Response to hypomethylating agents improves long-term outcomes for lower-risk patients with myelodysplastic syndrome in case-matched cohorts

Abstract

Predictive factors for initiating hypomethylating agents' (HMAs) treatment and the survival benefit of HMAs for lower-risk myelodysplastic syndrome (LR-MDS) are still unknown. This study evaluated the factors affecting the use of HMAs and compared long-term outcomes between best supportive care (BSC) and HMA groups after matching baseline clinical factors. Data of 353 patients diagnosed with LR-MDS by International Prognostic Scoring System between October 1992 and July 2013 were retrospectively analyzed. HMAs were administered continuously until a clinical response or progression. HMAs were administered to 243 patients with median 45 days (range 0–7078 days) after diagnosis, while 110 patients were treated with BSC. HMAs were administered over a median of 5 cycles and overall response was achieved in 104 patients (42.8%). The cumulative incidence of HMA treatment increased in higher-risk groups by other risk scoring systems. Three-year overall survival (OS) rate was higher in BSC group (69.1%) than HMA responders (47.4%, p = 0.065) or HMA non-responders (46.3%, p = 0.005). Among 162 case-matched cohorts, 3-year OS rates were comparable between the BSC group (67.1%) and HMA responders (58.1%, p = 0.914), while that of HMA non-responder was low (32.2%, p < 0.001). In the case-matched cohorts, HMA non-responder were associated with inferior OS rate in the multivariate analysis (hazard ratio 3.01, p = 0.001). Higher-risk groups by other clinical risk scoring systems among IPSS lower-risk patients showed an increased incidence of using HMAs. The OS rate of HMA responders among case-matched cohorts showed an improved OS rate similar to the BSC group.

https://ift.tt/2AAx4KG

Redox-Driven Proton Pumps of the Respiratory Chain

In aerobic cells, the proton gradient that drives ATP synthesis is created by three different proton pumps – membrane enzymes of the respiratory electron transport chain known as complex I, III, and IV. Despite the striking dissimilarity of structures, and apparent differences in molecular mechanisms of proton pumping, all three enzymes have much in common and employ the same universal physical principles of converting redox energy to proton pumping. In this paper, we describe a simple mathematical model that illustrates the general principles of redox-driven proton pumps and discuss their implementation in complex I, III, and IV of the respiratory chain.

https://ift.tt/2LLMSiU

The Screening of Nails for Selected Essential and Toxic Elements in Normotensive and Pre-Eclamptic Women

Abstract

To compare the concentrations of 13 different elements in nail samples from pre-eclamptic and normotensive pregnant women. The study site was a regional hospital in Durban, KwaZulu Natal. Nail samples were collected from normotensive (n = 33) and pre-eclamptic (n = 33) pregnant women. Approximately 0.02 g of nail samples were digested in 70% nitric acid and analyzed using inductively coupled plasma-optical emission spectrometry. Analytes of interest were the following essential elements calcium (Ca), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), nickel (Ni), selenium (Se) and Zinc (Zn) as well as toxic elements, arsenic (As), cadmium (Cd) and lead (Pb). The observed concentrations of bioelements (mean, μg/g), Ca: normotensive (N) 3467 ± 197 vs (PE) 2897 ± 190; Mg: (N) 736 ± 61 vs (PE) 695 ± 59, were lower in pre-eclampsia albeit not statistically significant. Similarly, the observed concentrations of bioelements (mean, μg/g), Cd: (N) 3 ± 0.3 vs (PE) 2 ± 0.4; Co: (N) 3 ± 0.3 (PE) not detected; Mn: (N) 7 ± 1 (PE) 4 ± 0.8, were significantly lower in pre-eclampsia (p = 0.004, 0.0001 and 0.022, respectively). Therefore, this study demonstrated significantly lower levels of Cd, Co and Mn in pre-eclampsia which justifies the need for further research on these elements towards the effective management or prevention of pre-eclampsia which could ultimately also aid in establishing its pathogenesis.

https://ift.tt/2LXyOls

Clinical Utility of Staging Laparoscopy for Advanced Obstructing Rectal Adenocarcinoma: Emerging Tool

Abstract

The multimodal treatment for advanced rectal adenocarcinoma mandates accurate preoperative staging with contrast-enhanced computed tomography (CECT) of the thorax, abdomen, and pelvis, and magnetic resonance imaging (MRI) of the pelvis. Unlike gastric cancer, the role of staging laparoscopy (SL) in advanced colorectal cancer has not been evaluated. This study aims to evaluate the clinical value of SL in treatment decision-making for advanced rectal cancer (RC) with near or complete obstructing tumors. Observational review of colorectal database at Tata Memorial Hospital from January 2013 to December 2016 identified 562 patients diagnosed and treated for advanced RC. Of the 562 cases, 48.7% (274) were clinically and radiologically diagnosed of near or complete obstructing advanced RC. Medical records of 34% (94/274) who underwent SL with diversion stoma (DS) were analyzed. In the absence of ascites, extensive peritoneal deposits, and unresectable liver metastases on SL, a curative treatment was offered, which entailed neoadjuvant chemoradiation (NACTRT), whereas the cohort of patients with extensive peritoneal disease received palliative therapy. Of the 94 patients with advanced RC, conventional imaging studies staged 73.5% (69/94) cohort as non-metastatic locally advanced and 26.5% (25/94) had potentially resectable metastatic RC. Pre-therapeutic SL upstaged the disease by 26% (18/69) and 8% (2/25) in locally advanced and potentially resectable metastatic RC cohorts, respectively. Treatment decision changed in 21.2% (20/94) of the patients, and midline laparotomy was thus avoided. In our observational study, SL was found to be a safe and effective staging modality in RC; it detected occult peritoneal disease and prevented midline laparotomy in 21.2% of the cohort, which was of value to determine treatment strategy in patients with advanced RC before initiating NACTRT. SL and laparoscopic-assisted de-functioning stoma were associated with minimal morbidity and led to early initiation of NACTRT.

https://ift.tt/2AuE5fK

Blood vessels and myocardial thickness within the left atrial appendage isthmus line

Clinical Anatomy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LIISQ2

Circulating 25-hydroxyvitamin D up to 3 decades prior to diagnosis in relation to overall and organ-specific cancer survival

Abstract

While vitamin D has been associated with improved overall cancer survival in some investigations, few have prospectively evaluated organ-specific survival. We examined the accepted biomarker of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], and cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Of 4616 cancer cases with measured serum 25(OH)D, 2884 died of their cancer during 28 years of follow-up and 1732 survived or died of other causes. Proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between pre-diagnostic 25(OH)D and overall and site-specific survival. Serum 25(OH)D was significantly lower among cases who subsequently died from their malignancy compared with those who did not (medians 34.7 vs. 36.5 nmol/L, respectively; p = 0.01). Higher 25(OH)D was associated with lower overall cancer mortality (HR = 0.76, 95% CI 0.67–0.85 for highest vs. lowest quintile, p-trend < 0.0001). Higher 25(OH)D was related to lower mortality from the following site-specific malignancies: prostate (HR = 0.74, 95% CI 0.55–1.01, p-trend = 0.005), kidney (HR = 0.59, 95% CI 0.35–0.98, p-trend = 0.28), and melanoma (HR = 0.39, 95% CI 0.20–0.78, p-trend = 0.01), but increased mortality from lung cancer (HR = 1.28, 95% CI 1.02–1.61, p-trend = 0.19). Improved survival was also suggested for head and neck, gastric, pancreatic, and liver cancers, though not statistically significantly, and case numbers for the latter two organ sites were small. Higher 25(OH)D status years prior to diagnosis was related to improved survival for overall and some site-specific cancers, associations that should be examined in other prospective populations that include women and other racial-ethnic groups.

https://ift.tt/2voZPUw

Rebuttal comments on “Glucocorticoids in breast cancer treatment: Real benefit or selection bias?”

https://ift.tt/2MaRECG

Hematology and serum biochemistry of growing New Zealand White (NZW) rabbits administered Panax ginseng extracts

Abstract

This study was conducted to evaluate the hematological and serum biochemical parameters of growing New Zealand White (NZW) rabbits administered Panax ginseng extracts (PGEs). A total of 48 NZW growing male (M) and female (F) rabbits (24 each) were used and the experiment lasted for 28 days. It was carried out in a randomized complete block design (RCBD), made up of T₁ (0.0 mg/ml of PGEs), T₂ (200.0 mg/ml of PGEs), and T₃ (400.0 mg/ml of PGEs) which was replicated thrice and sex served as the block. Packed cell volume (PCV) (34.03%), red blood cell (RBC) (5.52 × 10⁶/μl), white blood cell (WBC) (7.60 × 10³/μl), and heterophil (34.00%) counts of the growing male NZW rabbits were significantly (P < 0.05) higher in MT₃ rabbits. PGEs positively affected mean corpuscular volume (MCV) of the male rabbits which recorded a significantly (P < 0.05) higher value in MT₃ (400.0 mg/ml of PGEs), but negatively affected the female rabbits which recorded a significantly (P < 0.05) higher value in FT₁ (0.0 mg/ml of PGEs). Total protein values were significantly (P < 0.05) different among the experimental rabbits, with the lowest value obtained from FT₃ (4.58 g/dl) rabbits. Globulin values of the rabbits were significantly (P < 0.05) lower in MT₃ and FT₃ rabbits. Serum cholesterol of the experimental rabbits were significantly (P < 0.05) lower in PGE-treated rabbits (MT₂, MT₃, FT₂, and FT₃). Alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) values of the growing female NZW rabbits were significantly (P < 0.05) lower in PGE-treated female rabbits. The result of this study suggests improved PCV, RBC, and cellular immunity in growing male NZW rabbits. It also suggests that PGEs have an anti-cholesterolemic effect on both male and female growing NZW rabbits.

https://ift.tt/2KlpB1A

Leukocytes: A Potential Link between Obstructive Sleep Apnea and Cardiovascular Disease?

