DNA methyltransferase and alcohol dehydrogenase: gene-nutrient interactions in relation to risk of colorectal polyps.

Disturbances in DNA methylation are a characteristic of colorectal carcinogenesis. Folate-mediated one-carbon metabolism is essential for providing one-carbon groups for DNA methylation via DNA methyltransferases (DNMTs). Alcohol, a folate antagonist, could adversely affect one-carbon metabolism. In a case-control study of colorectal polyps, we evaluated three single nucleotide polymorphisms (-149C>T, -283T>C, -579G>T) in the promoter region of the DNMT3b gene, and a functional polymorphism in the coding region of the alcohol dehydrogenase ADH1C gene, ADH1C *2. Cases had a first diagnosis of colorectal adenomatous (n = 530) or hyperplastic (n = 202) polyps at the time of colonoscopy, whereas controls were polyp-free (n = 649). Multivariate logistic regression analysis was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). There were no significant main associations between the DNMT3b or ADH1C polymorphisms and polyp risk. However, DNMT3b -149TT was associated with an increase in adenoma risk among individuals with low folate and methionine intake (OR, 2.00; 95% CI, 1.06-3.78, P interaction = 0.10). The ADH1C *2/*2 genotype was associated with a possibly elevated risk for adenomatous polyps among individuals who consumed >26 g of alcohol/d (OR, 1.95; 95% CI, 0.60-6.30), whereas individuals who were wild-type for ADH1C were not at increased risk of adenoma (P interaction = 0.01). These gene-diet interactions suggest that polymorphisms relevant to DNA methylation or alcohol metabolism may play a role in colorectal carcinogenesis in conjunction with a high-risk diet.     

Estimating the role of casual contact from the community in transmission of Bordetella pertussis to young infants

The proportion of infant pertussis cases due to transmission from fcasual contact in the community has not been estimated since before the introduction of pertussis vaccines in the 1950s. This study aimed to estimate the proportion of pertussis transmission due to casual contact using demographic and clinical data from a study of 95 infant pertussis cases and their close contacts enrolled at 14 hospitals in France, Germany, Canada, and the U.S. between February 2003 and September 2004. A complete case analysis was conducted as well as multiple imputation (MI) to account for missing data for participants and close contacts who did not participate. By considering all possible close contacts, the MI analysis estimated 66% of source cases were close contacts, implying the minimum attributable proportion of infant cases due to transmission from casual contact with community members was 34% (95% CI = 24%, 44%). Estimates from the complete case analysis were comparable but less precise. Results were sensitive to changes in the operational definition of a source case, which broadened the range of MI point estimates of transmission from casual community contact to 20%–47%. We conclude that casual contact appears to be responsible for a substantial proportion of pertussis transmission to young infants.     

The role of the pediatrician in abolishing corporal punishment in schools. Committee on School Health, American Academy of Pediatrics

Corporal punishment in school is allowed in 30 states in the United States. The American Academy of Pediatrics, together with numerous other child-advocacy groups, has reaffirmed its position that corporal punishment in schools should be prohibited by state statute in all states. This article provides background information and recommendations regarding the potential role for pediatricians in attaining this goal.     

A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group

We obtained original individual data from 15 studies of magnetic fields or wire codes and childhood leukemia, and we estimated magnetic field exposure for subjects with sufficient data to do so. Summary estimates from 12 studies that supplied magnetic field measures exhibited little or no association of magnetic fields with leukemia when comparing 0.1-0.2 and 0.2-0.3 microtesla (microT) categories with the 0-0.1 microT category, but the Mantel-Haenszel summary odds ratio comparing >0.3 microT to 0-0.1 microT was 1.7 (95% confidence limits = 1.2, 2.3). Similar results were obtained using covariate adjustment and spline regression. The study-specific relations appeared consistent despite the numerous methodologic differences among the studies. The association of wire codes with leukemia varied considerably across studies, with odds ratio estimates for very high current vs low current configurations ranging from 0.7 to 3.0 (homogeneity P = 0.005). Based on a survey of household magnetic fields, an estimate of the U.S. population attributable fraction of childhood leukemia associated with residential exposure is 3% (95% confidence limits = -2%, 8%). Our results contradict the idea that the magnetic field association with leukemia is less consistent than the wire code association with leukemia, although analysis of the four studies with both measures indicates that the wire code association is not explained by measured fields. The results also suggest that appreciable magnetic field effects, if any, may be concentrated among relatively high and uncommon exposures, and that studies of highly exposed populations would be needed to clarify the relation of magnetic fields to childhood leukemia.     

