Maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of recurrent pregnancy loss.

Epidemiological studies have suggested that the condition of recurrent pregnancy loss (RPL) may be multifactorial, with both genetic predisposition and environmental factors potentially involved in its pathogenesis. The aim of this study is to elucidate the associations between maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of RPL. This case-control study, which involved 116 cases with two or more instances of RPL and 306 fertile controls, was performed in the city of Sapporo, Japan. The associations between eight single nucleotide polymorphisms of folate, alcohol and energy metabolism-related genes [methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), alcohol dehydrogenase 1B (ADH1B), aldehyde dehydrogenase 2 (ALDH2), beta-3-adrenergic receptor (ADRB3) and peroxisome proliferator-activated receptor gamma (PPARG)], and RPL were assessed. Without consideration of cigarette smoking or alcohol use, the risk of RPL significantly decreased in women with the MTHFR rs1801133 TT, MTR rs1805087 AG or ALDH2 rs671 AA genotype (P < 0.05). The risk of RPL associated with cigarette smoking and alcohol use decreased significantly in women carrying the MTHFR rs1801133 T allele [odds ratio (OR), 0.51; 95% confidence interval (CI), 0.27-0.95]. Similarly, the risk of RPL significantly decreased in women carrying the MTR rs1805087 G allele (OR, 0.44; 95% CI, 0.23-0.85). Our findings suggest that maternal gene polymorphisms related to folate metabolism may decrease the risk of RPL. Molecular epidemiological studies are needed to unequivocally elucidate the multifactorial effects of both genetic and environmental factors on human fecundity.

Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population.

Pregnancy and parturition involve a complex and poorly understood molecular and biological interplay between mother and fetus. Inflammatory cytokines have been reported to be associated with fetal growth and parturition. The aim of this study was to examine whether common proinflammatory cytokine polymorphisms are associated with preterm birth (PTB), low birthweight or intrauterine growth restriction in a Japanese population. We assessed a consecutive series of 414 women who had singleton deliveries in Sapporo, Japan between 2001 and 2005. Genotyping of IL1A -889C/T, +4845G/T (A114S), IL1B -511C/T, -31C/T, IL2 -384T/G and IL6 -634C/G polymorphisms was determined by an allelic discrimination assay. The risk of PTB significantly increased in women carrying the IL1A -889T allele (CC genotype [reference]; CT genotype, odds ratios (OR): 2.5; 95% confidence intervals (95% CI): 1.4-4.8; CT+TT genotypes [dominant genotype model], OR: 2.5, 95% CI: 1.3-4.6). Similarly, the risk of PTB significantly increased in women carrying the IL1A +4845T allele (GG genotype [reference]; GT genotype, OR: 2.4, 95% CI: 1.3-4.4; GT+TT genotypes [dominant genotype model], OR: 2.3, 95% CI: 1.2-4.2). The frequency of the IL1A TT haplotype in mothers with PTB was significantly higher than in mothers who had a term birth (P < 0.001), whereas the frequency of the IL1A CG haplotype in mothers who had a PTB was significantly lower (P < 0.001). Our findings suggest that the polymorphisms and haplotypes in the IL1A gene are associated with PTB in Japanese women.

Maternal smoking during pregnancy and genetic polymorphisms in the Ah receptor, CYP1A1 and GSTM1 affect infant birth size in Japanese subjects.

