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BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD).AimsWe aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation.MethodsThe study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course.ResultsGenealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, pConclusionsPreviously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.

We investigated toxicity of 2-3 layered >1 μm sized graphene oxide (GO) and reduced graphene oxide (rGO) in mice following single intratracheal exposure with respect to pulmonary inflammation, acute phase response (biomarker for risk of cardiovascular disease) and genotoxicity. In addition, we assessed exposure levels of particulate matter emitted during production of graphene in a clean room and in a normal industrial environment using chemical vapour deposition. Toxicity was evaluated at day 1, 3, 28 and 90 days (18, 54 and 162 μg/mouse), except for GO exposed mice at day 28 and 90 where only the lowest dose was evaluated. GO induced a strong acute inflammatory response together with a pulmonary (Serum-Amyloid A, Saa3) and hepatic (Saa1) acute phase response. rGO induced less acute, but a constant and prolonged inflammation up to day 90. Lung histopathology showed particle agglomerates at day 90 without signs of fibrosis. In addition, DNA damage in BAL cells was observed across time points and doses for both GO and rGO. In conclusion, pulmonary exposure to GO and rGO induced inflammation, acute phase response and genotoxicity but no fibrosis.

OBJECTIVES:To describe and compare temporal changes in prevalence and incidence of psychotropic use (antipsychotics, antidepressants and benzodiazepines and related drugs; BZDRs) in persons with newly diagnosed Alzheimer's disease (AD) between university hospital districts of Finland during 2005-2011. METHODS:The MEDALZ study includes all community-dwellers of Finland who received a clinically verified AD diagnosis in 2005-2011 (N = 70,718). Prevalent and incident use of psychotropics among those who had received AD diagnosis less than one year ago were compared in 2005-2011. RESULTS:Regional differences in psychotropic use between university hospital districts were more evident in 2005 than 2011 for prevalent use of any psychotropic, antipsychotic and BZDRs and incident use of any psychotropic and antipsychotics. Regional differences in prevalent antidepressant use and incident BZDR use remained similar during the follow-up, while differences in incident antidepressant use increased during the follow-up. The prevalence of any psychotropic use in 2005 varied between 44.7-50.7% and between 45.0-47.9% in 2011. Incidence of any psychotropic use in 2005 was between 8.6-12.1% and 6.2-8.2% in 2011. In 2005, the distribution of incident psychotropic use followed a large scale spatial variation that, however, did not correspond to university hospital districts. During the study period from 2005 to 2011 the cyclic spatial variation disappeared. No sign of adjacent hospital districts being more or less closely related to each other compared to hospital districts in general was detected. CONCLUSIONS:Except for antidepressants, regional differences in psychotropic use have mainly diminished between 2005 and 2011. Our findings highlight the importance of acknowledging regional differences in a country with relatively homogeneous healthcare system and conducting future studies assessing the reasons behind these differences.

In register-based pharmacoepidemiological studies, construction of drug exposure periods from drug purchases is a major methodological challenge. Various methods have been applied but their validity is rarely evaluated. Our objective was to conduct an expert-opinion based evaluation of the correctness of drug use periods produced by different methods.Drug use periods were calculated with three fixed methods: time windows, assumption of one Defined Daily Dose (DDD) per day and one tablet per day, and with PRE2DUP that is based on modelling of individual drug purchasing behavior. Expert-opinion based evaluation was conducted with 200 randomly selected purchase histories of warfarin, bisoprolol, simvastatin, risperidone and mirtazapine in the MEDALZ-2005 cohort (28,093 persons with Alzheimer's disease). Two experts reviewed purchase histories and judged which methods had joined correct purchases and gave correct duration for each of 1000 drug exposure periods.The evaluated correctness of drug use periods was 70-94% for PRE2DUP, and depending on grace periods and time window lengths 0-73% for tablet methods, 0-41% for DDD methods and 0-11% for time window methods. The highest rate of evaluated correct solutions for each method class were observed for 1 tablet per day with 180 days grace period (TAB_1_180, 43-73%), and 1 DDD per day with 180 days grace period (1-41%). Time window methods produced at maximum only 11% correct solutions. The best performing fixed method TAB_1_180 reached highest correctness for simvastatin 73% (95% CI 65-81%) whereas 89% (95% CI 84-94%) of PRE2DUP periods were judged as correct.This study shows inaccuracy of fixed methods and the urgent need for new data-driven methods. In the expert-opinion based evaluation, the lowest error rates were observed with data-driven method PRE2DUP.

AIM:Toll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients. METHODS:We performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses. RESULTS:The TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls. CONCLUSION:Among the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies.

Interleukin-10 (IL-10) has been associated with wheezing and asthma in children and the genetic variation of the IL-10 cytokine production may be linked to post-bronchiolitis lung function. We used impulse oscillometry (IOS) to evaluate the associations of IL10 polymorphisms with lung function at a median age of 6.3 years in children hospitalised for bronchiolitis before six months of age.We performed baseline and post-exercise IOS on 103 former bronchiolitis patients. Data on single nucleotide polymorphisms (SNP) of IL10 rs1800896 (-1082G/A), rs1800871 (-819C/T), rs1800872 (-592C/A) were available for 99 children and of IL10 rs1800890 (-3575T/A) for 98 children.IL10 rs1800896, rs1800871 and rs1800872 combined genotype AA+CT+CA and carriage of haplotype ATA, respectively, were associated with higher resistance and lower reactance in baseline IOS in adjusted analyses. At IL10 rs1800890, the A/A-genotype and carriers of A-allele were associated with lower reactance in baseline IOS. There were no significant associations between the studied SNPs and airway hyper-reactivity to exercise.Low-IL-10-producing polymorphisms in the IL-10 encoding gene were associated with obstructive lung function parameters, suggesting an important role for IL-10 in development of lung function deficit in early bronchiolitis patients.

