He had hyperpigmentation of his face, hands (Figure A), and feet; alopecia; and nail dystrophy (Figure A). An esophagogastroduodenoscopy and a colonoscopy showed multiple polyps carpeting the stomach, duodenum, ileum, and the colon (Figure B). Histology showed cystically dilated glands and mixed inflammatory infiltrate comprising eosinophils and neutrophils. Cronkhite–Canada syndrome was diagnosed on the basis of clinical and pathologic findings.

https://ift.tt/2EleQct

Actinomycotic Hepatic Abscess Mimicking Liver Tumor

A 70-year-old Asian man with a history of chronic hepatitis C, hepatocellular carcinoma, and an orthotopic liver transplantation 7 years ago, was referred to our institution for the evaluation of a liver mass in the transplanted liver. The patient was immunosuppressed with tacrolimus. He also had a remote history of gastric adenocarcinoma treated with gastrectomy and adjuvant chemotherapy. He reported weakness, fatigue, a 10-pound weight loss, and an intermittent low-grade fever for the past 3 months.

https://ift.tt/2GZac9y

Localized Gastrointestinal ALλ Amyloidosis

A 58-year-old man visited our hospital because of a positive fecal occult blood test. He did not complain of any symptoms. Physical findings and laboratory tests were unremarkable. Colonoscopic examination showed polypoid lesions on the ileocecal valve (Figure A), and stenosis owing to multiple elevated lesions in the terminal ileum (Figure B). Biopsy specimens showed significant amyloid depositions by Congo-red staining (Figure C), and they were positive for ALλ. Other lesions were not found except in the gastrointestinal tract, and the patient was diagnosed with localized gastrointestinal ALλ amyloidosis.

https://ift.tt/2EnjCGG

Diffuse Esophageal Squamous Papillomatosis Covering the Entire Esophagus

A 23-year-old woman presented to the clinic with complaints of heartburn and dysphagia with solid foods. Her family history was remarkable for gastric and lung cancer in first-degree relatives. Her physical examination and routine laboratory study results were normal. An upper endoscopy was performed and showed multiple polypoid lesions ranging in size from 3 to 11 mm, involving the entire esophagus (Figure A; Video). An endoscopic polypectomy of several of the larger polyps was performed. Histopathologic examination showed the lesions were squamous papillomas with areas of hyperkeratinization.

https://ift.tt/2Jpzkof

Validation of the Simplified Chinese Version of the Memorial Symptom Assessment Scale Short Form (MSAS-SF-SC) among Cancer Patients

Comprehensive symptom assessment is crucial for symptom management. The Memorial Symptom Assessment Scale Short Form (MSAS-SF) has been validated for symptom assessment in cancer patients, but there is no Simplified Chinese version.

https://ift.tt/2uOhOXz

Formation of Chromatin Subcompartments by Phase Separation

Chromatin is partitioned on multiple length scales into subcompartments that differ from each other with respect to their molecular composition and biological function. It is a key question how these compartments can form even though diffusion constantly mixes the nuclear interior and rapidly balances concentration gradients of soluble nuclear components. Different biophysical concepts are currently used to explain the formation of "chromatin bodies" in a self-organizing manner and without consuming energy.

https://ift.tt/2uQPSSP

Chromatin Higher-Order Folding: A Perspective with Linker DNA Angles

The mechanism by which the "beads-on-a-string" nucleosome chain folds into various higher-order chromatin structures in eukaryotic cell nuclei is still poorly understood. The various models depicting higher-order chromatin as regular helical fibers and the very opposite "polymer melt" theory imply that interactions between nucleosome "beads" make the main contribution to the chromatin compaction. Other models in which the geometry of linker DNA "strings" entering and exiting the nucleosome define the three-dimensional structure predict that small changes in the linker DNA configuration may strongly affect nucleosome chain folding and chromatin higher-order structure.

https://ift.tt/2Hcfyfp

Gastric adenomas in familial adenomatous polyposis: you only see them when you know what to look for

https://ift.tt/2EokOcK

Colorectal malakoplakia in a patient with hypogammaglobulinemia

https://ift.tt/2GVW4xT

Superficial esophageal squamous cell carcinoma resembling epidermoid metaplasia of the esophagus

https://ift.tt/2GGzwO3

Metastatic rhabdomyosarcoma mimicking autoimmune pancreatitis diagnosed by EUS-guided fine-needle biopsy

https://ift.tt/2JiDsXf

Gastric calcifying fibrous tumor mimicking GI stromal tumor

https://ift.tt/2GVhQ4K

Theragnostic target, prostate-specific membrane antigen—also specific for non-prostatic malignancies

https://ift.tt/2H1vnrK

Clinical outcomes for patients with Gleason Score 10 prostate adenocarcinoma: results from a multi-institutional consortium study

Gleason 10 prostate cancer is extremely aggressive, and clinical outcomes are largely unknown due to its rarity. This study provides benchmark clinical outcomes information for patients with Gleason 10 prostate cancer with data extracted from a large multi-institutional database. Though it follows an aggressive course, the majority of patients are free from disease at 5 years, and there may be benefits to treating with radiation and brachytherapy.

https://ift.tt/2GEkqsC

Dosimetric evaluation of incorporating patient geometric variations into adaptive plan optimization through probabilistic treatment planning in head-and-neck cancers

Dosimetric benefit of incorporating patient geometric variations into offline adaptive plan optimization through probabilistic treatment planning was investigated in head-and-neck cancer patients. The study results demonstrate that this novel adaptive planning approach (4D ART) can achieve improved organ-at-risk sparing while maintaining adequate target coverage.

https://ift.tt/2GE417s

Altered Long Non-Coding RNA Transcriptomic Profiles in Ischemic Stroke

Human Gene Therapy, Ahead of Print.


https://ift.tt/2uO7Ntn

Micro-Dystrophin Gene Therapy Goes Systemic in Duchenne Muscular Dystrophy Patients

