Telomeres and prognosis in patients with chronic lymphocytic leukaemia

In the present study, telomere length, telomerase activity, the mutation load of immunoglobulin variable heavy chain (IGHV) genes, and established prognostic factors were investigated in 78 patients with chronic lymphocytic leukaemia (CLL) to determine the impact of telomere biology on the pathogenesis of CLL. Telomere length was measured by an automated multi-colour flow-FISH, and an age-independent delta telomere length ( TL) was calculated. CLL with unmutated IGHV genes was associated with shorter telomeres (p = 0.002). Furthermore, we observed a linear correlation between the frequency of IGHV gene mutations and elongation of telomeres (r = 0.509, p < 0.001). With respect to prognosis, a threshold TL of -4.2 kb was the best predictor for progression-free and overall survival. TL was not significantly altered over time or with therapy. The correlation between the mutational load in IGHV genes and the TL in CLL might reflect the initial telomere length of the putative cell of origin (pre- versus post-germinal center B cells). In conclusion, the TL is a reliable prognostic marker for patients with CLL. Short telomeres and high telomerase activity as occurs in some patients with CLL with a worse prognosis might be an ideal target for treatment with telomerase inhibitors.

Incident cancer burden attributable to excess body mass index in 30 European countries

Excess adiposity is associated with increased risks of developing adult malignancies. To inform public health policy and guide further research, the incident cancer burden attributable to excess body mass index (BMI >or= 25 kg/m(2)) across 30 European countries were estimated. Population attributable risks (PARs) were calculated using European- and gender-specific risk estimates from a published meta-analysis and gender-specific mean BMI estimates from a World Health Organization Global Infobase. Country-specific numbers of new cancers were derived from Globocan2002. A ten-year lag-period between risk exposure and cancer incidence was assumed and 95% confidence intervals (CI) were estimated in Monte Carlo simulations. In 2002, there were 2,171,351 new all cancer diagnoses in the 30 countries of Europe. Estimated PARs were 2.5% (95% CI 1.5-3.6%) in men and 4.1% (2.3-5.9%) in women. These collectively corresponded to 70,288 (95% CI 40,069-100,668) new cases. Sensitivity analyses revealed estimates were most influenced by the assumed shape of the BMI distribution in the population and cancer-specific risk estimates. In a scenario analysis of a plausible contemporary (2008) population, the estimated PARs increased to 3.2% (2.1-4.3%) and 8.6% (5.6-11.5%), respectively, in men and women. Endometrial, post-menopausal breast and colorectal cancers accounted for 65% of these cancers. This analysis quantifies the burden of incident cancers attributable to excess BMI in Europe. The estimates reported here provide a baseline for future modelling, and underline the need for research into interventions to control weight in the context of endometrial, breast and colorectal cancer.

Cervical muscle area measurements in acute whiplash patients and controls

To quantitatively compare the muscle cross-sectional areas (CSAs) of the cervical muscles in symptomatic acute whiplash patients versus healthy controls. We hypothesized, that symptomatic whiplash patients have smaller cervical muscle CSAs than matched controls and that smaller cervical muscle CSAs in women might explain that women more frequently are symptomatic after whiplash injury than men.

Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery

Background and Purpose—To compare potential risk factors, clinical symptoms, diagnostic delay, and 3-month outcome between spontaneous internal carotid artery dissection (sICAD) and spontaneous vertebral artery dissection (sVAD). Methods—We compared patients with sICAD (n=668) and sVAD (n=302) treated in 3 university hospitals. Results—Patients with sICAD were older (46.3±9.6 versus 42.0±10.2 years; P<0.001), more often men (62.7% versus 53.0%; P=0.004), and presented more frequently with tinnitus (10.9% versus 3.4%; P<0.001) and more severe ischemic strokes (median National Institutes of Health Stroke Scale, 10±7.1 versus 5±5.9; P<0.001). Patients with sVAD had more often bilateral dissections (15.2% versus 7.6%; P<0.001) and were more often smokers (36.0% versus 28.7%; P=0.007). Thunderclap headache (9.2% versus 3.6%; P=0.001) and neck pain were more common (65.8% versus 33.5%; P<0.001) in sVAD. Subarachnoid hemorrhage (6.0% versus 0.6%; P<0.001) and ischemic stroke (69.5% versus 52.2%; P<0.001) were more frequent in sVAD. After multivariate analysis, sex difference lost its significance (P=0.21), and all other variables remained significant. Time to diagnosis was similar in sICAD and sVAD and improved between 2001 and 2012 compared with the previous 10-year period (8.0±10.5 days versus 10.7±13.2 days; P=0.004). In sVAD, favorable outcome 3 months after ischemic stroke (modified Rankin Scale, 0–2: 88.8% versus 58.4%; P<0.001), recurrent transient ischemic attack (4.8% versus 1.1%; P=0.001), and recurrent ischemic stroke (2.8% versus 0.7%; P=0.02) within 3 months were more frequent. Conclusions—sICAD and sVAD patients differ in many aspects. Future studies should perform separate analyses of these 2 entities.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Anti-inflammatory properties of alpha- and gamma-tocopherol

Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.