Etoposide protein binding in cancer patients

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r=–0.74), daily dose (r=–0.37) and age (r=–0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.     

Expression of cd44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential

Expression of CD44, particularly of certain splice variants, has been linked to tumor progression and metastasis formation in a number of different animal and human cancers. Because human cutaneous melanoma is among the most aggressive human cancers, we explored expression of CD44 isoforms (CD44v) in lesions of melanocytic tumor progression. In addition, by RT-PCR and FACS analysis we assessed CD44v RNA species and cell surface expression of CD44v in cultured melanocytes isolated from human foreskin and in a panel of 2 non-, 2 sporadically and 2 highly metastatic human melanoma cell lines. We observed that all melanocytic lesions examined showed strong uniform expression of standard CD44 (CD44s) epitopes. We did not detect CD44v6 expression in the melanocytic lesions. However, CD44 isoforms containing v5 or v10 were differentially expressed. V5 was expressed in 16%, 0%, 20%, 67% and 58% of common nevi, atypical nevi, early primary melanomas (± 1.5 mm), advanced primary melanomas (> 1.5 mm) and metastases, respectively, and hence was related to tumor progression. In contrast, CD44vl0 was expressed in all common nevi, whereas part of the atypical nevi and most primary melanomas and metastases lacked v10. CD44v RNA patterns were closely similar in cultured melanocytes and all melanoma cell lines. Melanocytes expressed high levels of CD44s but no CD44v, whereas all melanoma cell lines expressed CD44v at the surface. Interestingly, expression of v5 was strongly increased in the highly metastatic cell lines. Our results suggest a role for CD44 variant domains, particularly v5 and v10, in human melanocytic tumor progression. © 1995 Wiley-Liss, Inc.     

Prostaglandins and other metabolites of arachidonic acid. An overview for the otolaryngologist

Metabolites of arachidonic acid have important regulatory functions within several areas of concern to the otolaryngologist. Prostaglandins, composing one group, are involved in smooth-muscle contraction, regulation of renal glomerular blood flow, and in the modulation of immune and allergic responses, inflammation, fever, pain, and tumor growth. A second group, the leukotrienes, may be even more important than prostaglandins in allergy and inflammation. The elusive slow-reacting substance of anaphylaxis belongs in this group. Two other metabolites, thromboxane and prostacyclin, seem to be critical in hemostasis and the metastatic spread of tumors.     

Strain dependent effects of sex hormones on hepatocarcinogenesis in mice

In order to study the interaction of genetic and hormonal factorsduring murine hepatocarcinogenesis, we compared the number ofliver tumors induced by treatment of 12-day-old mice with N-N-diethyInitrosamine(DEN) (0.05µmol/ body wt) in intact mice and animals gonadectomizedat 8 weeks of age from the three inbred strains, C3H/HeJ (C3H),C57BL/6J (B6), and C57BR/cdJ (BR). At 50 weeks of age, the meanliver tumormultiplicity in intact BR females was 28 ±13, while that for intact female C3H and B6 mice was 1.4 ±4.7and0.5 ± 1.0, respectively. In ovariectomized mice, theyield of liver tumors was     

Outcome of treatment of respiratory tract infections due to Streptococcus pneumoniae,including drug-resistant strains,with pharmacokinetically enhanced amoxycillin/clavulanate

The efficacy of a new pharmacokinetically enhanced formulation of amoxycillin/clavulanate (AMX/CA) 2000/125 mg, twice daily, designed to provide adequate levels of amoxycillin over the 12-h dosing interval to eradicate penicillin-resistant Streptococcus pneumoniae (PRSP) with amoxycillin (+/-clavulanic acid) MICs of /=4 mg/l. In the pooled comparator group, the success rate at follow-up was 86.5% (45/52). For PRSP (AMX/CA MICs of 0.5-8 mg/l), the overall success rate was 98.2% (55/56) at follow-up for AMX/CA 2000/125 mg and 50.0% (2/4) for comparators. AMX/CA 2000/125 mg shows efficacy comparable to that of the comparators evaluated against S. pneumoniae infections. Due to its favorable pharmacokinetic/pharmacodynamic profile and promising clinical success, the new AMX/CA 2000/125 mg formulation should be considered for the empirical treatment of respiratory tract infections in regions with a high prevalence of antimicrobial-resistant S. pneumoniae and in patients at high risk of antimicrobial-resistant S. pneumoniae infection as this formulation covers many PRSP that are non-susceptible to amoxycillin (+/-clavulanic acid) (MICs of >/=4 mg/l) as well as common beta-lactamase-producing respiratory pathogens.     

McLeod syndrome resulting from a novel XK mutation

McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.