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 918-919, August 2018.


https://ift.tt/2OyZurr

Cystic Fibrosis: Translating Molecular Mechanisms into Effective Therapies

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 897-902, August 2018.


https://ift.tt/2AvK4RN

Test Performance Characteristics of the AIR, GAD-7, and HADS-Anxiety Screening Questionnaires for Anxiety in Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 926-934, August 2018.


https://ift.tt/2n2TMRZ

Time Is of the Essence: A Young Man with Recurrent Pneumothorax and Cavitating Lung Lesions

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 988-991, August 2018.


https://ift.tt/2AvJYtp

Immunosuppression and Heterogeneity in the Sepsis Volume–Outcome Relationship

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 916-918, August 2018.


https://ift.tt/2n22vDX

Response to Cookstove Trials and Tribulations: What Is Needed to Decrease the Burden of Household Air Pollution?

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 1001-1001, August 2018.


https://ift.tt/2AvJSC3

Predicting Mortality with Percent Predicted and z-Scores of FEV1: Not an EZ Task

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 912-913, August 2018.


https://ift.tt/2ODmhCb

Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 978-987, August 2018.


https://ift.tt/2Ozx1BE

Reply: Response to Cookstove Trials and Tribulations: What Is Needed to Decrease the Burden of Household Air Pollution?

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 1002-1002, August 2018.


https://ift.tt/2AvJIKX

Advising Families in Highly Polluted Settings: Challenges for Clinicians

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 908-911, August 2018.


https://ift.tt/2n2XzP9

Health Services Utilization in Asthma Exacerbations and PM10 Levels in Rural Colorado

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 947-954, August 2018.


https://ift.tt/2AzBrW8

Association between Obstructive Sleep Apnea and Cardiovascular Risk Factors: Variation by Age, Sex, and Race. The Multi-Ethnic Study of Atherosclerosis

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 970-977, August 2018.


https://ift.tt/2n4vFT5

Diagnostic Error in the Critically III: Defining the Problem and Exploring Next Steps to Advance Intensive Care Unit Safety

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 903-907, August 2018.


https://ift.tt/2AEDLeq

Airflow Obstruction Categorization Methods and Mortality

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 920-925, August 2018.


https://ift.tt/2Aw8evc

Acute Chronic Obstructive Pulmonary Disease Exacerbations and Cardiovascular Risk: A Time for Lung Disease–Specific Screening Strategies

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 913-915, August 2018.


https://ift.tt/2n9I9sF

Congenital Tracheobronchial Branching Anomalies

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 995-997, August 2018.


https://ift.tt/2AyCCVS

Risk Factors for Asthma Exacerbation and Treatment Failure in Adults and Adolescents with Well-controlled Asthma during Continuation and Step-Down Therapy

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 955-961, August 2018.


https://ift.tt/2n5bpAK

Reclassification of Acute Respiratory Distress Syndrome: A Secondary Analysis of the ARDS Network Trials

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 998-1001, August 2018.


https://ift.tt/2Ayxxgp

Rural PM10 and Respiratory Health

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 915-916, August 2018.


https://ift.tt/2OAm9DF

Hospital Volume of Immunosuppressed Patients with Sepsis and Sepsis Mortality

Annals of the American Thoracic Society, Volume 15, Issue 8, Page 962-969, August 2018.


https://ift.tt/2AIQCg3

Adjuvant tyrosine kinase inhibitors for renal cell carcinoma? No, thank you (at least for the present) reply

Future Oncology, Ahead of Print.


https://ift.tt/2n3qvGE

Adjuvant tyrosine kinase inhibitors for renal cell carcinoma? No, thank you (at least for the present)

Future Oncology, Ahead of Print.


https://ift.tt/2O0GxN8

Trends in incidence, mortality and survival in women with breast cancer from 1985 to 2012 in Granada, Spain: a population-based study

Abstract

Background

The incidence of breast cancer has increased since the 1970s. Despite favorable trends in prognosis, the role of changes in clinical practice and the introduction of screening remain controversial. We examined breast cancer trends to shed light on their determinants.

Methods

Data were obtained for 8502 new cases of breast cancer in women between 1985 and 2012 from a population-based cancer registry in Granada (southern Spain), and for 2470 breast cancer deaths registered by the Andalusian Institute of Statistics. Joinpoint regression analyses of incidence and mortality rates were obtained. Observed and net survival rates were calculated for 1, 3 and 5 years. The results are reported here for overall survival and survival stratified by age group and tumor stage.

Results

Overall, age-adjusted (European Standard Population) incidence rates increased from 48.0 cases × 100,000 women in 1985–1989 to 83.4 in 2008–2012, with an annual percentage change (APC) of 2.5% (95%CI, 2.1–2.9) for 1985–2012. The greatest increase was in women younger than 40 years (APC 3.5, 95%CI, 2.4–4.8). For 2000–2012 the incidence trend increased only for stage I tumors (APC 3.8, 95%CI, 1.9–5.8). Overall age-adjusted breast cancer mortality decreased (APC − 1, 95%CI, − 1.4 – − 0.5), as did mortality in the 50–69 year age group (APC − 1.3, 95%CI, − 2.2 – − 0.4). Age-standardized net survival increased from 67.5% at 5 years in 1985–1989 to 83.7% in 2010–2012. All age groups younger than 70 years showed a similar evolution. Five-year net survival rates were 96.6% for patients with tumors diagnosed in stage I, 88.2% for stage II, 62.5% for stage III and 23.3% for stage IV.

Conclusions

Breast cancer incidence is increasing – a reflection of the evolution of risk factors and increasing diagnostic pressure. After screening was introduced, the incidence of stage I tumors increased, with no decrease in the incidence of more advanced stages. Reductions were seen for overall mortality and mortality in the 50–69 year age group, but no changes were found after screening implementation. Survival trends have evolved favorably except for the 70–84 year age group and for metastatic tumors.

https://ift.tt/2LVbbdi

Gefitinib provides similar effectiveness and improved safety than erlotinib for east Asian populations with advanced non–small cell lung cancer: a meta-analysis

Abstract

Background

The first-generation epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have both been proven effective for treating advanced non–small cell lung cancer (NSCLC), especially in East Asian patients. We conducted this meta-analysis to compare their efficacy and safety in treating advanced NSCLC in this population.

Methods

We systematically searched PubMed, ScienceDirect, The Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar for the relevant studies. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) were analyzed as primary endpoints.

Results

We identified 5829 articles, among which 31 were included in the final analysis. Both gefitinib and erlotinib were effective for treating advanced NSCLC, with comparable PFS (95% confidence interval [CI]: 0.97–1.10, p = 0.26), OS (95% CI: 0.89–1.21, p = 0.61), ORR (95% CI: 1.00–1.18, p = 0.06), and DCR (95% CI: 0.93–1.05, p = 0.68). Erlotinib induced a significantly higher rate of dose reduction (95% CI: 0.13–0.65, p = 0.002) and grade 3–5 AEs (95% CI: 0.27–0.71, p = 0.0008). In subgroup analysis of AEs, the erlotinib group had a significantly higher rate and severity of skin rash, nausea/vomiting, diarrhea, fatigue and stomatitis.

Conclusions

With equal anti-tumor efficacy and fewer AEs compared with erlotinib, gefitinib is more suitable for treating advanced NSCLC in East Asian patients. Further large-scale, well-designed randomized controlled trials are warranted to confirm our findings.

https://ift.tt/2M7Hr9Y

GWAS with Heterogeneous Data: Estimating the Fraction of Phenotypic Variation Mediated by Gene Expression Data

Intermediate phenotypes such as gene expression values can be used to elucidate the mechanisms by which genetic variation causes phenotypic variation, but jointly analyzing such heterogeneous data is far from trivial. Here we extend a so-called mediation model to handle the confounding effects of genetic background, and use it to analyze flowering time variation in Arabidopsis thaliana, focusing in particular on the central role played by the key regulator FLOWERING TIME LOCUS C (FLC). FLC polymorphism and FLC expression are both strongly correlated with flowering time variation, but the effect of the former is only partly mediated through the latter. Furthermore, the latter also reflects genetic background effects. We demonstrate that it is possible to partition these effects, shedding light on the complex regulatory network that underlies flowering time variation.

https://ift.tt/2AA2aSG

Recursive Algorithms for Modeling Genomic Ancestral Origins in a Fixed Pedigree

The study of gene flow in pedigrees is of strong interest for the development of quantitative trait loci (QTL) mapping methods in multiparental populations. We developed a Markovian framework for modeling ancestral origins along two homologous chromosomes within individuals in fixed pedigrees. A highly beneficial property of our method is that the size of state space depends linearly or quadratically on the number of pedigree founders, whereas this increases exponentially with pedigree size in alternative methods. To calculate the parameter values of the Markov process, we describe two novel recursive algorithms that differ with respect to the pedigree founders being assumed to be exchangeable or not. Our algorithms apply equally to autosomes and sex chromosomes, another desirable feature of our approach. We tested the accuracy of the algorithms by a million simulations on a pedigree. We demonstrated two applications of the recursive algorithms in multiparental populations: design a breeding scheme for maximizing the overall density of recombination breakpoints and thus the QTL mapping resolution, and incorporate pedigree information into hidden Markov models in ancestral inference from genotypic data; the conditional probabilities and the recombination breakpoint data resulting from ancestral inference can facilitate follow-up QTL mapping. The results show that the generality of the recursive algorithms can greatly increase the application range of genetic analysis such as ancestral inference in multiparental populations.

https://ift.tt/2n2MIET

Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer

Abstract

Background

HER2 gene amplification generates an enormous number of HER2 transcripts, but the global effects on endogenous miRNA targets including HER family members in breast cancer are unexplored.

Methods

We generated a HER2–3'UTR expressing vector to test the tumor-promoting properties in HER2 low expressing T47D and MCF7 cells. Through microarray analysis and real-time PCR analysis we identified genes that were regulated by HER2–3'UTR. Positive and negative manipulation of miRNA expression, response element mutational studies and transcript reporter assays were performed to explore the mechanism of competitive sequestration of miR125a/miRNA125b by HER2 3'UTR.

To investigate if trastuzumab-induced upregulation of HER3 is also mediated through miRNA de-repression, we used the CRISPR/cas9 to mutate the endogenous HER2 mRNA in HER2 over-expressing Au565 cells. Finally, we looked at cohorts of breast cancer samples of our own and the TCGA to show if HER2 and HER3 mRNAs correlate with each other.

