Aim
Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for ...diuretic response, examine associated patient characteristics and relationships with outcome.
Methods and results
We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 response was used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses. We investigated predictors of diuretic response and relationships with outcome. The median diuretic response was −0.38 (−0.80 to −0.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P < 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11–1.81, P = 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14–1.59, P < 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24–2.01, P < 0.001) in multivariable models. The proposed metric—weight loss indexed to diuretic dose—better captures a dose–response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal.
Conclusions
Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study.
The administration of loop diuretics to achieve decongestion is the cornerstone of therapy for acute heart failure. Unfortunately, impaired response to diuretics is common in these patients and ...associated with adverse outcomes. Diuretic resistance is thought to result from a complex interplay between cardiac and renal dysfunction, and specific renal adaptation and escape mechanisms, such as neurohormonal activation and the braking phenomenon. However, our understanding of diuretic response in patients with acute heart failure is still limited and a uniform definition is lacking. Three objective methods to evaluate diuretic response have been introduced, which all suggest that diuretic response should be determined based on the effect of diuretic dose administered. Several strategies have been proposed to overcome diuretic resistance, including combination therapy and ultrafiltration, but prospective studies in patients who are truly unresponsive to diuretics are lacking. An enhanced understanding of diuretic response should ultimately lead to an improved, individualized approach to treating patients with acute heart failure.
Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining ...mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer.
The objective of this study was to validate an electronic system for monitoring individual feeding behavior and feed intake (Intergado Ltd., Contagem, Minas Gerais, Brazil) in freestall-housed dairy ...cattle. No data have been published that validate either the behavioral measurement or the feed intake of this system. Feeding behavior data were recorded for 12 Holstein cows over 5d using an Intergado system and time-lapse video. The cows were fitted with an ear tag containing a unique passive transponder and provided free access to 12 feed bins. The system documented the visit duration and feed intake by recording the animal identification number, bin number, initial and final times, and the difference between feed weight at start and end of each feed bin visit. These data were exported to Intergado web software and reports were generated. Electronic data on animal behavior were compared with video data collected during the same evaluation period. An external scale was used to manually measure and validate the electronic system’s ability to monitor dairy cow feed intake for each feed bin visit. The feed intake was manually measured for 4-h time periods and compared with the sum of the feed intake recorded by the monitoring system for each cow visit during the same time period. Video and manual weight data were regressed on the electronic feeding behavior and feeding intake data to evaluate the precision of the monitoring system. The Intergado system presented high values for specificity (99.9%) and sensitivity (99.6%) for cow detection. The visit duration and feed intake per visit collected using the electronic monitoring system were similar to the video and manual weighing data, respectively. The difference between the feed intake measured manually and the sum of the electronically recorded feed intake was less than 250g (25,635±2,428 and 25,391±2,428g estimated using manual weighing and the electronic system, respectively). In conclusion, the Intergado system is a reasonable tool to monitor feeding behavior and feed intake for freestall-housed dairy cows.
Although serotonin has been extensively studied in many species, there is a lack of information in ruminants, and no research has been evaluated if its precursor, 5-hydroxytryptophan (5-HTP), ...administered into the abomasum may be used as a means to manipulate serotonin metabolism. Thus, the objective of this study was to evaluate if intra-abomasal infusion of 5-HTP increases circulating serotonin in the steer. Eight Holstein steers (471 ± 8.9 kg) were used in a replicated 4 × 4 Latin Square design experiment. The treatments were intra-abomasal infusion of 5-HTP at 0.5, 1, 2.5, and 5 mg/kg BW. Blood was collected at 0, 2, 4, 6, 8, and 24 h after infusion. The serum concentration of 5-HTP increased quadratically (P = 0.005) with a peak at 2 h after administration. The 5-HTP administration increased (P < 0.05) serum serotonin in comparison with baseline with no difference (P > 0.05) between the doses of 5-HTP. When 5-HTP was dosed at 2.5 mg/kg BW or higher, intake decreased, and there was an altered manure consistency. The serum 5-hydroxyindole acetic acid concentrations followed the same pattern as 5-HTP. Plasma glucose content was not affected (P > 0.05) by 5-HTP dosing. However, free fatty acids concentration in the plasma was lower (P > 0.05) compared with baseline for the infusion levels of 0.5 and 1 mg/kg BW. Intra-abomasal infusion of 5-HTP efficiently increases serum serotonin cattle.
•Abomasal administration of 5-hydroxytryptophan has not been studied in adult cattle.•The 5-HTP administration increased serum serotonin.•High levels of 5-HTP decrease feed intake and altered fecal consistency.•Moderate doses of 5-HTP can increase serotonin synthesis without adverse effects.•Cattle appear sensitive to 5-HTP compared with nonruminants.