Human Gene Therapy, Ahead of Print.


https://ift.tt/2HejQTA

CAR T Cells in Trials: Recent Achievements and Challenges that Remain in the Production of Modified T Cells for Clinical Applications

Human Gene Therapy, Ahead of Print.


https://ift.tt/2EqWJlK

p53 Plays a Key Role in the Apoptosis of Human Ovarian Cancer Cells Induced by Adenovirus-Mediated CRM197

Human Gene Therapy, Ahead of Print.


https://ift.tt/2HejOuW

Acrodermatitis-Like Rash in Kawasaki Disease

A 2-year-old girl presented with fever for 6 days associated with a rash over her gluteal region and face, left side of her neck swelling, and redness of her eyes. She also had red lips and red tongue on day 2 of the fever. She had been treated with intravenous antimicrobials (ceftriaxone and amikacin). On examination, she was lethargic and had pallor, left cervical lymphadenopathy (1.5 cm), conjunctival injection, and cracked lips. She also had an erythematous scaly acrodermatitis like rash over her gluteal region, perioral, and periorbital area, tip of her nose, and over both pinna (Figure, A and B).

https://ift.tt/2GzEfoZ

Impact of Esophageal Atresia on the Success of Fundoplication for Gastroesophageal Reflux

Fundoplication is commonly performed in patients with a history of esophageal atresia (EA), however, the success of this surgery is reduced, as reflected by an increased rate of redo fundoplication. We aimed to determine whether EA impacts the prevalence of fundoplication, its timing, and performance of a redo operation.

https://ift.tt/2qaK2Gv

The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension

Congenital diaphragmatic hernia (CDH) is a complex syndrome that causes severe hypoxemic respiratory failure and is associated with high mortality. CDH is characterized by varying degrees of pulmonary hypoplasia and pulmonary vascular disease because of structural and functional pulmonary vascular abnormalities, often leading to pulmonary hypertension (PH). The impact of pulmonary vascular disease starts in utero and in concert with these changes, fetal circulatory changes and LV hypoplasia contribute to neonatal systolic and diastolic cardiac dysfunction in CDH after birth.

https://ift.tt/2q5P474

Catheter-Related Venous Thrombosis in Hospitalized Pediatric Patients with Inflammatory Bowel Disease: Incidence, Characteristics, and Role of Anticoagulant Thromboprophylaxis with Enoxaparin

To describe the incidence and characteristics of central venous catheter (CVC)-related thrombosis in hospitalized pediatric patients with active inflammatory bowel disease (IBD) and report the potential usefulness of anticoagulant thromboprophylaxis (AT).

https://ift.tt/2GAEQGW

Cannabis Use Tied to Increased Likelihood of Cigarette Smoking

THURSDAY, April 5, 2018 -- Cannabis use is associated with increased initiation of, persistence of, and relapse to cigarette smoking, according to a study published recently in the Journal of Clinical Psychiatry. Andrea H. Weinberger, Ph.D., from...

https://ift.tt/2Jicn6x

Composite Subretinal Implants May Lessen Vision Loss From AMD

THURSDAY, April 5, 2018 -- A composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), which consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin...

https://ift.tt/2EntO1z

Few Indoor Tanners Have Been Screened for Skin Cancer

THURSDAY, April 5, 2018 -- About 30 percent of indoor tanners (ITs) have been screened for skin cancer (SC), with correlates of screening including older age, history of melanoma or SC, and use of very high sun protection factor (SPF) sunscreen use,...

https://ift.tt/2GDFGms

ADHD Frequently Co-Occurs with Autism Spectrum Disorder

THURSDAY, April 5, 2018 -- Co-occurrence of attention-deficit/hyperactivity disorder (ADHD) is common in children with autism spectrum disorder (ASD), and children with both conditions have a higher risk of anxiety and mood disorders, according to a...

https://ift.tt/2q7Qm1m

Coffee Consumption Cuts Coronary Artery Calcification

THURSDAY, April 5, 2018 -- There is an inverse association between coffee consumption and coronary artery calcium (CAC), especially among never smokers, according to a study published online March 24 in the Journal of the American Heart...

https://ift.tt/2JnQO4s

Mood Disorders Up for Children of Consanguineous Parents

THURSDAY, April 5, 2018 -- Children of first-cousin consanguineous parents are more likely to be in receipt of antidepressant or anxiolytic medications and antipsychotic medications, according to a study published online April 4 in JAMA...

https://ift.tt/2En8hpU

Lactation Lowers Risk of T2DM After Gestational Diabetes

THURSDAY, April 5, 2018 -- For women with previous gestational diabetes mellitus (GDM), lactation is associated with reduced risk of type 2 diabetes mellitus (T2DM), although there is no benefit for long-term lactation, according to a review and...

https://ift.tt/2GDFDag

Smoking Status Associated With Poor Diet Quality

THURSDAY, April 5, 2018 -- Smokers have lower quality diets than former smokers and nonsmokers, according to a study published online April 4 in BMC Public Health. R. Ross MacLean, Ph.D., from Yale University in New Haven, Conn., and colleagues...

https://ift.tt/2EqseMM

mRNA Assay Less Sensitive Than DNA Assay for Latent HPV

THURSDAY, April 5, 2018 -- The human papillomavirus (HPV) mRNA assays are less sensitive than HPV DNA assays for detection of latent HPV infection, according to a study published online March 8 in Obstetrics & Gynecology. Sarah Cotton, from the...

https://ift.tt/2JnPOgv

New Map Improves Emergency, Trauma Care Referrals

THURSDAY, April 5, 2018 -- The Pittsburgh Atlas provides a new framework for emergency and trauma care regional referrals in the United States, according to a study published online March 28 in the Annals of Emergency Medicine. David J. Wallace,...

