Direct, gabapentin-insensitive interaction of a soluble form of the calcium channel subunit alpha(2)delta-1 with thrombospondin-4

The alpha(2)delta-1 subunit of voltage-gated calcium channels binds to gabapentin and pregabalin, mediating the analgesic action of these drugs against neuropathic pain. Extracellular matrix proteins from the thrombospondin (TSP) family have been identified as ligands of alpha(2)delta-1 in the CNS. This interaction was found to be crucial for excitatory synaptogenesis and neuronal sensitisation which in turn can be inhibited by gabapentin, suggesting a potential role in the pathogenesis of neuropathic pain. Here, we provide information on the biochemical properties of the direct TSP/alpha(2)delta-1 interaction using an ELISA-style ligand binding assay. Our data reveal that full-length pentameric TSP-4, but neither TSP-5/COMP of the pentamer-forming subgroup B nor TSP-2 of the trimer-forming subgroup A directly interact with a soluble variant of alpha(2)delta-1 (alpha(2)delta-1S). Interestingly, this interaction is not inhibited by gabapentin on a molecular level and is not detectable on the surface of HEK293-EBNA cells over-expressing alpha(2)delta-1 protein. These results provide biochemical evidence that supports a specific role of TSP-4 among the TSPs in mediating the binding to neuronal a2d-1 and suggest that gabapentin does not directly target TSP/alpha(2)delta-1 interaction to alleviate neuropathic pain

Body Mass Index and Early Kidney Function Decline in Young Adults: A Longitudinal Analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) Study

BACKGROUND: Identifying potentially modifiable risk factors is critically important for reducing the burden of chronic kidney disease. We sought to examine the association of body mass index (BMI) with kidney function decline in a cohort of young adults with preserved glomerular filtration at baseline. STUDY DESIGN: Longitudinal cohort. SETTING & PARTICIPANTS: 2,891 black and white young adults with cystatin C-based estimated glomerular filtration rate (eGFR(cys)) >90 ml/min/1.73 m(2) taking part in the year-10 examination (in 1995–1996) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. PREDICTOR: BMI, categorized as 18.5–24.9 (reference), 25.0–29.9. 30.0–39.9, and ≥40.0 kg/m(2). OUTCOMES: Trajectory of kidney function decline, rapid decline (>3% per year), and incident eGFR(cys) <60 ml/min/1.73 m(2) over 10 years of follow-up. MEASUREMENTS: GFR(cys) estimated from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation for calibrated cystatin C at CARDIA years 10, 15, and 20. RESULTS: At year 10, participants had a mean age of 35.1 years, median eGFR(cys) of 114 ml/min/1.73 m(2), and 24.5% had BMI ≥30.0 kg/m(2). After age 30 years, average eGFR(cys) was progressively lower with each increment of BMI after adjustment for baseline age, race, sex, hyperlipidemia, smoking status, and physical activity. Higher BMI category was associated with successively higher odds of rapid decline (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m(2), the adjusted ORs were 1.50 [95% CI, 1.21–1.87], 2.01 [95% CI, 1.57–2.87], and 2.57 [95% CI, 1.67–3.94], respectively). Eighteen participants (0.6%) had incident eGFR(cys) <60 ml/min/1.73 m(2). In unadjusted analysis, higher BMI category was associated with incident eGFR(cys) <60 ml/min/1.73 m(2) (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m(2), the ORs were 5.17 [95% CI, 1.10–25.38], 7.44 [95% CI, 1.54–35.95], and 5.55 [95% CI, 0.50–61.81], respectively); adjusted associations were no longer significant. LIMITATIONS: Inability to describe kidney function before differences by BMI category were already evident. Absence of data on measured GFR or GFR estimated from serum creatinine. CONCLUSIONS: Higher BMI categories are associated with greater declines in kidney function among a cohort of young adults with preserved GFR at baseline. Clinicians should vigilantly monitor overweight and obese patients for evidence of early kidney function decline

Homocysteine Levels and Risk of Hip Fracture in Postmenopausal Women

Background: Recent studies suggest that high homocysteine levels are associated with an increased risk of fractures. Homocysteine levels are known to be influenced by vitamin B and folate supply or status, and poor renal function can result in higher levels independent of nutritional adequacy

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health