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Background: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively., Objective: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers., Design: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440)., Setting: 31 liver disease and transplant centers in the United States., Patients: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070)., Measurements: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013)., Results: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period., Limitations: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers., Conclusion: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study., Primary Funding Source: National Institutes of Health.

Background: Intrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance., Methods: We use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones., Results: We found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAF(V600E) and ERK inhibition as clonally- derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell- ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and β1 integrin survived drug treatment., Conclusions: These data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance.

Background and Aims: Acetaminophen (APAP) is the most common cause of acute liver failure (ALF) in the west. It is unknown if APAP overdose in combination with diphenhydramine or opioids confers a different clinical presentation or prognosis. Study objectives were to compare (1) baseline patient characteristics; (2) initial clinical presentation; and (3) clinical outcomes among patients with ALF due to APAP alone or in combination with diphenhydramine or opioids., Methods: We analyzed 666 cases of APAP-related liver failure using the Acute Liver Failure Study Group database from 1998 to 2012. The database contains detailed demographic, laboratory, and clinical outcome data, including hemodialysis, transplantation, and death and in-hospital complications such as arrhythmia and infection., Results: The final sample included 666 patients with APAP liver injury. A total 30.3% of patients were overdosed with APAP alone, 14.1% with APAP/diphenhydramine, and 56.6% with APAP/opioids. Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose (all P<0.0001). On presentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone (P=0.001) The APAP/diphenhydramine group presented with the highest serum aminotransferase levels, no differences in laboratory values were noted at 3 days postenrollment. No significant differences were observed in clinical outcomes among the groups., Conclusions: Most patients with APAP-induced ALF were taking APAP combination products. There were significant differences in patient characteristics and clinical presentation based on the type of product ingested, however, there were no differences noted in delayed hepatotoxicity or clinical outcomes.

Background/aim: Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant., Methods: Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011)., Results: Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all)., Conclusion: OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.

Dysregulation of the EGFR signaling axis enhances bone metastases in many solid cancers. However, the relevant downstream effector signals in this axis are unclear. miR-1 was recently shown to function as a tumor suppressor in prostate cancer cells, where its expression correlated with reduced metastatic potential. In this study, we demonstrated a role for EGFR translocation in regulating transcription of miR-1-1, which directly targets expression of TWIST1. Consistent with these findings, we observed decreased miR-1 levels that correlated with enhanced expression of activated EGFR and TWIST1 in a cohort of human prostate cancer specimens and additional datasets. Our findings support a model in which nuclear EGFR acts as a transcriptional repressor to constrain the tumor-suppressive role of miR-1 and sustain oncogenic activation of TWIST1, thereby leading to accelerated bone metastasis., (©2015 American Association for Cancer Research.)

Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers., (©2014 American Association for Cancer Research.)

Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factor β (TGFβ)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFβ-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of genotype 1-infected patients. Antiviral agents specifically targeting either the HCV protease or polymerase, or other targets, are now in clinical development. In general, direct antivirals are potent inhibitors of HCV replication and can result in rapid declines in serum HCV RNA levels. Yet these agents drive selection pressure for mutant viruses that can reduce susceptibility to any given drug. Using pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with direct antivirals can suppress viral breakthrough and increase the likelihood of sustained virologic response. Direct antivirals also result in adverse events in a proportion of patients, adding to concerns of tolerability that exist with PEG-IFN and RBV. Direct antivirals are very likely to become an integral part of treatment within the next decade, and already their use in clinical trials has raised important issues related to duration of treatment, early stopping rules, retreatment of previously treated patients, and how or when direct antivirals should be combined. Here, we provide current information regarding the effectiveness of direct antivirals in treating chronic HCV infection and discuss the key questions and challenges now facing the field.

The purpose of this qualitative study was to explore staff nurses' perceptions of how turbulence in the internal environment affected their ability to provide patient care. The themes that emerged from the data point toward multiple factors impinging on a staff nurse's ability to provide quality care in today's healthcare environment. The authors discuss these factors, the consequences for staff nurses, patients, and the organization, and the implications for nursing administrators and their colleagues in hospital administration.

The effect of acute hyperinsulinemia on plasma cholesteryl ester (CE) transfer protein (CETP) activity was determined in 11 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 10 healthy subjects. Plasma CETP activity was reduced significantly in NIDDM patients (-37 +/- 59 nmol/mL/h, P < .05) but not in healthy subjects (-7 +/- 37 nmol/mL/h) during insulin infusion. Saline infusion did not alter plasma CETP activity significantly. The change in plasma CETP activity was correlated significantly with the baseline plasma triglyceride (TG) concentration (r = -.523, n = 21, P = .01) and marginally with the concomitant decrease in these levels with acute hyperinsulinemia (r = .413, n = 21, P = .06) in NIDDM patients and healthy subjects combined. These data indicate that acute hyperinsulinemia reduces plasma CETP activity and probably plasma CETP concentration in NIDDM patients, and suggest coordinated regulation of CETP levels and TG metabolism by insulin.