Genetic susceptibility to tobacco smoke might have relation to adverse pregnancy outcomes. To estimate the effects of maternal smoking and genetic polymorphisms on infant birth weight and length, we conducted a prospective cohort study of 293 women who delivered singleton live births in Sapporo, Japan. Birth weight and length were significantly lower among infants born to continuously smoking women having the aryl hydrocarbon receptor (AhR) wild type genotype (Arg/Arg; 211 g +/- 76 g; 1.2 cm +/- 0.4 cm, p < 0.01 and p < 0.01, respectively), the CYP1A1 variant genotype (m1/m2 + m2/m2; 170 g +/- 64 g, 0.8 cm +/- 0.3 cm, p < 0.01 and p < 0.05, respectively), or the GSTM1 null genotype (171 g +/- 58 g, 0.6 cm +/- 0.3 cm, p < 0.01 and p < 0.05, respectively). When combinations of these genotypes were considered, birth weight and length were significantly lower for infants of continuously smoking women in the AhR wild type + CYP1A1 variant group (315 g +/- 116 g; 1.7 cm +/- 0.6 cm, p < 0.01 and p < 0.01, respectively) and in the CYP1A1 variant + GSTM1 null group (237 g +/- 92 g; 1.3 cm +/- 0.5 cm, p < 0.05 and p < 0.01, respectively). These genotypes did not confer adverse effects among women who had never smoked; therefore, maternal smoking in combination with maternal AhR, CYP1A1 and GSTM1 genetic polymorphisms may adversely affect infant birth size.

Long-term results of treatments for varicose veins due to greater saphenous vein insufficiency.

AIM: The purpose of this study was to determine the long-term recurrence rates of greater saphenous vein (GSV) insufficiency after treatments for primary varicose veins, and to elucidate risk factors for recurrence. METHODS: This was a multicenter retrospective analysis of 376 limbs of 296 patients treated for primary varicose veins due to GSV insufficiency from January 1996 to December 1997. The recurrence-free rates after stripping surgery, saphenofemoral ligation, and sclerotherapy were estimated. The risk factors for the recurrence of primary varicose veins were estimated by multiple regression analysis. RESULTS: The follow-up period was 3.1+/-1.3 (mean+/-SD) years. The recurrence-free rates at 4 years after stripping, saphenofemoral ligation and sclerotherapy were 80.7%, 64.5%, and 51.3%, respectively. The saphenofemoral ligation group and sclerotherapy group had significantly higher recurrence rates than the stripping group (P=0.002, P<0.001, respectively). There was no difference in recurrence rates between the saphenofemoral ligation group and sclerotherapy group (P=0.074). Logistic regression analysis revealed that being female (P<0.029) and treatment without stripping (P<0.001) increased the recurrence rate. CONCLUSIONS: Stripping surgery may be the treatment of first choice for patients with varicose veins due to GSV insufficiency. Patients who have not received stripping surgery and female patients require closer follow-up.

Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias.

Hypospadias is one of the most common congenital anomalies. Increased exposure to environmental factors (endocrine-disrupting chemicals and smoking) or maternal endogenous estrogen may cause hypospadias because male sexual differentiation is dependent on normal androgen homeostasis. Moreover, interactions between genetic factors and cigarette smoking and other chemicals have been suggested. It has been demonstrated that the CYP1A1 metabolizes not only environmental chemicals but also estrogens, and glutathione-S-transferases (GSTs) are detoxification enzymes that protect cells from toxicants by conjugation with glutathione. In this study, to investigate the association of CYP1A1 (MspI), GSTM1 and GSTT1 polymorphisms with hypospadias, a case-control study of 31 case mothers who had boys with hypospadias and 64 control mothers was performed in Japan. These polymorphisms were investigated by PCR-based methods using DNA from peripheral lymphocytes. We found that the heterozygous CYP1A1 and heterozygous and homozygous CYP1A1 were less frequent in the case mothers than in the control mothers [adjusted odds ratio (OR)=0.17, 95% confidence interval (CI)=0.04-0.74, OR = 0.28, 95% CI = 0.08-0.97, respectively]. We found no effect of maternal smoking on the hypospadias risks among the gene polymorphisms. The results suggest that mothers with the CYP1A1 MspI variant allele may have a decreased risk for hypospadias.

Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss.

The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.

Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss.

The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. A case-control study of 115 cases with RPL and 160 controls was conducted. All cases and controls were women resident in Sapporo, Japan and the surrounding area. They were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1 null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36-3.66]. On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1 null genotype (OR = 0.95; 95% CI = 0.58-1.55). The results suggest that women with GSTM1 null polymorphism may therefore have an increased risk of RPL.

Relation between colour vision loss and occupational styrene exposure level.

