Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated in Primary Care (ZODIAC-10)

Background: Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study. Methodology and Principal Findings: We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA(1c) 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints 'all-cause' and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23-2.37), and HR 2.59 (95% CI 1.56-4.28); and albuminuria: HR 1.72 (95% CI 1.26-2.35), and HR 1.83 (95% CI 1.17-2.89), respectively, were significant predictors, whereas smoking, HbA(1c), systolic blood pressure and diabetes duration were not. Conclusions: This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients

Effectiveness of an online group course for adolescents and young adults with depressive symptoms: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Depression is a common condition whose first onset is usually in late adolescence or early adulthood. Internet-based interventions are an effective treatment approach to depression. The aim of this study is to investigate the effectiveness of a Dutch online cognitive-behavioural group course known as Master Your Mood (<it>Grip op Je Dip</it>) for young people reporting depressive symptoms. Secondary research questions involve maintenance of effect at 6 months, mediators, and predictors of better outcomes.</p> <p>Methods</p> <p>We will conduct a randomised controlled trial (RCT) in which 244 young people aged 16-25 are randomly allocated to the Grip op Je Dip (GOJD) online group course or to a waiting list control group. The participants will be recruited from the general population. The primary outcome measure will be the severity of depressive symptoms according to the Center for Epidemiological Studies Depression Scale (CES-D). Other outcomes will include anxiety (Hospital Anxiety and Depression Scale-Anxiety, HADS) and mastery (Mastery Scale). Assessments will take place in both groups at baseline and three months later. Effect maintenance will be studied in the GOJD group six months after baseline, with missing data imputed using the expectation-maximisation method. Mediators and predictors of better outcomes will also be identified.</p> <p>Discussion</p> <p>The trial should add to the body of knowledge on the effectiveness of Internet-based interventions for depression. To our knowledge, this will be the first RCT on an online group intervention in this field.</p> <p>Trial registration</p> <p><a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=NTR1694">NTR1694</a></p

Response rates and selection problems, with emphasis on mental health variables and DNA sampling, in large population-based, cross-sectional and longitudinal studies of adolescents in Norway

Background Selection bias is a threat to the internal validity of epidemiological studies. In light of a growing number of studies which aim to provide DNA, as well as a considerable number of invitees who declined to participate, we discuss response rates, predictors of lost to follow-up and failure to provide DNA, and the presence of possible selection bias, based on five samples of adolescents. Methods We included nearly 7,000 adolescents from two longitudinal studies of 18/19 year olds with two corresponding cross-sectional baseline studies at age 15/16 (10th graders), and one cross-sectional study of 13th graders (18/19 years old). DNA was sampled from the cheek mucosa of 18/19 year olds. Predictors of lost to follow-up and failure to provide DNA were studied by Poisson regression. Selection bias in the follow-up at age 18/19 was estimated through investigation of prevalence ratios (PRs) between selected exposures (physical activity, smoking) and outcome variables (general health, mental distress, externalizing problems) measured at baseline. Results Out of 5,750 who participated at age 15/16, we lost 42% at follow-up at age 18/19. The percentage of participants who gave their consent to DNA provision was as high as the percentage that consented to a linkage of data with other health registers and surveys, approximately 90%. Significant predictors of lost to follow-up and failure to provide DNA samples in the present genetic epidemiological study were: male gender; non-western ethnicity; postal survey compared with school-based; low educational plans; low education and income of father; low perceived family economy; unmarried parents; poor self-reported health; externalized symptoms and smoking, with some differences in subgroups of ethnicity and gender. The association measures (PRs) were quite similar among participants and all invitees, with some minor discrepancies in subgroups of non-western boys and girls. Conclusions Lost to follow-up had marginal impact on the estimated prevalence ratios. It is not likely that the invitation to provide DNA influenced the response rates of 18/19 year olds. Non-western ethnicity, male gender and characteristics related to a low social class and general and mental health problems measured at baseline are associated with lost to follow-up and failure to provide DNA

Vibration-induced extra torque during electrically-evoked contractions of the human calf muscles

<p>Abstract</p> <p>Background</p> <p>High-frequency trains of electrical stimulation applied over the lower limb muscles can generate forces higher than would be expected from a peripheral mechanism (i.e. by direct activation of motor axons). This phenomenon is presumably originated within the central nervous system by synaptic input from Ia afferents to motoneurons and is consistent with the development of plateau potentials. The first objective of this work was to investigate if vibration (sinusoidal or random) applied to the Achilles tendon is also able to generate large magnitude extra torques in the triceps surae muscle group. The second objective was to verify if the extra torques that were found were accompanied by increases in motoneuron excitability.</p> <p>Methods</p> <p>Subjects (n = 6) were seated on a chair and the right foot was strapped to a pedal attached to a torque meter. The isometric ankle torque was measured in response to different patterns of coupled electrical (20-Hz, rectangular 1-ms pulses) and mechanical stimuli (either 100-Hz sinusoid or gaussian white noise) applied to the triceps surae muscle group. In an additional investigation, M_maxand F-waves were elicited at different times before or after the vibratory stimulation.</p> <p>Results</p> <p>The vibratory bursts could generate substantial self-sustained extra torques, either with or without the background 20-Hz electrical stimulation applied simultaneously with the vibration. The extra torque generation was accompanied by increased motoneuron excitability, since an increase in the peak-to-peak amplitude of soleus F waves was observed. The delivery of electrical stimulation following the vibration was essential to keep the maintained extra torques and increased F-waves.</p> <p>Conclusions</p> <p>These results show that vibratory stimuli applied with a background electrical stimulation generate considerable force levels (up to about 50% MVC) due to the spinal recruitment of motoneurons. The association of vibration and electrical stimulation could be beneficial for many therapeutic interventions and vibration-based exercise programs. The command for the vibration-induced extra torques presumably activates spinal motoneurons following the size principle, which is a desirable feature for stimulation paradigms.</p

Visuomotor Cerebellum in Human and Nonhuman Primates

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula–nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Feasibility, safety and pharmacokinetic study of hepatic administration of drug-eluting beads loaded with irinotecan (DEBIRI) followed by intravenous administration of irinotecan in a porcine model

Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100–300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m2 of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m2 for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. Cmax values obtained during the IV arms of the study are approximately double that of the embolization arms whilst Tmax times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.Andrew L. Lewis, Rachel R. Holden, S. Ting Chung, Peter Czuczman, Timothy Kuchel, John Finnie, Susan Porter, David Foste