Allelic loss of chromosome 2p21-16.3 is associated with reduced survival in sporadic colorectal cancer

BACKGROUND: Since allelic loss of genes involved in the development of colorectal cancer could serve as prognostic markers, we examined the correlation between loss of markers linked to the hMSH2/hMSH6 (2p21-16.3), hMLH1 (3p21.3), APC (5q21-22), p53 (17p13.1) and DCC (18q21.3) loci and survival in a series of 64 consecutively collected colorectal cancers. METHODS: The association between allelic loss and survival was analysed by univariate and multivariate tests to identify independent variables of survival. RESULTS: Loss of chromosome 2p21-16.3 reduced the overall 5-year survival from 52% to 15% (P = 0.0003). The prognostic significance was evident in patients with Dukes' A + B as well as Dukes' C tumours. A multivariate analysis comparing Dukes' staging, age at diagnosis, tumour localization, sex, loss of chromosome 2p21-16.3, 3p21.3, 5q21-22, 17p13.1 or 18q21.3 and microsatellite instability showed that only Dukes' staging (hazard ratio 3.0; 1.4-6.5 with 95% confidence interval, P = 0.0065) and loss of 2p21-16.3 (hazard ratio 6.2; 2.3-16.8 with 95% confidence interval, P = 0.0006) were independent variables of survival. Loss of 2p21-16.3 was, moreover, associated with increased loss of the other tumour suppressor loci (P = 0.012). CONCLUSIONS: The results show that loss of 2p21-16.3 is an independent indicator of survival in patients with colorectal cancer.     

Postprandial glycemic control with biphasic insulin aspart in patients with type 1 diabetes

We sought to investigate the ability of biphasic insulin aspart 30 (BIAsp 30) to control postprandial hyperglycemia and hyperlipidemia in a meal-test comparison with biphasic human insulin 30 (BHI 30). In this randomised crossover trial, 50 patients with type 1 diabetes (mean age, 35.7 +/- 9.4 years; body mass index [BMI], 24.0 +/- 2.6 kg/m(2); HbA(1c), 8.6% +/- 1.1%) were studied on 3 separate days, where the following treatments were given in random order: BIAsp 30 injected immediately before a standard breakfast, BHI 30 injected 30 minutes before breakfast (BHI 30(t=-30)), and BHI 30 injected immediately before breakfast (BHI 30(t=0)). The dose was 0.40 U/kg for all 3 treatments. BIAsp 30 reduced the area under the baseline adjusted 4-hour postprandial serum glucose curve (AUC(0-4h)) by 23% compared with BHI 30(t=0) (P <.0001) and by 9% compared with BHI 30(t=-30) (P =.013). Maximum serum glucose concentration (C(max)) was lower for BIAsp 30 compared with BHI 30(t=0) (14.0 +/- 2.4 v 16.5 +/- 2.8 mmol/L, P <.0001), and time to maximal serum glucose concentration (t(max)) was approximately 20 minutes shorter for BIAsp 30, irrespective of timing of BHI 30 injection (P <.0001). There were no significant differences among the 3 treatments with respect to postprandial levels of free fatty acids or triglycerides. The pharmacokinetic results were consistent with the above observations, ie, significantly larger insulin AUC(0-4h), higher C(max) and shorter t(max) were observed for BIAsp 30 compared with BHI 30, irrespective of timing of BHI 30 injection. We conclude that postprandial glycemic control was more effective with BIAsp 30 than with BHI 30, irrespective of timing of BHI 30 injection.     

Identification and Characterization of a Nationwide Danish Adult Common Variable Immunodeficiency Cohort

