14.4.2008

Haukka, J., Suvisaari, J., Hakkinen, L. and Lonnqvist, J.

Psychol Med. 2008; 38(1): 63-70. IF 3.816

BACKGROUND: Foetal nutrition and growth seem to affect the risk of developing schizophrenia. Exposure to famine during foetal development and low birthweight increase the risk. However, few studies have investigated the association between schizophrenia and adult height and weight or patterns of growth.

METHOD: The study population consisted of two subpopulations: families with at least one member with schizophrenia, and families of offspring of mothers with psychotic disorder, and controls. Using a seven-parameter model of height growth curves, we compared the parameters of persons who later developed schizophrenia and their unaffected siblings from the same families. We also studied how growth curve parameters differed in children with genetic risk for schizophrenia and controls, and whether weight, height and body mass index (BMI) at different ages predicted later development of schizophrenia.

RESULTS: The predicted growth curves based on a parametric model were nearly identical for persons with schizophrenia and their unaffected siblings. Adult height of daughters of mothers with psychoses was borderline significantly (p=0.0536) lower compared to controls, while no difference was detected among sons (p=0.3283).

CONCLUSIONS: No association between growth characteristics and schizophrenia in families with at least one member with schizophrenia was found. Family-related factors should be taken into account as possible confounders in future studies on growth and schizophrenia.

Geographical variation of medicated parkinsonism in Finland during 1995 to 2000

Havulinna, A. S., Tienari, P. J., Marttila, R. J., Martikainen, K. K., Eriksson, J. G., Taskinen, O., Moltchanova, E. and Karvonen, M.

Mov Disord. 2008. IF 3.323

We performed a nation-wide study on geographical variation in the incidence and prevalence of medicated parkinsonism among the Finns aged >/=30 years using Bayesian spatial conditional autoregressive models.

Registry of reimbursed medication for parkinsonism and a prescription database of purchase of these drugs were used to identify the study subjects. They were located by the map coordinates of the place of residence and aggregated into regular 100 km(2) grid cells. A total of 7,190 incident and 10,616 prevalent cases were found. The age-adjusted annual incidence was 32.6/100,000 (95% HDR 31.8-33.4) during the years 1995 to 2000 and prevalence was 268/100,000 (95% HDR 263-274) in 2000. The male to female ratio was 1.45 (95% HDR 1.39-1.51) in incidence and 1.54 (95% HDR 1.47-1.61) in prevalence. There was strong evidence for geographic variation in incidence and prevalence. A zone with high incidence and prevalence was identified in the eastern and central part of Finland. There was no evidence for difference in incidence and prevalence between urban and rural areas.

The marked (more than two-fold) geographic variation can hardly be caused solely by practices of the registration and collection of data on diagnosis or by methodological issues, but rather suggests to geographic variation in protective and predisposing factors of Parkinsonism in Finland. (c) 2008 Movement Disorder Society.

Total cholesterol and the risk of Parkinson disease

Hu, G., Antikainen, R., Jousilahti, P., Kivipelto, M. and Tuomilehto, J.

Neurology. 2008. IF 5.690

OBJECTIVE: To examine the association between serum total cholesterol at baseline and the risk of Parkinson disease (PD).

METHODS: Study cohorts included 24,773 Finnish men and 26,153 women aged 25 to 74 years without a history of PD and stroke at baseline. Hazard ratios (HRs) of incident PD were estimated for different levels of total cholesterol.

RESULTS: During a mean follow-up period of 18.1 years, 321 men and 304 women developed incident PD. After adjustment for confounding factors (age, study years, body mass index, systolic blood pressure, education, leisure-time physical activity, smoking, alcohol consumption, coffee and tea consumption, and history of diabetes), the HRs of PD at different levels of total cholesterol (<5, 5-5.9, 6-6.9, and >/=7 mmol/L) were 1.00, 1.33, 1.53, and 1.84 (p for trend = 0.035) in men; 1.00, 1.55, 1.57, and 1.86 (p for trend = 0.113) in women; and 1.00, 1.42, 1.56, and 1.86 (p for trend = 0.002) in men and women combined (adjusted also for sex). In both sexes combined, the increased risk of PD associated with increasing levels of serum total cholesterol was present both in subjects aged 25-44 years and in subjects aged 45-54 years at baseline, and in never smokers and smokers; however, no association was found among subjects aged 55 years or older at baseline.