Results

The HER2 3'UTR pronouncedly promoted cell proliferation, colony formation, and breast tumor growth. High-throughput sequencing revealed a significant increase in HER3 mRNA and protein levels by the HER2 3'untranslated region (3'UTR). The HER2 3'UTR harboring a shared miR-125a/b response element induced miR-125a/b sequestration and thus resulted in HER3 mRNA derepression. Trastuzumab treatment upregulated HER3 via elevated HER2 mRNA expression, leading to trastuzumab resistance. Depletion of miR-125a/b enhanced the antitumor activity of trastuzumab. Microarray data from HER2-overexpressing primary breast cancer showed significant elevation of mRNAs for predicted miR-125a/b targets compared to non-targets.

Conclusions

These results suggest that HER2 3'UTR-mediated HER3 upregulation is involved in breast cell transformation, increased tumor growth, and resistance to anti-HER2 therapy. The combinatorial targeting of HER3 mRNA or miR-125a/b may offer an effective tool for breast cancer therapy.

https://ift.tt/2vaPyfA

Local phototherapy synergizes with immunoadjuvant for treatment of pancreatic cancer through induced immunogenic tumor vaccine

Purpose: To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice. Experimental Design: Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with non-invasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA. Results: Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen presenting cells and a T helper 1 (Th1) immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocytes response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time. Conclusions: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer.

https://ift.tt/2O6ijBh

A New Threat to Immigrants’ Health — The Public-Charge Rule

The United States is making major changes to its immigration policies that are spilling over into health policy. In one such change, the Trump administration is drafting a rule on "public charges" that could have important consequences for access to medical care and the health of millions of…

https://ift.tt/2n3Pslz

Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer

Purpose: Highly-aggressive triple negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate Receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. Experimental Design: We evaluated FRα expression in breast cancers by genomic (N = 3414) and immunohistochemical (N = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the anti-tumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro and in human TNBC xenograft models. Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in post-neoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1 and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. Conclusions: FRα is overexpressed in high-grade TNBC and post-chemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as antibody-drug conjugates, or passive immunotherapy priming Fc-mediated anti-tumor immune cell responses.

https://ift.tt/2v9CPcP

CD30 characterizes polylobated lymphocytes and disease progression in HTLV-1-infected individuals

Purpose: Although expression of CD30 is reported in a subset of adult T-cell leukemia/lymphoma (ATL) cases, its clinicopathological significance is poorly understood. We aimed to characterize CD30-positive cells, and clarify their tumorigenic role in human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells. Experimental Design: CD30-positive peripheral blood mononuclear cells from individuals with differing HTLV-1 disease status were characterized, and the role of CD30 signaling was examined using HTLV-1-infected cell lines and primary cells. Results: CD30-positive cells were detected in all samples examined, and the marker was co-expressed with both CD25 and CD4. This cell population expanded in accordance with disease progression. CD30-positive cells showed polylobation, with some possessing "flower cell" features, active cycling and hyperploidy. CD30 stimulation of HTLV-1 infected cell lines induced these features and abnormal cell division, with polylobation found to be dependent on the activation of phosphoinositide 3-kinase (PI3K). The results thus link the expression of CD30, which serves as a marker for HTLV-1 disease status, to an active proliferating cell fraction featuring polylobation and chromosomal aberrations. In addition, brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated with auristatin E, was found to reduce the CD30-positive cell fraction. Conclusions: Our results indicate that CD30-positive cells act as a reservoir for tumorigenic transformation and clonal expansion during HTLV-1 infection. The CD30-positive fraction may thus be a potential molecular target for those with differing HTLV-1 disease status.

https://ift.tt/2vwko1q

Interim PET analysis in first line therapy of multiple myeloma: Prognostic value of {Delta}SUVmax in the FDG-avid patients of the IMAJEM study

Purpose: To assess the prognostic value of interim FDG-PET analysis using decrease in maximum standardized uptake value (SUVmax) versus visual analysis in patients with multiple myeloma (MM). Experimental Design: We evaluated the prognostic value of FDG-PET after three cycles of lenalidomide, bortezomib and dexamethasone (RVD) in patients with FDG-avid MM included in the French prospective multicenter IMAJEM study. All images were centrally reviewed and interpreted using visual criteria and maximal standardized uptake value reduction (SUVmax). Known prognostic factors, such as the revised International Staging System and biochemical response after three cycles of chemotherapy were also evaluated. Results: In the multivariate analysis, only SUVmax (p<0.001, HR=5.56; 95% CI: 1.96 - 15.81) and biochemical response after three cycles of RVD, (p=0.025, HR=0.29; 95% CI: 0.1 - 0.85) appeared as independent prognostic factors, with a more discriminative HR for SUVmax. SUVmax analysis (>-25 vs ≤-25%) identified patients with improved median PFS (22.6 months and not reached, respectively). Conclusions:SUVmax appears to be a powerful tool for the prediction of long-term outcome in patients with FDG-avid MM. Other prospective studies are needed to further validate this prognostic biomarker.

https://ift.tt/2v9CGWP

SPOP mutated/ CHD1 deleted lethal prostate cancer and abiraterone sensitivity.

Purpose: CHD1 deletions and SPOP mutations frequently co-occur in prostate cancer (PCa) with lower frequencies reported in castration-resistant PCa (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1 deleted/ SPOP mutated metastatic CRPC (mCRPC). Experimental Design: We identified mCRPC 89 patients who had hormone naive and castration resistant tumor samples available: these were analyzed for CHD1, PTEN and ERG expression by immunohistochemistry (IHC). SPOP status was determined by targeted next generation sequencing (NGS). We studied the correlations between these biomarkers and a) overall survival from diagnosis; b) overall survival from CRPC; c) duration of abiraterone treatment and d) response to abiraterone. Relationship with outcome was analysed using Cox-regression and Log-Rank analyses. Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of HSPC and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with 6 of these mutations not reported previously in PCa. SPOP mutations and/ or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR=14.50 p=0.001; CHD1: OR=7.30, p=0.08) and a longer time on abiraterone (SPOP: HR=0.37, p=0.002, CHD1: HR=0.50, p=0.06). Conclusion:SPOP mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment.

https://ift.tt/2vt0xAm

Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non-small cell lung cancer

Purpose: The MEK inhibitor trametinib radiosensitizes KRAS-mutant NSCLC and is being tested clinically with chemoradiation. However, variability in response to trametinib suggests that additional pathways are involved. The mechanism of resistance to trametinib radiosensitization is still unknown. Experimental Design: We used a panel of KRAS-mutant NSCLC cells and tested the radiosensitization effects of trametinib by clonogenic survival assay. Then we investigated the mechanisms underlying the resistance to the combination therapy through several knockout and overexpression systems. Finally, we validated our findings in a syngeneic mouse models in a treatment setting that mimicked the standard of care in the clinic. Results: Radiosensitization by trametinib was effective only in KRAS-LKB1-mutated cells with wildtype p53, and that restoring LKB1 expression in those cells blocked that sensitization. Trametinib and radiation both induced senescence in a p53-dependent manner, but in WT LKB1 cells the combination also activated the AMPK-autophagy pathway to rescue damaged cells from senescence. LKB1 knockout or autophagy inhibition in WT LKB1 cells potentiated trametinib radiosensitization. In syngeneic animal models of Kras-mutant lung tumors, Lkb1-knockout tumors were resistant to trametinib and chemoradiation given separately, but the combination greatly controlled tumor growth and prolonged survival. Conclusions: The LKB1 mutation in KRAS-mutant NSCLC conferred enhanced radiosensitization in combination with trametinib. The WT LKB1 could activate autophagy through AMPK pathway to induce resistance to the combination of trametinib and radiation. The KRAS-LKB1 mutation could potentially be a biomarker to select patients for trametinib and radiation combination therapy.

https://ift.tt/2LLoZrK

CLINICAL UTILITY OF PROSPECTIVE MOLECULAR CHARACTERIZATION IN ADVANCED ENDOMETRIAL CANCER

Purpose: Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease revealed grade and histology-specific differences, facilitating enrollment onto clinical trials. Experimental Design: We integrated prospective clinical sequencing and immunohistochemical data with clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering. Results: Patients had advanced disease, high-grade histologies, and poor progression-free survival on first-line therapy (PFS1). Matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by The Cancer Genome Atlas (TCGA). Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein immunohistochemical staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared to other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months, p=0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials; 47% of these achieved clinical benefit. Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis aiding treatment decision-making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small proportion of all patients tested received investigational, genomically-matched therapy in clinical trials.

https://ift.tt/2vtmmQ5

Understanding Prostate Cancer in African-American Men [News in Brief]

Large-scale study will attempt to integrate data on genomics, lifestyle, social risk factors.

https://ift.tt/2LV3RhO

[ 11 C]SCH23390 binding to the D 1 -dopamine receptor in the human brain—a comparison of manual and automated methods for image analysis

Abstract

Background

The D₁-dopamine receptor radioligand [¹¹C]SCH23390 has been frequently used in PET studies. In drug-naïve patients with schizophrenia, the findings have been inconsistent, with decreases, increases, and no change in the frontal cortex D₁-dopamine receptors. While these discrepancies are likely primarily due to a lack of statistical power in these studies, we speculated that an additional explanation may be the differences due to methods of image analysis between studies, affecting reliability as well as bias between groups.

Methods

Fifteen healthy subjects underwent two PET measurements with [¹¹C]SCH23390 on the same day. The binding potential (BP_ND) was compared using a 95% confidence interval following manual and automated delineation of a region of interest (ROI) as well as with and without frame-by-frame realignment.

Results

Automated target region delineation produced lower BP_ND values, while automated delineation of the reference region yielded higher BP_ND values. However, no significant differences were observed for repeatability using automated and manual delineation methods. Frame-by-frame realignment generated higher BP_ND values and improved repeatability.

Conclusions

The results suggest that the choice of ROI delineation method is not an important factor for reliability, whereas the improved results following movement correction confirm its importance in PET image analysis. Realignment is therefore especially important for measurements in patient populations such as schizophrenia or Parkinson's disease, where motion artifacts may be more prevalent.

https://ift.tt/2LO5sad

The tetraamine chelator outperforms HYNIC in a new technetium-99m-labelled somatostatin receptor 2 antagonist

Abstract

Background

Somatostatin receptor targeting radiopeptides are successfully being used to image, stage, and monitor patients with neuroendocrine tumours. They are exclusively agonists that internalise upon binding to the relevant receptor. According to recent reports, antagonists may be preferable to agonists. To date, ^99mTc-labelled somatostatin receptor antagonists have attracted little attention. Here, we report on a new somatostatin receptor subtype 2 (sst2) antagonist, SS-01 (p-Cl-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH₂), with the aim of developing ^99mTc-labelled ligands for SPECT/CT imaging. SS-01 was prepared using Fmoc solid-phase synthesis and subsequently coupled to the chelators 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 6-carboxy-1,4,8,11-tetraazaundecane (N4), and 6-hydrazinonicotinic acid (HYNIC) to form the corresponding peptide-chelator conjugates SS-03, SS-04, and SS-05, respectively. SS-04 and SS-05 were radiolabelled with ^99mTc and SS-03 with ¹⁷⁷Lu. Binding affinity and antagonistic properties were determined using autoradiography and immunofluorescence microscopy. Biodistribution and small animal SPECT/CT studies were performed on mice bearing HEK293-rsst2 xenografts.