Plasma newly synthesised cholesteryl ester transfer (NCET) rates from high density lipoproteins (HDL) to very low density lipoproteins (VLDL) and low density lipoproteins lipoproteins (LDL) were measured in 26 patients with non-insulin dependent diabetes mellitus (NIDDM), 26 healthy subjects with closely matching plasma triglyceride (TG) levels and 10 normolipidaemic healthy individuals. In addition, insulin mediated glucose uptake was measured in the NIDDM patients and the normolipidaemic subjects. Rates of NCET were significantly (P < 0.05) elevated in NIDDM patients compared with healthy normolipidaemic individuals but were similar to rates in healthy subjects with closely matching TG levels. In all groups of subjects plasma NCET was significantly (P < 0.001) correlated with plasma TG concentration. In NIDDM patients correlations between NCET and plasma glucose (r = 0.489, P = 0.011) independently of plasma TG levels, and glycated haemoglobin levels (r = 0.430, P = 0.028) were also recorded. Insulin mediated glucose uptake was unrelated to plasma NCET rates in the study. These data suggest that in NIDDM patients under good diabetic control elevated plasma NCET rates are mainly due to hypertriglyceridaemia and a specific and possibly stimulatory effect of diabetes on these rates may be seen only in patients with poorly controlled diabetes.

The effect of acute hyperinsulinemia on plasma lipoprotein a [Lp(a)] concentration in 25 patients with non-insulin dependent diabetes mellitus (NIDDM) and in 10 healthy subjects was examined. Insulin was infused into the subjects for 2 hours while baseline plasma glucose concentrations were maintained. Plasma Lp(a) levels showed a small but significant mean (+/- SD) increase in NIDDM patients (12 +/- 26 U/l, p < 0.01) but did not vary significantly in healthy subjects (3 +/- 15 U/l) when insulin was infused. There was considerable individual variation (-35 to 98 U/l) in the response of Lp(a) to acute hyperinsulinemia and the response was correlated significantly with baseline Lp(a) levels (r = 0.399, p < 0.05). These data suggest that acute hyperinsulinemia at constant baseline glucose levels may raise plasma Lp(a) levels in NIDDM patients more particularly in those with high initial Lp(a) concentrations.

This is the fourth survey of physician clinical-nutrition training programs. As in previous reports, current fellowship training programs were identified, descriptive information obtained, and program content surveyed. In addition, a questionnaire developed by the American Board of Nutrition Committee on Fellowship Training Programs was used to determine the degree of emphasis given to content in the areas of basic nutrition science, clinical applications, and research training. Among the 38 programs identified, uniform ratings of importance were found in all major topic areas. There was also uniformity in most subtopics, with minor exceptions. As expected, in the area of nutrition in the life cycle, pediatric training programs emphasized infancy and childhood whereas medical-surgical programs emphasized adulthood and aging. Alcoholism was emphasized in medical-surgical training programs whereas cystic fibrosis and inborn errors of metabolism were emphasized in pediatric programs. Nutrition in burn patients received minor emphasis in all programs. The overall uniformity of curricular content in training programs confirms the contention that clinical nutrition has a defined clinical scope and should be considered for establishment as a recognized subspecialty in American medicine.

The purpose of this study was to identify priorities for nursing research in a naval hospital using the Delphi technique. A general objective was to provide empirically based information to guide the development of a nursing research program at a regional medical treatment facility. Via a three-round Delphi survey, priority research questions were identified for the nursing department of a naval regional medical treatment facility. A serendipitous result was the identification of nursing research priorities within a deployed naval fleet hospital.

The current medical and dental curricula at Tufts were evaluated to ascertain the breadth and depth of their nutrition programs. The program, which both schools plan to initiate, to enhance the level of nutrition education involves (1) development of nutrition units for the first and second year, (2) expansion of required nutrition courses in the second year, (3) diet lunches in the third year introducing the role of nutrition in the clinical setting, and (4) nutrition rounds in the fourth year. A combined medical-dental seminar will be presented each year. At the end of the five-year funding period, it is anticipated that a manual will be available to all medical and dental schools that includes (1) nutrition units, (2) methods of dietary assessment in medical-dental practices, (3) nutrition interaction for the prevention of chronic disease in medical-dental practices, and (4) nutrition support for chronic disease and cancer, and case studies on nutrition and disease. The success of this program will be evaluated on the basis of goals and a national nutritional literacy exam.

Tuberous sclerosis (epiloia, Bourneville-Pringle syndrome) is an inherited disease with an autosomal pattern. Both sexes are affected equally with varied expression in successive generations. Two cases of this unusual disorder in siblings are reported. They illustrate heredofamilial nature, dissimilar expression, mutations, and oral manifestations.

Recent research has shown that the actual capability of physical medicine and rehabilitation units to provide oral health services is less than the need as perceived by rehabilitation administrators. Three cases have been selected to illustrate the nature and diversity of health benefits that can be provided by a complete oral health service which focuses on rehabilitation patients. The advantages of offering a comprehensive oral health service include not only improvement of the oral health of the patient but also often directly aids the patients' achievement of overall rehabilitation goals. Furthermore, by synergistic interaction with the other rehabilitation disciplines, an oral health service can appreciably enhance the quality and the scope of the rehabilitation program itself. Additionally, a new adaptive device for oral grasping, designed for use by patients who lack the use of their upper extremities, is illustrated. The device is intended to provide the patient with a range of functions including recreational participation in board games as well as vocational activities which require the lifting or grasping of objects.