https://ift.tt/2EnUGyG

A Closed-chest Model to Induce Transverse Aortic Constriction in Mice

Here, we present a protocol of Transverse Aortic constriction (TAC) via a lateral thoracotomy. This technique is a minimally invasive, closed chest surgical procedure aiming to simulate pressure overload and heart failure in mice utilizing standard TAC laboratory settings.

https://ift.tt/2uUoymU

Measuring the Kinematics of Daily Living Movements with Motion Capture Systems in Virtual Reality

We designed a virtual reality test to assess instrumental activities of daily living (IADL) with a motion capture system. We propose a detailed kinematic analysis to interpret the participant's various movements, including trajectory, moving distance, and time to completion to evaluate IADL capabilities.

https://ift.tt/2qc0rdw

A Blood-based Test for the Detection of ROS1 and RET Fusion Transcripts from Circulating Ribonucleic Acid Using Digital Polymerase Chain Reaction

Detection of circulating ribonucleic acid (cRNA) from blood is an unmet need in clinical diagnostics. Here we describe methods that characterize cRNA from non-small cell lung cancer patients using sensitive and specific digital polymerase chain reaction. The tests meet design requirements to detect fusion variants within 72 hours.

https://ift.tt/2GAjmd7

Initiating a Robotic Thyroidectomy Program in India

Abstract

Robotic surgery has been successfully used for many surgical indications in head and neck surgery. Robotic thyroidectomy is getting accepted worldwide, but the majority of the literature is from South Korea. The purpose of the paper is to review and give a personal perspective on how a robotic thyroidectomy program was initiated in a tertiary care academic medical institution in India. Advantages of robotic approaches are the three-dimensional visualization, precision, dexterity, and surgeon ergonomics. Cost is an important concern. Training includes basic robotics skill training, cadaveric training, observership, and hands-on training. Sufficient preclinical and clinical training is essential before embarking onto the newer surgical modality. Surgeon credentialing, though institution dependent, has specific guidelines. Case selection is the key, especially in the initial learning curve. The authors prefer the retroauricular approach for robotic thyroidectomy, and our initial experience in the first ten cases of total thyroidectomy was encouraging.

https://ift.tt/2qbWYvw

An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues

Here, we describe an optimized high-throughput ChIP-sequencing protocol and computational analyses pipeline for the determination of genome-wide chromatin state patterns from frozen tumor tissues and cell lines.

https://ift.tt/2GCTtpf

Detergent-free Ultrafast Reconstitution of Membrane Proteins into Lipid Bilayers Using Fusogenic Complementary-charged Proteoliposomes.

Here we present two ultrafast protocols for reconstitution of membrane proteins into fusogenic proteoliposomes, and fusion of such proteoliposomes with target lipid bilayers for detergent-free delivery of these membrane proteins into the postfusion bilayer. The combination of these approaches enables fast and easily controlled assembly of complex multi-component membrane systems.

https://ift.tt/2GVdb2H

Effect of resource availability on evolution of virulence and competition in an environmentally transmitted pathogen

Abstract

Understanding ecological and epidemiological factors driving pathogen evolution in contemporary time scales is a major challenge in modern health management. Pathogens that replicate outside the hosts are subject to selection imposed by ambient environmental conditions. Increased nutrient levels could increase pathogen virulence by pre-adapting for efficient use of resources upon contact to a nutrient rich host or by favouring transmission of fast-growing virulent strains. We measured changes in virulence and competition in Flavobacterium columnare, a bacterial pathogen of freshwater fish, under high and low nutrient levels. To test competition between strains in genotype mixtures, we developed a quantitative real-time PCR assay. We found that a virulent strain maintained its virulence and outcompeted less virulent strains independent of the nutrient level and resource renewal rate while a less virulent strain further lost virulence in chemostats under low nutrient level and over long-term serial culture under high nutrient level. Our results suggest that increased outside-host nutrient levels might maintain virulence in less virulent strains and increase their contribution to epidemics in aquaculture. The results highlight a need to further explore the role of resource in the outside-host environment in maintaining strain diversity and driving evolution of virulence among environmentally growing pathogens.

https://ift.tt/2uTt2u6

https://ift.tt/2Jk4Bcc

Systematic review with meta‐analysis: association between acetaminophen and nonsteroidal anti‐inflammatory drugs (NSAIDs) and risk of Crohn's disease and ulcerative colitis exacerbation

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2GDX9XJ

An Atypical Case of Bartonella henselae Osteomyelitis and Hepatic Disease

Bartonella henselae is a Gram-negative bacterium and the causative agent of cat scratch disease (CSD). Atypical presentations of B. henselae that involve the musculoskeletal, hepatosplenic, cardiac, or neurologic systems are rare. In this case report, we describe a case of B. henselae osteomyelitis involving bilateral iliac bones complicated by hepatic lesions in a 12-year-old immunocompetent female patient. Although B. henselae is a rare cause of osteomyelitis, it should be considered when patients who present with fever, pain, and lymphadenopathy do not respond to routine osteomyelitis therapy.

https://ift.tt/2uRCgH4

A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development

Human hematopoietic stem cells (HSCs) display substantial transcriptional diversity during development. Here, we investigated the contribution of alternative splicing to such diversity by analyzing the dynamics of a key hematopoietic regulator, HMGA2. Next, we showed that CLK3, by regulating the splicing pattern of HMGA2, reinforces an HSC-specific program.

https://ift.tt/2IuI1we

To Be Young at Heart

Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure.

https://ift.tt/2JmYOmr

The Rules of Successful Speed Dating Are Complex, Even for Super-Enhancers

Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.

https://ift.tt/2IwQUoW

Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression

Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression.

https://ift.tt/2JmYEvl

Mentoring the Next Generation: Fiona Watt

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Fiona Watt about her views.

https://ift.tt/2uNpI3k

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Wang et al. investigate reciprocal signaling between glioma stem cells and their differentiated glioblastoma cell progeny. The authors demonstrate that differentiated tumor cells promote the glioblastoma hierarchy and tumor growth through a paracrine feedback loop of neurotrophin signaling in cooperation with stem cell-like tumor cells.

