Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.
The study was designed to determine the effects of breed, age, parity, feeding practice, Body Condition Score (BCS), timing of insemination, postpartum insemination interval and milk yield on first service pregnancy rates in cows (n = 308). The demographic factors were recorded by interviewing the farmers. All cows were examined for pregnancy diagnosis by rectal palpation of genital tract at 60-80 days post Artificial Insemination (AI). The pregnancy rate of different groups was compared and analyzed by Z test using SPSS software version 17. The overall pregnancy rate in cows was 52.6%. Though the age and parity of cows and milk yield did not affect significantly on pregnancy rate, the pregnancy rate was the highest in cows of 3-5 years of age (56.1%), in cows of parity 1-2 (57.4%) and in moderate yielding (2-5 liters milk/day) cows (62.1%). Balanced feeding and timing of insemination had a profound impact on the pregnancy rate of cows. The pregnancy rate in cows fed with combination of green grass, straw and concentrate was significantly (p<0.05) higher (63.5%) than cows fed only straw (38.5%). The pregnancy rate in cows with BCS 3-4 was significantly (p<0.05) higher (58.0%) than that of BCS 1.5-2 cows (35.0%). The pregnancy rate in cows inseminated at 6-12 h after the start of standing estrus was significantly (p<0.05) higher (58.8%) than those inseminated 13-24 h after start of standing estrus (40.4%). Cows with good BCS and AI at 6-12 h after the start of standing estrus are the best choice of selection for getting the best result in the first service pregnancy rate in cows.
Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylenetetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 19 smoking BD patients (13 men [2 siblings], ± women, 18 Caucasian, 1 African American), compared to 200 healthy Caucasian controls, BD patients were more likely to have 6A6A stromelysin-1 homozygosity (7/19 [37%] vs 46/200 [23%]) and to have eNOS T-786C homozygosity (3/19 [16%] vs 22/200 [11%]), but these patient-control differences were not significant, p = .4, 0.5. C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity did not differ in patients vs controls (6/19 [32%] vs 70/200 [35%]), p = .8. In 9 patients who stopped and 1 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In these 10 patients, to increase vasodilatory NO via endothelial NO synthase, L-arginine (15 g/day) was given, along with folic acid 5 mg, vitamin B6 (100 mg), and B12 (2,000 μg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months on L-arginine-folic acid, all 10 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo-heterozygous for stromelysin-1 5A/6A, eNOS T-786C, and C677T-A1298C MTHFR mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by L-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.
In 81 women referred for diagnosis-therapy of atherothrombotic and endocrine disorders, and found to be heterozygous (n = 49) or homozygous (n = 3) for the G1691A Factor V Leiden mutation (FV), or heterozygous (n = 29) for the G20210A prothrombin gene mutation (PTG), and having ≥ 1 pregnancy, our specific aim was to assess relationships of familial thrombophilia to previous pregnancy outcomes. The 52 women with FV (1 black, 43 white, 8 other, 47 ± 13 years old) had 164 pregnancies with 114 live births (70%) and 50 miscarriages (30%). The 29 women with PTG (1 black, 28 white, 51 ± 15 years old) had 64 pregnancies with 50 live births (83%) and 10 miscarriages (17%). In 130 normal control women referred for diagnosis-therapy of atherosclerotic and endocrine disorders, having wild-type normal FV and PTG, there were 125 pregnancies with 110 live births and 13 miscarriages (10.4%). The miscarriage rate in women with FV (30%) was 3 times higher (p<.0001) than in the 130 normal controls (10.4%). The miscarriage rate in women with PTG (17%) was not significantly (p = .24) higher than in the 130 normal controls (10.4%). Of the 52 women with FV, 38 had concurrent measurement of the hypofibrinolytic 4G4G plasminogen activator inhibitor-1 (PAI-1) mutation. In 15 (of 38) women with 4G4G homozygosity and the FV mutation, there were 22 miscarriages (44%) in 50 pregnancies; in the 23 (of 38) women with 4G5G/5G5G genotypes and the FV mutation, there were 27 miscarriages (39%) in 70 pregnancies, p = 0.6. Of the 52 women with FV, 43 had measurement of the thrombophilic C677T methylenetetrahydrofolate reductase (MTHFR) mutation. In 8 women with MTHFR homozygosity and the FV mutation, the miscarriage rate was 33% (7 of 21 pregnancies); in 35 MTHFR heterozygous/wild-type normal genotypic women and the FV mutation, the miscarriage rate was 35% (42 of 120 pregnancies), p = 0.9.Heterozygosity for the Factor FV mutation is a major risk factor for miscarriage, reversible by low molecular weight heparin thromboprophylaxis throughout pregnancy.
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