AIMS: To investigate the relation between colour vision loss and the exposure level of styrene. Exposure level included the current exposure concentration, past cumulative exposure, and the maximum exposure level in the past. METHODS: Colour vision was examined by the Lanthony desaturated panel D-15 test for 76 subjects exposed to styrene in a fibreglass reinforced plastics boat plant (as an exposed group) and 102 non-exposed subjects (as a control group). The current exposure level was expressed by the concentration of atmospheric styrene and end shift urinary mandelic acid (MA) and phenylglyoxylic acid (PGA) levels. The individual cumulative exposure index (CEI) was calculated, based on the exposure frequency and urinary MA concentrations measured for the past eight years. RESULTS: The Colour Confusion Index (CCI) of the exposed group showed a significant difference from the age matched controls. However, only a slight significant relation was found between CCI and the concentration of urinary MA plus PGA. In this study, the exposed group was further divided into two subgroups (as sub-MA+PGA groups) by the median of urinary MA plus PGA of each subject. The dividing line between the subgroups was 0.24 g/g creatinine, which was equivalent to an atmospheric concentration of styrene of about 10 ppm. The CCI values of both the sub-MA+PGA groups were significantly higher than that of the control group. The relation between CCI value and the maximum exposure concentration in the past eight years was examined. It was found that the CCI values of the group with the maximum exposure concentration of styrene over 50 ppm were significantly higher than that of the other groups. CONCLUSIONS: Exposure to styrene would impair colour vision even if the exposure concentration was lower than 10 ppm. Furthermore, if the maximum concentration of styrene exposure transiently exceeded 50 ppm in the past, the styrene related damage might remain. Thus, the safe limit of exposure to styrene and the relation between exposure to styrene and the degree of damage to ocular structure, retina, optic nerve, and brain need to be re-examined.

Prosthetic grafts for above-knee femoropopliteal bypass. A multicenter retrospective study of 564 grafts.

BACKGROUND: Many prosthetic grafts including expanded polytetrafluoroethylene (ePTFE) and polyethylene terephthalate (Dacron) have recently been used for above-knee femoropopliteal bypass. The purpose of this study was to identify the factors affecting patency performance and patient survival. METHODS: A multicenter retrospective analysis of 496 patients who received 564 grafts between 1990 and 1999 (325 ePTFE and 239 Dacron). Follow-up extended to 114.5 months, with a mean of 30.8 months (+/-25.9 months). RESULTS: The overall primary patency rate for all grafts was 71.4% at 5 years, 73.7% for ePTFE, and 68.9% for Dacron grafts. The secondary patency rates at 5 years were 84.1% for ePTFE, and 83.8% for Dacron. No significant differences were found. The logistic regression analysis revealed that younger age at operation and smoking history were correlated with decreased primary patency rate. The patency rates were unaffected by postoperative administration of oral anticoagulants or antiplatelet agents, although pharmacotherapy contributed to the improvement of survival rates. Renal failure, cerebral infarction and Dacron decreased survival rate. CONCLUSIONS: We conclude that the patency performances of prosthetic grafts are satisfying. However, the choice of prosthetic grafts for younger patients or patients with a smoking history need to be carefully considered. Cerebral infarction, chronic renal failure and Dacron grafts may decrease the survival rate. The operative indications should be determined carefully in these cases. The administration of beraprost sodium is recommended for postoperative pharmacotherapy.

[The epidemiology of prostate cancer--recent trends in prostate cancer incidence and mortality].

Prostate cancer is one of the major malignant diseases in Western countries. In Japan, the incidence and mortality of prostate cancer is not so high, but is continuously increasing. The recent drastic increase in incidence has been attributed to the growth of the elderly population, a westernized diet in daily life, widespread environmental contamination, and improved screening techniques such as the serum PSA test. The epidemiology of prostate cancer hints that its etiology is both environmental and genetic. Androgenic stimulation over time, perhaps due to a high fat diet, has been suggested as a cause of prostate cancer. Dietary factors such as phytoestrogens, vitamins and trace elements are suggested to have a protective effect against prostate cancer, and encourage us to search for means of prevention. Some have suggested that certain polymorphisms increase the risk of prostate cancer, whereas others are searching for genetic mutations that may also increase prostate cancer risk. The cause of prostate cancer is likely to be a combination of environmental and genetic factors.

CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behaviour.

Some 3-10% of Caucasians are deficient in CYP2D6 metabolism (poor metabolizers), due to inheritance of two defective alleles, whereas amplification of the CYP2D6 gene results in ultrarapid metabolism in 1-2% of Caucasian populations. To examine the possible association between CYP2D6 polymorphism and individual smoking behaviour, we analysed the prevalence of CYP2D6 genotypes among 292 long-term heavy smokers, 382 individuals with more variable smoking histories, and 302 never-smokers. The prevalence of ultrarapid metabolizers in heavy smokers (7.9%) was twofold compared to individuals with variable smoking habits (3.7%; odds ratio 2.3, 95% confidence interval 1.2-4.4), and fourfold compared with never-smokers (2.0%) (odds ratio 4.2, 95% confidence interval 1.8-9.8). The frequency of poor metabolizer genotype was approximately 2%, in each smoker group. However, when men and women were studied separately, the prevalence of poor metabolizer genotype was higher in male never-smokers (3.6%) than in variable smokers (2.7%) and heavy smokers (2.2%). Moreover, a trend test, adjusted by age, gender and cancer status, revealed a significant trend for the increased tobacco usage with increased metabolic capacity. Our results are in agreement with the assumption that increased CYP2D6 activity may contribute to the probability of being addicted to smoking.

Effects of smoking, aromatic amines, and chromates on CD4+ and CD8+ T lymphocytes in male workers.

To investigate effects of smoking, aromatic amines (AAs), and chromates (CRs) on T lymphocyte subpopulations, we measured CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood of 33 nonexposed workers, 25 AA-use workers, 27 AA-production workers, and 19 CR workers (all subjects were males). The number of CD4+ T lymphocytes in smokers of nonexposed workers was significantly larger than that of the nonsmokers; also, the numbers of CD4+ and CD3+ T lymphocytes in smokers of each group of AA-production and AA-use workers were significantly larger than those in nonsmokers. Number of CD4+ and CD3+ T lymphocytes in nonsmokers of AA-production and CR workers were significantly smaller than those in nonsmokers of nonexposed workers; the number of CD8+ T lymphocytes in nonsmokers of CR workers was significantly smaller than that in nonsmokers of nonexposed workers. The cross-sectional study suggests that (1) smoking increases CD4+ (and CD3+) T lymphocytes in all categories of workers except for CR workers; (2) exposure to CRs and AAs decreases CD4+ (and CD3+) T lymphocytes; (3) the magnitude of decrease in CD4+ T lymphocytes is large among CR workers, intermediate among AA-production workers, and small among AA-use workers regardless of smoking status; and (4) exposure to CRs also decreases CD8+ T lymphocytes.

Analysis of toxic gas produced by heating tar epoxy resin paint to assess work atmosphere.

Two male workers were acutely intoxicated with gas produced by heating tar epoxy resin paint, and developed peripheral neuropathy. To assess the work atmosphere, we analyzed the degradation products by GC-MS. The major toxic products emitted by heating tar epoxy resin were hydrogen cyanide, phenol, and benzene, as well as naphthalene. From 1 m2 of the surface of steel plates painted with tar epoxy resin, 2.4 g of hydrogen cyanide, 9.6 g of benzene, and 1.2 g of nephthalene were produced by heating at 1000 degrees C, At 700 degrees C, the amounts of phenol and p-isopropylphenol produced were 3.7 g and 0.57 g, respectively. Based on these results and the area of steel surface burned, the concentration of hydrogen cyanide, benzene, and phenol in the atmosphere of work environment was estimated to be 16, 64 and 24 mg/m3, respectively. Some of the symptoms of the workers including peripheral neuropathy might be related to the sole or cooperative action of the foregoing toxic chemicals mentioned above.