The proclivity of river networks to progressively carve mountain surfaces and preserve markers of landscape adjustments has made analyses of fluvial systems fundamental for understanding the ...topographic development of orogens. However, the transient nature of uplift and erosion has posed a challenge for inferring the roles that tectonics and/or climate have played on generating topographic relief. The Mt. Alpi region in the southern Apennines has a heterogeneous distribution of elevated topography, erosionally-resistant lithology and uplift, making the area optimal for conducting topographic and river analyses to better understand the landscape development of a transient orogen. Stream length-gradient, normalized channel steepness, stream convexity and first-order channel gradient indices from 10m digital elevation data from the region exhibit stream profile inconsistencies along the current drainage divide and a dominance of high values subparallel but inboard of the primary chain axis irrespective of known transient landscape factors, suggesting that the current river network may be in a state of transition. The location of these stream profile anomalies both near the modern drainage divide and subparallel to an isolated swath of high topography away from catchment boundaries is thought to be the topographic expression of an imminent drainage divide migration driven primarily by the ~northeast-vergent extension of the western chain axis.
Serotonin (5-HT) has many important functions in both central and peripheral nervous systems. Although it has been demonstrated that manipulation of serotonin metabolism is possible in many species, ...there is limited information about l-tryptophan (TRP), a serotonin precursor, in cattle, and these provide conflicting results. Furthermore, there is no study evaluating how different patterns of intra-abomasal infusion of TRP impact circulating 5-HT. The objective of this study was to evaluate if intra-abomasal infusion patterns of TRP can affect circulating 5-HT and other metabolites from TRP metabolism in the plasma and serum and circulating glucose and insulin in cattle. Eight ruminally cannulated Holstein steers were used in a replicated 4 × 4 Latin square design. Each received intra-abomasal water infusion (control) or intra-abomasal TRP infusion (50 mg/kg BW) in 3 different patterns: a pulse infusion once a day (pulse once), pulse infusion twice a day (pulse twice), or continuous infusion (continuous). For continuous treatment, the TRP dose was diluted in tap water and infused by a peristaltic pump (300 mL/h). To equalize conditions, the other treatments had a water infusion (300 mL/h). The steers were fed every 2 h, and blood was collected from a jugular vein catheter every 4 h for 24 h after the initial infusion. Urine produced during the 24 h period was collected. Serum and plasma TRP, 5-HT and kynurenine, plasma glucose, and serum insulin concentrations were analyzed. Urine was analyzed for concentrations of 5-hydroxyindoleacetic acid. Both serum TRP and kynurenine were increased (P < 0.05) by all TRP infusion treatments, but concentrations in pulse dose treatments were greater than those in continuous infusion. Serum 5-HT increased (P < 0.05) with both pulse TRP infusion treatments; however, the continuous TRP infusion did not increase the serum 5-HT. Plasma 5-HT, glucose, and insulin had a tendency to increase with TRP pulse infusions. The urinary 5-hydroxyindoleacetic acid excretion was highest for pulse dose treatments. An acute supply of TRP in 1 or 2 daily doses increases serum 5-HT and increases circulating glucose and insulin in cattle. The TRP and kynurenine concentrations are similar in plasma and serum. However, the serum 5-HT concentration is more responsive to TRP administration than plasma.
•Serotonin has been investigated in cattle, but serotonin metabolism and its manipulation have received limited study in growing cattle.•The pattern of postruminal administration of l-tryptophan affects blood serotonin.•Pulse infusion of l-tryptophan increases serotonin.•Serotonin may have effects on energy metabolism.
•5-hydroxytryptophan can be safely administered postruminally in cattle at doses up to 1 mg/ kg BW with no adverse effects.•Most of the induced increases of serum 5-HTP are rapidly metabolized in the ...first 240 min after administration; the elimination rate constant and half-life are dose-independent.•Abomasal administration of 5-HTP can increase serotonin for up to 2 days and maybe a potential nutraceutical candidate for serotonin manipulation in cattle.
Studies of serotonin in animal husbandry has received growing interest. However, there is limited information about serotonin manipulation using 5-HTP administered postruminally and its residual effects in cattle. The objective of this study was to evaluate the effectiveness of 5-HTP infused into the abomasum for enhancing circulating serotonin in cattle. Four Holstein steers (487 ± 7.6 kg) fitted with ruminal cannulas were used in a 4 × 4 Latin Square design experiment. The treatments were intra-abomasal infusion of 5-HTP at 0, 0.25, 0.5, and 1 mg/kg BW. Blood was collected from the jugular vein of each steer at -60, -30, 0, 30, 60, 120, 240, and 480 min from 5-HTP infusion for basal and short term evaluation and, at 1, 2, 4, and 7 d after 5-HTP infusion for long term evaluation. Dry matter intake was not affected (P > 0.05) by intra-abomasal infusions. The half-life of 5-HTP was dose-independent (128 min). The serum 5-HTP, serotonin, and 5-hydroxyindoleacetic acid area under the curve increased (P < 0.05) linearly with an increased dose of 5-HTP. Serum 5-HTP reached peak concentration in approximately 30 min after dosing while serum and plasma serotonin peaked after 240 min postinfusion. Serotonin was greater than control for all 5-HTP doses 1 d and 2 d after infusion in serum and plasma, respectively. Intra-abomasal infusion of 5-HTP at doses up to 1 mg/ kg BW increases circulating serotonin for up 2 days.
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