https://ift.tt/2uTelqW

Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate

The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.

https://ift.tt/2JoellA

De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate

DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.

https://ift.tt/2Iu1Kfy

Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications

In this Protocol Review, Yiangou et al. describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy.

https://ift.tt/2HdbLya

Coordinated Control of mRNA and rRNA Processing Controls Embryonic Stem Cell Pluripotency and Differentiation

Corsini et al. identify the splicing factor HTATSF1 as a regulator of intron retention specifically in ribosomal proteins and of ribosomal RNA transcription and processing to modulate levels of overall protein synthesis. They further demonstrate that HTATSF1-mediated protein synthesis dynamics control embryonic stem cell pluripotency and neuroectoderm differentiation.

https://ift.tt/2uUfPAS

Human Hippocampal Neurogenesis Persists throughout Aging

Boldrini et al. find persistent adult neurogenesis in humans into the eighth decade of life, despite declines in quiescent stem cell pools, angiogenesis, and neuroplasticity. Over a 65-year age span, proliferating neural progenitors, immature and mature granule neurons, glia, and dentate gryus volume were unchanged.

https://ift.tt/2HeiJTW

Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics

(Cell Stem Cell 22, 306–309; March 1, 2018)

https://ift.tt/2uQ8lyT

Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise

(Cell Stem Cell 22, 340–354; March 1, 2018)

https://ift.tt/2HdvXA7

Sending Cancer into the Fetal Position

Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers.

https://ift.tt/2uOT9lG

Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

Yamamoto et al. explore age-related changes to HSC function through large-scale clonal analysis using single-cell transplantation. They find large increases in myeloid-restricted repopulating progenitors (MyRPs) as well as a population of MyRPs that display a broader differentiation capacity only in secondary transplants, suggesting additional mechanisms contributing to hematopoietic aging.

https://ift.tt/2JodUHY

Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency

Cao et al. report an efficient protocol for chemical induction of pluripotency and its chromatin accessibility dynamics, which links small molecules and the reorganization of nuclear architecture in the context of cell-fate decisions.

https://ift.tt/2uOT95a

Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS

Abstract

Purpose

The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested.

Methods

Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated.

Results

In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen^® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%.

Conclusions

The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.

https://ift.tt/2IwxTDr

Postoperative intra-abdominal infection is an independent prognostic factor of disease-free survival and disease-specific survival in patients with stage II colon cancer

Abstract

Background

Recurrence occurs in up to 20% of patients with stage II colon cancer operated on for cure. Although postoperative intra-abdominal infection has been linked with an increased risk of recurrence, the association is controversial. The aim was to investigate the impact of postoperative intra-abdominal infection on disease-free survival and disease-specific survival in patients with stage II colon cancer.

Methods

Patients undergoing elective surgery for colon cancer stage II, between 2003 and 2014, were included. Patients with anastomotic leak or intra-abdominal abscess were included in the infection group. We used the Kaplan–Meier method to represent the distribution of survival and the Cox proportional hazards model to estimate the contribution of relevant clinicopathological factors with prognosis.

Results

Postoperative intra-abdominal infection was diagnosed in 37 of 363 (10.2%) patients. Perioperative blood transfusion was more frequent in patients with infection (p = 0.008). Overall 5-year disease-free survival rate was 85.1%. Disease-free survival at 5 years was lower in patients with postoperative intra-abdominal infection (52.8 vs 88.7%; p < 0.001), perineural invasion (p = 0.001), lymphovascular invasion (p = 0.001), pT4 (p = 0.013), and in patients with adjuvant chemotherapy (p = 0.013). Multivariate analysis showed that postoperative intra-abdominal infection (HR 4.275; p < 0.001), perineural invasion (HR 2.230; p = 0.007), and lymphovascular invasion (HR 2.052; p = 0.016) were all significant independent predictors of reduced disease-free survival. Regarding specific survival, independent significant prognostic factors were the number of lymph nodes, lymphovascular invasion, and postoperative intra-abdominal infection.

Conclusion

In this series of patients with stage II colon cancer, postoperative intra-abdominal infection has an independent negative impact on disease-free survival and disease-specific survival.

https://ift.tt/2GYcTYY

Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options

Abstract

At least 50% of surgically resected non-functioning pituitary adenomas (NFPA) recur. Either early or late adjuvant radiotherapy is highly efficacious in controlling recurrent NFPA but associates potentially burdensome complications like hypopituitarism, vascular complications or secondary neoplasm. Reoperation is indicated in bulky tumor rests compressing the optic pathway. To date, no standardized medical therapy is available for recurrent NFPA although cabergoline and temozolomide show promising results. Guidelines on the management of recurrent NFPAs are now available. The new 2017 WHO pituitary tumor classification, based on immunohistochemistry and transcription factor assessment, identifies a group of aggressive NFPA variants that may benefit from earlier adjuvant therapy. Nevertheless, NFPA patients exhibit a reduced overall life expectancy largely due to hypopituitarism and treatment-related morbidity. The management of recurrent NFPA benefits from a multidisciplinary teamwork of surgeons, endocrinologists, radiation oncologists, ophthalmologists, pathologists and neuro-radiologists in order to provide individualized therapy and anticipate deterioration.

https://ift.tt/2IxJwdf

The effect of dose escalation for large squamous cell carcinomas of the anal canal

Abstract

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805–1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757–1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233–1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382–2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097–1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047–1.611, p = 0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

https://ift.tt/2GUANoa

Prevalence of drug–drug interactions in geriatric patients at an ambulatory care pharmacy in a tertiary care teaching hospital

A cross-sectional study was performed from February to May 2015, to estimate the prevalence of drug–drug interactions in geriatric patients at the ambulatory care pharmacy at King Abdul-Aziz Medical City in Je...

https://ift.tt/2q7UcIK

Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss

The aim of this study was to identify the association of parental MTHFR C677T gene polymorphism in couples with and without RPL history.