In this study, we identified all adults living in Denmark diagnosed with common variable immunodeficiency (CVID) and characterized them according to clinical presentation and EUROclass classification. Using a retrospective, cross‐sectional design, possible CVID patients were identified in the Danish National Patient Register and Centers in Denmark treating patients with primary immunodeficiencies. The CVID diagnosis was verified by review of medical records. One‐hundred‐seventy‐nine adults with CVID were identified. This corresponds to a prevalence of 1:26,000. The median age at onset of symptoms was 29 years with no sex difference. The median age at diagnosis was 40 years. Males were diagnosed earlier with a peak in the fourth decade of life, whereas females were diagnosed later with a peak in the sixth decade. The median diagnostic delay was seven years. Recurrent sinopulmonary infections were seen in 92.7% of the patients. The prevalence of non‐infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%). Non‐infectious complications were strongly associated with B cell phenotype, with all having a reduced number of isotype‐switched memory B cells. One‐hundred‐seventy (95%) were treated with immunoglobulin replacement therapy, primarily administered subcutaneously. According to international guidelines, diagnostic evaluation was inadequate in most cases. This study emphasizes the need for improved diagnostic criteria and more awareness of CVID as a differential diagnosis. Diagnosis and management of CVID patients is a challenge requiring specialists with experience in the field of PID.     

<Emphasis Type="Italic">ASIP</Emphasis> genetic variants and the number of non-melanoma skin cancers

Patients with primary non-melanoma skin cancers (NMSCs) tend to develop these cancers at multiple independent sites. We examined the genetic factors in the development of multiple NMSCs among Caucasian women with 28 years of follow-up. We initially evaluated 19 SNPs in nine pigmentation genes with the number of NMSCs in 492 cases and 619 controls without a history of NMSC. We found nominal significant associations between two ASIP gene–related SNPs, rs1885120 and rs910873, and an ASIP haplotype (AH) (rs4911414 allele T and rs1015362 allele G) and an increased number of NMSCs, with p-values of 0.008, 0.01, and 0.01, respectively. We further evaluated these two SNPs and AH haplotype in three data sets. In a joint analysis with 1,507 cases and 4,335 controls, AH haplotype was independently associated with the number of NMSCs with odds ratio (OR) (95% confidence interval (CI)) of 1.45(1.25–1.68) (p-value = 6.2E–07). The AH haplotype was associated with an increased risk of developing one NMSC (OR 1.32; 95% CI, 1.07–1.63). The OR increased to 1.45(1.18–1.78) for those with 2–4 NMSCs and 1.84(1.34–2.53) for those with at least five. The findings suggest that ASIP locus is associated with the number of NMSCs.     

Evaluation of Blood-Brain Barrier Passage of a Muscarine M1 Agonist and a Series of Analogous Tetrahydropyridines Measured by In Vivo Microdialysis

Purpose. To investigate the blood-brain barrier (BBB) passage of theM1 muscarine agonist Lu 25-109(5-(2-Ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-methylpyridine) and potential metabolites using in vivomicrodialysis. Methods. Anesthetized rats were administered an intravenous infusionof one of seven analogs with a Log D_7.4 ranging from 0.35 to –2.4.Microdialysis probes were implanted in the brain and the jugular vein.The integrity of the BBB was evaluated using2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA), a compound notexpected to penetrate the BBB. The data was corrected for in vitrorecovery. Results. Lu 25-109, Lu 24-165 (demethylated Lu 25-109) and Lu25-077 (N-demethylated Lu 25-109) entered the brain in a 1:1 ratio withthe blood. Although Lu 29-081 (hydroxylated Lu 25-109) presented asimilar Log D_7.4 to Lu 25-109 and Lu 24-164, it entered the brain witha lower brain:blood ratio of 0.5. Lu 32-181 (Lu 25-109 N-oxide), Lu35-026 (deethylated and oxidized Lu 25-109) and Lu 31-126(deethylated Lu 25-109) were not detected in the brain samples, indicating nopenetration. Infusion of Lu 25-109 resulted in a time perspective ofthe formation and distribution of the two metabolites Lu 25-077 andLu 32-181. Although the hydroxylated compound (Lu 29-081) had aLog D_7.4 of –0.6, within the range 0.35 to –0.83 of the compoundspenetrating the BBB, it showed a brain: blood ratio of 0.5. Lu 35-026showed an unusual infusion profile with a t_max of 100–150 min and asubsequent decrease in blood concentration. Conclusions. Compounds with Log D_7.4 above –0.83 penetrated theBBB, whereas compounds below –1.5 did not. Knowledge of LogD_7.4 values is not sufficient to evaluate BBB passage because the valuedoes not predict the influence of active transport processes.     

Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study

Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992–1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83–1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92–1.02) and RR = 0.89 (95% CI: 0.78–1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (<120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake. Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke     

Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST)

It is considered that fruit and vegetable (F&V) protect against oesophagus and gastric cancer (GC). However, 2 recent meta-analyses suggest that the strength of association on GC seems to be weaker for vegetables than for fruit and weaker in cohort than in case-control studies. No evidence exists from cohort studies about adenocarcinoma of oesophagus (ACO). In 521,457 men and women participating in the EPIC cohort in 10 European countries, information of diet and lifestyle was collected at baseline. After an average of 6.5 years of follow-up, a total of 330 GC and 65 ACO, confirmed and classified by a panel of pathologists, was used for the analysis. We examined the relation between F&V intake and GC and ACO. A calibration study in a sub-sample was used to control diet measurement errors. In a sub-sample of cases and a random sample of controls, antibodies against Helicobacter pylori (Hp) were measured and interactions with F&V were examined in a nested case-control study. We observed no association with total vegetable intake or specific groups of vegetables and GC risk, except for the intestinal type, where a negative association is possible regarding total vegetable (calibrated HR 0.66; 95% CI 0.35-1.22 per 100 g increase) and onion and garlic intake (calibrated HR 0.70; 95% CI 0.38-1.29 per 10 g increase). No evidence of association between fresh fruit intake and GC risk was observed. We found a negative but non significant association between citrus fruit intake and the cardia site (calibrated HR 0.77; 95% CI 0.47-1.22 per 100 g increase) while no association was observed with the non-cardia site. Regarding ACO, we found a non significant negative association for vegetable intake and for citrus intake (calibrated HRs 0.72; 95% CI 0.32-1.64 and 0.77; 95% CI 0.46-1.28 per 100 and 50 g increase, respectively). It seems that Hp infection does not modify the effect of F&V intake. Our study supports a possible protective role of vegetable intake in the intestinal type of GC and the ACO. Citrus fruit consumption may have a role in the protection against cardia GC and ACO.     

Effects of one single bout of low-intensity exercise on postprandial lipaemia in type 2 diabetic men

Fighting type 2 diabetes and its high risk of CVD, lifestyle intervention with diet and exercise is of uttermost importance. Epidemiological studies strongly suggest an inverse association between increased physical activity, moderate alcohol drinking and the incidence of both type 2 diabetes and CVD. However, alcohol is known to increase postprandial lipaemia, a risk marker of CVD, and exercise to reduce postprandial lipaemia in healthy individuals. The aim of the present study was to investigate how type 2 diabetic men respond, in the postprandial period, to a single exercise session feasible to perform on a daily basis for type 2 diabetic men. The twelve participants ingested a test meal containing 100 g butter, 50 g carbohydrate, together with 40 g alcohol, at each meal test, imitating a social meal situation. Two protocols included exercise sessions with 40 min at 40% VO2max, one where they exercised 3.5 h after, and another the afternoon before the test meal. One protocol was without any exercise. No significant effect of low-intensity exercise on postprandial lipaemia following a fat-rich meal with alcohol was seen in the middle-aged type 2 diabetic men.     

Alcoholic beverage preference and risk of becoming a heavy drinker

BACKGROUND: Studies have suggested that wine drinkers are at lower risk of death than beer or spirits drinkers. The aim of this study is to examine whether the risk of becoming a heavy or excessive drinker differs among individuals who prefer different types of alcoholic beverages. METHODS: In a longitudinal study of 10,330 moderate drinkers from Copenhagen, Denmark, we used logistic regression analyses to address the risk of becoming a heavy or excessive drinker (above 14 and 21 drinks per week, respectively, for women and above 21 and 35 drinks per week for men) according to preference of wine, beer, or spirits. RESULTS: Compared with those who preferred wine, those who preferred beer tended to have increased risk of becoming heavy and excessive drinkers. Women who preferred beer had odds ratios of 1.14 (95% CI = 0.87-1.50) for becoming heavy drinkers and 1.50 (95% CI = 0.93-2.43) for becoming excessive drinkers. For men who preferred beer the ORs were 1.16 (95% CI = 0.84-1.58) and 1.81 (95% CI = 0.85-3.82). CONCLUSION: The finding that moderate wine drinkers appear to be at lower risk of becoming heavy and excessive drinkers may add to the explanation of the reported beverage-specific differences in morbidity and mortality.