Citations

Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3′-untranslated region (UTR) but not 5′-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3′-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways.

AbstractBackgroundEarly life events have been found to be associated with irritable bowel syndrome (IBS) suggesting a role in development of functional disorders. The study aim was to identify potential perinatal risk factors for adult IBS.MethodsUtilizing a population‐based nested case–control design, cases who met modified Rome III criteria for IBS and age‐ and‐gender matched controls were identified using responses from prior mailed surveys to a random sample of Olmsted County residents. Medical records of eligible respondents were reviewed for perinatal events of interest. The association of early life events with subsequent case status was assessed using conditional logistic regression.Key ResultsOf 3 417 respondents, 513 were born in Olmsted County and 108 met criteria for IBS. Due to missing records, 89 pairs were included in the final analyses. Logistic regression revealed only birth weight as a predictor of IBS. Lower birth weight increased the odds for IBS (OR = 1.54 [95% CI = (1.12, 2.08), p = 0.008]). Median birth weight was 3.35 kg (range: 1.96–5.24) and 3.57 kg (range: 2.18–4.59) for cases and controls, respectively. Maternal age, delivery method, and antibiotic exposure were not associated with IBS status but this study was only powered to detect large odds ratios.Conclusions and InferencesLower birth weight was observed as a risk factor for IBS. It is not clear if in utero developmental delays directly lead to IBS or if low birth weight is a prospective marker for subsequent early life problems leading to IBS.

ABSTRACT Introduction Male hypogonadism is a common condition, with an increasing body of literature on diagnosis, implications, and management. Given the significant variability in testosterone (T) from a physiologic and assay perspective, a thorough understanding of factors affecting T values and study methodology is essential to interpret reported study outcomes appropriately. However, despite the large number of publications on T, there are no reference materials consolidating all relevant and potentially confounding factors necessary to interpret T studies appropriately. Aims To create a resource document that reviews sources of T variability, free vs total T, assay techniques and questionnaires, and study methodology relevant to interpreting outcomes. Methods A PubMed search was performed of all the T literature published on T variability, assay techniques, and T-specific questionnaires. Results were summarized in the context of their impact on interpreting T literature outcomes and methodology. Main Outcome Measures Effect of various factors on T variability and their relevance to study methodology and outcomes. Results Several factors affect measured T levels, including aging, circadian rhythms, geography, genetics, lifestyle choices, comorbid conditions, and intraindividual daily variability. The utility of free T over total T is debatable and must be compared using appropriate threshold levels. Among various assay techniques, mass spectrometry and equilibrium dialysis are gold standards. Calculated empirical estimates of free T also are commonly used and accepted. Hypogonadism-specific questionnaires have limited utility in screening for hypogonadism, and their role as objective end points for quantifying symptoms remains unclear. Numerous aspects of study methodology can directly or indirectly affect reported outcomes, including design (randomized, prospective, retrospective), duration, populations studied (age, comorbid conditions), low T threshold, therapeutic agent used, objective measurements and end points selected, and statistical interpretation. Conclusion Critical appraisal of the T literature requires an understanding of numerous factors resulting in T variability, study design and methodology, and limitations of assay techniques and objective measurement scales.

Purpose To examine medical student attitudes toward cost-conscious care and whether regional health care intensity is associated with reported exposure to physician role-modeling behaviors related to cost-conscious care. Method Students at 10 U.S. medical schools were surveyed in 2015. Thirty-five items assessed attitudes toward, perceived barriers to and consequences of, and observed physician role-modeling behaviors related to cost-conscious care (using scales for cost-conscious and potentially wasteful behaviors; Cronbach alphas of 0.82 and 0.81, respectively). Regional health care intensity was measured using Dartmouth Atlas End-of-Life Chronic Illness Care data: ratio of physician visits per decedent compared with the U.S. average, ratio of specialty to primary care physician visits per decedent, and hospital care intensity index. Results Of 5,992 students invited, 3,395 (57%) responded. Ninety percent (2,640/2,932) agreed physicians have a responsibility to contain costs. However, 48% (1,1416/2,960) thought ordering a test is easier than explaining why it is unnecessary, and 58% (1,685/2,928) agreed ordering fewer tests will increase the risk of malpractice litigation. In adjusted linear regression analyses, students in higher-health-care-intensity regions reported observing significantly fewer cost-conscious role-modeling behaviors: For each one-unit increase in the three health care intensity measures, scores on the 21-point cost-conscious role-modeling scale decreased by 4.4 (SE 0.7), 3.2 (0.6), and 3.9 (0.6) points, respectively (all P < .001). Conclusions Medical students endorse barriers to cost-conscious care and encounter conflicting role-modeling behaviors, which are related to regional health care intensity. Enhancing role modeling in the learning environment may help prepare future physicians to address health care costs.

IntroductionHyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined.MethodsRetrospective review of our institutional experience with HILP for MCC was conducted (2009–2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria.ResultsFour patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow‐up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69–78] years and 56% were men. Of the patients with reported follow‐up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local–regional recurrence and six distant metastases, all within 6 months. Overall median follow‐up time was 15 [7–36] months.ConclusionAmong a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco‐regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187–192. © 2016 Wiley Periodicals, Inc.

SummaryInfluenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age‐related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post‐vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses – haemagglutination inhibition (HAI) assay, virus neutralizing antibody (VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B‐cell ELISPOT results. Increased expression of HLA‐DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers (HLA‐DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals.

Abstract Purpose: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472–9. ©2016 AACR.