https://ift.tt/2GF4DK5

Hyperparasitaemia during clinical malaria episodes in infants aged 0–24 months and its association with in utero exposure to Plasmodium falciparum

Existing information has shown that infants who are prenatally exposed to P. falciparum are susceptible to subsequent malaria infections. However, the effect of prenatal exposure to P. falciparum on parasite dens...

https://ift.tt/2q9AWKM

Invasive Lobular Carcinoma of the Breast with Extracellular Mucin: Case Report of a New Variant of Lobular Carcinoma of the Breast

Invasive carcinoma of no special type (NST) or ductal carcinoma is the largest group of invasive breast cancers. Invasive lobular carcinoma (ILC) is the second most common histological type; it comprises 5%–15% of all invasive breast cancers. Historically, lobular neoplasia and invasive lobular carcinoma may produce intracellular mucin that pushes the nucleus to one side, creating the characteristic signet ring cell morphology. The extracellular mucin secretion is essentially described in mucinous breast carcinoma. Mucinous differentiation can be seen in small areas of NST carcinoma, but recently a few cases of invasive lobular carcinoma with extracellular mucin are reported in the literature. It is important for pathologists to recognize this new entity because it mimics a NST carcinoma, as such a diagnosis may require a different approach in clinical management and surveillance. We report a new case of ILC with extracellular mucin and a review of the literature.

https://ift.tt/2Hb8zTT

The Immune Landscape of Cancer

Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.

https://ift.tt/2q8htcQ

Abdominal imaging findings in adult patients with Fontan circulation

Abstract

The Fontan procedures, designed to treat paediatric patients with functional single ventricles, have markedly improved the patient's survival into adulthood. The physiology of the Fontan circuit inevitably increases systemic venous pressure, which may lead to multi-system organ failure in the long-term follow-up. Fontan-associated liver disease (FALD) can progress to liver cirrhosis with signs of portal hypertension. Focal nodular hyperplasia-like nodules commonly develop in FALD. Imaging surveillance is often performed to monitor the progression of FALD and to detect hepatocellular carcinoma, which infrequently develops in FALD. Other abdominal abnormalities in post-Fontan patients include protein losing enteropathy and pheochromocytoma/paraganglioma. Given that these abdominal abnormalities are critical for patient management, it is important for radiologists to become familiar with the abdominal abnormalities that are common in post-Fontan patients on cross-sectional imaging.

Teaching points

• Fontan procedure for functional single ventricle has improved patient survival into adulthood.

• Radiologists should be familiar with unique imaging findings of Fontan-associated liver disease.

• Focal nodular hyperplasia-like nodules commonly develop in Fontan-associated liver disease.

• Hepatocellular carcinoma, protein-losing enteropathy, pheochromocytoma/paraganglioma may develop.

https://ift.tt/2Gz9D6Y

The Efficacy of Gait Training Using a Body Weight Support Treadmill and Visual Biofeedback in Patients with Subacute Stroke: A Randomized Controlled Trial

Background. This study was designed to determine whether or not gait training based on the use of treadmill with visual biofeedback and body weight support (BWS) would produce better effects in patients with subacute stroke compared to BWS treadmill training with no visual biofeedback. Materials and Methods. 30 patients with subacute stroke were randomly assigned to do body weight supported treadmill training with visual biofeedback (BB group) or BWS treadmill training without visual biofeedback. Their gait was assessed with a 3D system (spatiotemporal gait parameters and symmetry index) and by means of 2-minute walk test (2 MWT), 10-metre walk test (10 MWT), and Timed Up & Go test. Subjects in both groups participated in 15 treadmill training sessions (30 minutes each). Results. The participants from both groups achieved a statistically significant improvement in spatiotemporal gait parameters, walking speed, endurance, and mobility. The average change in the BB group after the end of the programme did not differ significantly compared to the change in the control group. The change in the symmetry index value of stance phase in the BB group was 0.03 (0.02) and in the control group was 0.02 (0.02). The difference was not statistically significant (). The statistically significantly higher improvement in the BB group was found in the range of walking speed () and endurance (), but the difference between groups was of low clinical significance. Conclusions. The findings do not confirm that BWS treadmill training with the function of visual biofeedback leads to significantly greater improvement in gait compared to BWS treadmill training with no visual biofeedback at an early stage after stroke. This study was registered at ClinicalTrials.gov, ID: ACTRN12616001283460.

https://ift.tt/2Ji11zf

EMCrit RACC Wee – Debate re: Idarucizumab with @First10em

So my friend, Justin Morgenstern recently put up a post on Idarucizumab, aka Praxbind. He seemed pretty fired up on the issue, so I got him on the line to talk about it. What follows is a conversation on evidence and what to do when there is not a good amount of it. Schtuff The […]

EMCrit Project by Scott Weingart.

https://ift.tt/2HcDxuU

Synergistic effect of phytochemicals on cholesterol metabolism and lipid accumulation in HepG2 cells

Crocin (CRO), chlorogenic acid (CGA), geniposide (GEN), and quercetin (QUE) are all natural compounds with anti-obesity properties, in particular, hypolipidemic effects, which have been widely used for the tre...

https://ift.tt/2Gyy2tb

In vitro antioxidant and cholinesterase inhibitory activities of Elatostema papillosum leaves and correlation with their phytochemical profiles: a study relevant to the treatment of Alzheimer’s disease

Alzheimer's disease (AD), one of the major causes of dementia, is an overwhelming neurodegenerative disease that particularly affects the brain, leading to memory loss and impairment of language and judgment c...

https://ift.tt/2q4O8jk

Presence of hepatitis B surface antibody in addition to hepatitis B core antibody confers protection against hepatitis B virus infection in hepatitis B surface antigen–negative patients undergoing kidney transplantation

