Dizygotic twinning is not associated with methylenetetrahydrofolate reductase haplotypes

Background: Folate metabolism is critical to embryonic development, influencing neural tube defects (NTD) and recurrent early pregnancy loss. Polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with dizygotic (DZ) twinning through pregnancy loss. Methods: The C677T and A1298C polymorphisms in MTHFR were genotyped in 258 Australasian families (1016 individuals) and 118 Dutch families (462 individuals) of mothers of DZ twins and a population sample of 462 adolescent twin families (1861 individuals). Haplotypes were constructed from the alleles, and transmission of the MTHFR haplotypes to mothers of DZ twins and from parents to twins in the adolescent twin families analysed. Results: The C677T and A1298C were common in all three populations (frequencies > 0.29). There was strong linkage disequilibrium (D'=1) between the variants, showing that specific combinations of alleles (haplotypes) were transmitted together. Three haplotypes accounted for nearly all the variation. There was no evidence of any association between MTHFR genotype and twinning in mothers of twins, or of the loss of specific MTHFR genotypes during twin pregnancies. Conclusions: It is concluded that variation in twinning frequency is not associated with MTHFR genotype.

Provision of 4-1BB ligand enhances effector and memory CTL responses generated by immunization with dendritic cells expressing a human tumor-associated antigen

Up-regulation of receptor-ligand pairs during interaction of an MHC-presented epitope on dendritic cells (DCs) with cognate TCR may amplify, sustain, and drive diversity in the ensuing T cell immune response. Members of the TNF ligand superfamily and the TNFR superfamily contribute to this costimulatory molecule signaling. In this study, we used replication deficient adenoviruses to introduce a model tumor-associated Ag (the E7 oncoprotein of human papillomavirus 16) and the T cell costimulatory molecule 4-IBBL into murine DCs, and monitored the ability of these recombinant DO to elicit E7-directed T cell responses following immunization. Splenocytes from mice immunized with DCs expressing E7 alone elicited E7-directed effector and memory CTL responses. Coexpression of 4-1BBL in these E7-expressing DO increased effector and memory CTL responses when they were used for immunization. 4-1BBL expression up-regulated CD80 and CD86 second signaling molecules in DO. We also report an additive effect of 4-IBBL and receptor activator of NF-kappaB/receptor activator of NF-kappaB ligand coexpression in E7-transduced DC inummogens on E7-directed effector and memory CTL responses and on MHC class II and CD80/86 expression in DCs. Additionally, expression of 4-1BBL in E7-transduced DCs reduced nonspecific T cell activation characteristic of adenovirus vector-associated immunization. The results have generic implications for improved or tumor Ag-expressing DC vaccines by incorporation of exogenous 4-1BBL. There are also specific implications for an improved DC-based vaccine for human papillomavirus 16-associated cervical carcinoma.

Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis

Background The mechanisms responsible for disturbed iron homoeostasis in hereditary haemochromatosis are poorly understood. However, results of some studies indicate a link between hepcidin, a liver-derived peptide, and intestinal iron absorption, suggesting that this molecule could play a part in hepatic iron overload. To investigate this possible association, we studied the hepatic expression of the gene for hepcidin (HAMP) and a gene important in iron transport (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe-knockout mice. Methods We extracted total RNA from the liver tissue of 27 patients with HFE-associated haemochromatosis, seven transplant donors (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were examined by ribonuclease protection assays and expressed relative to the housekeeping gene GAPD. Findings There was a significant decrease in HAMP expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3-7.5; p

Link invariants associated with gauge equivalent solutions of the Yang-Baxter equation: The one-parameter family of minimal typical representations of Uq[gl(2|1)]

In this paper we investigate the construction of state models for link invariants using representations of the braid group obtained from various gauge choices for a solution of the trigonometric Yang-Baxter equation. Our results show that it is possible to obtain invariants of regular isotopy (as defined by Kauffman) which may not be ambient isotopic. We illustrate our results with explicit computations using solutions of the trigonometric Yang-Baxter equation associated with the one-parameter family of minimal typical representations of the quantum superalgebra U-q,[gl(2/1)]. We have implemented MATHEMATICA code to evaluate the invariants for all prime knots up to 10 crossings.

