Early vs. late enoxaparin for the prevention of venous thromboembolism in patients with ICH: A double blind placebo controlled multicenter study.

BACKROUND: Venous thromboembolism (VTE) after primary intracerebral hemorrhage (ICH) worsens patient prognosis. Administering low-molecular weight heparins (LMWH) to prevent VTE early (24 h) may increase the risk of hematoma enlargement, whereas administering late (72 h) after onset may decrease its effect on VTE prevention. The authors investigated when it is safe and effective to start LMWH in ICH patients. METHODS: In the setting of double blinded, placebo controlled randomization, patients >18 years of age with paretic lower extremity, and admitted to the emergency room within 12 h of the onset of ICH, were randomized into two groups. Patients in the enoxaparin group received 20 mg twice a day 24 h (early) after the onset of ICH and in the placebo group 72 h (late) after onset respectively. Both groups immediately received intermittent pneumatic compression stockings at the ER. Patients were prospectively and routinely screened for VTE and hemorrhagic complications 1 day after entering the study and again before discharge. RESULTS: 139 patients were included for randomization in this study. Only 3 patients developed VTE, 2 in the early enoxaparin group and one in the late enoxaparin group. No patients developed PE. Thromboembolic events (p = 0.901), risk of hematoma enlargement (p = 0.927) and overall outcome (P = 0.904) did not differ significantly between the groups. CONCLUSION: Administering 40 mg/d LMWH for prevention of VTE to a spontaneous ICH patient is safe regardless of whether it is started 24 h (early) or 72 h (late) after the hemorrhage. Risk of hemorrhage enlargement is not associated with early LMWH treatment. Administering LMWH late did not increase VTEs.

A randomized clinical trial of the effectiveness of a Web-based health behaviour change support system and group lifestyle counselling on body weight loss in overweight and obese subjects: 2-year outcomes.

BACKGROUND: Weight loss can prevent and treat obesity-related diseases. However, lost weight is usually regained, returning to the initial or even higher levels in the long term. New counselling methods for maintaining lifestyle changes are urgently needed. OBJECTIVES: An information and communication technology-based health behaviour change support system (HBCSS) that utilizes persuasive design and methods of cognitive behavioural therapy (CBT) was developed with the aim of helping individuals to maintain body weight. The purpose of this study was to assess whether CBT-based group counselling combined with HBCSS or HBCSS alone helps to maintain improved lifestyle changes needed for weight loss compared to self-help guidance or usual care. METHODS: A randomized lifestyle intervention for overweight or obese persons (BMI 27-35 kg m-2 and age 20-60 years), recruited from the population registry in the city of Oulu, Finland, was conducted. This study comprised six randomly assigned study arms: CBT-based group counselling (eight sessions led by a nutritionist), self-help guidance-based group counselling (SHG; two sessions led by a nurse) and control, each with or without HCBSS, for 52 weeks. Subjects visited the study centre for anthropometric measurements, blood sample collection and to complete questionnaires at baseline, 12 and 24 months. The main outcome was weight change from baseline to 12 months and from baseline to 24 months. RESULTS: Of the 1065 volunteers screened for the study, 532 subjects (51% men) met the inclusion criteria and were enrolled. The retention rate was 80% at 12 months and 70% at 24 months. CBT-based counselling with HBCSS produced the largest weight reduction without any significant weight gain during follow-up. The mean weight change in this arm was 4.1% [95% confidence interval (CI), -5.4 to -2.8, P < 0.001) at 12 months and 3.4% (95% CI, -4.8 to -2.0, P < 0.001) at 24 months. HBCSS even without any group counselling reduced the mean weight by 1.6% (95% CI, -2.9 to -0.3, P = 0.015) at 24 months. CONCLUSION: The combination of CBT-based group counselling and HBCSS-based weight management is feasible for overweight or obese individuals. Moreover, HBCSS alone could be disseminated to the population at large as an effective means of treating obesity.

Mechanical analysis of cranial distractor attachment with three different resorbable fixation systems.