Background The American Gastroenterological Association (AGA) and European Association for the Study of the Liver (EASL) recommend that hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (anti-HBc)-positive patients who receive immunosuppression should be monitored for hepatitis B virus (HBV) infection regardless of hepatitis B surface antibody (anti-HBs) status. However, anti-HBs may provide protection against infection. To investigate whether the presence of anti-HBs in addition to anti-HBc confers protection, we classified HBsAg(-) kidney transplantation (KT) patients into 4 groups according to anti-HBc and anti-HBs status, and compared the HBV infection rate between the anti-HBc(+)anti-HBs(+) group and the other 3 groups. Methods In this single-center retrospective study, we classified 1,959 patients into 4 groups: anti-HBc(-)anti-HBs(-) (n=356), anti-HBc(-)anti-HBs(+) (n=652), anti-HBc(+)anti-HBs(-) (n=142), and anti-HBc(+)anti-HBs(+) (n=809). Results HBV infection was noted in 31 patients (1.6%) after KT. There was a significant difference in HBV infection rate between anti-HBc(+)anti-HBs(+) (1.2%) and anti-HBc(+)anti-HBs(-) (5.6%) (p

https://ift.tt/2q7r3NU

Prediction of the Development of Persistent Massive Ascites after Living Donor Liver Transplantation Using a Perioperative Risk Score

Background Persistent massive ascites (PMAS) >14 days after living donor liver transplantation (LDLT) is not uncommon and associated with worse outcome. A predictive risk scoring system was constructed after analysis of recipient, graft and surgery related factors. Methods We retrospectively reviewed adult LDLT recipients from 2005 to 2011 after excluding cases that experienced any intervention for perioperative vascular-related events. Two groups were identified; PMAS and non-PMAS. The score was constructed from significant factors using weighted odds ratios (OR). Results The study population included 439 recipients. PMAS was evident in 74 cases (17%). Five significant risk predictors were identified in multivariate analysis; pretransplant serum creatinine > 1.5 mg/dl (OR: 5.693, weighted OR=2), recipient spleen to graft volume ratio > 1.3 (OR: 4.466, weighted OR=2), left lobe graft (OR: 3.196, weighted OR=1), more than 1000 mL ascites at laparotomy (OR: 2.541, weighted OR=1), and graft recipient weight ratio

https://ift.tt/2uTTqUi

A Randomized Controlled Trial of Chinese Patent Medicine Xiao’er Biantong Granules in the Treatment of Functional Constipation in Children

Objective. To confirm the effect and safety of Xiao'er Biantong (XEBT) granules for treating chronic constipation in children. Methods. This randomized, double-blind, multicenter study enrolled 480 children with age of 1–14 years who had FC. All of them were randomly assigned to receive either XEBT granules or its placebo in the ratio of 3 : 1. The primary efficacy outcome was the frequency of spontaneous bowel movements (SBM) for 14 days, and secondary outcomes were effectual time, score of main symptoms, effect of constipation, disappearance rate of accompanying symptoms, and recurrence rate. We also observed the adverse event (AE) and adverse drug reaction (ADR) to evaluate safety. Results. The sociodemographic characteristics and efficiency data were comparable in the two groups at baseline. The mean values of SBM for 14 days were 8.89 and 5.63 in the XEBT group and the placebo group, respectively, and there were 86.87% and 30.91% subjects in two groups up to SBM ≥ 3/week, respectively. There were significant differences between the two groups. The effects in the XEBT group on median effectual time of defecation, main symptom score, disappearance rate of symptoms, and the differences were significant. The conclusions based on full analysis set (FAS) and per protocol set (PPS) were consistent. Nine AEs were reported, of which 7 were in the XEBT group (2.02%) while 2 were in the placebo group (1.77%). There were no significant differences in the occurrence rate of AE and ADR between the two groups. Conclusions. Xiao'er Biantong granules have superior efficacy compared to the placebo for the treatment of functional constipation in children and are well tolerated.

https://ift.tt/2Ixq3ZV

Immune-mediated cholangitis: is it always nivolumab’s fault?

https://ift.tt/2GDmcdB

Syntactical Informational Structural Realism

Abstract

Luciano Floridi's informational structural realism (ISR) takes a constructionist attitude towards the problems of epistemology and metaphysics, but the question of the nature of the semantical component of his view remains vexing. In this paper, I propose to dispense with the semantical component of ISR completely. I outline a Syntactical version of ISR (SISR for short). The unified entropy-based framework of information has been adopted as the groundwork of SISR. To establish its realist component, SISR should be able to dissolve the latching problem. We have to be able to account for the informational structures–reality relationship in the absence of the standard semantical resources. The paper offers a pragmatic solution to the latching problem. I also take pains to account for the naturalistic plausibility of this solution by grounding it in the recent computational neuroscience of the predictive coding and the free energy principle.

https://ift.tt/2uQE4QE

Drosophila melanogaster Models of Friedreich’s Ataxia

Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene. FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research since the characterization of the fly frataxin ortholog more than 15 years ago. Fly models have provided a comprehensive characterization of the defects associated with frataxin deficiency and have revealed genetic modifiers of disease phenotypes. In addition, these models are now being used in the search for potential therapeutic compounds for the treatment of this severe and still incurable disease.

https://ift.tt/2q7s5Jw

Inhibition of Acetylcholinesterase and Butyrylcholinesterase by a Plant Secondary Metabolite Boldine

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two enzymes sensitive to various chemical compounds having ability to bind to crucial parts of these enzymes. Boldine is a natural alkaloid and it was mentioned in some older works that it can inhibit some kinds of AChE. We reinvestigated this effect on AChE and also on BChE using acetyl (butyryl) thiocholine and Ellman's reagents as standard substances for spectrophotometric assay. We found out IC50 of AChE equal to 372 μmol/l and a similar level to BChE, 321 μmol/l. We conclude our experiment by a finding that boldine is cholinesterase inhibitor; however we report significantly weaker inhibition than that suggested in literature. Likewise, we tried to investigate the mechanism of inhibition and completed it with in silico study. Potential toxic effect on cholinesterases in real conditions is also discussed.

