Medicine by Alexandros G.Sfakianakis: 08/03/17

Πέμπτη 3 Αυγούστου 2017

Midwives experiences of participating in a midwifery research project: A qualitative study

Publication date: Available online 3 August 2017
Source:Women and Birth
Author(s): Susanne Åhlund, Sofia Zwedberg, Ingegerd Hildingsson, Malin Edqvist, Helena Lindgren
Problem and backgroundIn an earlier research project midwives were asked to perform women-centered care focusing on the assumption that the physiological process in the second stage of labour could be trusted and that the midwives role should be encouraging and supportive rather than instructing. There is no knowledge about how midwives participating in such a research project, uses their skills and experience from the study in their daily work.AimThe aim in this study was to investigate how midwives experienced implementing woman-centered care during second stage of labour.MethodsA qualitative study was designed. Three focus groups and two interviews were conducted. The material was analysed using content analysis.FindingsThe participating midwives' experiences were understood as increased awareness of their role as midwives. The overarching theme covers three categories 1) establishing a new way of working, 2) developing as midwife, 3) being affected by the prevailing culture. The intervention was experienced as an opportunity to reflect and strengthen their professional role, and made the midwives see the women and the birth in a new perspective.ConclusionsImplementing woman-centered care during second stage of labour gave the midwives an opportunity to develop in their professional role, and to enhance their confidence in the birthing women and her ability to have a physiological birth. To promote participation in, as well as conduct midwifery research, can enhance the development of the midwives professional role as well as contribute new knowledge to the field.

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Postoperative seizure freedom does not normalize altered connectivity in temporal lobe epilepsy

Summary

Objectives

Specific changes in the functional connectivity of brain networks occur in patients with epilepsy. Yet whether such changes reflect a stable disease effect or one that is a function of active seizure burden remains unclear. Here, we longitudinally assessed the connectivity of canonical cognitive functional networks in patients with intractable temporal lobe epilepsy (TLE), both before and after patients underwent epilepsy surgery and achieved seizure freedom.

Methods

Seventeen patients with intractable TLE who underwent epilepsy surgery with Engel class I outcome and 17 matched healthy controls took part in the study. The functional connectivity of a set of cognitive functional networks derived from typical cognitive tasks was assessed in patients, preoperatively and postoperatively, as well as in controls, using stringent methods of artifact reduction.

Results

Preoperatively, functional networks in TLE patients differed significantly from healthy controls, with differences that largely, but not exclusively, involved the default mode and temporal/auditory subnetworks. However, undergoing epilepsy surgery and achieving seizure freedom did not lead to significant changes in network connectivity, with postoperative functional network abnormalities closely mirroring the preoperative state.

Significance

This result argues for a stable chronic effect of the disease on brain connectivity, with changes that are largely "burned in" by the time a patient with intractable TLE undergoes epilepsy surgery, which typically occurs years after the initial diagnosis. The result has potential implications for the treatment of intractable epilepsy, suggesting that delaying surgical intervention that may achieve seizure freedom may lead to functional network changes that are no longer reversible by the time of epilepsy surgery.

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The Role of Public–Private Partnerships in Catalyzing the Critical Path

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Issue Information

Cover of this issue. DDX4 is localized on the mitotic spindle. See also Schudrowitz et al. (pages 1612–1619 of this issue).

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In This Issue

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Quinine-Induced Thrombotic Microangiopathy: A Report of 19 Patients

Quinine can cause diverse and severe immune-mediated adverse reactions, including thrombotic microangiopathy (TMA). Our objective was to describe the presenting features and long-term outcomes of patients with quinine-induced TMA.

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Abduction: Can Non-human Animals Make Discoveries?

Abstract

The aim of this paper is to investigate the relationship between information and abductive reasoning in the context of problem-solving, focusing on non-human animals. Two questions guide our investigation: (1) What is the relation between information and abductive reasoning in the context of human and non-human animals? (2) Do non-human animals perform discovery based on inferential processes such as abductive reasoning? In order to answer these questions, we discuss the semiotic concept of information in relation to the concept of abductive reasoning and, more specifically, to the notion of manipulative abduction proposed by Magnani (2009). Finally, we investigate a case study of corvids' intelligence, namely, their capacity of causal cognition.

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89Zr-anti-{gamma}H2AX-TAT but not 18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma

Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of < 5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is found to be futile. We have evaluated the ability of the PET imaging agent, ⁸⁹Zr-anti-H2AX-TAT, to monitor DNA damage in response to fluouracil (5-FU), gemcitabine, or capecitabine treatment in a mouse model of pancreatic cancer. We have also compared the utility of this approach against the standard clinical PET radiotracer, ¹⁸F-FDG. Experimental Design: C57BL/6 mice bearing subcutaneous pancreatic cancer (KPC; B8484) allografts were treated with 5-FU, gemcitabine, or capecitabine. Therapeutic response was monitored by positron emission tomography and ex vivo biodistribution experiments using either ⁸⁹Zr-anti-H2AX-TAT or ¹⁸F-FDG as imaging agents. To further examine the effect of therapeutic response upon uptake of these imaging agents, immunohistochemical analysis of harvested tumour allograft tissue was also performed. Results: Accumulation of ⁸⁹Zr-anti-H2AX-TAT in the tumours of mice that received chemotherapy was higher compared with vehicle-treated mice and was shown to be specifically mediated by H2AX. In contrast, ¹⁸F-FDG did not provide useful indications of therapeutic response. Conclusions: ⁸⁹Zr-anti-H2AX-TAT has shown a superior ability to monitor early therapeutic responses to chemotherapy by PET imaging compared with ¹⁸F-FDG in an allograft model of PDAC in mice.

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FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen

On October 23, 2015, the U.S. Food and Drug Administration approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m² as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks to dacarbazine 1000 mg/m² i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS) of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively. (HR= 0.55; 95% CI: 0.44, 0.70; unstratified log-rank test p<0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A post-marketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was use of PFS as an endpoint to support regular approval of trabectedin.

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A Comprehensive Pipeline for Multi-Resolution Modeling of the Mitral Valve: Validation, Computational Efficiency, and Predictive Capability

Abstract

Multiple studies have demonstrated that the pathological geometries unique to each patient can affect the durability of mitral valve (MV) repairs. While computational modeling of the MV is a promising approach to improve the surgical outcomes, the complex MV geometry precludes use of simplified models. Moreover, the lack of complete in-vivo geometric information presents significant challenges in the development of patient-specific computational models. There is thus a need to determine the level of detail necessary for predictive MV models. To address this issue, we have developed a novel pipeline for building attribute-rich computational models of MV with varying fidelity directly from the in-vitro imaging data. The approach combines high-resolution geometric information from loaded and unloaded states to achieve a high level of anatomic detail, followed by mapping and parametric embedding of tissue attributes to build a high resolution, attribute-rich computational models. Subsequent lower resolution models were then developed, and evaluated by comparing the displacements and surface strains to those extracted from the imaging data. We then identified the critical levels of fidelity for building predictive MV models in the dilated and repaired states. We demonstrated that a model with a feature size of ~5 mm and mesh size of ~1 mm was sufficient to predict the overall MV shape, stress, and strain distributions with high accuracy. However, we also noted that more detailed models were found to be needed to simulate microstructural events. We conclude that the developed pipeline enables sufficiently complex models for biomechanical simulations of MV in normal, dilated, repaired states.

