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Na+/H+exchanger 3 (NHE3) provides one of the major Na+absorptive pathways of the intestine and kidney in mammals, and recent studies of aquatic vertebrates (teleosts and elasmobranchs) have demonstrated that NHE3 is expressed in the gill and plays important roles in ion and acid-base regulation. To understand the role of NHE3 in elasmobranch osmoregulatory organs, we analyzed renal and intestinal expressions and localizations of NHE3 in a marine elasmobranch, Japanese banded houndshark ( Triakis scyllium). mRNA for Triakis NHE3 was most highly expressed in the gill, kidney, spiral intestine, and rectum. The kidney and intestine expressed a transcriptional isoform of NHE3 (NHE3k/i), which has a different amino terminus compared with that of NHE3 isolated from the gill (NHE3g), suggesting that NHE3k/i and NHE3g arise from a single gene by alternative promoter usage. Immunohistochemical analyses of the Triakis kidney demonstrated that NHE3k/i is expressed in the apical membrane of a part of the proximal and late distal tubules in the sinus zone. In the bundle zone of the kidney, NHE3k/i was expressed in the apical membrane of the early distal tubules known as the diluting segment. In the spiral intestine and rectum, NHE3k/i was localized toward the apical membrane of the epithelial cells. The transcriptional levels of NHE3k/i were increased in the kidney when Triakis was acclimated in 130% seawater, whereas those in the spiral intestine were increased in fish acclimated in diluted seawater. These results suggest that NHE3 is involved in renal Na+reabsorption, urine acidification, and intestinal Na+absorption in elasmobranchs.

Background— To assess the prevalence, determinants, and prognosis value of right ventricular (RV) ejection fraction (EF) impairment in organic mitral regurgitation. Methods and Results— Two hundred eight patients (62±12 years, 138 males) with chronic organic mitral regurgitation referred to surgery underwent an echocardiography and biventricular radionuclide angiography with regional function assessment. Mean RV EF was 40.4±10.2%, ranging from 10% to 65%. RV EF was severely impaired (≤35%) in 63 patients (30%), and biventricular impairment (left ventricular EF<60% and RV EF≤35%) was found in 34 patients (16%). Pathophysiologic correlates of RV EF were left ventricular septal function (β=0.42, P <0.0001), left ventricular end-diastolic diameter index (β=−0.22, P =0.002), and pulmonary artery systolic pressure (β=−0.14, P =0.047). Mitral effective regurgitant orifice size (n=84) influenced RV EF (β=−0.28, P =0.012). In 68 patients examined after surgery, RV EF increased strongly (27.5±4.3–37.9±7.3, P <0.0001) in patients with depressed RV EF, whereas it did not change in others ( P =0.91). RV EF ≤35% impaired 10-year cardiovascular survival (71.6±8.4% versus 89.8±3.7%, P =0.037). Biventricular impairment dramatically reduced 10-year cardiovascular survival (51.9±15.3% versus 90.3±3.2%, P <0.0001; hazard ratio, 5.2; P <0.0001) even after adjustment for known predictors (hazard ratio, 4.6; P =0.004). Biventricular impairment reduced also 10-year overall survival (34.8±13.0% versus 72.6±4.5%, P =0.003; hazard ratio, 2.5; P =0.005) even after adjustment for known predictors ( P =0.048). Conclusions— In patients with organic mitral regurgitation referred to surgery, RV function impairment is frequent (30%) and depends weakly on pulmonary artery systolic pressure but mainly on left ventricular remodeling and septal function. RV function is a predictor of postoperative cardiovascular survival, whereas biventricular impairment is a powerful predictor of both cardiovascular and overall survival.

AbstractBackground and objectiveDespite significant recent progress in the understanding of idiopathic pulmonary fibrosis (IPF), the early phase of the disease is still poorly understood. We studied patients with IPF without pulmonary function impairment in order to determine the clinical features, natural history and key findings for physiological progression.MethodsTwenty‐five patients without pulmonary function impairment were identified from among patients with previously diagnosed IPF who underwent surgical lung biopsies between January 1997 and December 2006 at our institutions. ‘Without pulmonary function impairment’ was defined as both forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) >80% predicted. Patients diagnosed with IPF through multidisciplinary discussion based on the new IPF guidelines were the subjects of this study.ResultsSixteen patients had a confirmed diagnosis of IPF. Eleven patients presented with chest X‐ray abnormality found during an annual health examination. Seven patients were asymptomatic. Eleven patients showed physiological disease progression (median time; 19.9 ± 12.3 months) defined by a decline of at least 10% in FVC or at least 15% in DLco. Univariate analysis revealed that both usual interstitial pneumonia pattern and extent of honeycombing on high‐resolution computed tomography (HRCT) were factors associated with disease progression (odds ratio 5.634, 95% confidence interval 1.364–23.278; odds ratio 2.371/5%, 95% confidence interval 1.042–5.395).ConclusionsIPF patients without pulmonary function impairment have a progressive but slow clinical course. The existence and extent of honeycombing on HRCT are predictive of disease progression.

Pulsatile growth hormone (GH) secretion putatively reflects integrated regulation by GH-releasing hormone (GHRH), somatostatin (SST), and GH-releasing peptide (GHRP). GHRH and SST secretion is itself pulsatile. However, how GHRH and SST pulses act along with GHRP to jointly determine pulsatile GH secretion is unclear. Moreover, how testosterone (T) modulates such interactions is unknown. These queries were assessed in a prospectively randomized, placebo-controlled double-blind cohort comprising 26 healthy older men randomized to testosterone (T) vs. placebo supplementation. Pulses of GHRH, SST, or saline were infused intravenously at 90-min intervals for 13 h, along with either continuous saline or ghrelin analog (GHRP-2). The train of pulses was followed by a triple stimulus (combined l-arginine, GHRH, and GHRP-2) to estimate near-maximal GH secretion over a final 3 h. Testosterone vs. placebo supplementation doubled pulsatile GH secretion during GHRH pulses combined with continuous saline (GHRH/saline) ( P < 0.01). Pulsatile GH secretion correlated positively with T concentrations (270–1,170 ng/dl) in the 26 men during saline pulses/saline ( P = 0.015, R2 = 0.24), GHRH pulses/saline ( P = 0.020, R2 = 0.22), and combined GHRH pulses/GHRP-2 ( P = 0.016, R2 = 0.25) infusions. Basal nonpulsatile GH secretion correlated with T during saline pulses/GHRP-2 drive ( P = 0.020, R2 = 0.16). By regression analysis, pulsatile GH secretion varied negatively with body mass index (BMI) during saline/GHRP-2 infusion ( P = 0.001, R2 = 0.36), as well as after the triple stimulus preceded by GHRH/GHRP-2 ( P = 0.013, R2 = 0.23). Mean (10-h) GH concentrations under GHRP-2 were predicted jointly by estradiol (positively) and BMI (negatively) ( P < 0.001, R2 = 0.520). These data indicate that estradiol, T, and BMI control pulsatile secretagogue-specific GH-regulatory mechanisms in older men.

Coverage with evidence development and parallel review for molecular diagnostics aid regulation and reimbursement.

SummaryMyelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT‐I,) a double‐blind trial, where patients with intermediate‐2 or high‐risk MF were randomized to twice‐daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post‐polycythaemia vera, post‐essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib‐treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT‐I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT‐I.