https://ift.tt/2GzqId2

Filaria specific antibody response profiling in plasma from anti-retroviral naïve Loa loa microfilaraemic HIV-1 infected people

In West and Central Africa areas of endemic Loa loa infections overlap with regions of high prevalence of human immunodeficiency virus type 1 (HIV-1) infections. Because individuals in this region are exposed to ...

https://ift.tt/2JiGkmS

Severe inflammatory ileitis resulting in ileal perforation in association with combination immune checkpoint blockade for metastatic malignant melanoma

Immune checkpoint inhibitors have become standard of care in metastatic malignant melanoma management. Despite superior effectiveness to chemotherapy, significant immune-related adverse events (irAE) may occur, particularly if used in combination. Gastrointestinal irAEs were reported with different patterns of involvement. Here, we report the case of a patient who had ileal perforation as a complication of terminal ileitis, without colitis, induced by combination immune checkpoint blockade.

https://ift.tt/2q91RWu

More than meets the eye: infant presenting with hypoxic ischaemic encephalopathy

We report a newborn infant who presented with poor Apgar scores and umbilical artery acidosis leading to the diagnosis of hypoxic ischaemic encephalopathy. During the course of the infant's hospitalisation, subsequent workup revealed an underlying genetic cause that masqueraded as hypoxic ischaemic encephalopathy.

https://ift.tt/2JmmzLo

Paediatric non-ketotic hyperglycaemic hemichorea-hemiballismus

Non-ketotic hyperglycaemic hemichorea–hemiballismus (NHHH) is commonly seen among elderly Asian women with type 2 diabetes mellitus. Here, we present a case of a 16-year-old Filipina with type 1 diabetes mellitus who is poorly compliant to her medications and subsequently developed right hemichorea–hemiballismus (HH). She was initially admitted with hyperglycaemia but was negative for ketonuria or metabolic acidosis. Neuroimaging showed bilateral lentiform nuclei and left caudate hyperdensities on CT and T1-weighted hyperintensity on MRI. Blood glucose was controlled with insulin. Haloperidol and clonazepam were started for the HH with gradual resolution of symptoms in 6 weeks. This is the fifth reported case of NHHH seen among the paediatric age group. NHHH in the paediatric population is clinically and radiographically similar to NHHH seen among adults. Correction of hyperglycaemia results in clinical improvement and radiographic resolution of lesions but persistent cases may necessitate specific treatment targeted towards the abnormal movements.

https://ift.tt/2qd6IWL

Mucinous adenocarcinoma arising from chronic perianal fistula mimicking horseshoe abscess

Perianal fistulae are commonly seen clinical entity. Development of malignancy within a perianal fistula is rare. Even rarer is the development of mucinous adenocarcinoma in a chronic fistula-in-ano. Only a handful of such cases have been reported in the past. A case of mucinous adenocarcinoma arising in chronic perianal fistula in a 34-year-old woman is being described. She presented with complaints of perineal fullness, pain and recurrent pus discharge from perianal fistula for 4 years. On radiological workup, a large solid-cystic pelvic mass was seen in relation to the fistula. On MRI, the lesion was mimicking a large horseshoe abscess. Transrectal ultrasound-guided biopsy and subsequent histopathological examination confirmed the presence of mucinous adenocarcinoma with tumour cells immunopositive for CK7 and CK20.

https://ift.tt/2JmZDLK

Klebsiella endophthalmitis as the herald of occult colorectal cancer

A 67-year-old Chinese man presented with acute loss of vision and pain in the left eye with hypopyon in the anterior chamber. The patient was afebrile with no systemic symptoms at presentation. Diagnosis of endogenous endophthalmitis was made with vitreous tap yielding Klebsiella pneumoniae. Pars plana vitrectomy was performed twice to clear the infection. Thorough investigations showed no septic foci. Whole body positron emission tomography CT revealed a rectal tumour and biopsy showed adenocarcinoma. He was treated with neoadjuvant chemoirradiation followed by surgery to resect the tumour. Vision in the left eye was hand movement at 12 months postoperatively. This case illustrates Klebsiella endogenous endophthalmitis might be a herald of occult colorectal cancer. Bacteria might gain access into bloodstream via mucosal defect in the tumour.

https://ift.tt/2q8f29T

Native valve endocarditis, fusarium and end-stage renal disease

We would like to report a case of invasive Fusariosis involving the native mitral valve and complicated by septic thromboembolism. The patient was a known case of end-stage renal disease on maintenance haemodialysis and did not have any of the known risk factors for invasive Fusariosis like neutropaenia, severe T cell immunodeficiency, postsolid organ transplant recipients, posthaematopoietic stem cell transplant recipients and patients who received cytotoxic and/or high-dose corticosteroid therapy.

https://ift.tt/2JmPvmk

Epidermoid cyst within an intrapancreatic accessory spleen

This is a case of an epidermoid cyst in an intrapancreatic accessory spleen at the tail of the pancreas. Concurrent epidermoid cyst within the accessory spleen is an exceedingly rare entity. The patient initially presented with abdominal pain, nausea and vomiting. Imaging studies revealed a 3.6 cm cystic mass in the tail of the pancreas that was concerning for a mucinous cystic neoplasm (MCN). The patient underwent a robotic distal pancreatectomy for a suspected diagnosis of MCN, which following histologically examination was found to be an epidermoid cyst of an intrapancreatic accessory spleen. Further imaging characteristics are needed to characterise and differentiate these lesions from those of malignant potential. Robotic distal pancreatectomy is a safe alternative with many benefits including decreased length of stay and decreased blood loss.

https://ift.tt/2GA5orF

Infectious causes of Addisons disease: 1 organ--2 organisms!

