The prevalence of hepatitis C in survivors of paediatric malignancy

Objective: To assess the prevalence of hepatitis C in 200 patients with paediatric malignancies, surviving in remission more than 5 years from diagnosis, who had received blood product transfusions before 1990 when routine screening of blood products for hepatitis C began.
Method: The second and third generation Abbott Diagnostics ELISA was used to assess hepatitis C seropositivity. Seropositive patients and those with abnormal liver transaminases were assessed by hepatitis C virus RNA polymerase chain reaction (PCR).
Results: A low incidence (4%) of seropositivity for hepatitis C was found in survivors of paediatric malignancy who were transfused prior to routine screening of blood products in this cohort.
Conclusions: All patients identified have evidence of hepatitis and may be at high risk of developing cirrhosis.     

Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta- carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.      

Estrogen treatment enhances hereditary renal tumor development in Eker rats

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.      

Virulent Salmonella typhimurium has two periplasmic Cu, Zn-superoxide dismutases

Periplasmic Cu, Zn-cofactored superoxide dismutase (SodC) protects Gram-negative bacteria from exogenous oxidative damage. The virulent Salmonella typhimurium strain ATCC 14028s has been found to contain two discrete periplasmic Cu, Zn-SOD enzymes that are only 57% identical at the amino acid level. SodCI is carried by a cryptic bacteriophage, and SodCII is closely related to the Cu, Zn-superoxide dismutase of Escherichia coli. All Salmonella serotypes appear to carry the sodCII locus, but the phage-associated sodCI gene is found only in certain strains belonging to the most highly pathogenic serotypes. Expression of either sodC locus appears to be enhanced during stationary phase, but only sodCII is regulated by the alternative sigma factor sigmas (RpoS). Mutants lacking both sodC genes are less lethal for mice than mutants possessing either sodC locus alone, indicating that both Cu, Zn-SOD enzymes contribute to Salmonella pathogenicity. The evolutionary acquisition of an additional sodC gene has contributed to the enhanced virulence of selected Salmonella strains.     

Linkage disequilibrium mapping of the Nova Scotia variant of Niemann–Pick disease

Niemann-Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13-cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232-235) recently demonstrated that one of these ESTs is the Niemann-Pick type C (NPCI) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097-->T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1-cM (1.3-1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5-cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.     

Prevalence of HLA sensitization in female apheresis donors

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a serious complication of plasma-containing blood components. Studies have implicated HLA antibodies along with biologically active lipids in stored blood in the pathogenesis of TRALI. It has been proposed that the exclusion of HLA-untested, multiparous donors of plasma-rich components, including plasma and single-donor apheresis platelets, would substantially reduce the risk of TRALI. STUDY DESIGN AND METHODS: To investigate the feasibility of such an exclusion, 332 female plateletpheresis donors with a record of over 9000 donations, none of which were associated with TRALI, were studied. RESULTS: Seventeen percent of female donors demonstrated HLA sensitization. Parity and HLA sensitization were significantly correlated (p<0.0001), with sensitized donors having an average of 2.9 (+/− 0.6 95% CI) prior pregnancies and unsensitized donors having an average of 1.8 (+/− 0.2 95% CI) prior pregnancies. The percentage of HLA-sensitized women with 0, 1 to 2, and > or = 3 pregnancies was 7.8, 14.6, and 26.3, respectively. CONCLUSION: These findings confirm the hypothesis that multiparous women (> or = 3 pregnancies) represent an increased potential risk for TRALI. However, the exclusion of multiparous plateletpheresis donors would eliminate one-third of our female donor pool. Screening such donors for HLA sensitization may represent the optimal approach for identifying donors at risk for causing TRALI, but this still would result in the deferral of 8 percent of female plateletpheresis donors. At present, prospective screening to identify donors at risk for causing TRALI is not justified.     

2Endoscopic temporary gastric electrical stimulation – results of 140 consecutive patients

Background: Gastric emptying is a function of gastric contraction, electrical activity, pyloric and duodenal resistance. Pylorospasm (basal pyloric pressures >10 mmHg; Mearin et al. Gastro 1986) has been implicated in gastroparesis. Currently, pyloric pressures can be measured invasively, using a Dent sleeve (Mui Scientific, Inc.) manometry catheter. Electrogastrography (EGG) is a noninvasive tool for measuring gastric myoelectrical activity. EGG has been shown to distinguish gastric outlet obstruction from idiopathic gastroparesis (Brzana et al. Amer J Gastro 1998). Aims: The aims of this study were to 1) determine whether EGG can distinguish patients with gastroparesis who have pylorospasm and 2) correlate basal pyloric pressure with various EGG parameters. Methods and Results: 23 patients with gastroparesis (19 diabetics, mean age 40.4 ± 2.3, mean 4 hr gastric retention 43.0 ± 5.1%) had basal pyloric pressure measurements and EGG. Stationary basal pyloric pressures were measured using a Dent sleeve that was placed across the pyloric channel during endoscopy with fluoroscopic guidance. 60.9% (14/23) of patients had elevated pyloric pressures (21.8 ± 3.4 mmHg vs. 5.5 ± 0.8 mmHg). There was no difference in the postprandial power ratio and gastric emptying as measured by scintigraphy between the 2 groups. The fasting dominant slow wave frequency (SWF) in the elevated pyloric pressure group was significantly higher compared to the normal pyloric pressure group (3.1 ± 0.1 cpm vs. 2.4 ± 0.3 cpm; p = 0.013). There was significantly less dysrhythmia in the elevated pyloric pressure group (75.5 ± 6.0% normal rhythm vs. 54.8 ± 9.7% normal; p = 0.03). More patients in the elevated pyloric pressure group had normal fasting electrical rhythm (>70% normal electrical rhythm) compared to the normal pyloric pressure group (64.3% vs. 22.2%; p = 0.03). There was a correlation between pyloric pressure and fasting slow wave frequency (r = 0.53, p = 0.005) but no correlation with the percentage of dysrhythmia, postprandial power ratio or gastric emptying. Conclusion: Patients with normal pyloric pressure and delayed gastric emptying have significantly more abnormalities in slow wave frequency and dysrhythmia compared to patients with abnormal pyloric pressure. This suggests that patients with delayed gastric emptying with normal pyloric pressures have abnormalities in gastric conduction as a cause of their gastroparesis.     

Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations

PURPOSE： Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities.     

Magnetic resonance imaging and spectroscopy of hepatic iron overload

Experimental animals that had been given excess iron in their diet were studied by magnetic resonance (MR) imaging in vivo and by magnetic resonance (MR) spectroscopy in vitro. Hepatic iron overload in patients with transfusional iron excess was studied by MR imaging, and isolated iron protein fractions were studied in vitro by MR spectroscopy. The spin echo image intensity of livers with iron overload was decreased because of the extreme decreases in T2 compared with normal; T1 was decreased only moderately. The relaxation rates 1/T2 and 1/T1 both showed a linear relationship to hepatic iron levels. Ferritin solutions showed moderate decreases in T2 and mild decreases in T1. The T2 relaxivity of ferritin, which is due to the iron core rather than the apoferritin protein shell, does not appear sufficient to account for the extreme decrease in T2 observed in hepatic iron overload. Low molecular weight cytosol iron is present in lower concentrations than ferritin but potentially has much greater relaxivity and may contribute to the MR findings. These techniques may be useful in other studies of iron metabolism.