Distraction osteogenesis (DO) has become increasingly popular to correct craniosynostosis. Disadvantages of DO include the secondary operation needed for device removal and titanium screw related dura injury. To reduce invasiveness of the secondary device removal operation and to overcome titanium-related problems, fixation of the cranial distractor with resorbable materials is a potential alternative. New resorbable fixation methods, such as ultrasound-activated pins (UAPs) or heat-activated pins (HAPs), allow faster attachment on thinner bone than conventional resorbable screws (CRSs) since tapping is not required. However, resorbable materials are designed to be attached with a resorbable plate, not with a titanium distractor. We evaluated the suitability of CRSs, HAPs and UAPs for the cranial distractor fixation in a laboratory setting with a mechanical testing machine. Fracture tests were conducted in two directions with respect to the longitudinal axis; vertical i.e. axial pull-out strength, and horizontal i.e. shear strength. Mean maximum pull-out strength for CRS, HAP and UAP was 48.9 N, 32.5 N and 14.7 N, respectively. Mean maximum shear strength for CRS, HAP and UAP was 40.8 N, 77.9 N and 38.9 N, respectively. According to our in vitro tests, the cranial distractor attachment with four CRSs or six HAPs per footplate would provide sufficient fixation stability.

Force measurements during posterior calvarial vault osteodistraction: A novel measurement method.

Posterior calvarial vault osteodistraction (PCVO) has become increasingly popular in the correction of craniosynostosis. When compared to cranioplasty, PCVO offers a shorter, less invasive operation, greater intracranial volume advancement and a lower rate of relapse. In general, distraction protocols are based primarily on clinical observations rather than systematic research. Faster distraction protocols may reduce complications. However, distraction protocols producing higher forces can increase complications. Thus, we need to understand these forces in order to improve distraction protocols and devices. We developed a force measurement method that can be used on PCVO devices. Here, we present preliminary data about the forces developed during PCVO. We measured the forces in four bicoronal craniosynostosis patients during PCVO. We observed a linear-like trend between the force increase and the distraction distance within distraction sessions. We also observed a step-wise force increase between distraction sessions and found that the distraction force relaxed rapidly shortly after the distraction session. The mean maximum pre-distraction force for one distracter was 20.4 N, while the mean maximum end-distraction force for one distracter was 57.6 N. Our data suggests that current treatment protocols might be re-evaluated favouring shorter distraction distances and more frequent distraction sessions.

Promoting ossification of calvarial defects in craniosynostosis surgery by demineralized bone plate and bone dust in different age groups.

Correction of calvarial defects after calvarial vault reconstruction (CVR) is challenging in craniosynostosis patients of advanced age and typically employs autologous bone. Demineralized bone matrix (DBM) is a potential alternative material for autologous bone, but its use has not been extended to correct calvarial defects. CVR patients operated at the Department of Plastic Surgery, Helsinki University Hospital, during 2008-2010 were retrospectively reviewed. Inclusion criteria of the study were CVR patients who received DBM plate, with or without bone dust, on calvarial defects and who had suitable uncovered defect on the contralateral side as control. This study included 17 craniosynostosis and one positional plagiocephaly patient, whose mean age was 6.9 years (range 0.9-19 years). The mean follow-up time was 5.6 years. The fusion degree of all defects was measured from 1 week to 1 year postoperatively using three-dimensional computed tomography (3D CT) images by the OsiriX© method. Medical records were reviewed for DBM-related complications. A total of 26 defects were covered with a DBM plate (mean area 11.1 cm2) and 26 control defects were identified (mean area 7.8 cm2). The mean fusion degree of the DBM defects was 74% and 54% for the controls (p < 0.001). The mean fusion degree of nine DBM defects that lacked bone dust deposition was 66% and 55% for the nine controls (p < 0.059). The difference between the DBM and control defects was statistically significant for patients older than 30 months (p < 0.03). No DBM-related complication was observed. DBM plate is a safe and useful material to promote ossification in calvarial defects in CVR. Furthermore, DBM appears to be more effective in older patients (>30 months) than in younger patients or when used with bone dust.

The effect of pregnane X receptor agonists on postprandial incretin hormone secretion in rats and humans.