Results

The conjugates showed low nanomolar sst2 affinity and antagonistic properties. ¹⁷⁷Lu-DOTA-SS-01 (¹⁷⁷Lu-SS-03) and ^99mTc-N4-SS-01 (^99mTc-SS-04) demonstrated high cell binding and low internalisation, whereas ^99mTc-HYNIC/edda-SS-01 (^99mTc-SS-05) showed practically no cellular uptake in vitro. The ^99mTc-SS-04 demonstrated impressive tumour uptake at early time points, with 47% injected activity per gram tumour (%IA/g) at 1 h post-injection. The tumour uptake persisted after 4 h and was 32.5 %IA/g at 24 h. The uptake in all other organs decreased much more rapidly leading to high tumour-to-normal organ ratios, which was reflected in high-contrast SPECT/CT images.

Conclusions

These data indicate a very promising ^99mTc-labelled sst2-targeting antagonist. The results demonstrate high sensitivity of the ^99mTc-labelling strategy, which was shown to strongly influence the receptor affinity, contrary to corresponding agonists. ^99mTc-SS-04 exhibits excellent pharmacokinetics and imaging properties and appears to be a suitable candidate for SPECT/CT clinical translation.

https://ift.tt/2O5sW7j

Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus

Abstract

Background

While neoadjuvant chemoradiation therapy (nCRT) with subsequent surgery is the treatment of choice for patients with locally advanced or node-positive squamous cell carcinoma of the esophagus (SCC) suitable for surgery, patients who are unsuitable for surgery or who refuse surgery should be treated with definite chemoradiation therapy (dCRT). Purpose of this study was to compare toxicity and oncologic outcome of dCRT with either cisplatin and 5-fluoruracil (CDDP/5FU) or carboplatin and paclitaxel (Carb/TAX) in patients with SCC.

Methods

Twenty-two patients who received dCRT with carboplatin (AUC2, weekly) and paclitaxel (50 mg per square meter of body-surface area, weekly) were retrospectively compared to 25 patients who were scheduled for dCRT with cisplatin (20 mg/m²/d) and 5-fluoruracil (500 mg/m²/d) on day 1–5 and day 29–33. For the per-protocol (PP) analysis, PP treatment was defined as complete radiation therapy with at least 54Gy and at least three complete cycles of Carb/TAX or complete radiation therapy with at least 54Gy and at least one complete cycle of CDDP/5FU. While patients who were scheduled for dCRT with Carb/TAX received a significantly higher total radiation dose (median dose 59.4Gy vs. 54Gy, p < 0.001) than patients who were scheduled for dCRT with CDDP/5FU, no significant differences were seen for other parameters (age, sex, TNM-stage, grading and tumor extension).

Results

Forty-seven patients (25 patients treated with CDDP/5FU and 22 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 41 of 47 patients (23 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis. Severe myelotoxicity (≥ III°) was seen in 52% (CDDP/5FU) and 55% of patients (Carb/TAX), respectively (p = 1.000). In the univariate binary logistic regression analysis, patients age was the only factor associated with an increased risk of ≥ III° myelotoxicity (hazard ratio 1.145, 95% CI 1.035; 1.266; p = 0.009). Regarding treatment efficiency, no significant differences were seen for overall survival (OS) and freedom from relapse (FFR) between both treatment groups.

Conclusion

Myelotoxicity and oncologic outcome under dCRT were not different for patients with SCC of the esophagus treated with either CDDP/5FU or Carb/TAX. The putative equivalence of dCRT with Carb/TAX in this setting should be further investigated in prospective trials. However, our data reveal that the risk of significant myelotoxicity increases with patient age and therefore other chemotherapy regimens might be evaluated in elderly patients.

https://ift.tt/2M9X14U

Overexpression of the Kininogen-1 inhibits proliferation and induces apoptosis of glioma cells

Abstract

Background

Glioma is the most common primary central nervous system tumor derived from glial cells. Kininogen-1 (KNG1) can exert antiangiogenic properties and inhibit proliferation of endothelial cells. The effect of KNG1 on the glioma is rarely reported, so our purpose in to explore its mechanism in glioma cells.

Methods

The differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) database. The KNG1-vector was transfected into the two glioma cells. The viability, apoptosis and cell cycle of glioma cells and microvessel density (MVD) were detected by cell counting kit-8 assay, flow cytometry and immunohistochemistry, respectively. The expression were measured by quantitative real-time PCR and Western blot, respectively. A tumor mouse model was established to determine apoptosis rate of brain tissue by terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis.

Results

KNG1 was identified as the core gene and lowly expressed in the glioma cells. Overexpression of KNG1 inhibited cell viability and angiogenesis of glioma cells. Overexpression of KNG1 promoted the apoptosis and G1 phase cell cycle arrest of glioma cells. Moreover, the expressions of VEGF, cyclinD1, ki67, caspase-3/9 and XIAP were regulated by overexpression of KNG1. In addition, overexpression of KNG1 inhibited the activity of PI3K/Akt. Furthermore, overexpression of KNG1 decreased the tumor growth and promoted the apoptosis of decreased by overexpression of KNG1 in vivo. .

Conclusions

Overexpression of KNG1 suppresses glioma progression by inhibiting the proliferation and promoting apoptosis of glioma cells, providing a therapeutic strategy for the malignant glioma.

https://ift.tt/2O46rPR

Non-traumatic splenic rupture - a rare first presentation of diffuse large B-cell lymphoma and a review of the literature

Abstract

Background

Cases of non-traumatic splenic rupture are rare and entails a potentially grave medical outcome. Hence, it is important to consider the differential diagnosis of a non-traumatic splenic rupture in patients with acute or insidious abdominal pain. The incidence of rupture in Diffuse B-cell non-Hodgkin Lymphoma is highly infrequent (Paulvannan and Pye, Int J Clin Pract 57:245–6, 2003; Gedik et el., World J Gastroenterol 14:6711–6716, 2008), despite reports of various non-traumatic splenic rupture in the literature (Orloff and Peksin, Int Abstr Surg 106:1-11, 1958; Paulvannan and Pye, Int J Clin Pract 57:245–6, 2003). In this article, we attempt to highlight the features of a rare cause of splenic rupture that might serve as a future reference point for the detection of similar cases during routine clinical practice.

Case presentation

A 40-year-old man presented with 1 week history of left hypochondriac pain associated with abdominal distention. There was no history of preceding trauma or fever. Clinical examination revealed signs of tachycardia, pallor and splenomegaly. He had no evidence of peripheral stigmata of chronic liver disease. In addition, haematological investigation showed anemia with leucocytosis and raised levels of lactate dehydrogenase enzyme. However, peripheral blood film revealed no evidence of any blast or atypical cells. In view of these findings, imaging via ultrasound and computed tomography of the abdomen was performed. The results of these imaging tests showed splenic collections that was suggestive of splenic rupture and hematoma. Patient underwent emergency splenectomy and the histopathological report confirmed the diagnosis as DLBCL.

Conclusions

The occurrence of true spontaneous splenic rupture is uncommon. In a recent systematic review of 613 cases of splenic rupture, only 84 cases were secondary to hematological malignancy. Acute leukemia and non-Hodgkin lymphoma were the most frequent causes of splenic rupture, followed by chronic and acute myelogeneous leukemias. At present, only a few cases of diffuse large B-cell lymphoma (DLBCL) have been reported. The morbidity and mortality rate is greatly increased when there is a delay in the diagnosis and intervention of splenic rupture cases. Hence, there should be an increased awareness amongst both physicians and surgeons that a non-traumatic splenic rupture could be the first clinical presentation of a DLBCL.

https://ift.tt/2LTITQC

Update on Salmonella Outbreak Tied to Hy-Vee Spring Pasta Salad

WEDNESDAY, Aug. 1, 2018 -- A Salmonella outbreak linked to Hy-Vee Spring Pasta Salad has now sickened 79 people in nine states. Eighteen people have been hospitalized. No deaths have been reported, the U.S. Centers for Disease Control and Prevention...

https://ift.tt/2MaPUsU

Alcohol Exposure Via Breastmilk May Affect Infant Development

WEDNESDAY, Aug. 1, 2018 -- Exposing infants to alcohol through breastfeeding may reduce their cognitive ability at age 6 to 7 years, according to a study published online July 30 in Pediatrics. Louisa Gibson and Melanie Porter, Ph.D., from Macquarie...

https://ift.tt/2KkcvBT

Dog's Saliva Caused Bacterial Infection Leading to Amputations

WEDNESDAY, Aug. 1, 2018 -- A Wisconsin man had his lower legs and hands amputated after developing a rare blood infection caused by bacteria in dog saliva. The patient -- Greg Manteufel -- first developed flu-like symptoms such as fever and...

https://ift.tt/2LSG9Tu

National Guideline Clearinghouse Offline Due to Funding Cuts

WEDNESDAY, Aug. 1, 2018 -- The National Guideline Clearinghouse (NGC) and National Quality Measures Clearinghouse (NQMC) websites were taken down on July 16 when funding for these federal databases ended, according to an announcement by the Agency...

https://ift.tt/2M1e6S1

Summer Sounds Can Cause Hearing Damage

WEDNESDAY, Aug. 1, 2018 -- The sounds of summer can cause hearing damage, warn experts from Penn State University. Huseyin Isildak, M.D., director of otology and neurotology in the Division of Otolaryngology -- Head and Neck Surgery at the Penn...

https://ift.tt/2MaQ3MY

The Influence of Formulation and Excipients on Propranolol Skin Permeation and Retention

