Examining the "Repletion Reflex": The Association between Serum Potassium and Outcomes in Hospitalized Patients with Heart Failure.

BACKGROUND: In patients hospitalized with heart failure (HF) exacerbations, physicians routinely supplement potassium to maintain levels ≥4.0 mEq/L. The evidence basis for this practice is relatively weak. We aimed to evaluate the association between serum potassium levels and outcomes in patients hospitalized with HF. METHODS: We identified patients admitted with acute HF exacerbations to hospitals that contributed to an electronic health record-derived dataset. In a subset of patients with normal admission serum potassium (3.5-5.0 mEq/L), we averaged serum potassium values during a 72-hour exposure window and categorized as follows: <4.0 mEq/L (low normal), 4.0-4.5 mEq/L (medium normal), and >4.5 mEq/L (high normal). We created multivariable models examining associations between these categories and outcomes. RESULTS: We included 4,995 patients: 2,080 (41.6%), 2,326 (46.6%), and 589 (11.8%) in the <4.0, 4.0-4.5, and >4.5 mEq/L cohorts, respectively. After adjustment for demographics, comorbidities, and presenting severity, we observed no difference in outcomes between the low and medium normal groups. Compared to patients with levels <4.0 mEq/L, patients with a potassium level of >4.5 mEq/L had a longer length of stay (median of 0.6 days; 95% CI = 0.1 to 1.0) but did not have statistically significant increases in mortality (OR [odds ratio] = 1.51; 95% CI = 0.97 to 2.36) or transfers to the intensive care unit (OR = 1.78; 95% CI = 0.98 to 3.26). CONCLUSIONS: Inpatients with heart failure who had mean serum potassium levels of <4.0 showed similar outcomes to those with mean serum potassium values of 4.0-4.5. Compared with mean serum potassium level of <4.0, mean serum levels of >4.5 may be associated with increased risk of poor outcomes.

Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats.

Clinical studies have suggested that estrogens may affect the symptoms of schizophrenia. The novel object recognition task (NORT) in female rats treated with sub-chronic phencyclidine (PCP) was used as an animal model of the cognitive deficits in schizophrenia. The current studies investigated whether chronic estradiol (E) could alleviate sub-chronic PCP-induced cognitive deficits in the NORT. Adult Sprague-Dawley rats were ovariectomized (ovx) and treated with either sub-chronic PCP (2 mg/kg bidaily i.p. for seven days), or with 0.9% saline and their object recognition memory was tested with the NORT using an acquisition trial, 1 min inter-trial interval, and retention trial. Sub-chronic PCP administration did not reliably affect behavior in the acquisition trial but significantly impaired object recognition in the retention trial for 1-2 and 27-29 weeks. Ovx females spent significantly (p<0.05) more time exploring the novel compared to the familiar object, whereas PCP-treated ovx females did not. This effect of PCP was attenuated by long-lasting E capsules implanted prior to PCP treatment. PCP-treated females implanted with E again spent significantly more time exploring the novel compared to the familiar object (p<0.01). When ovx rats were treated with sub-chronic PCP and a long-lasting E capsule was implanted either before or after PCP treatment, estradiol alleviated the PCP-induced deficits when administered in either regimen (p=0.01 and p=0.047 respectively). These data suggest that further exploration of estradiol as a possible therapeutic compound to treat the cognitive deficits of schizophrenia is warranted.

Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers.

Reduction in cortical presynaptic markers, notably parvalbumin (PV), for the chandelier subtype of inhibitory γ-amino-butyric acid (GABA) interneurons is a highly replicated post-mortem finding in schizophrenia. Evidence from genetic and pharmacological studies implicates hypofunction of N-methyl-d-aspartate receptor (NMDAR)-mediated glutamatergic signaling as a critical component of the pathophysiology of schizophrenia. Serine racemase (SR) produces the endogenous NMDAR co-agonist d-serine, and disruption of the SR gene results in reduced NMDAR signaling. SR null mutant (-/-) mice were used to study the link between NMDAR hypofunction and decreased PV expression, assessed by immunoreactive (IR) cell density in the medial prefrontal cortex and hippocampus and protein levels in brain homogenates from the frontal cortex and hippocampus. Contrary to expectations, SR -/- mice showed modest elevations in PV-IR cell density and no difference in PV expression in brain homogenate. To control for these surprising results, we investigated PV expression in mice and rats following subchronic phencyclidine or ketamine treatments in adulthood. PV expression was not affected by drug these treatment in either species, failing to reproduce previously published findings. Our findings challenge the hypothesis that pathological deficits in PV expression are simply a consequence of NMDAR hypofunction.