Summary Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of NLRP3 inflammasome. Neutrophil-mediated production of IL-1β drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here we identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal induced gout without impairing immune-defense against bacterial infection. BHB inhibited Nlrp3 inflammasome in S100A9 fibril-primed and urate crystal activated macrophages which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in Nlrp3-dependent manner in mice and humans irrespective of age Mechanistically, BHB inhibited the Nlrp3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel is also an anti-inflammatory molecule that may serve as a treatment for gout.

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Remote monitoring of pulmonary artery pressure has reduced heart failure (HF) hospitalizations in chronic HF as elevation of pulmonary artery pressure provides information that can guide treatment. The venous system is characterized by high capacitance, thus substantial increases in intravascular volume can occur before filling pressures increase. The inferior vena cava (IVC) is a highly compliant venous conduit and thus a candidate for early detection of change in intravascular volume. We aimed to compare IVC cross-sectional area using a novel sensor with cardiac filling pressures during experimental manipulation of volume status, vascular tone, and cardiac function.

Background and objectivesDiuretic resistance can limit successful decongestion of patients with heart failure. Because loop diuretics tightly bind albumin, low serum albumin and high urine albumin can theoretically limit diuretic delivery to the site of action. However, it is unknown if this represents a clinically relevant mechanism of diuretic resistance in human heart failure.Design, setting, participants, & measurementsIn total, 208 outpatients with heart failure at the Yale Transitional Care Center undergoing diuretic treatment were studied. Blood and urine chemistries were collected at baseline and 1.5 hours postdiuretic administration. Urine diuretic levels were normalized to urine creatinine and adjusted for diuretic dose administered, and diuretic efficiency was calculated as sodium output per doubling of the loop diuretic dose. Findings were validated in an inpatient heart failure cohort (n=60).ResultsSerum albumin levels in the outpatient cohort ranged from 2.4 to 4.9 g/dl, with a median of 3.7 g/dl (interquartile range, 3.5–4.1). Serum albumin had no association with urinary diuretic delivery (r=−0.05; P=0.52), but higher levels weakly correlated with better diuretic efficiency (r=0.17; P=0.02). However, serum albumin inversely correlated with systemic inflammation as assessed by plasma IL-6 (r=−0.35; P<0.001), and controlling for IL-6 eliminated the diuretic efficiency-serum albumin association (r=0.12; P=0.12). In the inpatient cohort, there was no association between serum albumin and urinary diuretic excretion (r=0.15; P=0.32) or diuretic efficiency (r=−0.16; P=0.25). In the outpatient cohort, 39% of patients had microalbuminuria, and 18% had macroalbuminuria. There was no correlation between albuminuria and diuretic efficiency after adjusting for kidney function (r=−0.02; P=0.89). Results were similar in the inpatient cohort.ConclusionsSerum albumin levels were not associated with urinary diuretic excretion, and urinary albumin levels were not associated with diuretic efficiency.

Aims In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. Methods and results Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13–17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (&lt;20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P &lt; 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P &lt; 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). Conclusion On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.

Psychosocial stress exposure is linked to a disruption of emotional regulation that can manifest as anxiety and depression. Women are more likely to suffer from such psychopathologies than men, indicating that gender-based differences in gonadal steroids may be a key factor in the etiology of stress-induced adverse health outcomes. Estradiol (E2) positively influences mood and cognition in females, an effect likely related to E2’s ability to modulate the serotonin and dopamine neurotransmitter systems. Furthermore, genetic variation due to the polymorphism in the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5HTTLPR) also can influence E2’s ability to modulate behavior and physiology. However, it remains uncertain whether exposure to social stress interacts with the 5HTTLPR to influence E2-induced changes in behavior and physiology. The present study used ovariectomized adult female rhesus monkeys to investigate acute and chronic effects of E2 on central monoamine metabolite concentrations using CSF sampling. We further assessed how E2-induced changes in monoamine metabolite levels are modified by the unpredictable stress of social subordination and the 5HTTLPR polymorphism. Levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) decreased significantly during chronic E2 treatment only in dominant females with the long promoter length of SLC6A4. Chronic administration of E2 decreased levels of the dopamine metabolite dihydrophenylacetic acid (DOPAC) in a manner independent of the social status, 5HTTLPR genotype, or their interactions. Overall levels of dopamine and serotonin metabolites were increased in subordinate females but this effect of social stress was not influenced by 5HTTLPR genotype. Together, these data emphasize how E2 can modulate central neurotransmitter systems and indicate that social subordination in female monkeys is a valid model for examining how chronic psychosocial stress alters sensitivity to E2. Future studies are necessary to elaborate how changes in central neurotransmitter metabolism due to E2 and prolonged exposure to stress affect behavior and physiology.

At present, global immunity to SARS-CoV-2 resides within a heterogeneous combination of susceptible, naturally infected and vaccinated individuals. The extent to which viral shedding and transmission occurs on re-exposure to SARS-CoV-2 is an important determinant of the rate at which COVID-19 achieves endemic stability. We used Sialodacryoadenitis Virus (SDAV) in rats to model the extent to which immune protection afforded by prior natural infection via high risk (inoculation; direct contact) or low risk (fomite) exposure, or by vaccination, influenced viral shedding and transmission on re-exposure. On initial infection, we confirmed that amount, duration and consistency of viral shedding, and seroconversion rates were correlated with exposure risk. Animals were reinfected after 3.7–5.5 months using the same exposure paradigm. 59% of seropositive animals shed virus, although at lower amounts. Previously exposed seropositive reinfected animals were able to transmit virus to 25% of naive recipient rats after 24-hour exposure by direct contact. Rats vaccinated intranasally with a related virus (Parker’s Rat Coronavirus) were able to transmit SDAV to only 4.7% of naive animals after a 7-day direct contact exposure, despite comparable viral shedding. Cycle threshold values associated with transmission in both groups ranged from 29–36 cycles. Observed shedding was not a prerequisite for transmission. Results indicate that low-level shedding in both naturally infected and vaccinated seropositive animals can propagate infection in susceptible individuals. Extrapolated to COVID-19, our results suggest that continued propagation of SARS-CoV-2 by seropositive previously infected or vaccinated individuals is possible.