We recently showed that pregnane X receptor (PXR) agonists cause hyperglycaemia during oral glucose tolerance test (OGTT) in rats and healthy volunteers (Rifa-1 study). We now aimed to determine if the secretion of incretin hormones, especially glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are affected by PXR agonists since these gut-secreted hormones are major regulators of postprandial glucose metabolism. The Rifa-2 study had a one-phase, open-label design. Twelve subjects were given 600 mg of rifampicin a day for a week. OGTT with glucose, insulin, and incretin hormone measurements was performed before and after the rifampicin dosing. Incretins and insulin were analysed in previously collected rat OGTT samples after pregnenolone 16α-carbonitrile (PCN) or control treatment for 4 days. Rifampicin treatment did not affect glucose, insulin, GLP-1, GIP, glucagon, and peptide YY levels statistically significantly. Incremental AUCs (AUCincr) of glucose and insulin tended to increase (41% increase in glucose AUCincr, P = 0.21, 95% confidence interval (CI) of the difference -47, 187; 24% increase in insulin AUCincr, P = 0.084, CI of the difference -110, 1493). Glucagon AUC was increased in women (53% increase, P = 0.028) and decreased in men (19% decrease, P < 0.001) after rifampicin dosing. In combined analysis of human Rifa-1 and Rifa-2 studies, glucose AUCincr was elevated by 63% (P = 0.010) and insulin AUCincr by 37% (P = 0.011). PCN increased rat insulin level at 60 min time point but did not affect incretin and insulin AUCs statistically significantly. In conclusion, PXR agonists do not affect the secretion of incretin hormones. The regulation of glucagon secretion by PXR may be sexually dimorphic in humans. The mechanism of disrupted glucose metabolism induced by PXR activation requires further study.

Plasma alkylresorcinols C17:0/C21:0 ratio, a biomarker of relative whole-grain rye intake, is associated to insulin sensitivity: a randomized study.

BACKGROUND/OBJECTIVES: Few studies have used biomarkers of whole-grain intake to study its relation to glucose metabolism. We aimed to investigate the association between plasma alkylresorcinols (AR), a biomarker of whole-grain rye and wheat intake, and glucose metabolism in individuals with metabolic syndrome (MetS). SUBJECTS/METHODS: Participants were 30-65 years of age, with body mass index 27-40 kg/m(2) and had MetS without diabetes. Individuals were recruited through six centers in the Nordic countries and randomized to a healthy Nordic diet (ND, n=96), rich in whole-grain rye and wheat, or a control diet (n=70), for 18-24 weeks. In addition, associations between total plasma AR concentration and C17:0/C21:0 homolog ratio as an indication of the relative whole-grain rye intake, and glucose metabolism measures from oral glucose tolerance tests were investigated in pooled (ND+control) regression analyses at 18/24 weeks. RESULTS: ND did not improve glucose metabolism compared with control diet, but the AR C17:0/C21:0 ratio was inversely associated with fasting insulin concentrations (P=0.002) and positively associated with the insulin sensitivity indices Matsuda ISI (P=0.026) and disposition index (P=0.022) in pooled analyses at 18/24 weeks, even after adjustment for confounders. The AR C17:0/C21:0 ratio was not significantly associated with insulin secretion indices. Total plasma AR concentration was not related to fasting plasma glucose or fasting insulin at 18/24 weeks. CONCLUSIONS: The AR C17:0/C21:0 ratio, an indicator of relative whole-grain rye intake, is associated with increased insulin sensitivity in a population with MetS.

Programming effects of FTO in the development of obesity.

It is becoming increasingly recognized that early-life nutritional, metabolic and environmental factors can have a long-term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to their adult lifestyle and nutritional environment depends not only on their genetic susceptibility but also on their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to 'non- or epi-genetic' causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life course modelling and diet-induced foetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarize current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of foetal nutrition. Ultimately, we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues.

Determining the effect of environmental accidents on responses to a Gulf of Mexico recreational for-hire fishing industry survey.

A survey designed to collect economic, attitudinal and policy data from the recreational for-hire (RFH) fishing industry in the U.S. Gulf of Mexico was conducted before and during the largest marine oil spill in U.S. history (the April 2010 Deepwater Horizon blowout). Respondents were grouped into two time periods based on when the survey was completed, where the break in groups was determined through the examination of the Pew Research Center's media coverage index and the per cent of fishing area closures due to the oil spill. A logistic regression was used to test variables that might predict the time period of a response. Results indicated that recall bias was not present in the financial variables examined, but that firm operating and demographic characteristics (i.e. vessel size, annual number of trips, number of vessels operating in the firm, tenure and household income) were significant in explaining the time period in which surveys were completed.