CONCLUSION: This large prospective study suggests that high total cholesterol at baseline is associated with an increased risk of Parkinson disease.

Joint effects of history of hypertension at baseline and type 2 diabetes at baseline and during follow-up on the risk of coronary heart disease

Hu, G., Jousilahti, P. and Tuomilehto, J.

Eur Heart J. 2007; 28(24): 3059-66. IF 7.286

AIMS: To evaluate the joint associations of history of hypertension at baseline and type 2 diabetes at baseline and during follow-up on the incidence of coronary heart disease (CHD) and CHD mortality.

METHODS AND RESULTS: Study cohorts included 49 775 Finnish subjects aged 25-74 without history of CHD and stroke. The multivariable-adjusted hazard ratios (HRs) of CHD incidence were 1.25, 1.69, 1.25, 1.83, 1.85, 2.39, 2.15, and 3.31 (P-value for trend <0.001), respectively, among men with hypertension I (blood pressure 140-159/90-94 mmHg or using antihypertensive drugs at baseline but blood pressure <160/95 mmHg) only, with hypertension II (blood pressure > or =160/95 mmHg) only, with incident diabetes during follow-up only, with both hypertension I and incident diabetes, with both hypertension II and incident diabetes, with history of diabetes at baseline only, with both hypertension I and history of diabetes, and with both hypertension II and history of diabetes compared with men without either of these diseases. The corresponding HRs of CHD incidence among women were 1.52, 2.37, 2.45, 3.78, 4.56, 5.63, 6.10, and 7.41 (P-value for trend <0.001), respectively. The impact on CHD mortality associated with the different strata of hypertension and diabetes was almost the same or a little stronger compared with that on the CHD incidence.

CONCLUSION: Hypertension and type 2 diabetes increase the CHD risk independently, and their combination increases the risk dramatically, particularly in women.

FEV1 response to bronchodilation in an adult urban population

Kainu, T. A., Lindqvist, A. E., Sarna, S. J., Lundback, B. E. and Sovijarvi, A. R.

Chest. 2008. IF 3.924

Background Most studies evaluating bronchodilation in flow-volume spirometry have been conducted in patients with obstructive airways diseases, but less is known about bronchodilation responses in the general population or in healthy subjects.

Methods We evaluated an urban population sample of 628 adults (260 men, 368 women) aged 25-74 years with flow-volume spirometry using 0.4 mg of inhaled salbutamol aerosol with a spacer device for bronchodilation. On the basis of a structured interview, a subgroup of 219 healthy asymptomatic non-smokers was selected.

Results In the population sample, the average increase of forced expiratory volume in one second (FEV1) from baseline after inhaled salbutamol was 77.2 ml (s.d. 109.7 ml) or 2.5% (3.9%). In healthy asymptomatic non-smokers, the mean change of FEV1 was 62.0 ml (89.7 ml) or 1.8% (2.6%). In the whole population, the 95(th) percentile limit of the increase of FEV1 was 8.5%, while it was 5.9% among healthy asymptomatic non-smokers. The absolute change of FEV1 correlated significantly with the baseline FVC (p<0.01). The ratio of FEV1 to forced vital capacity (FEV1/FVC) at baseline was the strongest influencing factor for bronchodilation response.

Conclusions The results indicate that a significant increase of FEV1 from the baseline in a bronchodilation test is around 9% in an urban population. The level of the significant absolute increase of FEV1 seems to depend on FVC. Low baseline FEV1/FVC, reflecting airflow limitation, is the strongest determinant for FEV1 response to bronchodilation.

One-Year Course and Predictors of Outcome of Adolescent Depression: A Case-Control Study in Finland

Karlsson, L., Kiviruusu, O., Miettunen, J., Heila, H., Holi, M., Ruuttu, T., Tuisku, V., Pelkonen, M. and Marttunen, M.

J Clin Psychiatry. 2008: e1-e10. IF 5.533

BACKGROUND: Clinical studies on the outcome of adolescent depression beyond treatment trials are scarce.