Changes in pre-pregnancy weight and weight gain during pregnancy: retrospective comparison between 1986 and 2004

QUESTIONS UNDER STUDY: To compare the incidence of pre-pregnancy overweight, obesity, and difference in weight gain during pregnancy in the years 1986 and 2004, in women delivered at the maternity unit of our hospital. METHODS: Retrospective study. Maternity records of patients delivered in the years 1986 and 2004 were compared. Data extraction included booking weight, height, weight gain, birth weight as well as information on mode of delivery and gestational age at delivery. RESULTS: During the year 1986 and 2004 a total of 690 and 668 patients respectively were included in the analysis. The pre-pregnancy BMI > or =25 doubled over the 18-year period (from 15.9 to 30.1%). In 1986 only 2.6% of all pregnant women gained more than 20 kg, while in 2004 14.2% (p <0.0001) did so. The caesarean section rate was significantly higher in 2004 than 18 years earlier (28.3 and 9.3%, p <0.0001). CONCLUSIONS: We found a significant increase in all parameters between these two groups. Pregnant women are today heavier at the booking visit, are more overweight, and gain more weight during pregnancy. A similar trend is seen in the newborn babies, who have a higher birth weight than those born 18 years ago.

Predictors of attempted suicide among Swiss patients with alcohol-use disorders

Objective: Suicide attempts are common in patients being treated for alcohol-use disorders (AUDs). However, clinical assessment of suicide risk is difficult. In this Swiss multisite study, we propose a decision tree to facilitate identification of profiles of AUD patients at high risk for suicidal behavior. Method: In this retrospective study, we used a sample of 700 patients (243 female), attending 1 of 12 treatment programs for AUDs in the German-speaking part of Switzerland. Sixty-nine patients who reported a suicide attempt in the 3 months before the index treatment were compared using risk factors with 631 patients without a suicide attempt. Receiver operating characteristic (ROC) analyses were used to identify patients at risk of having had a suicide attempt in the previous 3 months. Results: Consistent with previous empirical findings in AUD patients, a prior history of attempted suicide and severe symptoms of depression and aggression considerably increased the risk of a suicide attempt and, in combination, raised the likelihood of a prior suicide attempt to 52%. In addition, one third of AUD patients who had a history of suicide attempts and previous inpatient psychiatric treatment, or who were male and had previous inpatient psychiatric treatment, also reported a suicide attempt. Conclusions: The empirically supported decision tree helps to identify profiles of suicidal AUD patients in Switzerland and supplements clinicians' judgments in making triage decisions for suicide management.

In search of optimal compression therapy for venous leg ulcers: a meta-analysis of studies comparing diverse [corrected] bandages with specifically designed stockings

OBJECTIVE: In search of an optimal compression therapy for venous leg ulcers, a systematic review and meta-analysis was performed of randomized controlled trials (RCT) comparing compression systems based on stockings (MCS) with divers bandages. METHODS: RCT were retrieved from six sources and reviewed independently. The primary endpoint, completion of healing within a defined time frame, and the secondary endpoints, time to healing, and pain were entered into a meta-analysis using the tools of the Cochrane Collaboration. Additional subjective endpoints were summarized. RESULTS: Eight RCT (published 1985-2008) fulfilled the predefined criteria. Data presentation was adequate and showed moderate heterogeneity. The studies included 692 patients (21-178/study, mean age 61 years, 56% women). Analyzed were 688 ulcerated legs, present for 1 week to 9 years, sizing 1 to 210 cm(2). The observation period ranged from 12 to 78 weeks. Patient and ulcer characteristics were evenly distributed in three studies, favored the stocking groups in four, and the bandage group in one. Data on the pressure exerted by stockings and bandages were reported in seven and two studies, amounting to 31-56 and 27-49 mm Hg, respectively. The proportion of ulcers healed was greater with stockings than with bandages (62.7% vs 46.6%; P < .00001). The average time to healing (seven studies, 535 patients) was 3 weeks shorter with stockings (P = .0002). In no study performed bandages better than MCS. Pain was assessed in three studies (219 patients) revealing an important advantage of stockings (P < .0001). Other subjective parameters and issues of nursing revealed an advantage of MCS as well. CONCLUSIONS: Leg compression with stockings is clearly better than compression with bandages, has a positive impact on pain, and is easier to use.