Pregnane X receptor agonists impair postprandial glucose tolerance.

We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.

Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome -- a randomized study (SYSDIET).

BACKGROUND: Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. METHODS: We conducted a randomized dietary study lasting for 18-24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m(-2) , 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. RESULTS: Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmol L(-1) 95% CI -0.35; -0.01, P = 0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37 ng L(-1) , P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, -0.23, -0.41; -0.05, P = 0.012) were associated with IL-1 Ra. CONCLUSIONS: Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.

Triglyceride-cholesterol imbalance across lipoprotein subclasses predicts diabetic kidney disease and mortality in type 1 diabetes: the FinnDiane Study.

BACKGROUND: Circulating cholesterol (C) and triglyceride (TG) levels are associated with vascular injury in type 1 diabetes (T1DM). Lipoproteins are responsible for transporting lipids, and alterations in their subclass distributions may partly explain the increased mortality in individuals with T1DM. DESIGN AND SUBJECTS: A cohort of 3544 individuals with T1DM was recruited by the nationwide multicentre FinnDiane Study Group. At baseline, six very low-density lipoprotein VLDL, one intermediate-density lipoprotein IDL, three low-density lipoprotein LDL and four higher high-density lipoprotein HDL subclasses were quantified by proton nuclear magnetic resonance spectroscopy. At follow-up, the baseline data were analysed for incident micro- or macroalbuminuria (117 cases in 5.3 years), progression from microalbuminuria (63 cases in 6.1 years), progression from macroalbuminuria (109 cases in 5.9 years) and mortality (385 deaths in 9.4 years). Univariate associations were tested by age-matched cases and controls and multivariate lipoprotein profiles were analysed using the self-organizing map (SOM). RESULTS: TG and C levels in large VLDL were associated with incident albuminuria, TG and C in medium VLDL were associated with progression from microalbuminuria, and TG and C in all VLDL subclasses were associated with mortality. Large HDL-C was inversely associated with mortality. Three extreme phenotypes emerged from SOM analysis: (i) low C (<3% mortality), (ii) low TG/C ratio (6% mortality), and (iii) high TG/C ratio (40% mortality) in all subclasses. CONCLUSIONS: TG-C imbalance is a general lipoprotein characteristic in individuals with T1DM and high vascular disease risk.

Comparison of motor performance, brain biochemistry and histology of two A30P α-synuclein transgenic mouse strains.

Three point mutations in the SNCA gene encoding α-synuclein (aSyn) have been associated with autosomal dominant forms of Parkinson's disease. To better understand the role of the A30P mutant aSyn, we compared two transgenic mouse strains: a knock-in mouse with an introduced A30P point mutation in the wild-type (WT) gene (Snca(tm(A30P))) and a transgenic (Tg) mouse overexpressing the human A30P aSyn gene under the prion promoter [tg(Prnp-SNCA A30P)]. The brain aSyn load, motor performance, brain dopamine (DA) and sensitivity to 6-hydroxydopamine (6-OHDA) were studied in these mice. aSyn was evidently accumulating with age in all mice, particularly in tg(Prnp-SNCA A30P) Tg mice. There were no robust changes in basal locomotor activities of the mice of either line at 6 months, but after 1 year, tg(Prnp-SNCA A30P) Tg mice developed severe problems with vertical movements. However, the younger Tg mice had a reduced locomotor response to 1mg/kg of d-amphetamine. Snca(tm(A30P)) mice with the targeted mutation (Tm) were slightly hyperactive at all ages. Less 6-OHDA was required in tg(Prnp-SNCA A30P) Tg (1 µg) than in WT (3µg) mice for an ipsilateral rotational bias by d-amphetamine. That was not seen with the Snca(tm(A30P)) strain. A small dose of 6-OHDA (0.33 µg) led to contralateral rotations and elevated striatal DA in Tg/Tm mice of both lines but otherwise 6-OHDA-induced striatal DA depletion was similar in all mice, indicating no A30P-aSyn-related toxin sensitivity. 3,4-Dihydroxyphenylacetic acid/DA-ratio was elevated in tg(Prnp-SNCA A30P) mice, suggesting an enhanced DA turnover. This ratio and homovanillic acid/DA-ratio were declined in Snca(tm(A30P)) mice. Our results demonstrate that the two differently constructed A30P-aSyn mouse strains have distinct behavioral and biochemical characteristics, some of which are opposite. Since the two lines with the same background were not identically produced, the deviations found may be partially caused by factors other than aSyn-related genetic differences.