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JCAD Promotes Progression of Non-alcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared to peri-carcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation; whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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Loss of IGF2 gene imprinting in murine prostate promotes widespread neoplastic growth

Loss of imprinting (LOI) is an epigenetic event which relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a pre-malignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways.

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Identification of Novel Breast Cancer Risk Loci

It has been estimated that >1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤ 40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF) >1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population. Through prioritization and stringent selection criteria, we selected 24 SNPs for further genotyping in 1,516 breast cancer cases and 1,189 non-cancer controls. Overall, we identified the JAK2 SNP rs56118985 to be significantly associated with overall breast cancer risk. Subtype analysis performed for patient subgroups defined by ER, PR and HER2 status suggested additional associations of the NOTCH3 SNP rs200504060 and the HIF1A SNP rs142179458 with breast cancer risk. In silico analysis indicated that coding amino acids encoded at these three SNP sites were conserved evolutionarily and associated with decreased protein stability, suggesting a likely impact on protein function. Our results offer proof of concept for identifying novel cancer risk loci from next-generation sequencing data, with iterative data analysis from targeted, whole-exome or whole-genome sequencing a wellspring to identify new SNPs associated with cancer risk.

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Aneuploid cell survival relies upon sphingolipid homeostasis.

Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard of care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacological evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.

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EZH2 palmitoylation mediated by ZDHHC5 in p53 mutant glioma drives malignant development and progression

Gilomas with mutant p53 occurring in 30% of giloma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared to normal brain tissue and that this event to be tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas.

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Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support

Extracorporeal membrane oxygenation (ECMO) or pumpless extracorporeal lung assist (pECLA) requires effective anticoagulation. Knowledge on the use of argatroban in patients with acute respiratory distress synd...

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How to reduce cisatracurium consumption in ARDS patients: the TOF-ARDS study

Neuromuscular blocking agents (NMBAs) have been shown to improve the outcome of the most severely hypoxemic, acute respiratory distress syndrome (ARDS) patients. However, the recommended dosage as well as the ...

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Evaluation of Metals Exposure in Adults on a Gluten-Free Diet

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High Prevalence of Ibuprofen Drug-induced Liver Injury in Spanish and Latin-American Registries

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EDITORIAL: Can we Accurately Predict Survival in Patients with Perihilar Cholangiocarcinoma?

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Reappraisal of Endoscopic Papillary Balloon Dilation vs Sphincterotomy for Choledocholithiasis —Time for a New Trial

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Bringing Assessment of Patient-reported Outcomes to Hepatology Practice’

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Plasmablastic Lymphoma in a Patient with Crohn's Disease After Extensive Immunosuppressive Therapy

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Reply to "More benefits from interrupted time series in evaluating recent market release of DAAs..."

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Prevalence of Dyspepsia in Individuals with Gastro-Esophageal Reflux-Type Symptoms in the Community: A Systematic Review and Meta-Analysis

Dyspepsia and gastro-esophageal reflux are highly prevalent in the general population, but they are believed to be separate entities. We conducted a systematic review and meta-analysis to estimate the prevalence of dyspepsia in individuals with gastro-esophageal reflux symptoms (GERS), and to quantify overlap between the disorders.

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Features of Autoimmune Pancreatitis Associated with Inflammatory Bowel Diseases

Few people know of autoimmune pancreatitis (AIP), a rare disorder associated with inflammatory bowel diseases (IBD). We aimed to describe phenotype and outcomes of AIP in patients with AIP.

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6-thioguanine is a safe and effective second-line treatment for autoimmune hepatitis

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Hepatitis C Treatment is Cost-Saving Irrespective of the Perspective

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ANAL ULCERATIONS IN CROHN’S DISEASE: NATURAL HISTORY IN THE ERA OF BIOLOGICAL THERAPY

The natural history of anal ulcerations in Crohn's disease remains unknown.

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The Emergency Department's Impact on Inpatient Critical Care Resources

Abstract

Critical care is an expensive and limited resource in the United States. Estimates from more than a decade ago suggest that over $100 billion a year is spent on critical care services.¹ Over the past two decades, the number of patients presenting to the Emergency Department (ED) requiring critical care services has increased at a much higher rate than the growth in overall ED volume.^2,3 The proportion of ED patients requiring Intensive Care Unit (ICU) admission has increased 75% over the first decade of the twenty-first century. In addition to the increase in the absolute number of patients requiring critical care admission, the ED length of stay for critically ill patients increased by 60 minutes. This resulted in a total nationwide increase in critical care provided in the ED by more than threefold. This disproportionate increase in critical care time reflects both the increase in critical care volume and the increase in ED boarding of critically ill patients. Data from 2008 reported the median boarding time for a patient waiting in the ED for an ICU bed was more than 5 hours, and 30% of patients waited more than 6 hours for an ICU bed.^2,3

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The contribution of the International Pain Policy Fellowship in improving opioid availability in Georgia

In the Republic of Georgia, the incidence and prevalence of cancer is increasing, signifying a growing need for palliative care and pain relief, including with controlled opioid medicines. As a signatory to the Single Convention, the Georgian government has a responsibility to ensure the adequate availability of controlled medicines for medical purposes, however the consumption of morphine is very low, suggesting a high occurrence of unrelieved pain. In Georgia, palliative care development began in the 2000s including the adoption of a policy document in 2005, the creation of the National Palliative Care Coordinator in 2006 and important changes in Georgian legislation in 2007 and 2008, which served to lay a foundation for improving opioid availability.

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Preferences for life-sustaining treatments examined by hidden Markov modeling are mostly stable in terminally ill cancer patients’ last 6 months of life

Stability of life-sustaining treatment (LST) preferences at end of life (EOL) has not been well established for terminally ill cancer patients nor have transition probabilities been explored between different types of preferences. We assessed the stability of cancer patients' LST preferences at EOL by identifying distinct LST-preference states and examining the probability of each state transitioning to other states between consecutive time points.

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A systematic review of end of life care communication skills training for generalist palliative care providers: research quality and reporting guidance

End of life care (EoLC) communication skills training for generalist palliative care providers is recommended in policy guidance globally. Whilst many training programmes now exist, there has been no comprehensive evidence synthesis to inform future training delivery and evaluation.

