Background and Purpose-The mechanisms of ischemic stroke in young adults are poorly understood. During the last years, several studies suggested a role for genetic factors predisposing to thrombophilia and for moderate hyperhomocysteinemia in this setting. Methods-We evaluated in 132 consecutive patients (66 males, 66 females; meanϮSD age, 38.4Ϯ11.7 years; meanϮSD age at first event, 34.8Ϯ10.9 years; range, 6 months to 50 years) referred to our center between January 1997 and December 1999 for a history of young adult ischemic stroke (age at first event, Ͻ51 years) the prevalence of factor V (FV) Leiden, prothrombin (FII) G20210A, and C677T and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutations and fasting serum total homocysteine levels.

Background-Severe hyperhomocysteinemia due to cystathionine ␤-synthase deficiency (C␤SD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F 2␣ , a platelet-active product of arachidonic acid peroxidation, is enhanced in C␤SD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion. Methods and Results-Urine and blood samples were obtained from patients with homozygous C␤SD (nϭ13) and age-matched healthy subjects. Urinary 8-iso-PGF 2␣ excretion was significantly higher in C␤SD patients than in control subjects (640Ϯ384 versus 213Ϯ43 pg/mg creatinine; Pϭ0.0015) and correlated with plasma homocysteine (ϭ0.398, Pϭ0.0076). Similarly, urinary 11-dehydro-TXB 2 excretion was enhanced in C␤SD (1166Ϯ415 versus 324Ϯ72 pg/mg creatinine; Pϭ0.0015) and correlated with urinary 8-iso-PGF 2␣ (ϭ0.362, Pϭ0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6Ϯ4.6 to 40.4Ϯ8.7 mol/L, Pϭ0.0002) and with reductions in 8-iso-PGF 2␣ (from 790Ϯ159 to 559Ϯ111 pg/mg creatinine, Pϭ0.018) and 11-dehydro-TXB 2 (from 1273Ϯ383 to 913Ϯ336 pg/mg creatinine, Pϭ0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF 2␣ and plasma vitamin E levels (ϭϪ0.745, Pϭ0.0135). Conclusions-The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F 2 -isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in C␤SD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.

Background: we have observed the effect of insomnia treatment in clinical and prognostic differences of patients admitted for COVID-19 pneumonia in respiratory sub-intensive units that were administered a prolonged-release melatonin 2 mg (PRM 2 mg) therapy versus a group of patients out of therapy. Materials and Methods: We evaluated 40 patients on prolonged-release melatonin 2 mg (PRM 2 mg) therapy versus a control group of 40 patients out of therapy. Results: patients in the PRM 2 mg group had a shorter duration of therapy with non-invasive ventilation (5.2 ± 3.0 vs. 12.5 ± 4.2; p < 0.001), with a shorter stay in sub-intensive care (12.3 ± 3.2 vs. 20.1 ± 6.1; p < 0.001), and, therefore, a shorter overall duration of hospitalization (31.3 ± 6.8 vs. 34.3 ± 6.9 p = 0.03). In addition, a lower incidence of delirium was found (2.2 ± 1.1 vs. 3.3 ± 1.3; p < 0.001). Conclusions: A significant increase in sleep hours and a reduction in delirium episodes occurs in hospitalized insomniac patients treated with PRM 2 mg, compared to untreated patients. Based on these preliminary results, we can assume that there are benefits of prolonged-release melatonin 2 mg in COVID-19 therapy.

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SummaryTotal fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 ± 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 ± 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 µM in men and >15 µM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78–5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42; 0.84–2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61–14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = −0.42 and −0.25) than with the 677CC or CT MTHFR genotype (r = −0.37 and −0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 ± 206 vs. 408 ± 185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p ≤0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p ≤0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B12 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.

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