Maternal-fetal interactions and birth order influence insulin variable number of tandem repeats allele class associations with head size at birth and childhood weight gain

Polymorphism of the insulin gene (INS) variable number of tandem repeats (VNTR; class I or class III alleles) locus has been associated with adult diseases and with birth size. Therefore, this variant is a potential contributory factor to the reported fetal origins of adult disease. In the population-based Avon Longitudinal Study of Pregnancy and Childhood birth cohort, we have confirmed in the present study the association between the INS VNTR III/III genotype and larger head circumference at birth (odds ratio [OR] 1.92, 95% CI 1.23-3.07; P = 0.004) and identified an association with higher cord blood IGF-II levels (P = 0.05 to 0.0001). The genotype association with head circumference was influenced by maternal parity (birth order): the III/III OR for larger head circumference was stronger in second and subsequent pregnancies (OR 5.0, 95% CI 2.2-11.5; P = 0.00003) than in first pregnancies (1.2, 0.6-2.2; P = 0.8; interaction with birth order, P = 0.02). During childhood, the III/III genotype remained associated with larger head circumference (P = 0.004) and was also associated with greater BMI (P = 0.03), waist circumference (P = 0.03), and higher fasting insulin levels in girls (P = 0.02). In addition, there were interactions between INS VNTR genotype and early postnatal weight gain in determining childhood BMI (P = 0.001 for interaction), weight (P = 0.005), and waist circumference (P = 0.0005), such that in the approximately 25% of children (n = 286) with rapid early postnatal weight gain, class III genotype-negative children among this group gained weight more rapidly. Our results indicate that complex prenatal and postnatal gene-maternal/fetal interactions influence size at birth and childhood risk factors for adult disease.     

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.     

Oxidative DNA damage in peripheral leukocytes and its association with expression and polymorphisms of hOGG1： A study of adolescents in a high risk region for hepatocellular carcinoma in China

AIM: To study the oxidative DNA damage to adolescents of hepatocellular carcinoma (HCC) families in Guangxi Zhuang Autonomous Region, China. METHODS: Peripheral leukocytes‘‘ DNA 7, 8-dihydro-8-oxoguanine (8-oxoG) and repair enzyme hOGG1 were quantified by flow-cytometry, hOGG1-Cys326Ser single nucleotide polymorphism (SNP) was distinguished by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) assay. RESULTS: There was a positive correlation between 8-oxoG and repair enzyme hOGG1 expression (P&lt;0.001). HCC children (n=21) in Fusui county had a higher level of hOGG1(P&lt;0.01) and a lower level of 8-oxoG (P&lt;0.05) than the controls (n=63) in Nanning city. Children in Nanning exposed to passive-smoking had a higher hOGG1 expression (P&lt;0.05)than the non-exposers. 8-oxoG and hOGG1 were negatively correlated with body mass index, while hOGG1 was positively correlated with age. There was a peak of 8-oxoG level nearby the 12 year point. Individuals with the hOGG, 326Ser allele had a significantly marginal higher concentration of leukocyte 8-oxoG level than hOGG1 326Cys allele. CONCLUSION: This is the first report using flow-cytometry to simultaneously quantify both the DNA oxidative damage and its repairing enzyme hOGG1. The results provide new insights towards a better understanding of the mechanisms of oxidative stress in a population highly susceptible to hepatocarcinogenesis.     

The streptozotocin-diabetic rat as a model of the chronic complications of human diabetes

BACKGROUND: Diabetes in humans induces chronic complications such as cardiovascular damage, cataracts and retinopathy, nephropathy and polyneuropathy. The most common animal model of human diabetes is streptozotocin (STZ)-induced diabetes in the rat. METHODS: This project assessed cardiovascular, ocular and neuropathic changes over a period of 24 weeks post STZ administration in rats. RESULTS: STZ-diabetic rats (n = 96) showed stable signs of diabetes (hyperglycaemia, increased water and food intake with no increase in bodyweight): 52% of untreated STZ-diabetic rats (n = 50) survived 24 weeks after STZ administration. STZ-diabetic rats were normotensive with slowly developing systolic and diastolic dysfunction and an increased ventricular stiffness. Ventricular action potential durations were markedly prolonged. STZ-diabetic rats developed stable tactile allodynia. Cataracts developed to presumed blindness at 16 weeks but proliferative retinopathy was not observed even after 24 weeks. CONCLUSION: The chronic STZ-diabetic rat mimics many but not all of the chronic complications observed in the diabetic human. The chronic STZ-diabetic rat may be a useful model to test therapeutic approaches for amelioration of chronic diabetic complications in humans.     