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Granulomas in the gastrointestinal tract: deciphering the Pandora’s box

Abstract

Granulomas are organised collection of activated histiocytes induced by a persistent antigen stimulus. A wide variety of antigens encountered by the gastrointestinal tract are of this nature and hence the resulting granulomatous inflammation represents a tissue reaction pattern. The potential causes can be broadly classified as infections or non-infectious immune reactions. There is also a group where a cause is never identified. Granulomas may be of varying morphological appearance, most commonly epithelioid, foreign body type, suppurative and necrotizing. This may provide a clue as to the aetiology; however, in most cases, the cause requires further inquiry. Pathologists may need to cut deeper levels to look for foreign material and apply special stains to look for microorganisms. Pathologists also need to be certain that the process is a true granuloma and not a mimic. The site of occurrence in the gastrointestinal tract and the clinical setting is often paramount in establishing the aetiology. For instance, infections are more likely the cause in developing countries or when there is immunosuppression. Similarly, granulomas in the stomach are usually due to Crohn's disease; however, it is only rarely the cause of granulomas isolated to the appendix.

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Stretch-reflex threshold modulation during active elbow movements in post-stroke survivors with spasticity

Spasticity is a common complication of stroke, occurring in ∼20-50% of patients in the first year (Wissel et al., 2013) and often associated with other sensory and motor impairments (e.g., muscle weakness, loss of dexterity). Spasticity is generally assessed by resistance or EMG responses to passive muscle stretches and has been attributed to exaggerated spinal stretch reflexes (SRs) and alterations in intrinsic muscle properties (Dietz and Sinkjaer, 2007). For example, motor units of spastic muscles often have an impaired ability to relax (Lewek et al., 2007), prolonged spontaneous firing (Mottram et al., 2010) and low firing rates (Young and Mayer, 1982; Gemperline et al., 1995).

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Cortical involvement in myopathies: insights from transcranial magnetic stimulation

There is increasing evidence that a significant brain dysfunction occurs in patients affected by several myopathies. For instance, some patients with muscle diseases, such as dystrophinopathies, exhibit intellectual disabilities and mental retardation (Emery, 1987; North et al., 1996; Mehler, 2000), while in subjects with facioscapulohumeral muscular dystrophy (FSHD) epilepsy is one of the most frequent manifestations of cerebral involvement (Saito et al., 2007; Grosso et al., 2011).

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Subepithelial esophageal tumors: a single-center review of resected and surveilled lesions

Subepithelial esophageal tumors (SETs) are frequent incidental findings. Although symptomatic tumors are surgically or endoscopically resected, there is no consensus on the management of asymptomatic esophageal leiomyomas.

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Local protocol variations for Image-Guided Radiotherapy in the multicenter Dutch hypofractionation (HYPRO) trial: impact of rectal balloon and MRI delineation on anorectal dose and gastrointestinal toxicity levels

The effects of differences in techniques and treatment protocols on patient-reported rectal toxicity were compared between treatment centers participating in the prospective prostate XXX trial. All included centers applied image-guided-IMRT using identical anorectal dose constraints. As compared to reference center A (5-6mm PTV margins), favorable anorectal dose distributions were found for center B (MRI delineation, 7mm margins) and center C (endorectal balloon application, 7mm margins). This translated into significantly lower incidences of rectal complaints within both centers.

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Hypofractionated nodal radiation therapy for breast cancer was not associated with increased patient-reported arm or brachial plexopathy symptoms

Among 708 women treated with CT-planned regional nodal radiation therapy (RT) for breast cancer, self-reported arm symptoms were similar or less debilitating following modestly hypofractionated (2.25-2.5 Gy/day) versus conventionally fractionated (≤ 2 Gy/day) RT at a median of 5.7 years after treatment.

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Editorial introductions

No abstract available

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Emerging therapeutic options for managing diabetic kidney disease

No abstract available

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Parathyroid hormone and the regulation of renal tubular calcium transport

Purpose of review: Renal tubule excretion of calcium is carefully and complexly regulated. At the center of this process, parathyroid hormone (PTH) is the chief regulator of renal calcium reabsorption. This review outlines our current understanding of PTH's effects on renal tubular calcium transport, focusing on the more recent discoveries beyond its direct regulation of epithelial Ca2+ channel transient receptor potential vanilloid 5 (TRPV5) and looking at its interaction with sodium transport and the hormones fibroblast growth factor 23 (FGF23) and klotho. Recent findings: PTH affects not only TRPV5 directly but other intracellular calcium transport proteins as well. In addition, PTH alters sodium transport that indirectly leads to enhanced TRPV5 activity. FGF23 and klotho have their own effects on TRPV5 as well as effects on PTH secretion. Summary: These discoveries and the interactions between these hormones have direct effects on our understanding of nephrolithiasis and have implications in the development of bone mineral disease in chronic kidney disease and may provide future treatment options.

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Endothelin A receptor antagonists in diabetic kidney disease

Purpose of review: Despite optimal therapy of diabetic nephropathy with agents blocking the renin–angiotensin–aldosterone system, the residual risk of nephropathy progression to end-stage renal disease (ESRD) remains high. The purpose of this review is to discuss the potential role of endothelin antagonism as a therapeutic tool to reduce residual proteinuria and delay kidney injury progression among patients with diabetic nephropathy. Recent findings: Preclinical studies have shown that endothelin receptor antagonists (ERAs) exert proteinuria lowering and nephroprotective actions in experimental models of diabetic nephropathy. ERAs reduce proteinuria in phase 2 trials that included therapy with renin–angiotensin–aldosterone system blockers. Safety of these agents and protection from ESRD needs to be demonstrated in phase 3 trials. Excess risk of fluid retention and heart failure risk remains. Summary: The hypothesis that the antiproteinuric effect of endothelin antagonism may be translated into a slower progression of diabetic nephropathy to ESRD is investigated in ongoing randomized trials assessing 'hard' renal endpoints. ERAs may represent a promising tool toward renoprotection in diabetic nephropathy by individualizing therapy and mitigating the risk of heart failure, if these trials are positive.

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Hypoxia-inducible factor activation in diabetic kidney disease

Purpose of review: Tissue hypoxia is present in kidneys from diabetic patients and constitutes a central pathway to diabetic kidney disease (DKD). This review summarizes regulation of hypoxia inducible factor (HIF) and interventions towards the same for treatment of DKD. Recent findings: In the hypoxic diabetic kidney, HIF activity and the effects of HIF signaling seem to be cell-specific. In mesangial cells, elevated glucose levels induce HIF activity by a hypoxia-independent mechanism. Elevated HIF activity in glomerular cells promotes glomerulosclerosis and albuminuria, and inhibition of HIF protects glomerular integrity. However, tubular HIF activity is suppressed and HIF activation protects mitochondrial function and prevents development of diabetes-induced tissue hypoxia, tubulointerstitial fibrosis and proteinuria. No clinical treatment targeting kidney hypoxia is currently available, but development of prolyl hydroxylase inhibitors to promote HIF activity to treat renal anemia could potentially also target diabetes-induced kidney hypoxia. Summary: Increasing HIF activity in the diabetic kidney may possess a novel target for treatment of DKD by improving kidney oxygen homeostasis. However, HIF-mediated glomerulosclerosis may be a concern. The kidney outcomes from the ongoing clinical trials using prolyl hydroxylase inhibitors may provide additional insights into the complex role of HIF signaling in the diabetic kidney.