The objective of this work was to study in vitro propranolol permeation and skin retention after topical application of different semisolid vehicles, with the final aim of developing new topical formulations intended for the treatment of infantile hemangioma, able to produce therapeutic drug levels in the skin, avoiding systemic absorption. Propranolol ointments, creams, and gels were prepared and tested on pig skin, an accepted model of human skin. From the results obtained in the present work it is clear that the permeation of propranolol across the skin is a poor predictor of its skin retention, at least in the time-frame considered. With an application time of 4 h, reasonably close to the permanence time of a semisolid formulation on the skin surface, the best performance (high retention and low skin penetration) was obtained with lipophilic formulations, in particular with a lipophilic cream containing olive oil. Hydrophilic formulations, such as gels, are characterized by a significant permeation across the skin, probably leading to systemic side effects, accompanied by a limited skin retention. Overall, the results obtained in the present work pose the basis for the development of new topical formulations, containing propranolol, with better performance and reduced systemic absorption.

https://ift.tt/2OzVxCL

Quantitative Assessment of the Effects of Reducing Agents on Biological Macromolecules and on the Possible Repair of Oxidative Damage

Objective. To quantitatively assess the influence of reducing agents on biological macromolecules and on the possible repair of oxidative damage. Methods. Samples (antibody, enzyme, DNA, and diluted serum) were treated with reducing agents (ammonium ferrous sulfate, ascorbic acid, potassium iodide, and sodium hyposulfite) in the experimental group and with NaCl in the control group. Enzyme-linked immunosorbent assay and quantitative PCR were used to determine the activity of antibody, enzyme, and DNA. Native gel electrophoresis (Native-PAGE) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) were used to determine protein structure. Reducing agents that had no inhibitory effect on biological macromolecules were selected. Antibodies were treated with oxidants to caused oxidative damage and then treated with reducing agents, and the possible repair of oxidative damage was assessed. Results. Certain concentrations of ammonium ferrous sulfate resulted in significant inhibition of antibody, enzyme, DNA, and diluted serum. Certain concentrations of ascorbic acid resulted in significant inhibition of antibody. Sodium hyposulfite and potassium iodide had no effect on antibody, enzyme, DNA, and diluted serum. The OD values in group A (in which HBsAb was treated by oxidation and then a reductant) were significantly higher than those in group B (HBsAb treated by oxidation). Conclusion. Ammonium ferrous sulfate, ascorbic acid, sodium hyposulfite, and potassium iodide had different effects on antibody, enzyme, DNA, and diluted serum. The reduction in antibody activity due to an oxidant was partially repaired by a reductant.

https://ift.tt/2AEMcXw

Investigating Object Representations in the Macaque Dorsal Visual Stream Using Single-unit Recordings

A detailed protocol to analyze object selectivity of parieto-frontal neurons involved in visuomotor transformations is presented.

https://ift.tt/2n3WWVJ

A Strain Gauge Monitor (SGM) for Continuous Valve Gape Measurements in Bivalve Molluscs in Response to Laboratory Induced Diel-cycling Hypoxia and pH

Understanding the behavioral responses of bivalve suspension-feeders to environmental variables, such as dissolved oxygen, can explain some ecosystem processes. We have developed an inexpensive, laboratory-based, strain gauge monitor (SGM) to measure valve gape responses of oysters, Crassostrea virginica, to diel-cycling hypoxia and cyclical pH.

https://ift.tt/2Az0qsE

Preparation of Functional Silica Using a Bioinspired Method

Here, we present a protocol to synthesize bioinspired silica materials and immobilize enzymes therein. Silica is synthesized by combining sodium silicate and an amine 'additive', which neutralize at a controlled rate. Material properties and function can be altered either by in situ enzyme immobilization or post-synthetic acid elution of encapsulated additives.

https://ift.tt/2OCSWI3

Identification of Pharmaceuticals in The Aquatic Environment Using HPLC-ESI-Q-TOF-MS and Elimination of Erythromycin Through Photo-Induced Degradation

We present a protocol for non-targeted analysis using time of flight mass spectrometry as a perfect tool to identify pharmaceuticals in waters. We demonstrate the application of UV irradiation for their elimination. Analysis involving irradiation, compound isolation, identification and kinetic modelling of the degradation profiles is illustrated.

https://ift.tt/2AyZPao

Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

We present a protocol for the construction of thioether/vinyl sulfide-tethered helical peptides using photo-induced thiol-ene/thiol-yne hydrothiolation.

https://ift.tt/2n6mW2p

A typical presentation of TB in cirrhosis

https://ift.tt/2vawkqj

Common Gastrostomy Feeding Tube Complications and Troubleshooting

https://ift.tt/2O24TG8

Promyelocytic leukemia protein in mesenchymal stem cells is essential for leukemia progression

Abstract

The dynamic interactions between leukemic cells and cells resident within the bone marrow microenvironment are vital for leukemia progression. The lack of detailed knowledge about the cellular and molecular mechanisms involved in this cross-talk restricts the design of effective treatments. Guarnerio et al. (2018) by using state-of-the-art techniques, including sophisticated Cre/loxP technologies in combination with leukemia mouse models, reveal that mesenchymal stem cells via promyelocytic leukemia protein (Pml) maintain leukemic cells in the bone marrow niche. Strikingly, genetic deletion of Pml in mesenchymal stem cells raised survival of leukemic mice under chemotherapeutic treatment. The emerging knowledge from this research provides a novel target in the bone marrow niche for therapeutic benefit in leukemia.

https://ift.tt/2NYTKWL

Survival of non-transplant patients with multiple myeloma in routine care differs from that in clinical trials—data from the prospective German Tumour Registry Lymphatic Neoplasms

Abstract

Despite increasing treatment options, multiple myeloma (MM) remains incurable for most patients. Data on improvement of outcomes are derived from selected patient populations enrolled in clinical trials and might not be conferrable to all patients. Therefore, we assessed the trial eligibility, sequential treatment, and survival of non-transplant patients with MM treated in German routine care. The prospective clinical cohort study TLN (Tumour Registry Lymphatic Neoplasms) recruited 285 non-transplant patients with symptomatic MM at start of first-line treatment in 84 centres from 2009 to 2011. Demographic and clinical data were collected until August 2016. Trial-ineligibility was determined by presence of at least one of the common exclusion criteria: heart/renal failure, liver/renal diseases, polyneuropathy, HIV positivity. All other patients were considered potentially trial-eligible. Thirty percent of the patients in our study were classified as trial-ineligible. Median first-line progression-free survival (PFS) and overall survival (OS) of trial-ineligible patients were inferior to that of potentially trial-eligible patients: PFS 16.2 months (95% CI (confidence interval) 11.1–20.4) vs. 27.3 months (95% CI 23.3–33.0); OS 34.2 months (95% CI 21.6–48.1) vs. 58.6 months (95% CI 48.6–64.4). A high percentage of non-transplant patients with MM in German routine care would be ineligible for participation in clinical trials. Despite similar treatment algorithms, their first-line PFS and OS were shorter than those of potentially trial-eligible patients; the survival data of the latter were similar to results from clinical trials. Physicians should be aware of the fact that results from clinical trials may not mirror "real world" patient outcomes when discussing outcome expectations with patients. Trial registration: Clinicaltrials.gov identifier: NCT00889798.

https://ift.tt/2LGC59D

Gastric lanthanum phosphate deposition masquerading as white globe appearance

https://ift.tt/2O0dtW8

Congenital biliary atresia in an infant born to hepatitis B mother treated with telbivudine before and during pregnancy

https://ift.tt/2LMNlRK

MELD is the Only Predictor of Short-Term Mortality in Cirrhotic Patients with C. difficile Infection

Clostridium difficile infection (CDI) is the most common nosocomial infection in the US and cirrhotic patients have increased risk for poor outcome.

https://ift.tt/2vsRAXz

Erratum

Integrative and Comparative Biology;doi.org/10.1093/icb/icy044.

https://ift.tt/2AtVBB6

Making science meaningful for broad audiences through stories

Synopsis

Science is a search for evidence, but science communication must be a search for meaning. General audiences will only care about science if it is presented in a meaningful context. One of the most effective ways to do this is through storytelling. Stories are integral to all cultures. Studies indicate that stories even help audiences to process and recall new information. Scientists sometimes worry that storytelling will conflate empirical evidence with fabrication. But when telling non-fiction stories, it is a process of recognizing the story elements already present in the subject material and distilling the most concise and compelling account for a target audience. In this paper, I review literature, offer examples, and draw from my experience as a scientist and a communication trainer to explore how storytelling makes science comprehensible and meaningful for general audiences.

https://ift.tt/2n0Xrzw

EUS-guided antegrade intervention for benign biliary diseases in patients with surgically altered anatomy (with videos)

Although balloon enteroscopy-assisted ERCP (BE-ERCP) is effective and safe for benign biliary diseases in patients with surgically altered anatomy (SAA), BE-ERCP is not always successful. Recently, EUS-guided antegrade intervention (EUS-AI) including a 1-stage or 2-stage procedure has been developed for BE-ERCP failure cases. The aim of the present study was to evaluate the outcome of EUS-AI for benign biliary diseases with SAA.

https://ift.tt/2Kjosrh

Radiofrequency ablation compared with argon plasma coagulation after endoscopic resection of high-grade dysplasia or T1 adenocarcinoma in Barrett’s esophagus: a randomized pilot study (BRIDE)

Endoscopic resection (ER) is safe and effective for Barrett's esophagus (BE) containing high-grade dysplasia (HGD) or mucosal adenocarcinoma (T1A); risk of metachronous neoplasia is reduced by ablation of residual BE using radiofrequency ablation (RFA) or argon plasma coagulation (APC). These have not been directly compared. We aimed to recruit up to 100 patients with BE and HGD or T1A confirmed by ER over 1 year in 6 centres in a randomized pilot study.

https://ift.tt/2vuAwR5

Performance Indicators in Colonoscopy after Certification for Independent Practice: Outcomes and Predictors of Competence

Robust real-world performance data of newly independent colonoscopists are lacking. In the United Kingdom, provisional colonoscopy certification (PCC) marks the transition from training to newly independent practice. We aimed to assess changes in key performance indicators (KPIs) such as cecal intubation rate (CIR) in the periods pre- and post-PCC, particularly regarding rates and predictors of trainees exhibiting a drop-in performance (DIP), defined as CIR <90% in the first 50 procedures post-PCC.

