Uric acid and metabolic syndrome: Importance of hyperuricemia cut-off.

BACKGROUND: The relationship between HyperUricemia (HU) and Metabolic Sindrome (MS) and if Uric Acid (UA) should be inserted into MS definitions is a matter of debate. Aim of our study was to evaluate the correlation between UA and HU with Insulin Resistance (IR) and MS in a population of hypertensive patients. HU was defined with two cut-offs (the classic one of ≥6 mg/dL for women and ≥ 7 for men; the newly proposed URRAH one with ≥5.6 mg/dL for both sexes). METHODS: We enrolled 473 Hypertensive patients followed by the Hypertension Unit of San Gerardo Hospital (Monza, Italy). IR was defined through TG/HDL ratio and NCEP-ATP-III criteria were used for MS diagnosis. RESULTS: MS was found in 33.6 % while HU affected 14.8 % of subjects according to the traditional cut-off and 35.9 % with the URRAH cut-off. 9.7 % (traditional cut-off) and 17.3 % (URRAH's threshold) of the subjects had both HU and MS. UA level was significantly higher in MS group (5.7 vs 4.9 mg/dL, p < 0.0001) as well as for HU (29.0 vs 7.6 % and 51.6 vs 28.0 %, for classic and URRAH cut-off respectively, p < 0.0001 for both comparison). Logistic multivariable regression models showed that UA is related to MS diagnosis (OR = 1.608 for each 1 mg/dL), as well as HU with both cut-off (OR = 5.532 and OR = 3.379, p < 0.0001 for all comparison, for the classic cut-off and the URRAH one respectively). CONCLUSIONS: The main finding of our study is that UA and HU significantly relate to IR and MS. The higher the values of UA and the higher the cut-off used, the higher the strength of the relationship.

Hyperuricemia in Cardiac Rehabilitation Patients: Prevalence and Association with Functional Improvement and Left Ventricular Ejection Fraction.

INTRODUCTION: The role of uric acid (UA) and Hyper Uricemia (HU) in cardiac rehabilitation (CR) patients have been very little studied. AIM: To evaluate the prevalence of HU and if it is associated to the functional improvement obtained or the left ventricular Ejection Fraction (EF) in CR patients after Acute or Chronic Coronary Syndrome (ACS and CCS respectively). METHODS: We enrol 411 patients (62.4 ± 10.2 years; males 79.8%) enrolled in the CR program at Niguarda Hospital (Milan) from January 2012 to May 2023. HU was defined both as the classic cut-off (> 6 for females, > 7 mg/dL for males) and with the newly identified one by the URRAH study (> 5.1 for females, > 5.6 mg/dL for males). All patients performed a 6MWT and an echocardiography at the beginning and at the end of CR program. RESULTS: Mean UA values were within the normal range (5.6 ± 1.4 mg/dL) with 19.5% (classic cut-off) HU patients with an increase to 47.4% with the newer one. Linear regression analysis showed no role for UA in determining functional improvement, while UA and hyperuricemia (classic cut-off) were associated to admission and discharge EF. The same was not with the URRAH cut-off. CONCLUSIONS: HU is as frequent in CR patients as in those with ACS and CCS. UA didn't correlate with functional recovery while it is associated with admission and discharge EF as also is for HU (classic cut-off). Whit the URRAH cut-off HU prevalence increases significantly, however, it doesn't show any significant association with EF.

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.

Introduction: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression. Methods: Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity. Results: We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles. Conclusion: In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.

Age-Related Effects of Exogenous Melatonin on Anxiety-like Behavior in C57/B6J Mice.

The synthesis of melatonin (MLT) physiologically decreases during aging. Treatment with MLT has shown anxiolytic, hypnotic, and analgesic effects, but little is known about possible age-dependent differences in its efficacy. Therefore, we studied the effects of MLT (20 mg/kg, intraperitoneal) on anxiety-like behavior (open field (OFT), elevated plus maze (EPMT), three-chamber sociability, and marble-burying (MBT) tests), and the medial prefrontal cortex (mPFC)-dorsal hippocampus (dHippo) circuit in adolescent (35-40 days old) and adult (three-five months old) C57BL/6 male mice. MLT did not show any effect in adolescents in the OFT and EPMT. In adults, compared to vehicles, it decreased locomotor activity and time spent in the center of the arena in the OFT and time spent in the open arms in the EPMT. In the MBT, no MLT effects were observed in both age groups. In the three-chamber sociability test, MLT decreased sociability and social novelty in adults, while it increased sociability in adolescents. Using local field potential recordings, we found higher mPFC-dHippo synchronization in the delta and low-theta frequency ranges in adults but not in adolescents after MLT treatment. Here, we show age-dependent differences in the effects of MLT in anxiety paradigms and in the modulation of the mPFC-dHippo circuit, indicating that when investigating the pharmacology of the MLT system, age can significantly impact the study outcomes.