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Pathophysiology of antenatal Bartter's syndrome

Purpose of review: Antenatal Bartter syndrome (aBS) is a heterogenous disease resulting from defective ion transport in the thick ascending limb of the loop of Henle. Novel insights into the pathophysiology, as well as the recent identification of a novel genetic cause of aBS, merit an update on this topic. Recent findings: In aBS, severe salt losing is further aggravated by defective salt sensing in the macula densa, where a reduced tubular salt concentration is perceived and glomerular filtration is increased instead of decreased. As patients with aBS come of age, there is an increased incidence of proteinuria and impaired renal function. Moreover, we recently reported a new form of aBS. Indeed, we described a series of nine families in whom pregnancies with male fetuses where complicated by acute polyhydramnios, preterm delivery and with severe but transient polyuria. We identified mutations in melanoma-associated antigen D2 in all study participants and showed, in vivo and in vitro, reduced expression of the furosemide and thiazide sensitive transporters sodium–potassium-2–chloride cotransporter and sodium chloride cotransporter, respectively. Summary: Genetic studies revealed the complexity of ion transport in the thick ascending limb of the loop of Henle and will help to clarify the pathophysiology, which is essential to design new therapies.

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The kallikrein–kinin system in diabetic kidney disease

Purpose of review: Diabetic kidney disease (DKD) is one of the most common complications in diabetes mellitus and accounts for a large proportion of clinical nephrology practice. Studies have shown that the kallikrein–kinin system (KKS) may be involved in several pathogenic mechanisms that contribute to DKD, including oxidative stress, inflammatory cytokines, and profibrotic autacoids. This review focuses on recent research advance on the potential role of the KKS in the development of DKD and its clinical relevance. Recent findings: A number of recent studies support the idea that there is a protective role of the KKS in diabetes. For example, agents that activate the KKS have shown strong renal protective effects that might highlight its potential to change the clinical practice. In addition, diabetic mice lacking both bradykinin B2 and B1 receptors have worse kidney lesions as compared with wild-type diabetic mice. Summary: Current basic research has demonstrated that pharmacological activation of the KKS improves renal outcomes in diabetes. These findings suggest that this system may be a therapeutic target in preventing and treating DKD.

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Novel roles for mucin 1 in the kidney

Purpose of review: Recent studies in the kidney have revealed that the well characterized tumor antigen mucin 1 (MUC1/Muc1) also has numerous functions in the normal and injured kidney. Recent findings: Mucin 1 is a transmembrane mucin with a robust glycan-dependent apical targeting signal and efficient recycling from endosomes. It was recently reported that the TRPV5 calcium channel is stabilized on the cell surface by galectin-dependent cross-linking to mucin 1, providing a novel mechanism for regulation of ion channels and normal electrolyte balance. Our recent studies in mice show that Muc 1 is induced after ischemia, stabilizing hypoxia-inducible factor 1 (HIF-1)α and β-catenin levels, and transactivating the HIF-1 and β-catenin protective pathways. However, prolonged induction of either pathway in the injured kidney can proceed from apparent full recovery to chronic kidney disease. A very recent report indicates that aberrant activation of mucin 1 signaling after ischemic injury in mice and humans is associated with development of chronic kidney disease and fibrosis. A frameshift mutation in MUC1 was recently identified as the genetic lesion causing medullary cystic kidney disease type 1, now appropriately renamed MUC1 Kidney Disease. Summary: Studies of mucin 1 in the kidney now reveal significant functions for the extracellular mucin-like domain and signaling through the cytoplasmic tail.

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Do effects of sodium–glucose cotransporter-2 inhibitors in patients with diabetes give insight into potential use in non-diabetic kidney disease?

Purpose of review: Our aim was to review the rationale for the role of sodium–glucose cotransporter-2 inhibitors (SGLT-2i) as renoprotective therapy in patients with and without diabetes. Recent findings: SGLT-2i are antihyperglycemic agents, approved for treating type 2 diabetes to reduce glycosylated hemoglobin, type A1c. Primary glucoregulatory effects occur through selective inhibition of SGLT-2 at the renal proximal tubule promoting glucosuria leading to blood glucose lowering. From a hemodynamic perspective, SGLT-2 inhibition is also associated with decreased glomerular hyperfiltration, an effect that is mediated through natriuresis and tubuloglomerular feedback. With renal injury and progressive nephron loss, diabetic kidney disease, and nondiabetic chronic kidney diseases share overlapping phenotypes exhibiting single nephron hyperfiltration, along with increased proteinuria. Importantly, the impact of SGLT-2 inhibition on renal and systemic hemodynamic function, including effects on lowering blood pressure, hyperfiltration, and plasma volume, are independent of blood glucose lowering and instead are because of natriuresis. Accordingly, large clinical trials with SGLT-2i investigating the potential use of SGLT-2i in patients without diabetes are now underway. Summary: Based on prominent nonglycemic effects, the clinical use of SGLT-2i as renoprotective therapy may extend to nondiabetic chronic kidney diseases subtypes, which could help to address a large, unmet clinical need.

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Paracellular transport and energy utilization in the renal tubule

Purpose of review: Paracellular transport across the tight junction is a general mechanism for transepithelial transport of solutes in epithelia, including the renal tubule. However, why paracellular transport evolved, given the existence of a highly versatile system for transcellular transport, is unknown. Recent findings: Recent studies have identified the paracellular channel, claudin-2, that is responsible for paracellular reabsorption of sodium in the proximal renal tubule. Knockout of claudin-2 in mice impairs proximal sodium and fluid reabsorption but is compensated by upregulation of sodium reabsorption in the loop of Henle. This occurs at the expense of increased renal oxygen consumption, hypoxia of the outer medulla and increased susceptibility to ischemic kidney injury. Summary: Paracellular transport can be viewed as a mechanism to exploit the potential energy in existing electrochemical gradients to drive passive transepithelial transport without consuming additional energy. In this way, it enhances the efficiency of energy utilization by transporting epithelia.

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Nonsteroidal mineralocorticoid antagonists in diabetic kidney disease

Purpose of review: Current data highlight the pathological aspects of excess aldosterone in promoting glomerular hypertrophy, glomerulosclerosis, and proteinuria in diabetic kidney disease (DKD). The role of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in DKD is being evaluated in ongoing clinical trials. Recent findings: Recent studies demonstrate beneficial effects of adding MRAs to the treatment regimen of patients with type 2 diabetes with nephropathy. The MRAs spironolactone and eplerenone can protect against organ damage caused by elevated levels of serum aldosterone in patients with heart failure and DKD but are limited by their side effects, for example, hyperkalemia. Finerenone is more selective for the mineralocorticoid receptor than spironolactone and has greater affinity for the mineralocorticoid receptor than eplerenone. It reduces the concentration of aldosterone without causing significant elevation in serum potassium. Summary: MRAs have a clear role in reducing albuminuria when used with other renin–angiotensin system blockers in DKD; however, hyperkalemia limits their use. This article provides an overview of clinical studies with a novel MRA, finerenone, and several nonsteroidal MRAs being studied for treatment in DKD.

