MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.     

Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway.

INTRODUCTION: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Although inhibition of cyclooxygenase (COX)-2 is generally thought to be the relevant mechanism, aspirin-like drugs apparently are involved in other pathways and mechanisms. We explore the associations between aspirin/NSAIDs, the insulin-related pathway, and the risk of colorectal cancer. METHODS: Genetic polymorphisms of five genes identified as being involved in an insulin-related pathway were genotyped using data collected in a case-control study of 1346 incident colon cancer cases and 1544 population-based controls and 952 incident rectal cancer cases and 1205 controls. Genotypes assessed were the 3' untranslated region poly(A) and the intron 8 BsmI polymorphisms of the VDR gene, a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the Gly972Arg polymorphism of the IRS1 gene, and the Gly1057Asp polymorphism of the IRS2 gene. RESULTS: Use of aspirin and NSAIDs was associated with a decreased risk of colorectal cancer, with slightly greater protection from NSAIDs than aspirin for rectal cancer. We observed a significant interaction between IRS1 genotype and aspirin/NSAIDs use and risk of colorectal cancer. Relative to the GR/RR IRS1 genotype, a protective effect from the GG IRS1 genotype was seen in those who did not use NSAIDs; use of NSAIDs was protective for all genotypes. These associations were especially strong for those diagnosed prior to age 65 (P interaction = 0.0006). We also observed a significant interaction between aspirin/NSAIDs use and the VDR gene. Having the SS or BB VDR genotypes reduced risk of colorectal cancer among non-aspirin/NSAID users; however, aspirin/NSAIDs reduced risk for all VDR genotypes. CONCLUSIONS: These data support the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs and IRS1 and VDR genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.     

Immune deficiencies in chronic intestinal pseudo-obstruction

Aim: Chronic intestinal pseudo-obstruction has been associated with urinary disorders, myopathy, and ophthalmoplegia in adults and cholelithiasis in children. We observed a high percentage of total-parenteral-nutrition-dependent patients with pseudo-obstruction and recurrent infections requiring gammaglobulin infusions. Methods: AH records for 23 children with chronic intestinal pseudo-obstruction (10 females and 13 males, mean age 9.8 y ± 4.9 y, range 4–24 y) referred for a nutritional evaluation from 1992 to 1995 were reviewed. Chronic intestinal pseudo-obstruction was diagnosed by clinical, radiographic findings and antroduodenal manometry. Intestinal full-thickness biopsies were performed in seven children. Results: Hypogammaglobulinemia was diagnosed in 18 patients (78%): 16 patients had various immunoglobulin deficiencies and 2 had selective antibody deficiency. Intravenous gammaglobulin was administered in 14 patients. Other medical conditions affecting the children are summarized as follows: autonomic dysfunction in 10 patients (43%), recurrent hypoglycemia in 9 (39%), asthma in 9 (39%), cholecystitis in 7 (30%), low serum carnitine level in 6 (26%), urinary dysfunction in 6 (26%), pancreatitis in 5 (22%), behavioral problems in 5 (22%), myopathy in 2 (9%), idiopathic thrombocytopenia in 2 (8%), velopharyngeal insufficiency in 1 (4%), oculocutaneous albinism in 1 (4%), Pierre-Robin syndrome in 1 (4%), and protein C deficiency in 1 (4%). Munchausen syndrome was suspected in two patients. Conclusions: Chronic intestinal pseudo-obstruction appears to be associated with immune deficiencies. It is unclear if the immune deficiencies, intestinal pseudo-obstruction, and the other medical conditions have a common underlying etiology. Repeated infections may be due to impaired immune function in children with chronic intestinal pseudo-obstruction. We recommend screening for immune deficiencies in children with chronic intestinal pseudo-obstruction.     

The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies

The objective of this study was to examine the effects of the intakeof dietary fat upon colorectal cancer risk in a combined analysis of datafrom 13 case-control studies previously conducted in populations withdiffering colorectal cancer rates and dietary practices. Original datarecords for 5,287 cases of colorectal cancer and 10,470 controls werecombined. Logistic regression analysis was used to estimate odds ratios (OR)for intakes of total energy, total fat and its components, and cholesterol.Positive associations with energy intake were observed for 11 of the 13studies. However, there was little, if any, evidence of anyenergy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01,1.02, and 0.92 for quintiles of residuals of total fat intake (P trend =0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (Ptrend = 0.39). The analysis suggests that, among these case-control studies,there is no energy-independent association between dietary fat intake andrisk of colorectal cancer. It also suggests that simple substitution of fatby other sources of calories is unlikely to reduce meaningfully the risk ofcolorectal cancer.     

The evolution of surgical approaches for posterior fossa meningiomas.

OBJECTIVE: To evaluate surgical outcomes for the treatment of posterior fossa meningiomas at the House Ear Clinic from 1987 to 2001. We review our current treatment algorithm and present our postoperative outcomes with attention to facial and auditory neural preservation. STUDY DESIGN: Retrospective review. SETTING: Tertiary care center. PATIENTS: Medical records of 71 patients who underwent posterior fossa meningioma surgery at the House Ear Clinic were reviewed. INTERVENTION: All patients had surgical removal of their meningioma via translabyrinthine, transcochlear, retrosigmoid, extended middle fossa, or combined petrosal approaches by House Ear Clinic neurotologists and neurosurgeons. MAIN OUTCOME MEASURES: Preoperative and postoperative auditory and facial nerve function data were collected. Patient and tumor characteristics including presenting symptoms, completion of tumor resection, and complications secondary to surgery were also recorded. RESULTS: The most common presenting symptoms in this series were otologic, with hearing loss (61%), tinnitus (58%), and imbalance (58%) as the three most common. Gross total resection was achieved in 67 (94%) patients. Hearing-preservation surgery was attempted in 37 (52%) patients (68% via extended middle fossa or combined approach). Twenty-one patients with preoperative Class A hearing had follow-up audiometric data and 18 (86%) had serviceable hearing preserved. Excluding transcochlear craniotomies, 85% of patients had normal facial nerve function postoperatively. Cerebrospinal fluid leak (6%) was the most common complication. CONCLUSIONS: Advances in microsurgical techniques have greatly changed our management of patients with posterior fossa meningiomas. These changes have reduced postoperative morbidity. Specifically, use of the anterior and posterior petrosal approaches has facilitated facial and auditory neural preservation while not compromising the extent of tumor excision.     

Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects.

OBJECTIVE: To determine the amount of growth in vestibular schwannomas in Neurofibromatosis type 2 (NF2) patients from diagnosis through short-term (up to 2 yr) and long-term (up to 4 yr) follow-up. STUDY DESIGN: Retrospective magnetic resonance imaging (MRI) films were obtained on subjects enrolled in the NF2 Natural History study and examined for changes in vestibular schwannoma size over time. SETTING: Data were collected from nine foreign and domestic NF2 centers, including hospital-based, academic, and tertiary care centers. SUBJECTS: NF2 patients with MRI data and at least one follow-up examination within 9 months to 2 years of diagnosis were included; n=56 patients with 84 lesions for evaluation of growth. INTERVENTION: Routine, clinically obtained, magnetic resonance images were digitized and measured using image management software. Short-term follow-up was defined as up to 2 years (n=84 lesions), and long-term follow-up was defined as 3 to 4 years (n=29 lesions). OUTCOME MEASURES: Vestibular schwannoma size was assessed using anterior-posterior, medial-lateral, and greatest diameter linear measurements. RESULTS: Vestibular schwannomas increased in size (at least 5 mm) in 8% of the vestibular schwannomas across short-term follow-up. At long-term follow-up, 13% of the tumors had increased in size. On average, schwannomas increased in greatest diameter 1.3 mm per year across short-term follow-up. CONCLUSION: Slightly greater than 1 in 10 diagnosed NF2-related vestibular schwannomas increased in size by at least 5 mm by 4 years of follow-up, if still untreated at that time.     

Does nonsteroidal anti-inflammatory drug use modify the effect of a low-fat, high-fiber diet on recurrence of colorectal adenomas?

The Polyp Prevention Trial was designed to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), low-fat (20% energy) diet on recurrence of adenomatous polyps. Participants > or =35 years of age, with histologically confirmed colorectal adenoma(s) removed in the prior 6 months, were randomized to the intervention or control group. Demographic, dietary, and clinical information, including use of nonsteroidal anti-inflammatory drugs (NSAID), was collected at baseline and four annual visits. Adenoma recurrence was found in 754 of 1,905 participants and was not significantly different between groups. NSAID use was associated with a significant reduction in recurrence [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.63-0.95]. In this analysis, NSAIDs modified the association between the intervention and recurrence at baseline (P = 0.02) and throughout the trial (P = 0.008). Among participants who did not use NSAIDs, the intervention was in the protective direction but did not achieve statistical significance (OR, 0.87; 95% CI, 0.69-1.09). The intervention was protective among males who did not use NSAIDs at baseline (OR, 0.71; 95% CI, 0.54-0.94), but not among NSAIDs users (OR, 1.09; 95% CI, 0.74-1.62). For females, corresponding OR estimates were 1.28 (95% CI, 0.86-1.90) and 2.30 (95% CI, 1.24-4.27), respectively. The protective association observed for NSAID use was stronger among control (OR, 0.63; 95% CI, 0.47-0.84) than for intervention group participants (OR, 0.97; 95% CI, 0.74-1.28). These results should be interpreted cautiously given that they may have arisen by chance in the course of examining multiple associations and Polyp Prevention Trial study participants were not randomly assigned to both dietary intervention and NSAID use. Nevertheless, our results suggest that adopting a low-fat, high-fiber diet rich in fruits and vegetables may lower the risk of colorectal adenoma recurrence among individuals who do not regularly use NSAIDs.     

Pharmacokinetics of ethanol in pigtailed macaques: intersubject variability and effect of subchronic administration

The pharmacokinetics of IV ethanol (0.6 g/kg) were examined in 11 male colony-bred pigtailed macaques (Macaca nemestrina) aged 3 to 13 years. The animals were either chaired during blood sampling (4 hr) or connected to a tether system that allowed injections and blood sampling while the animal moved freely about its cage. In all instances, ethanol pharmacokinetics could be described by a single Michaelis-Menten function; inclusion of a parallel first-order rate constant to account for non-alcohol dehydrogenase elimination of ethanol did not improve the fit. Volume of distribution was 0.802 +/- 0.054 L/kg (mean +/- SD), Km (the apparent in vivo Michaelis constant) was 0.063 +/- 0.022 micrograms/ml, and Vmax was 0.199 +/- 0.039 g/kg/hr. The pharmacokinetic parameter values of chaired and tethered monkeys did not differ. Three of the tethered monkeys received 3 g/kg of ethanol daily for two weeks by IV infusion (subchronic administration). Ethanol pharmacokinetics, determined on five occasions before and five occasions after subchronic ethanol administration, showed that the treatment did not alter the volume of distribution or Km in any of the three monkeys. The value of Vmax increased approximately 23% in one of the three monkeys that received subchronic ethanol; this increase may have been due to a single, inadvertent administration of a 4.5-g/kg dose over a 20-min period. Vmax did not change in the other two monkeys.