OBJECTIVE: To investigate the impact of characteristics of the depressive episode and current comorbidity on the 1-year outcome of depression.

METHOD: A sample of 174 consecutive adolescent psychiatric outpatients (aged 13 through 19 years) and 17 school-derived matched controls, all with unipolar depressive disorders at baseline, were reinterviewed for DSM-IV Axis I and Axis II disorders at 12 months. The study was conducted between January 1998 and May 2002.

RESULTS: The outpatients had equal recovery rate and episode duration but shorter time to recurrence than the controls. Among the outpa-tients, Axis II comorbidity predicted shorter time to recurrence (p = .02). Longer time to recovery was predicted by earlier lifetime age at onset for depression (p = .02), poor psychosocial functioning (p = .003), depressive disorder diagnosis (p

CONCLUSIONS: Characteristics of depression generally predicted the outcome better than co-morbidity. Axis II comorbidity has prognostic value in adolescent depression.

Association of DISC1 with autism and Asperger syndrome

Kilpinen, H., Ylisaukko-Oja, T., Hennah, W., Palo, O. M., Varilo, T., Vanhala, R., Nieminen-von Wendt, T., von Wendt, L., Paunio, T. and Peltonen, L.

Mol Psychiatry. 2008; 13(2): 187-96. IF 11.804

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders.

Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, n(affected)=138) and Asperger syndrome (29 families, n(affected)=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1.

These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.

Daylight saving time transitions and hospital treatments due to accidents or manic episodes

Lahti, T. A., Haukka, J., Lonnqvist, J. and Partonen, T.

BMC Public Health. 2008; 8: 74. IF 1.603

BACKGROUND: Daylight saving time affects millions of people annually but its impacts are still widely unknown. Sleep deprivation and the change of circadian rhythm can trigger mental illness and cause higher accident rates. Transitions into and out of daylight saving time changes the circadian rhythm and may cause sleep deprivation. Thus it seems plausible that the prevalence of accidents and/or manic episodes may be higher after transition into and out of daylight saving time. The aim of this study was to explore the effects of transitions into and out of daylight saving time on the incidence of accidents and manic episodes in the Finnish population during the years of 1987 to 2003.

METHODS: The nationwide data were derived from the Finnish Hospital Discharge Register. From the register we obtained the information about the hospital-treated accidents and manic episodes during two weeks before and two weeks after the transitions in 1987-2003.

RESULTS: The results were negative, as the transitions into or out of daylight saving time had no significant effect on the incidence of accidents or manic episodes.

CONCLUSION: One-hour transitions do not increase the incidence of manic episodes or accidents which require hospital treatment.

Differences in outcome of DSM-IV bipolar I and II disorders

Mantere, O., Suominen, K., Valtonen, H. M., Arvilommi, P., Leppamaki, S., Melartin, T. and Isometsa, E.

Bipolar Disord. 2008; 10(3): 413-25. IF 3.494

Objectives: To investigate whether the course of bipolar disorder (BD) type II is more depressive than that of BD I, and, if so, to explore the underlying factors that cause this difference.

Methods: In a prospective, naturalistic study of 191 secondary care psychiatric in- and outpatients diagnosed in an acute phase of BD I or II, 160 patients (85.1%) were followed for 18 months. Using a life chart, the exact timing of symptom states in follow-up was examined. Differences between BD I (n = 75) and II (n = 85) in duration of index phase and episode, time to full remission and recurrence, and time in any mood episode were investigated.

Results: Patients with BD II spent a higher proportion of time ill (47.5% versus 37.7%; p = 0.02) and in depressive symptom states (58.0% versus 41.7%; p = 0.003) than BD I patients. This was a result of the higher proportion (61.7% versus 48.6%; p = 0.03) and mean number (1.69 versus 1.11; p = 0.006) of depressive illness phases in BD II, rather than of differences in the duration of depressive phases. Type of index phase strongly predicted the outcome. In linear regression models, both BD II and type of index phase predicted more time spent in depressive symptom states.

Conclusions: In medium-term follow-up, BD II patients spend about 40% more time in depressive symptom states than BD I patients because a higher proportion of BD II patients have depressive phases and the frequency of these is higher. Differences in type of index phase may markedly confound differences in outcome between BD I and II.