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The renal response to potassium stress: integrating past with present

Purpose of review: The current review combines past findings with recent advances in our understanding of the homeostatic response to potassium imbalance. Recent findings: Following the ingestion of a dietary potassium load, a combination of extrarenal and renal mechanisms act to maintain extracellular K+ within a tight window. Through hormonal regulation and direct K+ sensing, the nephron is ideally suited to respond to wide shifts in external K+ balance. Current evidence indicates that dietary K+ loading triggers a coordinated kaliuretic response that appears to involve voltage-dependent changes in sodium transport across multiple nephron segments, including the proximal tubule, medullary loop of Henle, and distal tubule. Inhibition of sodium transport in these segments would accomplish the final goal of enhancing distal NaCl delivery, luminal flow, and K+ secretion in the aldosterone sensitive distal nephron (ASDN). Summary: Ongoing research seeks to define the relationship between potassium and volume homeostasis by elucidating pathways that couple renal K+ sensing and tubular function during the potassium stress response.

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α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1

Purpose of review: This review describes the recent discoveries about a powerful electroneutral NaCl reabsorption mechanism in intercalated cells, and its regulation by an intrarenal metabolite paracrine, α-ketoglutartate, and the G-protein coupled receptor, Oxgr1. Recent findings: The distal nephron fine-tunes sodium, chloride, potassium, hydrogen, bicarbonate and water transport to maintain electrolyte homeostasis and blood pressure. Intercalated cells have been traditionally viewed as the professional regulators of acid-base balance, but recent studies reveal that a specific population of intercalated cells, identified by the pendrin-transporter, have a surprising role in the regulation of salt balance. The pendrin-positive intercalated cells (PP-ICs) facilitate electroneutral NaCl reabsorption through the cooperative activation of multitransport protein network. α-Ketoglutartate is synthesized and secreted into the proximal tubule lumen in the combined state of metabolic alkalosis and intravascular volume contraction to activate Oxgr1 in PP-IC, which in turn activates the multitransport protein network to drive salt reabsorption and bicarbonate secretion by these cells. Summary: Recent studies identify a novel salt transport pathway in intercalated cells that is activated by an intrarenal paracrine system, α-ketoglutartate/Oxgr1. Activation of the paracrine system and transport pathway, particularly during alkalosis and volume contraction, mitigates deleterious salt wasting while restoring acid-base balance.

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The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

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Non-conventional role of haemoglobin beta in breast malignancy

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Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

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Comment on ‘Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion’

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Reply to ‘Comment on ‘Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion’ ’

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Choosing wisely: a model-based analysis evaluating the trade-offs in cancer benefit and diagnostic referrals among alternative HPV testing strategies in Norway

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The inflammatory potential of diet and ovarian cancer risk: results from two prospective cohort studies

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Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

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The Ensemble Kalman filter: a signal processing perspective

The ensemble Kalman filter (EnKF) is a Monte Carlo-based implementation of the Kalman filter (KF) for extremely high-dimensional, possibly nonlinear, and non-Gaussian state estimation problems. Its ability to ...

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Evaluation of candidemia in epidemiology and risk factors among cancer patients in a cancer center of China: an 8-year case-control study

Candidemia is the worldwide life-threaten disease, especially in cancer patients. This study was aimed to identify and evaluate the risk factors of candidemia in cancer patients, which will prompt the improvem...

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Two confirmed cases of severe fever with thrombocytopenia syndrome with pneumonia: implication for a family cluster in East China

Severe fever with thrombocytopenia syndrome (SFTS) was first reported in China in 2011. Human-to-human transmission of the virus occurred occasionally in family clusters. However, pneumonia as an onset syndrom...

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The association between Bacillus Calmette-Guérin vaccination (1331 SSI) skin reaction and subsequent scar development in infants

The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar...

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Role of meteorological conditions in reported chickenpox cases in Wuhan and Hong Kong, China

Chickenpox is a common contagious disease that remains an important public health issue worldwide. Over 90% of unvaccinated individuals become infected, but infection occurs at different ages in different part...

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Design and implementation of a BSN-based system for plantar health evaluation with exercise load quantification

Plantar pressure measurement has become increasingly useful in the evaluation of plantar health conditions thanks to the recent progression in sensing technology. Due to the large volume and high energy consum...

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Damping ratio analysis of tooth stability under various simulated degrees of vertical alveolar bone loss and different root types

The purpose of this study was to evaluate the feasibility of using damping ratio (DR) analysis combined with resonance frequency (RF) and periotest (PTV) analyses to provide additional information about natura...

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Effectiveness of spinal cord stimulation for painful camptocormia with Pisa syndrome in Parkinson’s disease: a case report

Spinal cord stimulation (SCS) has recently been reported to be effective for truncal postural abnormalities such as camptocormia and Pisa syndrome in Parkinson's disease. In this case report, we describe a cas...

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Plasmid-mediated mcr-1 colistin resistance in Escherichia coli and Klebsiella spp. clinical isolates from the Western Cape region of South Africa

Colistin is a last resort antibiotic for the treatment of carbapenem-resistant Gram negative infections. Until recently, mechanisms of colistin resistance were limited to chromosomal mutations which confer a h...

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Unique EMS Leadership Training Video Series in the Works

Triple Zilch Productions, LLC will develop an EMS leadership training video series in conjunction with NEMSMA ST. LOUIS — Triple Zilch Productions, LLC and the National EMS Management Association, Inc. (NEMSMA) announce the development of a new and unique EMS Leadership training video series. The series will be produced and developed by Triple Zilch Productions in St. Louis, Missouri which specializes ...

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Polarity directed optimization of phytochemical and in vitro biological potential of an indigenous folklore: Quercus dilatata Lindl. ex Royle

Plants have served either as a natural templates for the development of new chemicals or a phytomedicine since antiquity. Therefore, the present study was aimed to appraise the polarity directed antioxidant, c...

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Fungal endophytes associated with Viola odorata Linn. as bioresource for pancreatic lipase inhibitors

As per the recent statistical reports of World Health Organisation (WHO), 13% of total global population is obese. Orlistat remains to be the only drug approved for the long term treatment of obesity. Recent f...

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Inhibitory effects of Ponciri Fructus on testosterone-induced benign prostatic hyperplasia in rats

Benign prostatic hyperplasia (BPH) is non-cancerous condition of enlargement of the prostate, a common occurrence in older men. The immature fruits of Poncirus trifoliata (L.) Rafinesque (Rutaceae), Ponciri Fruct...

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Diocto Liquid and Diocto Syrup by Rugby Laboratories: Recall - Possible Product Contamination

Audience: Pharmacy, Patient, Consumer [Posted 08/03/2017] ISSUE: Rugby Laboratories is voluntarily recalling all lots of Diocto Liquid and Diocto Syrup, (docusate sodium solutions) manufactured by PharmaTech, LLC due to a risk of product...