https://ift.tt/2LIrx9O

Tumor control probability analysis for single fraction carbon ion radiotherapy of early-stage non-small cell lung cancer

The suitability of the LQ and USC models to accurately forecast the 3-year local control rate of early stage NSCLC after CIRT is investigated in this study. The results suggest that the USC model is more appropriate in predicting the single fraction clinical outcome. However, for the 4, 9 and 18 fractionation schedules, the LQ and USC models predicted comparable local control rates. An USC-based SOBP was then developed, providing a better clinical dose estimate for optimum local control.

https://ift.tt/2LNGR5n

Alteration in cognitive behaviour, brain antioxidant enzyme activity and their gene expression in F1 generation mice, following Cd exposure during the late gestation period: modulation by quercetin

Abstract

We investigated whether in-utero Cd(II) chloride exposure of the dams between 14th to 21st day of gestation affects memory and learning, oxidative stress, antioxidant enzyme activity and their gene expression in brain of the pups in their adulthood. In the Morris water maze, cadmium (Cd) exposure impaired spatial memory which was reversed following co-treatment with quercetin (100 mg/kg). In the passive avoidance paradigm, retention memory was adversely affected but was significantly reversed by co treatment with quercetin (25, 50, 100 mg/kg). The malondialdehyde and catalase (CAT) levels and glutathione-S-transferase (GST) activity were increased significantly in Cd-treated group, but were reversed by quercetin (all doses). The gene expression for CAT and GST in brain tissue of Cd treated animals also increased many folds as compared to the control, and this effect was decreased on co-treatment with quercetin (all doses), thus matching with the respective enzyme activities. Quercetin (25 mg/kg) when co-treated with Cd caused a decrease in GST activity compared to control, which points towards a complex interplay with oxidative free radicals and promoters and transcription factors. Thus, Cd exposure during late gestation causes impaired spatial and retention memory in the next generation which may be due to alteration of activity as well as gene expression of the antioxidant enzymes, CAT and GST. Quercetin may offer some protection of memory impairment probably by modulating these effects.

https://ift.tt/2n4xq2x

The auditory cortex network in the posterior superior temporal area

The superior temporal gyrus (STG) plays a critical role in hearing, speech, and language (Penfield and Jasper 1954) (Campbell 1905) (Hoppe 2008). Previous studies have reported that the primary auditory cortex is located deep within the lateral fissure on a small patch of the transverse Heschl's gyrus (HG), with distinctive cyto- and myelo-architectonic features (Campbell 1905). Penfield et al. reported that auditory sensations were induced by stimulation of a narrow region of the STG that bordered the posterior third of the Sylvian fissure (Penfield and Jasper 1954).

https://ift.tt/2v8kwoE

FASCICULATION INTENSITY AND DISEASE PROGRESSION IN AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive degeneration of upper and lower motor neurons, with resultant muscle weakness and paralysis.

https://ift.tt/2Kj1xwg

MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status: a cohort study

Abstract

Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.

https://ift.tt/2AyX6ho

July 2018 Briefing - Radiology

Here are what the editors at HealthDay consider to be the most important developments in Radiology for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

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Steps Can Be Taken by Doctors to Minimize Risk of Lawsuits

WEDNESDAY, Aug. 1, 2018 -- Targeted steps can be taken to minimize future risks of lawsuits, according to an article published in Physicians Practice. In order to reduce the risks of lawsuits, practices should be mindful of legal obligations and...

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Tamsulosin Does Not Appear to Promote Urinary Stone Passage

WEDNESDAY, Aug. 1, 2018 -- Tamsulosin does not significantly increase the urinary stone passage rate compared with placebo, according to a study published online June 18 in JAMA Internal Medicine. Andrew C. Meltzer, M.D., from the George Washington...

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Telemedicine Cuts Inter-Hospital ICU Transfers of Critically Ill

WEDNESDAY, Aug. 1, 2018 -- Telemedicine is associated with a decrease in inter-hospital intensive care unit (ICU) transfers, according to a study published in the July issue of CHEST. Spyridon Fortis, M.D., from the Iowa City VA Health Care System,...

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Nurse Navigators Can Help to Improve Oncology Care

WEDNESDAY, Aug. 1, 2018 -- Nurse navigators are playing an important role in oncology care at the Montefiore Medical Center in Bronx, N.Y., according to a report published in Managed Healthcare Executive. According to Annmarie Flannery, R.N.,...

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Evidence Exists for Persistence, Transmission of Ebola Virus

WEDNESDAY, Aug. 1, 2018 -- There is evidence for persistence of Ebola virus and transmission from a persistently infected individual, according to case study published online July 23 in The Lancet Infectious Diseases. After a 15-year-old boy tested...

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Protease Inhibitors May Worsen Outcomes for HIV + Heart Failure

WEDNESDAY, Aug. 1, 2018 -- Ritonavir-boosted protease inhibitor (PI) therapy is associated with worse outcomes, including death, in patients with HIV and heart failure, according to a study published in the July 31 issue of the Journal of the...

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Several Invasive Procedures Linked to Infective Endocarditis

WEDNESDAY, Aug. 1, 2018 -- Several invasive medical procedures, including cardiovascular procedures and procedures of the skin and management of wounds, are associated with increased risk of infective endocarditis, according to a study published in...

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Nut Intake Reduces HbA1c Among Adults With T2DM

WEDNESDAY, Aug. 1, 2018 -- Nut intake reduces hemoglobin A1c (HbA1c) among individuals with type 2 diabetes, according to a study published in the August issue of Diabetologia. David J.A. Jenkins, M.D., Ph.D., Sc.D., from the University of Toronto,...

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July 2018 Briefing - Nephrology

Here are what the editors at HealthDay consider to be the most important developments in Nephrology for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

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July 2018 Briefing - Pain Management

Here are what the editors at HealthDay consider to be the most important developments in Pain Management for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...

https://ift.tt/2O2j91z

July 2018 Briefing - Geriatrics

Here are what the editors at HealthDay consider to be the most important developments in Geriatrics for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

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July 2018 Briefing - Critical Care

Here are what the editors at HealthDay consider to be the most important developments in Critical Care for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

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July 2018 Briefing - Orthopedics

Here are what the editors at HealthDay consider to be the most important developments in Orthopedics for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

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July 2018 Briefing - Pediatrics

Here are what the editors at HealthDay consider to be the most important developments in Pediatrics for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

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July 2018 Briefing - Anesthesiology

Here are what the editors at HealthDay consider to be the most important developments in Anesthesiology for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...

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July 2018 Briefing - Urology

Here are what the editors at HealthDay consider to be the most important developments in Urology for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...

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July 2018 Briefing - Emergency Medicine

Here are what the editors at HealthDay consider to be the most important developments in Emergency Medicine for July 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...

https://ift.tt/2LWm12G

Grid-Cell Activity on Linear Tracks Indicates Purely Translational Remapping of 2D Firing Patterns at Movement Turning Points

Grid cells in rodent medial entorhinal cortex are thought to play a critical role for spatial navigation. When the animal is freely moving in an open arena the firing fields of each grid cell tend to form a hexagonal lattice spanning the environment. For movements along a linear track the cells seem to respond differently. They show multiple firing fields that are not periodically arranged and whose shape and position change when the running direction is reversed. In addition, peak firing rates vary widely from field to field. Measured along one running direction only, firing fields are, however, compatible with a slice through a two-dimensional (2D) hexagonal pattern. It is an open question, whether this is also true if leftward and rightward runs are jointly considered. By analyzing data from 15 male Long–Evans rats, we show that a single hexagonal firing pattern explains the linear-track data if translational shifts of the pattern are allowed at the movement turning points. A rotation or scaling of the grid is not required. The agreement is further improved if the peak firing rates of the underlying 2D grid fields can vary from field to field, as suggested by recent studies. These findings have direct consequences for experiments using linear tracks in virtual reality.

SIGNIFICANCE STATEMENT Various types of neurons support spatial navigation. Their response properties are often studied in reduced settings and might change when the animal can freely explore its environment. Grid cells in rodents, for example, exhibit seemingly irregular firing fields when animal movement is restricted to a linear track but highly regular patterns in two-dimensional (2D) arenas. We show that linear-track responses of a cell for both leftward and rightward running directions can be explained as cuts through a single hexagonal pattern if translational remapping is allowed at movement turning points; neither rotations nor scale transformations are needed. These results provide a basis to quantify grid-cell activity in 1D virtual reality and could help to detect and categorize grid cells without experiments in 2D environments.

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A Hierarchy of Time Scales for Discriminating and Classifying the Temporal Shape of Sound in Three Auditory Cortical Fields

Auditory cortex is essential for mammals, including rodents, to detect temporal "shape" cues in the sound envelope but it remains unclear how different cortical fields may contribute to this ability (Lomber and Malhotra, 2008; Threlkeld et al., 2008). Previously, we found that precise spiking patterns provide a potential neural code for temporal shape cues in the sound envelope in the primary auditory (A1), and ventral auditory field (VAF) and caudal suprarhinal auditory field (cSRAF) of the rat (Lee et al., 2016). Here, we extend these findings and characterize the time course of the temporally precise output of auditory cortical neurons in male rats. A pairwise sound discrimination index and a Naive Bayesian classifier are used to determine how these spiking patterns could provide brain signals for behavioral discrimination and classification of sounds. We find response durations and optimal time constants for discriminating sound envelope shape increase in rank order with: A1 < VAF < cSRAF. Accordingly, sustained spiking is more prominent and results in more robust sound discrimination in non-primary cortex versus A1. Spike-timing patterns classify 10 different sound envelope shape sequences and there is a twofold increase in maximal performance when pooling output across the neuron population indicating a robust distributed neural code in all three cortical fields. Together, these results support the idea that temporally precise spiking patterns from primary and non-primary auditory cortical fields provide the necessary signals for animals to discriminate and classify a large range of temporal shapes in the sound envelope.

SIGNIFICANCE STATEMENT Functional hierarchies in the visual cortices support the concept that classification of visual objects requires successive cortical stages of processing including a progressive increase in classical receptive field size. The present study is significant as it supports the idea that a similar progression exists in auditory cortices in the time domain. We demonstrate for the first time that three cortices provide temporal spiking patterns for robust temporal envelope shape discrimination but only the ventral non-primary cortices do so on long time scales. This study raises the possibility that primary and non-primary cortices provide unique temporal spiking patterns and time scales for perception of sound envelope shape.