To determine whether there are differences in age and sex distribution and presence of comorbidities between participants included in randomized controlled trials of acetylcholinesterase inhibitors and nationwide cohort of persons with Alzheimer's disease.PubMed, Scopus and Cochrane Library databases were searched for original articles from their inception to January 4, 2015. Double-blind randomized controlled trials with donepezil, rivastigmine or galantamine compared to placebo in participants with Alzheimer's disease were included. Data from a nationwide cohort of persons with clinically verified diagnoses of Alzheimer's disease was defined as a reference population.128 full-text articles were assessed for eligibility, 31 of them fulfilled criteria. Mean age of participants in randomized controlled trials (n = 15,032) was 5.8 years lower (95% CI 5.7 to 5.9, P < 0.001), compared to the mean age of 79.7 years in the reference population with Alzheimer's disease (n = 28,093). Most of the articles did not report age distribution of participants. The proportion of women was 63.2% (9,475/14,991) in randomized controlled trials and 67.8% (19,043/28,093) (P < 0.001) in the reference population. Information on comorbidities and use of concomitant drugs were lacking or poorly reported in most articles.There is a discrepancy between participants in randomized controlled trials of acetylcholinesterase inhibitors and real-life population with Alzheimer's disease. Participants in randomized controlled trials were significantly younger. Further, more detailed reporting of age distribution, comorbidities and concomitant drugs would be important information for clinicians when evaluating conclusions from randomized controlled trials to real-life practice. The existing recommendations of inclusion of older people should be followed to ensure safe pharmacotherapy for older people.

BACKGROUND: Evidence is lacking about outcomes associated with the cumulative use of anticholinergic and sedative drugs in people with Alzheimer's disease (AD). This retrospective cohort study investigated the relationship between cumulative exposure to anticholinergic and sedative drugs and hospitalization and mortality in people with and without AD in Finland. METHODS: Community-dwelling people aged 65 years and over, with AD on December 31(st) 2005 (n = 16,603) and individually matched (n = 16,603) comparison persons (age, sex, region of residence) were identified by the Social Insurance Institution of Finland. Drug utilization data were extracted from the Finnish National Prescription Register. Exposure to anticholinergic and sedative drugs was defined using the Drug Burden Index (DBI). Hospitalization and mortality data were extracted from national registers. Cox and zero-inflated negative binomial analyses were used to investigate the relationship between DBI and hospitalization and mortality over a one-year follow-up. RESULTS: In total, 5.8% of people with AD and 3.7% without AD died during 2006. For every unit increase in DBI, the adjusted hazard ratio for mortality was 1.21 (95% confidence intervals [CI]: 1.09-1.33) among people with AD, and 1.37 (95%CI: 1.20-1.56) among people without AD. Overall, 44.3% of people with AD and 33.4% without AD were hospitalized. When using no DBI exposure as the reference group, the adjusted incidence rate ratio for length of hospital stay among high DBI group (≥1) in people with AD was 1.15 (95%CI: 1.05-1.26) and 1.63 (95%CI: 1.41-1.88) in people without AD. CONCLUSION: There is a dose-response relationship between cumulative anticholinergic and sedative drug use and hospitalization and mortality in people with and without AD.

Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999-2001 at the age of 33-35 years. A follow-up was conducted 9 years later during 2008-2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions.

The Tonle Sap Lake in Cambodia is a dynamic flood-pulsed ecosystem that annually increases its surface area from roughly 2,500 km(2) to over 12,500 km(2) driven by seasonal flooding from the Mekong River. This flooding is thought to structure many of the critical ecological processes, including aquatic primary and secondary productivity. The lake also has a large fishery that supports the livelihoods of nearly 2 million people. We used a state-space oxygen mass balance model and continuous dissolved oxygen measurements from four locations to provide the first estimates of gross primary productivity (GPP) and ecosystem respiration (ER) for the Tonle Sap. GPP averaged 4.1±2.3 g O2 m(-3) d(-1) with minimal differences among sites. There was a negative correlation between monthly GPP and lake level (r = 0.45) and positive correlation with turbidity (r = 0.65). ER averaged 24.9±20.0 g O2 m(-3) d(-1) but had greater than six-fold variation among sites and minimal seasonal change. Repeated hypoxia was observed at most sampling sites along with persistent net heterotrophy (GPP

Aim: Toll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients., Methods: We performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses., Results: The TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls., Conclusion: Among the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies.

Aim: Interleukin-10 (IL-10) has been associated with wheezing and asthma in children and the genetic variation of the IL-10 cytokine production may be linked to post-bronchiolitis lung function. We used impulse oscillometry (IOS) to evaluate the associations of IL10 polymorphisms with lung function at a median age of 6.3 years in children hospitalised for bronchiolitis before six months of age., Methods: We performed baseline and post-exercise IOS on 103 former bronchiolitis patients. Data on single nucleotide polymorphisms (SNP) of IL10 rs1800896 (-1082G/A), rs1800871 (-819C/T), rs1800872 (-592C/A) were available for 99 children and of IL10 rs1800890 (-3575T/A) for 98 children., Results: IL10 rs1800896, rs1800871 and rs1800872 combined genotype AA+CT+CA and carriage of haplotype ATA, respectively, were associated with higher resistance and lower reactance in baseline IOS in adjusted analyses. At IL10 rs1800890, the A/A-genotype and carriers of A-allele were associated with lower reactance in baseline IOS. There were no significant associations between the studied SNPs and airway hyper-reactivity to exercise., Conclusion: Low-IL-10-producing polymorphisms in the IL-10 encoding gene were associated with obstructive lung function parameters, suggesting an important role for IL-10 in development of lung function deficit in early bronchiolitis patients.