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Diocto Liquid and Diocto Syrup by Rugby Laboratories: Recall - Possible Product Contamination

Overexpression and Purification of Human Cis-prenyltransferase in Escherichia coli

A simple protocol for overexpression and purification of codon-optimized, human cis-prenyltransferase, under non-denaturing conditions, from Escherichia coli, is described, along with an enzymatic activity assay. This protocol can be generalized for production of other cis- prenyltransferase proteins in quantity and quality suitable for mechanistic studies.

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Phagocytosis Assay for Apoptotic Cells in Drosophila Embryos

We herein describe a phagocytosis assay using the dispersed embryonic cells of Drosophila. It enables us to easily and precisely quantify in vivo phagocytosis levels, and to identify new molecules required for the phagocytosis of apoptotic cells.

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Progressive Spontaneous Resolution of an Anterior Communicating Artery Berry Aneurysm Following Radiation Treatment for Nasopharyngeal Carcinoma

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Identification of an atypical microdeletion generating the RNF135 - SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth

Abstract

Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4–11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype–phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities. The extent of the deletion was determined by means of array comparative genomic hybridisation, and its breakpoints were isolated by means of long-range polymerase chain reaction. Sequence analysis of the deletion junction fragment revealed the occurrence of an Alu-mediated recombination that led to the generation of a chimeric gene consisting of three exons of RNF135 and eleven exons of SUZ12. Interestingly, the deletion shares a common RNF135-centred region with another deletion described in a non-NF1 patient with overgrowth. In comparison with the normal RNF135 allele, the chimeric transcript was 350-fold over-expressed in peripheral blood, and the ADAP2 gene located upstream of RNF135 was also up-regulated. In line with this, the deletion causes the loss of a chromatin TD boundary, which entails the aberrant adoption of distal cis-acting regulatory elements. These findings suggest that RNF135 haploinsufficiency is related to overgrowth in patients with NF1 microdeletion syndrome and, for the first time, strongly indicate a position effect that warrants further genotype–phenotype correlation studies to investigate the possible existence of previously unknown pathogenic mechanisms.

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Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer

Abstract

Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations

Abstract

Cancer cells must alter their metabolism in order to satisfy the demands of necessary energy and cellular building blocks. These metabolic alterations are mediated by many oncogenic changes that affect cellular signalling pathways, which result in sustained cell growth and proliferation. Recently, metabolomics, has received great attention in the field of cancer research and as the essential metabolic pathways that drive tumour growth and progression are determined, the possibilities of new targets for therapeutic intervention are opened. More specifically, as breast cancer is a heterogeneous disease there is growing evidence that differences in metabolic changes exist between molecular subtypes.

In this review, the most recent findings in breast cancer cell metabolism are discussed, with particular emphasis on glutamine and its transporters which is considered one of the key amino acids fuelling cancer growth. Furthermore, the metabolic differences between the molecular subtypes of breast cancer are examined, highlighting the clinical utility for breast cancer diagnosis and treatment.

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Believing the Future Will Be Favorable May Prevent Action

People tend to believe that others will come around to their point of view over time, according to findings from a series of studies published in Psychological Science, a journal of the Association for Psychological Science. The findings show that this "belief in a favorable future" holds across various contexts and cultures, shedding light on some of the causes and consequences of the political polarization evident today.

"It often seems that partisans believe they are so correct that others will eventually come to see the obviousness of their correctness," says behavioral scientist Todd Rogers of the Harvard Kennedy School, lead author on the research. "Ironically, our findings indicate that this belief in a favorable future may diminish the likelihood that people will take action to ensure that the favorable future becomes reality."

In six related studies, Rogers and colleagues Don A. Moore (UC Berkeley Haas School of Business) and Michael I. Norton (Harvard Business School) explored how widely held the belief in a favorable future is, why the belief emerges, and what some of its consequences are.

In one online study, the researchers asked 254 participants to report their views on nine topics: abortion, same-sex marriage, climate change, ideology, party affiliation, President Trump, soda, the National Basketball Association, and phone preferences. The participants also reported how they thought other people's views on the same topics would change between now and the future. For all nine topics, participants' own current beliefs were associated with their estimation of how others' future beliefs will change. For example, 91% of participants who supported easier access to abortion predicted that more people would support easier access to abortion in the future compared with only 47% of those who supported making access to abortion more difficult.

Data from over 800 people in China, Japan, the Netherlands, and the United Kingdom indicated that the belief in a favorable future is a cross-cultural phenomenon, and additional findings revealed that the biased belief is distinct from other phenomena such as optimism and the false-consensus effect. Even when people are given an incentive to make accurate predictions about how people's beliefs will change between now and the future, they tend to believe others' attitudes will change over time to fall in line with their own current beliefs.

Importantly, field experiment data suggest that believing in a favorable future can influence people's behavior in the here and now. Working with the Democratic Governors Association, Rogers and colleagues sent out two variations of a fundraising email to more than 660,000 supporters. Recipients were less likely to open the email if the subject indicated that a Democrat had the lead in a closely contested race compared with a message that suggested he was trailing in a closely contested race. Of those who opened the email, people were less likely to click the donation link and were less likely to make a donation when the Democrat was portrayed as having the lead compared to when the Democrat was portrayed as being behind.

"The most interesting aspect of this to me is how robust it is," says Rogers. "This pattern of findings emerges for an unexpectedly diverse range of preferences, views, and beliefs – and it emerges across cultures. People biasedly believe that others will change in ways that align with their current preferences, views, and beliefs."

According to the researchers, this bias could help to explain a whole host of behavioral phenomena, from staying in a bad job or relationship to underestimating future opposition to a specific political view.

This research was supported by Harvard Kennedy School's Center for Public Leadership and by Harvard Business School.

All data and materials have been made publicly available via the Open Science Framework and the design and analysis plans for Study 1, Study 2, Study 4, and Study 5 were preregistered at the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received badges Open Data, Open Materials, and Preregistration.

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Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect

Abstract

Purpose

Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics. The current study was performed to evaluate the pharmacokinetics and safety of this novel formulation in healthy volunteers.

Methods

The study was conducted in 11 healthy men aged 47–57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data were compared with pharmacokinetic and safety data reported for 1000 mg Zytiga, the marketed drug.

Results

The novel formulation of AA allows rapid absorption of the compound with t _max values within 1 hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated; actually, a slight, but statistically significant negative food effect was observed. Variability of exposure was significantly reduced when compared to Zytiga. AA administered in the novel formulation was well tolerated with no IMP-related safety AEs reported.

Conclusion

The novel formulation might allow a 75% dose reduction with significant reduction of inter-individual variability. The negative food effect observed requires further investigations; however, elimination of the significant positive food effect could be adequate to negate the restriction of a food label.

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A Novel Mammary Fat Pad Transplantation Technique to Visualize the Vessel Generation of Vascular Endothelial Stem Cells

This work demonstrates a novel approach to assess the proliferation, differentiation, and vessel-forming potential of vascular endothelial stem cells (VESCs) through mammary fat pad transplantation followed by whole-mount tissue preparation for microscopic observation. A lineage tracing strategy to investigate the behavior of VESCs in vivo is also presented.

