Inpatient versus outpatient intravenous diuresis for the acute exacerbation of chronic heart failure.

BACKGROUND: We established an IV outpatient diuresis (IVOiD) clinic and conducted a quality improvement project to evaluate safety, effectiveness and costs associated with outpatient versus inpatient diuresis for patients presenting with acute decompensated heart failure (ADHF) to the emergency department (ED). METHODS: Patients who were clinically diagnosed with ADHF in the ED, but did not have high-risk features, were either diuresed in the hospital or in the outpatient IVOiD clinic. The dose of IV diuretic was based on their home maintenance diuretic dose. The outcomes measured were the effects of diuresis (urine output, weight, hemodynamic and laboratory abnormalities), 30-90 day readmissions, 30-90 day death and costs. RESULTS: In total, 36 patients (22 inpatients and 14 outpatients) were studied. There were no significant differences in the baseline demographics between groups. The average inpatient stay was six days and the average IVOiD clinic days were 1.2. There was no significant difference in diuresis per day of treatment (1159 vs. 944 ml, p = 0.46). There was no significant difference in adverse outcomes, 30-90 day readmissions or 30-90 day deaths. There was a significantly lower cost in the IVOiD group compared to the inpatient group ($839.4 vs. $9895.7, p=<0.001). CONCLUSIONS: Outpatient IVOiD clinic diuresis may be a viable alternative to accepted clinical practice of inpatient diuresis for ADHF. Further studies are needed to validate this in a larger cohort and in different sites.

Applying indirect open-circuit calorimetry to study energy expenditure in gnotobiotic mice harboring different human gut microbial communities.

Given the increasing use of gnotobiotic mouse models for deciphering the effects of human microbial communities on host biology, there is a need to develop new methods for characterizing these animals while maintaining their isolation from environmental microbes. We describe a method for performing open-circuit indirect calorimetry on gnotobiotic mice colonized with gut microbial consortia obtained from different human donors. In this illustrative case, cultured collections of gut bacterial strains were obtained from obese and lean co-twins. The approach allows microbial contributions to host energy homeostasis to be characterized.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), previously known as senile cardiac amyloidosis: clinical presentation, diagnosis, management and emerging therapies.

Cardiac amyloidosis is thought to be a rare group of diseases caused by extracellular deposition of misfolded proteins in the extracellular cardiac matrix resulting in heart failure with preserved ejection fraction (HFpEF). This review focuses on the similarities and differences between the pathophysiology, clinical presentation and diagnostic tests of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) compared to immunoglobulin light chain amyloidosis and hereditary cardiac amyloidosis. We address some obstacles to timely diagnosis and opportunities for management of the clinical symptoms as well as possibility of future novel disease modifying therapies.

Characterization of leptin-responsive neurons in the caudal brainstem.

The central melanocortin system plays a key role in the regulation of energy homeostasis. Neurons containing the peptide precursor proopiomelanocortin (POMC) are found at two sites in the brain, the arcuate nucleus of the hypothalamus (ARC) and the caudal region of the nucleus of the solitary tract (NTS). ARC POMC neurons, which also express cocaine- and amphetamine-regulated transcript (CART), are known to mediate part of the response to factors regulating energy homeostasis, such as leptin and ghrelin. In contrast, the physiological role(s) of the POMC neurons in the caudal brainstem are not well characterized. However, development of a transgenic mouse expressing green fluorescent protein under the control of the POMC promoter [POMC-enhanced green fluorescent protein (EGFP) mouse] has aided the study of these neurons. Indeed, recent studies have shown significant activation of NTS POMC-EGFP cells by the gut released satiety factor cholecystokinin (CCK). Here we show that peripheral leptin administration induces the expression of phospho-signal transducer and activator of transcription 3 immunoreactivity (pSTAT3-IR), a marker of leptin receptor signaling, in more than 50% of NTS POMC-EGFP neurons. Furthermore, these POMC-EGFP neurons comprise 30% of all pSTAT3-IR cells in the NTS. Additionally, we also show that in contrast to the ARC population, NTS POMC-EGFP neurons do not coexpress CART immunoreactivity. These data suggest that NTS POMC neurons may participate with ARC POMC cells in mediating some of the effects of leptin and thus comprise a novel cell group regulated by both long-term adipostatic signals and satiety factors such as CCK.