Peri-implant soft tissue integration of immediately loaded implants in the posterior macaque mandible: a histomorphometric study

BACKGROUND: Today, one critical goal in implant placement is the achievement of optimal soft tissue integration. Reports thus far have demonstrated successful soft tissue preservation in delayed loaded implants placed in anterior jaws. The aim of this study was to histomorphometrically examine the soft tissues around immediately loaded implants placed in the macaque posterior mandible. METHODS: Splinted crowns on screw-shaped titanium implants (8 mm length, 3.5 mm diameter) were utilized. Three implants each were placed in the premolar-molar edentulous mandibular segments of 6 adult monkeys (Macaca fascicularis); one side served as the control (delayed loading) and the other as the test sites (immediate loading). The animals were sacrificed after 3 months of loading. Histomorphometry of 6 soft tissue indices including the sulcus depth (SD), junctional epithelium (JE), connective tissue contact (CTC), biologic width (BW = SD + JE + CTC), DIM (distance between the implant top and coronal gingiva), and DIB (distance between the implant top and first implant-to-bone contact) was performed on non-decalcified sections. RESULTS: No significant differences in the mean soft tissue scores (mm) between the test (SD = 0.68 +/- 0.63; JE = 1.71 +/- 1.04; CTC = 1.51 +/- 1.14; DIM = 2.27 +/- 1.18; DIB = 1.32 +/- 1.21; BW = 3.9) and control (SD = 0.88 + 0.57; JE = 1.66 + 0.77; CTC = 1.24 +/- 0.92; DIM = 2.38 +/- 0.81; DIB = 1.19 +/- 0.91; BW = 3.78) groups were observed (P > 0.01). CONCLUSION: These findings suggest that the dimensions of the peri-implant soft tissues were within the biologic range and were not influenced by immediate functional loading or posterior location of the implants in the macaque mandible.     

Effect of plasma-glow discharge as a sterilization of titanium surfaces

In this study, in vitro osteoblast responses to glow-discharged, commercially pure titanium (Ti) surfaces were investigated. It was hypothesized that the glow-discharge treatment would be an effective sterilization procedure for Ti implantations before implantation. The Ti surfaces were prepared by grinding to 600 grits followed by cleaning. These were then divided into two groups, with one group being the control and the other group undergoing glow-discharge treatment using oxygen. Human embryonic palatal mesenchyme cells, an osteoblast precursor, were used to evaluate the cell responses to glow-discharged and control Ti surfaces. It was observed from this study that protein production and osteocalcin production on both surfaces exhibited no significant differences during the 10-day study. Similarly, no significant differences were observed for alkaline phosphatase (ALP) specific activity during the first 7 days of incubation. However, at day 10, the ALP specific activity for control Ti surfaces was significantly higher than the ALP activity for the glow-discharged surface. Overall, this study suggested that the use of glow discharge as an alternative sterilization procedure for medical and dental implants did not inhibit osteoblast phenotypic expression.     

Simultaneous determination of tocotrienols, tocopherols, retinol, and major carotenoids in human plasma

BACKGROUND: Epidemiologic evidence suggests that the concentrations of antioxidant vitamins in human plasma may play an important role in numerous chronic diseases, such as cancer and cardiovascular disease. However, methods for simultaneous measurement of these antioxidants are scarce. We developed and validated a new HPLC method for simultaneous determination of these vitamers in human plasma that uses a novel column-switching approach. METHODS: The new method uses liquid-liquid extraction and isocratic separation with two monomeric C(18) columns maintained at 35 and 4 degrees C coupled with ultraviolet-visible and fluorometric detection. This method could separate 14 vitamers and 3 internal standards within 27 min. No additional modifier was required; the mobile phase was acetonitrile-methanol (65:35 by volume), and the flow rate was 1 mL/min. RESULTS: For photodiode array detection, the detection limits (signal-to-noise ratio >3) were 0.02 mg/L for beta-carotene, lutein, zeaxanthin, and canthaxanthin; 0.01 mg/L for all-trans-retinol, beta-cryptoxanthin, alpha-carotene, and lycopene; and 0.1 mg/L for all tocopherols and tocotrienols. The detection limit was at least 25-fold lower (0.004 mg/L) when fluorometry was used for measurement of delta-, gamma-, and alpha-tocotrienol and delta-tocopherol compared with ultraviolet detection. The recovery and imprecision of the assay were generally >90% and <10%, respectively. CONCLUSIONS: This new method separates a wide range of fat-soluble antioxidant vitamins in human plasma, including six carotenoids, three isoforms of tocotrienols and tocopherols (delta-, gamma-, and alpha-), and all-trans-retinol. The overall findings suggest that our method is faster, more sensitive, and more comprehensive than existing methods.     

Endocarditis caused by Staphylococcus lugdunensis

We describe a case of native valve endocarditis caused by Staphylococcus lugdunensis, a perineal skin commensal, and review 28 other cases from the medical literature. Correctly identifying this coagulase-negative organism is critical because endocarditis is usually associated with left sided valvular disruption and life-threatening embolic complications, reminiscent of disease caused by Staphylococcus aureus. Urgent surgical intervention is necessary in most cases.