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The efficacy of lymphaticovenular anastomosis in breast cancer-related lymphedema

Abstract

Introduction

Lymphedema can be a debilitating condition, causing a great decrease in a person's quality of life (QoL). Treatment with lymphaticovenular anastomosis (LVA), in which an anastomosis is created between the lymphatic and venous system, may attenuate lymphedema symptoms and reduce swelling. In this study, we share the results using LVA to treat breast cancer-related lymphedema (BCRL) at our institution.

Materials and methods

Patients were eligible for inclusion if they suffered from unilateral BCRL, if functional lymphatics were available, if compression therapy was used for at least 6 months, and if the follow-up was 12 months at minimum. Lymph vessel functionality was assessed preoperatively using indocyanine green (ICG). During surgery, 1–3 anastomoses were created and shunt patency was confirmed using ICG. Arm volumes were measured before surgery and at 6- and 12-month follow-up. QoL was measured before surgery and at 6-month follow-up. Arm volume differences between the healthy arm and affected arm were compared between the time points.

Results

Twenty-nine consecutive female patients with unilateral BCRL were included. The preoperative mean difference in arm volumes was 701 ± 435 ml (36.9%). This was reduced to 496 ± 302 ml (24.7%) at 6-month follow-up (p = 0.00). At 12-month follow-up, the mean difference in arm volume was 467 ± 303 ml (23.5%) (p = 0.02). The overall perceived QoL was increased from 5.8 ± 1.1 to 7.4 ± 0.7 (p = 0.00). The functionality score decreased from 2.2 to 1.8 (p = 0.00), the appearance score decreased from 2.6 to 1.9 (p = 0.00), the symptoms score decreased from 2.8 to 1.8 (p = 0.00), and the mood score decreased from 2.7 to 1.5 (p = 0.00). Fifteen patients (53.6%) were able to discontinue the use of compression garment.

Conclusion

Treatment with LVAs is effective in reducing arm volume difference in patients suffering from BCRL. Although no complete reduction of the edema was achieved at 12-month follow-up, the procedure significantly increased the patients' QoL.

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Weekly carboplatin–paclitaxel regimen is active and well tolerated in mBC treatment. Prospective studies should be conducted to compare its efficacy and tolerability with standard single-agent paclitaxel or docetaxel treatment schedules, as well as with more recent combination regimens.

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Women with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.

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Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Objective

Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP.

Design

We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens.

Results

p21 deficiency in LT mice (LTp21^–/–) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-B) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21^–/– mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-B pathway activation remained impaired in LTp21^–/– pancreata.

Conclusions

Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.

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Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients

Objective

Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking.

Design

We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%).

Results

Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005).

Conclusion

In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.

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Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD

Objective

Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.

Design

Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.

Results

Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na⁺-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.

Conclusions

The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

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Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: a randomised controlled study in Kenyan infants

Objective

Iron-containing micronutrient powders (MNPs) reduce anaemia in African infants, but the current high iron dose (12.5 mg/day) may decrease gut Bifidobacteriaceae and Lactobacillaceae, and increase enteropathogens, diarrhoea and respiratory tract infections (RTIs). We evaluated the efficacy and safety of a new MNP formula with prebiotic galacto-oligosaccharides (GOS) combined with a low dose (5 mg/day) of highly bioavailable iron.

Design

In a 4-month, controlled, double-blind trial, we randomised Kenyan infants aged 6.5–9.5 months (n=155) to receive daily (1) a MNP without iron (control); (2) the identical MNP but with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) (Fe group); or (3) the identical MNP as the Fe group but with 7.5 g GOS (FeGOS group).

Results

Anaemia decreased by 50% in the Fe and FeGOS groups (p<0.001). Compared with the control or FeGOS group, in the Fe group there were (1) lower abundances of Bifidobacterium and Lactobacillus and higher abundances of Clostridiales (p<0.01); (2) higher abundances of virulence and toxin genes (VTGs) of pathogens (p<0.01); (3) higher plasma intestinal fatty acid-binding protein (a biomarker of enterocyte damage) (p<0.05); and (4) a higher incidence of treated RTIs (p<0.05). In contrast, there were no significant differences in these variables comparing the control and FeGOS groups, with the exception that the abundance of VTGs of all pathogens was significantly lower in the FeGOS group compared with the control and Fe groups (p<0.01).

Conclusion

A MNP containing a low dose of highly bioavailable iron reduces anaemia, and the addition of GOS mitigates most of the adverse effects of iron on the gut microbiome and morbidity in African infants.

Trial registration number

NCT02118402.

http://ift.tt/2vwFGyx

Improving iron supplements: cooking with GOS

Iron is essential for oxygen transport, generation of energy, synthesis of DNA and multiple enzymatic systems. Iron deficiency impairs these functions and a familiar and important manifestation of advanced iron deficiency is anaemia. Around a quarter of a billion children worldwide are anaemic, and at least half of childhood anaemia is caused in part by a lack of iron; a heavy burden of anaemia is especially present in sub-Saharan Africa and South Asia.1 Iron replenishments, including iron-containing multiple micronutrient powders (MNPs) can be effective treatments to increase haemoglobin. However, despite the use of such agents for many years, the estimated prevalence of anaemia worldwide in preschool children only decreased from 47% to 43% between 1993 and 2011.2 Furthermore, iron replenishments have been associated with adverse events, including infections, intestinal inflammation and diarrhoea in some (but not all) trials. There is a need to make iron treatments...

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Pretreatment glycemic control status is an independent prognostic factor for cervical cancer patients receiving neoadjuvant chemotherapy for locally advanced disease

Abstract

Background

To investigate whether poor glycemic control status has a negative impact on survival outcomes and tumor response to chemotherapy in patients receiving neoadjuvant chemotherapy (NACT) for locally advanced cervical cancer (LACC).

Methods

A retrospective cohort study was conducted to examine LACC patients undergoing NACT and radical hysterectomy between 2002 and 2011. Patients were divided into three groups: patients without diabetes mellitus (DM), diabetic patients with good glycemic control, and diabetic patients with poor glycemic control. Hemoglobin A_1c (HbA_1c) levels were used to indicate glycemic control status. Recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed using log-rank tests and Cox proportional hazards models.

Results

In total, 388 patients were included and had a median follow-up time of 39 months (range: 4–67 months). Diabetes mellitus (DM) was diagnosed in 89 (22.9%) patients, only 35 (39.3%) of whom had good glycemic control prior to NACT (HbA_1c < 7.0%). In survival analysis, compared with patients with good glycemic control and patients without DM, patients with poor glycemic control (HbA_1c ≥ 7.0%) exhibited decreased recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). In multivariate analysis, HbA_1c ≥ 7.0% was identified as an independent predictor for decreased RFS (hazard ratio [HR] = 3.33, P < 0.0001), CSS (HR = 3.60, P < 0.0001) and OS (HR = 4.35, P < 0.0001). In the subgroup of diabetic patients, HbA_1c ≥ 7.0% prior to NACT had an independent negative effect on RFS (HR = 2.18, P = 0.044) and OS (HR = 2.29, P = 0.012). When examined as a continuous variable, the HbA_1c level was independently associated with decreased RFS (HR = 1.39, P = 0.002), CSS (HR = 1.28, P = 0.021) and OS (HR = 1.27, P = 0.004). Both good (odds ratio [OR] = 0.06, P < 0.0001) and poor glycemic control (OR = 0.04, P < 0.0001) were independently associated with a decreased likelihood of complete response following NACT.