Acquired myasthenia gravis associated with a non-invasive thymic carcinoma in a dog

An 8 1/2-year-old neutered male Beagle was diagnosed with acquired myasthenia gravis associated with a non-invasive thymic carcinoma. The thymic mass was surgically excised and the dog was treated with pyridostigmine, prednisolone and azathioprine. Serial acetylcholine receptor antibody titres were increased initially but slowly declined to normal values over a period of 24 weeks. Improved exercise tolerance was seen following therapy, however, oesophageal dysfunction persisted. The dog was euthanased 26 weeks after initial presentation due to a complicating illness. A necropsy showed no regrowth or metastasis of the thymic carcinoma.

Effects of combined low-density lipoprotein apheresis and aggressive statin therapy on coronary calcified plaque as measured by computed tomography

Eight patients with heterozygous familial hypercholesterolemia who received combined long-term low-density lipoprotein apheresis and high-dose statin therapy showed a significant decrease in volume of coronary calcium over a period of 29 months as measured by, computed tomography. This suggests that the effects of aggressive lipid-lowering therapy can be assessed non-invasively and may be used as surrogate end points when testing new therapies.

In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy

Background/Aims: Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression. Methods: Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin. Results: Patients with viral genotype 3 had more severe steatosis (P = 0.0001) and developed stages 1 and 2 fibrosis at a younger age (P < 0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P = 0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P = 0.046) but not inflammation (P = 0.83). There was no association between serum leptin levels and stage of fibrosis. Conclusions: Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Obesity is associated with worse peritoneal dialysis outcomes in the Australia and New Zealand patient populations

Although obesity is associated with increased risks of morbidity and death in the general population, a number of studies of patients undergoing hemodialysis have demonstrated that increasing body mass index (BMI) is correlated with decreased mortality risk. Whether this association holds true among patients treated with peritoneal dialysis (PD) has been less well studied. The aim of this investigation was to examine the association between BMI and outcomes among new PD patients in a large cohort, with long-term follow-up monitoring. Using data from the Australia and New Zealand Dialysis and Transplant Registry, an analysis of all new adult patients (n = 9679) who underwent an episode of PD treatment in Australia or New Zealand between April 1, 1991, and March 31, 2002, was performed. Patients were classified as obese (BMI of greater than or equal to30 kg/m(2)), overweight (BMI of 25.0 to 29.9 kg/m(2)), normal weight (BMI of 20 to 24.9 kg/m(2)), or underweight (BMI of

Gender differences in CF phenotype associated with low bone mineral density

Adolescents and adults with CF have lower bone mineral density (BMD) than normal, but its relationship with phenotype is not well understood. Point FEV1% predicted (FEV) and rate of change of FEV are biased estimates of disease severity, because progressively older subjects represent a selected survivor population, with females at greater risk of death than males. To investigate the relationship between BMD and phenotype we used an index (predicted age at death) derived from Bayesian estimates of slope and intercept of FEV, age at last measurement and survival status. Predictive equations for the index were derived from 97 subjects (78 survivors) from the RCH CF clinic, and applied to a group of 102 comparable subjects who had BMD measured, classified as having‘mild’ ()75th), ‘moderate’ (25– 75th), or ‘severe’ (-25th centile) phenotype. Total body (TB) and lumbar spine (LS) BMD z-scores (Z) were compared, adjustingfor gender effects, using 2-way ANOVA. Annual mean change in FEV segregated, as expected, according to phenotype, ‘severe’ (ns25), ‘moderate’ (ns51) and ‘mild’ (ns25) y3.01(y3.73 to y2.30)%, y0.85(y1.36 to y0.35)%, 2.70(1.92 to 3.46)%, respectively, with no gender difference. LS and TB BMDZ were different in each phenotype (P-s 0.002), LS BMDZ for ‘severe’, ‘moderate’ and ‘mild’ y1.63(CI: y2.07 to y 1.19), y0.86(CI: y1.17 to y0.55), y0.06(CI: y0.54 to 0.41). Males had lower LS BMDZ than females overall (y1.22 (CI: y1.54 to y0.91) vs. y0.48(CI: y 0.84 to y0.12) Ps0.002). In the ‘severe’ group, males had lower TB BMDZ and LS BMDZ (PF0.002). Low BMD is associated with ‘moderate’ and ‘severe’ phenotypes, with relative preservation in females in the ‘severe’ group. Female biology (reproductive fitness) might promote resistance to bone resorption at a critical level of BMD loss.