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Chrna5-Expressing Neurons in the Interpeduncular Nucleus Mediate Aversion Primed by Prior Stimulation or Nicotine Exposure

Genetic studies have shown an association between smoking and variation at the CHRNA5/A3/B4 gene locus encoding the α5, α3, and β4 nicotinic receptor subunits. The α5 receptor has been specifically implicated because smoking-associated haplotypes contain a coding variant in the CHRNA5 gene. The Chrna5/a3/b4 locus is conserved in rodents and the restricted expression of these subunits suggests neural pathways through which the reinforcing and aversive properties of nicotine may be mediated. Here, we show that, in the interpeduncular nucleus (IP), the site of the highest Chrna5 mRNA expression in rodents, electrophysiological responses to nicotinic acetylcholine receptor stimulation are markedly reduced in α5-null mice. IP neurons differ markedly from their upstream ventral medial habenula cholinergic partners, which appear unaltered by loss of α5. To probe the functional role of α5-containing IP neurons, we used BAC recombineering to generate transgenic mice expressing Cre-recombinase from the Chrna5 locus. Reporter expression driven by Chrna5^Cre demonstrates that transcription of Chrna5 is regulated independently from the Chrna3/b4 genes transcribed on the opposite strand. Chrna5-expressing IP neurons are GABAergic and project to distant targets in the mesopontine raphe and tegmentum rather than forming local circuits. Optogenetic stimulation of Chrna5-expressing IP neurons failed to elicit physical manifestations of withdrawal. However, after recent prior stimulation or exposure to nicotine, IP stimulation becomes aversive. These results using mice of both sexes support the idea that the risk allele of CHRNA5 may increase the drive to smoke via loss of IP-mediated nicotine aversion.

SIGNIFICANCE STATEMENT Understanding the receptors and neural pathways underlying the reinforcing and aversive effects of nicotine may suggest new treatments for tobacco addiction. Part of the individual variability in smoking is associated with specific forms of the α5 nicotinic receptor subunit gene. Here, we show that deletion of the α5 subunit in mice markedly reduces the cellular response to nicotine and acetylcholine in the interpeduncular nucleus (IP). Stimulation of α5-expressing IP neurons using optogenetics is aversive, but this effect requires priming by recent prior stimulation or exposure to nicotine. These results support the idea that the smoking-associated variant of the α5 gene may increase the drive to smoke via loss of IP-mediated nicotine aversion.

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Challenges to Body Fluid Homeostasis Differentially Recruit Phasic Dopamine Signaling in a Taste-Selective Manner

The internal environment of an organism must remain stable to ensure optimal performance and ultimately survival. The generation of motivated behaviors is an adaptive mechanism for defending homeostasis. Although physiological state modulates motivated behaviors, the influence of physiological state on phasic dopamine signaling, an underlying neurobiological substrate of reward-driven behavior, is underexplored. Here, we use sodium depletion and water restriction, manipulations of body fluid homeostasis, to determine the flexibility and specificity of dopamine responses. Changes in dopamine concentration were measured using fast-scan cyclic voltammetry in the nucleus accumbens shell of male rats in response to intraoral infusions of fluids that either satisfied or did not satisfy homeostatic need. Increases in dopamine concentration during intraoral infusions were observed only under conditions of physiological deficit. Furthermore, dopamine increases were selective and limited to those that satisfied the need state of the animal. Thus, dopamine neurons track fluid balance and respond to salt and water stimuli in a state- and taste-dependent manner. Using Fluoro-Gold tracing and immunohistochemistry for c-Fos and Foxp2, a marker of sodium-deprivation responsive neurons, we revealed brainstem populations of neurons that are activated by sodium depletion and project directly to the ventral tegmental area. The identified projections may modulate dopamine neuron excitability and consequently the state-specific dopamine release observed in our experiments. This work illustrates the impact of physiological state on mesolimbic dopamine signaling and a potential circuit by which homeostatic disruptions are communicated to mesolimbic circuitry to drive the selective reinforcement of biologically-required stimuli under conditions of physiological need.

SIGNIFICANCE STATEMENT Motivated behaviors arise during physiological need and are highly selective for homeostasis-restoring stimuli. Although phasic dopamine signaling has been shown to contribute to the generation of motivated behaviors, the state and stimulus specificity of phasic dopamine signaling is less clear. These studies use thirst and sodium appetite to show that dopamine neurons dynamically track body fluid homeostasis and respond to water and salt stimuli in a state- and taste-dependent manner. We also identify hindbrain sodium deprivation-responsive neurons that project directly to the ventral tegmental area, where dopamine neuron cell bodies reside. This work demonstrates command of homeostasis over dopamine signaling and proposes a circuit by which physiological need drives motivated behavior by state- and taste-selective recruitment of phasic dopamine signaling.

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Binocular Neuronal Processing of Object Motion in an Arthropod

Animals use binocular information to guide many behaviors. In highly visual arthropods, complex binocular computations involved in processing panoramic optic flow generated during self-motion occur in the optic neuropils. However, the extent to which binocular processing of object motion occurs in these neuropils remains unknown. We investigated this in a crab, where the distance between the eyes and the extensive overlapping of their visual fields advocate for the use of binocular processing. By performing in vivo intracellular recordings from the lobula (third optic neuropil) of male crabs, we assessed responses of object-motion-sensitive neurons to ipsilateral or contralateral moving objects under binocular and monocular conditions. Most recorded neurons responded to stimuli seen independently with either eye, proving that each lobula receives profuse visual information from both eyes. The contribution of each eye to the binocular response varies among neurons, from those receiving comparable inputs from both eyes to those with mainly ipsilateral or contralateral components, some including contralateral inhibition. Electrophysiological profiles indicated that a similar number of neurons were recorded from their input or their output side. In monocular conditions, the first group showed shorter response delays to ipsilateral than to contralateral stimulation, whereas the second group showed the opposite. These results fit well with neurons conveying centripetal and centrifugal information from and toward the lobula, respectively. Intracellular and massive stainings provided anatomical support for this and for direct connections between the two lobulae, but simultaneous recordings failed to reveal such connections. Simplified model circuits of interocular connections are discussed.

SIGNIFICANCE STATEMENT Most active animals became equipped with two eyes, which contributes to functions like depth perception, objects spatial location, and motion processing, all used for guiding behaviors. In visually active arthropods, binocular neural processing of the panoramic optic flow generated during self-motion happens already in the optic neuropils. However, whether binocular processing of single-object motion occurs in these neuropils remained unknown. We investigated this in a crab, where motion-sensitive neurons from the lobula can be recorded in the intact animal. Here we demonstrate that different classes of neurons from the lobula compute binocular information. Our results provide new insight into where and how the visual information acquired by the two eyes is first combined in the brain of an arthropod.

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Vasoactive Intestinal Polypeptide-Immunoreactive Interneurons within Circuits of the Mouse Basolateral Amygdala

In cortical structures, principal cell activity is tightly regulated by different GABAergic interneurons (INs). Among these INs are vasoactive intestinal polypeptide-expressing (VIP+) INs, which innervate preferentially other INs, providing a structural basis for temporal disinhibition of principal cells. However, relatively little is known about VIP+ INs in the amygdaloid basolateral complex (BLA). In this study, we report that VIP+ INs have a variable density in the distinct subdivisions of the mouse BLA. Based on different anatomical, neurochemical, and electrophysiological criteria, VIP+ INs could be identified as IN-selective INs (IS-INs) and basket cells expressing CB1 cannabinoid receptors. Whole-cell recordings of VIP+ IS-INs revealed three different spiking patterns, none of which was associated with the expression of calretinin. Genetic targeting combined with optogenetics and in vitro recordings enabled us to identify several types of BLA INs innervated by VIP+ INs, including other IS-INs, basket and neurogliaform cells. Moreover, light stimulation of VIP+ basket cell axon terminals, characterized by CB1 sensitivity, evoked IPSPs in ~20% of principal neurons. Finally, we show that VIP+ INs receive a dense innervation from both GABAergic inputs (although only 10% from other VIP+ INs) and distinct glutamatergic inputs, identified by their expression of different vesicular glutamate transporters.

In conclusion, our study provides a wide-range analysis of single-cell properties of VIP+ INs in the mouse BLA and of their intrinsic and extrinsic connectivity. Our results reinforce the evidence that VIP+ INs are structurally and functionally heterogeneous and that this heterogeneity could mediate different roles in amygdala-dependent functions.

SIGNIFICANCE STATEMENT We provide the first comprehensive analysis of the distribution of vasoactive intestinal polypeptide-expressing (VIP+) interneurons (INs) across the entire mouse amygdaloid basolateral complex (BLA), as well as of their morphological and physiological properties. VIP+ INs in the neocortex preferentially target other INs to form a disinhibitory network that facilitates principal cell firing. Our study is the first to demonstrate the presence of such a disinhibitory circuitry in the BLA. We observed structural and functional heterogeneity of these INs and characterized their input/output connectivity. We also identified several types of BLA INs that, when inhibited, may provide a temporal window for principal cell firing and facilitate associative plasticity, e.g., in fear learning.

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Neural Processing of Acoustic and Electric Interaural Time Differences in Normal-Hearing Gerbils

Bilateral cochlear implants (CIs) provide benefits for speech perception in noise and directional hearing, but users typically show poor sensitivity to interaural time differences (ITDs). Possible explanations for this deficit are deafness-induced degradations in neural ITD sensitivity, between-ear mismatches in electrode positions or activation sites, or differences in binaural brain circuits activated by electric versus acoustic stimulation. To identify potential limitations of electric ITD coding in the normal-hearing system, responses of single neurons in the dorsal nucleus of the lateral lemniscus and in the inferior colliculus to ITDs of electric (biphasic pulses) and acoustic (noise, clicks, chirps, and tones) stimuli were recorded in normal-hearing gerbils of either sex. To maintain acoustic sensitivity, electric stimuli were delivered to the round window. ITD tuning metrics (e.g., best ITD) and ITD discrimination thresholds for electric versus transient acoustic stimuli (clicks, chirps) obtained from the same neurons were not significantly correlated. Across populations of neurons with similar characteristic frequencies, however, ITD tuning metrics and ITD discrimination thresholds were similar for electric and acoustic stimuli and largely independent of the spectrotemporal properties of the acoustic stimuli when measured in the central range of ITDs. The similarity of acoustic and electric ITD coding on the population level in animals with normal hearing experience suggests that poorer ITD sensitivity in bilateral CI users compared with normal-hearing listeners is likely due to deprivation-induced changes in neural ITD coding rather than to differences in the binaural brain circuits involved in the processing of electric and acoustic ITDs.