High vitreous concentration of IL-6 and IL-8, but not of adhesion molecules in relation to plasma concentrations in proliferative diabetic retinopathy.

BACKGROUND/AIM: Inflammatory markers have been observed in proliferative diabetic retinopathy (PDR). We assessed vitreous concentrations of adhesion molecules and cytokines in PDR and non-diabetic controls and plasma concentrations to differentiate local inflammation from the breakdown of the blood-retina barrier. METHODS: 38 patients with PDR and 16 controls with macular hole or epiretinal membrane underwent vitrectomy. Vitreous and plasma soluble adhesion molecules [sE-selectin, intercellular adhesion molecule (sICAM)-1 and -3, platelet-endothelial cell adhesion molecule (sPECAM)-1, sP-selectin, vascular cell adhesion molecule (sVCAM)-1] and cytokines [interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p70), tumour necrosis factor-α and -ß, γ-interferon] were detected by the multiplex assay. RESULTS: Levels of IL-6 and IL-8 were 26-fold (p = 0.001) and 6-fold higher (p = 0.001) in vitreous than in plasma in PDR. Vitreous IL-10 (p = 0.004), sPECAM-1, sE-selectin, sICAM-1 and sVCAM-1 were higher in PDR than controls (p = 0.001 for all). Adhesion molecule concentrations in vitreous in PDR were less than 10% of those in plasma. IL-10 was lower in vitreous than plasma (3.0 vs. 12.8 pg/ml, p = 0.007), and the vitreous IL-10/IL-8 ratio was significantly lower in PDR than in controls (0.10 vs. 0.55 pg/ml, p = 0.003). CONCLUSION: The elevated IL-6 and IL-8 levels in vitreous, but not in plasma, are evidence favouring local over systemic inflammation in PDR. Furthermore, there was imbalance between inflammatory and anti-inflammatory cytokines in the vitreous.

Alcohol-induced premature permeability in mouse placenta-yolk sac barriers in vivo.

OBJECTIVE: Acute alcohol exposure induces malformation and malfunction of placenta-yolk sac tissues in rodents, reducing the labyrinth zone in the placenta and altering the permeability and fluidity of the cell membrane. During normal mouse placentation the cells line up in an optimal way to form a hemotrichorial placenta where layers II and III are connected through gap junctions. These act as molecular sieves that limit the passage of large molecules. PlGF is a developmentally regulated protein that controls the passage of molecules in the vasculosyncytial membranes and media of large blood vessels in the placental villi. In addition to the chorioallontoic placenta, rodents also have another type of placenta that consists of Reichert's membrane within the trophoblast cell layer on the maternal side and the parietal endodermal cells on the embryonic site. This forms a separate materno-fetal transport system. We study here whether alcohol affects these two placental barriers, leading to placental malfunction that in turn diminishes the nutrient supply to the embryo. STUDY DESIGN: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals at 8.75 days post coitum (dpc). The placentas were collected on 9.5, 11.5 and 14.5 dpc and used for histopathological protein studies. Hemotrichorial cell layer structure interactions through connective tissue and gap junction were analyzed by electron microscopy. The permeability of the feto-maternal barrier was visualized with Evans Blue. RESULTS: VEGF, a permeability inducer, was found to be up-regulated in the mouse placenta after acute alcohol exposure, and permeability was also affected by altered structures in the barriers that separate the feto-maternal blood circulation which destroyed the gap junctions in the hemotrichorial cell layer, reduced the thickness of Reichert's membrane and interfered with with Reichert's trophoblast/Reichert's parietal interaction. These defects together could have caused the permeability malfunction of the placenta-yolk sac tissues as visualized and quantified here by Evans Blue leakage. CONCLUSIONS: An altered PlGF/VEGF ratio together with barrier malformation may contribute to placental malfunction by altering the permeability of the feto-maternal barriers. Further studies are needed in order to show whether premature permeability is involved in the intrauterine growth restriction observed in human FAS embryos.