Interactions between gut peptides and the central melanocortin system in the regulation of energy homeostasis.

Genetic and pharmacological studies have shown that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Animals and humans with defects in the central melanocortin system display a characteristic melanocortin obesity phenotype typified by increased adiposity, hyperphagia, metabolic defects and increased linear growth. In addition to interacting with long-term regulators of energy homeostasis such as leptin, more recent data suggest that the central melanocortin system also responds to gut-released peptides involved in mediating satiety. In this review, we discuss the interactions between these systems, with particular emphasis on cholecystokinin (CCK), ghrelin and PYY(3-36).

Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice.

Peptide YY (PYY) is a postprandially released gut hormone. Peripheral administration of one form of the peptide PYY3-36 produces a short-term reduction in food intake in rodents. Initial reports suggested that effects of PYY3-36 on food intake are mediated by increasing the anorexigenic drive from melanocortin neurons in the hypothalamic arcuate nucleus. However, more recent data have demonstrated that the anorexigenic activity of PYY3-36 is not dependent on melanocortin ligands or their receptors in the CNS. We demonstrate here that the anorexigenic actions of PYY3-36 are also not dependent on the vagus nerve, a common pathway of satiety signaling. Peripherally administered PYY3-36 activates neurons in the area postrema and nucleus tractus solitarius, brainstem areas known to mediate effects of certain aversive stimuli. Furthermore, peripheral administration of PYY3-36 causes conditioned taste aversion in mice. Thus, inhibition of food intake by PYY3-36 may result in part from induction of an aversive response.

Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system.

Hypothalamic pro-opiomelanocortin (POMC) neurons help regulate long-term energy stores. POMC neurons are also found in the nucleus tractus solitarius (NTS), a region regulating satiety. We show here that mouse brainstem NTS POMC neurons are activated by cholecystokinin (CCK) and feeding-induced satiety and that activation of the neuronal melanocortin-4 receptor (MC4-R) is required for CCK-induced suppression of feeding; the melanocortin system thus provides a potential substrate for integration of long-term adipostatic and short-term satiety signals.

Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism.

Peptide YY(3-36) (PYY(3-36)), a peptide released postprandially by the gut, has been demonstrated to inhibit food intake. Little is known about the mechanism by which PYY(3-36) inhibits food intake, although the peptide has been shown to increase hypothalamic proopiomelanocortin (POMC) mRNA in vivo and to activate POMC neurons in an electrophysiological slice preparation. Understanding the physiology of PYY(3-36) is further complicated by the fact that some laboratories have had difficulty demonstrating inhibition of feeding by the peptide in rodents. We demonstrate here that, like cholecystokinin, PYY(3-36) dose-dependently inhibits food intake by approximately 20-45% over a 3- to 4-h period post ip administration, with no effect on 12-h food intake. This short-lived satiety effect is not seen in animals that are not thoroughly acclimated to handling and ip injection, thus potentially explaining the difficulty in reproducing the effect. Surprisingly, PYY(3-36) was equally efficacious in inducing satiety in wild-type and melanocortin-4 receptor (MC4-R)-deficient mice and thus does not appear to be dependent on MC4-R signaling. The expression of c-Fos, an indirect marker of neuronal activation, was also examined in forebrain and brainstem neurons after ip treatment with a dose of PYY(3-36) shown to induce satiety. The peptide induced no significant neuronal activation in the brainstem by this assay, and only modest activation of hypothalamic POMC neurons. Thus, unlike cholecystokinin, PYY(3-36)-induced satiety is atypical, because it does not produce detectable activation of brainstem satiety centers and is not dependent on MC4-R signaling.