Background

Infectious aetiologies are the most common causes of primary adrenal failure (Addison's disease) in low/middle-income countries while in the western world autoimmune causes predominate. The infections attributed to cause Addison's include disseminated gonococcal infection, tuberculosis, histoplasmosis, cryptococcosis and cytomegalovirus (CMV) infection. Here, we describe two classical cases of Addison's due to infections of the adrenal gland.

Case presentationCase 1

A 55-year-old woman from North India was admitted with history of multiple episodes of vomiting. She had history of severe loss of appetite and loss of weight. There was also history of increased body pigmentation for the last 6 months. At admission, she was drowsy with tachycardia of 116 beats per minute and her blood pressure was 80/50 mm Hg in supine position associated with a significant postural drop. There was hyperpigmentation of fingers, face, oral mucosa and flexures. The rest of the system examination did not reveal any significant...

https://ift.tt/2qa5LOD

Uncommon presentation, rare complication and previously undescribed oncologic association of pheochromocytoma; the great masquerader

We describe the case of a 67-year-old man presenting with ventricular tachycardia (VT) and systolic heart failure secondary to a left adrenal phaeochromocytoma. After treatment with amiodarone, the patient's VT resolved. However, his course was complicated by femoral deep venous thrombosis secondary to an incidentally discovered dedifferentiated liposarcoma of the thigh, for which he was prescribed a course of enoxaparin. The patient was discharged with plans for adrenalectomy following achievement of sufficient preoperative heart rate and blood pressure control with alpha-adrenergic receptor blockade, but re-presented to an outside facility in haemorrhagic shock, where he ultimately expired. Autopsy determined his death to be caused by spontaneous haemorrhage of the phaeochromocytoma. Cardiac manifestations, complications and oncological associations of phaeochromocytoma are discussed.

https://ift.tt/2JnPlLC

Varicella-zoster virus necrotising retinitis, retinal vasculitis and panuveitis following uncomplicated chickenpox in an immunocompetent child

A 4-year-old girl presented with acute left visual loss 4 weeks after uneventful chickenpox. She was found to have left necrotising retinitis and profound retinal vasculitis and vitritis. Aqueous humour was PCR positive for varicella-zoster virus. Combined intravenous and intravitreal antiviral treatment led to rapid improvement with settled retinitis, no vascular occlusion and good recovery of vision. Her recent coinfection with Epstein-Barr virus may have acted to provoke the retinitis.

https://ift.tt/2EmnhUU

Isolated cystic lymphangiomatosis of spleen in an adult: a diagnostic conundrum

Lymphangiomatosis is a rare developmental disorder characterised by diffuse proliferation of anastomosing lymphatic channels (lymphangiomas). It is believed to result from anomalous lymphatic development and usually presents in childhood. It typically occurs as a part of systemic lymphangiomatosis and isolated organ involvement is rare. Only nine cases of isolated cystic lymphangiomatosis of spleen have been reported between 1990 and 2010. Tuberculosis is a significant health problem in India and varied forms of this disease are seen in clinical practice. Isolated splenic tuberculosis, though a rare entity, has been described in the Indian population. We present a case of isolated splenic lymphangiomatosis in a 42-year-old woman that was initially misdiagnosed as splenic tuberculosis and was treated accordingly. Unresponsive to medical treatment, the patient underwent splenectomy and on histopathological examination, cystic lymphangiomatosis was diagnosed. The patient's symptoms resolved after surgery and she is doing well at a follow-up of 3 months.

https://ift.tt/2Jld9PX

Hypocalcaemia in an adult: the importance of not overlooking the cause

A 58-year-old male patient was admitted at the São Bernardos's Hospital (Setúbal, Portugal) with generalised muscle spasms, dyspnoea, laryngospasm and bronchospasm in the context of severe hypocalcaemia. Despite efforts to correct serum calcium, it remained below average, leading to question the true cause of hypocalcaemia. Low parathyroid hormone and 25-hydroxyvitamin D, along with facial anomalies, palate defect and cognitive impairment with concomitant psychiatric disorder led to a suspicion of a DiGeorge/velocardiofacial/22q11.2 deletion syndrome (DS), which was confirmed through genetic testing. The 22q11.2 DS has a wide phenotypic expression and there are growing reports of diagnosis being made in adulthood. This case report highlights the importance of understanding the cause of refractory hypocalcaemia and alerts medical community to carefully access these patients, for this metabolic disorder may only present in later stages of life.

https://ift.tt/2qahCfF

Chiari malformation and tuberculous meningitis: aetiology and management

This is the first reported case of a Chiari 1 malformation in association with tuberculous (TB) meningitis. We present a case of a 23-year-old woman with a 2-week history nocturnal fever, vertigo, headache and projectile vomiting. She had nystagmus, scanning speech, bilateral papilloedema and ataxia. Cranial imaging showed a 10 mm tonsillar herniation. Posterior fossa decompression was done. Because the patient's gamut of symptoms was highly suspicious for a central nervous system infection, a lumbar tap was done which revealed TB meningitis. Four years later, after anti-TB medications and rehabilitation, all her symptoms except gait instability resolved.

https://ift.tt/2Gz3ism

Bilateral multifocal acute lobar nephronia caused by Enterococcus faecalis

An 8-year-old boy presented to our hospital with complaints of fever, epigastric pain and headache. Enterococcus faecalis were isolated from urine and blood culture, bacteraemic urinary tract infection was clinically diagnosed. Although vancomycin and ampicillin were administrated, fever did not subside. Contrast-enhanced CT (CECT) revealed bilateral and multiple wedge-shaped defects, thus prompting a diagnosis of acute lobar nephronia (ALN). After 7 days of antibiotic treatment, the patient's fever subsided. ALN can be classified into two subgroups based on features of CECT; simple and complicated ALN. The treatment response to antibiotics tends to be delayed in complicated ALN, it is important that we understand the natural course of complicated ALN and should not escalate antibiotics hastily. According to previous studies, ALN has a wide regional variety of causative organisms. Therefore, the physician should recognise a local pattern of microbiological aetiology of ALN.

https://ift.tt/2EmM1fM