Conclusions

Poor glycemic control is an independent predictor of survival and tumor response to chemotherapy for patients receiving NACT for LACC.

http://ift.tt/2v3m1mK

Frequency of Human papillomavirus in women attending cervical cancer screening program in Chile

Abstract

Background

Human papillomavirus (HPV) is the etiological factor for cervical cancer and its precursor lesions. The characterization of HPV genotypes in preneoplastic lesions and cervical cancer could establishes the effectiveness of vaccination plan in Chilean population. The aim of this study was to determine HPV frequency in a group of women including in a cervical screening program in the public health care system in Chile.

Methods

We analyzed 985 cervical smears samples from women with different histological diagnosis, attending to public health care in Temuco-Chile between 2004 and 2012, to detect HPV genotypes, through PCR followed by reverse line blotting assay.

Results

HPV was found present in 80.8% (n = 796) of samples. Only a 5.6% of 985 samples were infected with a low-risk HPV, considering multiple infections. 10.5% (n = 8/76) of normal cervical epithelia, 83.5% (n = 208/249) and 87.6% (n = 557/636) of low and high grade squamous intraepithelial lesions, respectively, and 95.8% (n = 23/24) of squamous cervical carcinomas tested positive for HPV. HPV 16 was the most frequent genotype found (Overall 44.9%, n = 442/985; SCC: 62.5%, n = 15/24). A high variability of HPV types was also found in preneoplastic lesions, whereas there was a selection of genotypes in neoplasia. Also, there was a higher risk of infection with HPV 16 in women ≤26 years and 34–41 years old (p < 0.05), meanwhile infections with HPV 16 or HPV 18 have related with cancer development (p < 0.01).

Conclusions

These data provide further information about the frequency of HPV genotypes in women with cervical lesions in Chile, and the introduction of new targeted vaccines against a wider spectrum of HPV is suggested.

http://ift.tt/2vmfXbo

Senators reintroduce act to build national EMS memorial

By EMS1 Staff WASHINGTON — A group of senators are beginning a second push for an act concerning the construction of an EMS memorial. WDTV reported that Senators Shelley Moore Capito, Chris Coons, Tom Cotton, Bill Cassidy, Jeanne Shaheen and Elizabeth Warren reintroduced the National Emergency Medical Services Commemorative Work Act. The act would allow a commemorative work honoring EMS providers ...

http://ift.tt/2hrxYzD

Whole-cell Patch-clamp Recordings of Isolated Primary Epithelial Cells from the Epididymis

We present a protocol that combines cell isolation and whole-cell patch-clamp recording to measure the electrical properties of the primary dissociated epithelial cells from the rat cauda epididymides. This protocol allows for investigation of the functional properties of primary epididymal epithelial cells to further elucidate the physiological role of the epididymis.

http://ift.tt/2u7vaO5

College graduates travel Calif. coast in ambulance

Before moving to Florida to start their careers, Christa and JD Hammer are spending the summer in a refurbished ambulance

http://ift.tt/2u4Afm6

Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis

Abstract

Background

Ferritin plays a central role in the intracellular iron metabolism; the molecule is a nanocage of 24 subunits of the heavy and light types. The heavy subunit (FHC) is provided of a ferroxidase activity and thus performs the key transformation of iron in a non-toxic form. Recently, it has been shown that FHC is also involved in additional not iron-related critical pathways including, among the others, p53 regulation, modulation of oncomiRNAs expression and chemokine signalling. Epithelial to mesenchymal transition (EMT) is a cellular mechanism by which the cell acquires a fibroblast-like phenotype along with a decreased adhesion and augmented motility. In this work we have focused our attention on the role of the FHC on EMT induction in the human cell lines MCF-7 and H460 to elucidate the underlying molecular mechanisms.

Methods

Targeted silencing of the FHC was performed by lentiviral-driven shRNA strategy. Reconstitution of the FHC gene product was obtained by full length FHC cDNA transfection with Lipofectamine 2000. MTT and cell count assays were used to evaluate cell viability and proliferation; cell migration capability was assayed by the wound-healing assay and transwell strategy. Quantification of the CXCR4 surface expression was performed by flow cytometry.

Results

Experimental data indicated that FHC-silenced MCF-7 and H460 cells (MCF-7^shFHC, H460^shFHC) acquire a mesenchymal phenotype, accompanied by a significant enhancement of their migratory and proliferative capacity. This shift is coupled to an increase in ROS production and by an activation of the CXCR4/CXCL12 signalling pathway. We present experimental data indicating that the cytosolic increase in ROS levels is responsible for the enhanced proliferation of FHC-silenced cells, while the higher migration rate is attributable to a dysregulation of the CXCR4/CXCL12 axis.

Conclusions

Our findings indicate that induction of EMT, increased migration and survival depend, in MCF-7 and H460 cells, on the release of FHC control on two pathways, namely the iron/ROS metabolism and CXCR4/CXCL12 axis. Besides constituting a further confirmation of the multifunctional nature of FHC, this data also suggest that the analysis of FHC amount/function might be an important additional tool to predict tumor aggressiveness.

http://ift.tt/2v2yCqs

Treating cancerous large airway stenosis with staging radioactive particle implantation guided by computed tomography and fiber bronchoscopy: a clinical study

Abstract

Background

The purpose of this study is to investigate the clinical effectiveness of staging radioactive particle implantation guided by computed tomography (CT) and fiber–optic bronchoscopy in treating cancerous large airway stenosis.

Methods

A total of 102 patients were included; 57 had undergone staging radioactive particle implantation guided by CT and fiber bronchoscopy and 45 did not. Patients were evaluated by CT and fiber–optic bronchoscopy to determine the feasibility of the implantation of radioactive seeds for the treatment of cancerous large airway stenosis. The treatment planning system (TPS) was used to plan the doses. Radioactive seeds were implanted using fiber–optic bronchoscopy. One week later, CT-guided implantation of radioactive seeds was performed.

Results

The clinical evaluation showed complete, partial, slight, and non-response in 38, 14, 5, and 0 patients, respectively. None of the patients were found with serious complications. The diameter of the affected airway, Karnofsky score, dyspnea index, survival, and quality of life of the patients in both groups was significantly higher and significantly different after the treatment (P < 0.05). The dyspnea index was significantly lower in the treatment group as compared with the control group (P < 0.001).

Conclusion

CT- and fiber bronchoscopy-guided staging radioactive particle implantation has definite treatment effectiveness in treating cancerous large airway stenosis. It should be widely used in clinical practices.

http://ift.tt/2hrA1nh

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Αναζήτηση αυτού του ιστολογίου

Πέμπτη 3 Αυγούστου 2017

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