SIGNIFICANCE STATEMENT Small differences in the arrival time of sound at the two ears (interaural time differences, ITDs) provide important cues for speech understanding in noise and directional hearing. Deaf subjects with bilateral cochlear implants obtain only little benefit from ITDs. It is unclear whether these limitations are due to between-ear mismatches in activation sites, differences in binaural brain circuits activated by electric versus acoustic stimulation, or deafness-induced degradations in neural ITD processing. This study is the first to directly compare electric and acoustic ITD coding in neurons of known characteristic frequencies. In animals with normal hearing, populations of auditory brainstem and midbrain neurons demonstrate general similarities in electric and acoustic ITD coding, suggesting similar underlying central auditory processing mechanisms.

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Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein

The C terminus of HSC70-interacting protein (CHIP, STUB1) is a ubiquitously expressed cytosolic E3-ubiquitin ligase. CHIP-deficient mice exhibit cardiovascular stress and motor dysfunction before premature death. This phenotype is more consistent with animal models in which master regulators of autophagy are affected rather than with the mild phenotype of classic E3-ubiquitin ligase mutants. The cellular and biochemical events that contribute to neurodegeneration and premature aging in CHIP KO models remain poorly understood. Electron and fluorescent microscopy demonstrates that CHIP deficiency is associated with greater numbers of mitochondria, but these organelles are swollen and misshapen. Acute bioenergetic stress triggers CHIP induction and relocalization to mitochondria, where it plays a role in the removal of damaged organelles. This mitochondrial clearance is required for protection following low-level bioenergetic stress in neurons. CHIP expression overlaps with stabilization of the redox stress sensor PTEN-inducible kinase 1 (PINK1) and is associated with increased LC3-mediated mitophagy. Introducing human promoter-driven vectors with mutations in either the E3 ligase or tetracopeptide repeat domains of CHIP in primary neurons derived from CHIP-null animals enhances CHIP accumulation at mitochondria. Exposure to autophagy inhibitors suggests that the increase in mitochondrial CHIP is likely due to diminished clearance of these CHIP-tagged organelles. Proteomic analysis of WT and CHIP KO mouse brains (four male, four female per genotype) reveals proteins essential for maintaining energetic, redox, and mitochondrial homeostasis undergo significant genotype-dependent expression changes. Together, these data support the use of CHIP-deficient animals as a predictive model of age-related degeneration with selective neuronal proteotoxicity and mitochondrial failure.

SIGNIFICANCE STATEMENT Mitochondria are recognized as central determinants of neuronal function and survival. We demonstrate that C terminus of HSC70-Interacting Protein (CHIP) is critical for neuronal responses to stress. CHIP upregulation and localization to mitochondria is required for mitochondrial autophagy (mitophagy). Unlike other disease-associated E3 ligases such as Parkin and Mahogunin, CHIP controls homeostatic and stress-induced removal of mitochondria. Although CHIP deletion results in greater numbers of mitochondria, these organelles have distorted inner membranes without clear cristae. Neuronal cultures derived from animals lacking CHIP are more vulnerable to acute injuries and transient loss of CHIP renders neurons incapable of mounting a protective response after low-level stress. Together, these data suggest that CHIP is an essential regulator of mitochondrial number, cell signaling, and survival.

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Hypoglycemic events: Can you leave them be?

A review of hypoglycemia treat and release protocol recommendations

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Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats

Here we describe a detailed protocol for invasive measurements of hemodynamic parameters including portal pressure, splanchnic blood flow, and systemic hemodynamics in order to characterize the portal hypertensive syndrome in rats.

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How infectious is the hepatitis B virus? Readings from the occult

Occult HBV infection (OBI) is defined as the presence of the virus in the liver, with detectable or undetectable HBV DNA in the serum of individuals testing hepatitis B surface antigen (HBsAg) undetectable in blood, using the most sensitive commercial assays.1 OBI can be either seropositive (anti-HBc and/or anti-HBs positive) or seronegative (anti-HBc and anti-HBs negative), and when detectable, the amount of HBV DNA in the serum is usually very low (<200 IU/mL). OBI is a relatively new aspect of the natural history of HBV infection that has now been observed worldwide. Its prevalence varies according to the levels of HBV endemicity and viral genotype.2 The identification of OBI in asymptomatic blood donors and attempts by blood transfusion services worldwide to eliminate the 'window period' of HBV transmissibility, has prompted the introduction in many countries of nucleic acid testing (NAT) in order to detect HBV infection in...

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Characteristics of Headache and Relationship to Acute Mountain Sickness at 4559 Meters

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2KhOeMD

Frostbite Injuries in the Austrian Alps: A Retrospective 11-Year National Registry Study

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2OB6Hak

Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material

Nucleic acid degradation in archival tissue, tumor heterogeneity, and a lack of fresh frozen tissue specimens can negatively impact cancer diagnostic services in pathology laboratories worldwide. This manuscript describes the optimization of a panel of biomarkers using a multiplex magnetic bead assay to classify breast cancers.

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How do people with dementia use the ambulance service? A retrospective study in England: the HOMEWARD project

Objectives

An increasing number of older people are calling ambulances and presenting to accident and emergency departments. The presence of comorbidities and dementia can make managing these patients more challenging and hospital admission more likely, resulting in poorer outcomes for patients. However, we do not know how many of these patients are conveyed to hospital by ambulance. This study aims to determine: how often ambulances are called to older people; how often comorbidities including dementia are recorded; the reason for the call; provisional diagnosis; the amount of time ambulance clinicians spend on scene; the frequency with which these patients are transported to hospital.

Methods

We conducted a retrospective cross-sectional study of ambulance patient care records (PCRs) from calls to patients aged 65 years and over. Data were collected from two ambulance services in England during 24 or 48 hours periods in January 2017 and July 2017. The records were examined by two researchers using a standard template and the data were extracted from 3037 PCRs using a coding structure.

Results

Results were reported as percentages and means with 95% CIs. Dementia was recorded in 421 (13.9%) of PCRs. Patients with dementia were significantly less likely to be conveyed to hospital following an emergency call than those without dementia. The call cycle times were similar for patients regardless of whether or not they had dementia. Calls to people with dementia were more likely to be due to injury following a fall. In the overall sample, one or more comorbidities were reported on the PCR in over 80% of cases.

Conclusion

Rates of hospital conveyance for older people may be related to comorbidities, frailty and complex needs, rather than dementia. Further research is needed to understand the way in which ambulance clinicians make conveyance decisions at scene.

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Outcomes of patients with systolic heart failure presenting with sepsis to the emergency department of a tertiary hospital: a retrospective chart review study from Lebanon

Objectives

Patients with congestive heart failure (CHF) may be at a higher risk of mortality from sepsis than patients without CHF due to insufficient cardiovascular reserves during systemic infections. The aim of this study is to compare sepsis-related mortality between CHF and no CHF in patients presenting to a tertiary medical centre.

Design

A single-centre, retrospective, cohort study.

Setting

Conducted in an academic emergency department (ED) between January 2010 and January 2015. Patients' charts were queried via the hospital's electronic system. Patients with a diagnosis of sepsis were included. Descriptive analysis was performed on the demographics, characteristics and outcomes of patients with sepsis of the study population.

Participants

A total of 174 patients, of which 87 (50%) were patients with CHF.

Primary and secondary outcomes

The primary outcome of the study was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and differences in interventions between the two groups.

Results

Patients with CHF had a higher in-hospital mortality (57.5% vs 34.5%). Patients with sepsis and CHF had higher odds of death compared with the control population (OR 2.45; 95% CI 1.22 to 4.88). Secondary analyses showed that patients with CHF had lower instances of bacteraemia on presentation to the ED (31.8% vs 46.4%). They had less intravenous fluid requirements in first 24 hours (2.75±2.28 L vs 3.67±2.82 L, p =0.038), had a higher rate of intubation in the ED (24.2% vs 10.6%, p=0.025) and required more dobutamine in the first 24 hours (16.1% vs 1.1%, p<0.001). ED length of stay was found to be lower in patients with CHF (15.12±24.45 hours vs 18.17±26.13 hours, p=0.418) and they were more likely to be admitted to the ICU (59.8% vs 48.8%, p=0.149).

Conclusion

Patients with sepsis and CHF experienced an increased hospital mortality compared with patients without CHF.

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Defining and measuring health equity effects in research on task shifting interventions in high-income countries: a systematic review protocol

Introduction

Task shifting interventions are intended to both deliver clinically effective treatments to reduce disease burden and address health inequities or population vulnerability. Little is known about how health equity and population vulnerability are defined and measured in research focused on task shifting. This systematic review will address the following questions: Among task shifting interventions in high-income settings that have been studied using randomised controlled trials or variants, how are health inequity or population vulnerability identified and defined? What methods and indicators are used to describe, characterise and measure the population's baseline status and the intervention's impacts on inequity and vulnerability?

Methods and analysis

Studies were identified through database searches (MEDLINE, Embase, CINAHL, PsycINFO and Web of Science). Eligible studies will be randomised controlled trials published since 2004, conducted in high-income countries, concerning task shifting interventions to treat any disease, in any population that may face health disadvantage as defined by the PROGRESS-Plus framework (place of residence, race/ethnicity/culture/language, occupation, gender/sex, religion, social capital, socioeconomic position, age, disability, sexual orientation, other vulnerable groups). We will conduct independent and duplicate title and abstract screening, then identify related papers from the same programme of research through further database and manual searching. From each programme of research, we will extract study details, and definitions and measures of health equity or population vulnerability based on the PROGRESS-Plus framework. Two investigators will assess the quality of reporting and measurement related to health equity and vulnerability using a scale developed for this study. A narrative synthesis will highlight similarities and differences between the gathered studies and offer critical analyses and implications.

Ethics and dissemination

This review does not involve primary data collection, does not constitute research on human subjects and is not subject to additional institutional ethics review or informed consent procedures. Dissemination will include open-access peer-reviewed publication and academic conference presentations.

PROSPERO Registration Number CRD42017049959.

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