Mild cognitive impairment associates with concurrent decreases in serum cholesterol and cholesterol-related lipoprotein subclasses.

BACKGROUND AND OBJECTIVE: Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years. DESIGN: Longitudinal. SETTING: City of Kuopio, Finland. PARTICIPANTS: 45 elderly individuals of which 20 developed mild cognitive impairment (MCI) during the follow-up. MEASUREMENTS: On each visit participants underwent an extensive neuropsychological and clinical assessment. Lipoprotein levels were measured via 1H NMR from native serum samples. RESULTS: Serum cholesterol and many primarily cholesterol-associated lipoprotein measures clearly decreased in MCI while the trends were increasing for those elderly people who maintained normal cognition. CONCLUSION: These findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

OBJECTIVE: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

The association of body mass index, waist and hip circumference, and waist-hip ratio with Chlamydia pneumoniae IgG antibodies and high-sensitive C-reactive protein at 31 years of age in Northern Finland Birth Cohort 1966.

BACKGROUND: Viruses and bacteria like Chlamydia pneumoniae and Helicobacter pylori have been suggested to have a role in pathogenesis of overweight and obesity. OBJECTIVE: We studied whether C. pneumoniae-specific IgG antibodies are associated with elevated body mass index (BMI), waist and hip circumference, and/or waist-hip ratio (WHR), and whether the risk is more pronounced in the simultaneous presence of an ongoing inflammation as measured by elevated high-sensitive C-reactive protein (hsCRP) levels. SUBJECTS AND METHODS: Our study population was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), a general population sample of 12,058 live-born children. This cross-sectional study consisted of 5044 persons at 31 years of age. Serum C. pneumoniae IgG titers were measured by microimmunofluorescence test, and hsCRP levels by immunoenzymometric assay. RESULTS: C. pneumoniae IgG positivity (titer ≥ 32), both alone and jointly with elevated hsCRP (≥ 1.64 mg l(-1), an upper quartile), was found to significantly associate with elevated BMI in the whole study population and with elevated hip and waist circumference in women, yet no association with WHR was seen. The analyses were adjusted for sex (when appropriate), smoking, socioeconomic position, glucose, insulin, high- and low-density lipoprotein cholesterols, triglycerides, leukocytes and pulse pressure. CONCLUSION: These findings suggest that especially in women, persistent C. pneumoniae infection may be associated with overweight/obesity, independently of more traditional risk factors.

Polymorphism of the manganese superoxide dismutase gene but not of vascular endothelial growth factor gene is a risk factor for diabetic retinopathy.

BACKGROUND: In diabetic retinopathy, the vascular endothelium is damaged due to oxidative stress and inflammation, and vitreous VEGF concentration becomes elevated. The association of diabetic retinopathy with single nucleotide polymorphisms (SNPs) was studied on two genes: VEGF, an important mediator of neovascularisation, and MnSOD, a major antioxidant enzyme. METHODS: The study population was 755 individuals consisting of 131 diabetic (type 1 or type 2) patients with diabetic retinopathy (DR group), 98 diabetic controls without retinopathy (DC group) and 526 non-diabetic controls. VEGF SNPs rs699947, rs2010963, rs2146232, rs3025033, rs3025039 and Ala16Val polymorphism of the MnSOD gene were genotyped. RESULTS: The frequencies of allele and genotype of the single genotyped VEGF SNPs or reconstructed haplotypes of these single SNPs did not differ between DR and DC groups. A higher frequency of the AlaAla genotype (p = 0.03) and Ala16 allele (p = 0.04) of the MnSOD gene in the DR group was found when compared with the DC group. CONCLUSIONS: In conclusion, the studied VEGF SNPs were not associated with the risk of diabetic retinopathy, and so it is unlikely that the VEGF gene is a major locus determining the risk of diabetic retinopathy. A statistically significant association of MnSOD Ala16Val polymorphism with diabetic retinopathy was found.

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy.

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.