Comparison of body mass index with waist circumference, waist-to-hip ratio, and waist-to-stature ratio as a predictor of hypertension incidence in Mauritius

Nyamdorj, R., Qiao, Q., Soderberg, S., Pitkaniemi, J., Zimmet, P., Shaw, J., Alberti, G., Nan, H., Uusitalo, U., Pauvaday, V., Chitson, P. and Tuomilehto, J.

J Hypertens. 2008; 26(5): 866-870. IF 4.021

OBJECTIVE: Comparison of BMI with waist circumference, waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) as a predictor of hypertension incidence.

METHODS: A total of 1658 men and 1976 women of Mauritian Indian and Mauritian Creole ethnicity, aged 25-74 years, free of hypertension, diabetes, cardiovascular disease, and gout at baseline in 1987 or 1992, were re-examined in 1992 and/or 1998 using the same survey methodology. Hazard ratios (HRs) for hypertension incidence were estimated applying an interval censored survival analysis (R program) using age as timescale based on baseline obesity indicators.

RESULTS: A total of 787 incident hypertension cases were identified during the follow-up. HRs for hypertension incidence adjusting for baseline systolic blood pressure and cohort corresponding to a 1 SD increase in BMI, waist circumference, WHR, and WSR were 1.20 (1.24), 1.19 (1.21), 1.14 (1.10), and 1.20 (1.26) in Mauritian Indian men (women) and 1.23 (1.32), 1.34 (1.23), 1.41 (1.13), and 1.43 (1.33) in Mauritian Creoles, respectively, indicating that all obesity indicators significantly predicted hypertension incidence except for WHR in Mauritian Creole women. Paired homogeneity tests showed that there was no difference between BMI and the other three indicators for most of the comparisons with two exceptions: WSR was stronger than BMI (P = 0.002) in Mauritian Creole men but BMI was stronger than WHR (P = 0.047) in Mauritian Indian women in predicting the incident cases of hypertension.

CONCLUSION: The relation of the development of hypertension with BMI was as strong as that with central obesity indicators in the population studied.

Roadside oral fluid testing: comparison of the results of drugwipe 5 and drugwipe benzodiazepines on-site tests with laboratory confirmation results of oral fluid and whole blood

Pehrsson, A., Gunnar, T., Engblom, C., Seppa, H., Jama, A. and Lillsunde, P.

Forensic Sci Int. 2008; 175(2-3): 140-8. IF 1.397

Drugged drivers pose a serious threat to other people in traffic as well as to themselves. Reliable oral fluid screening devices for on-site screening of drugged drivers would be both a useful and convenient means for traffic control.

In this study we evaluated the appropriateness of Drugwipe 5 and Drugwipe Benzodiazepines oral fluid on-site tests for roadside drug screening. Drivers suspected of driving under the influence of drugs were screened with the Drugwipe tests. Oral fluid and whole blood samples were collected from the drivers and tested for amphetamine-type stimulant drugs, cannabis, opiates, cocaine and benzodiazepines by immunological methods, GC and GC-MS. The performance evaluations of the tests were made by comparing the results of the Drugwipe tests with laboratory GC-MS confirmation results of oral fluid or whole blood. In addition to the performance evaluations of the Drugwipe tests based on laboratory results, a questionnaire on the practical aspects of the tests was written for the police officers who performed the tests. The aim of the questionnaire was to obtain user comments on the practicality of the tests as well as the advantages and weak points of the tests. The results of the performance evaluations were: for oral fluid (sensitivity; specificity; accuracy) amphetamines (95.5%; 92.9%; 95.3%), cannabis (52.2%; 91.2%; 85.1%), cocaine (50.0%; 99.3%; 98.6%), opiates (100%; 95.8%; 95.9%), benzodiazepines (74.4%; 84.2%; 79.2%) and for whole blood accordingly, amphetamines (97.7%; 86.7%; 95.9%), cannabis (68.3%; 87.9%; 84.9%), cocaine (50.0%; 98.5%; 97.7%), opiates (87.5%; 96.9%; 96.6%) and benzodiazepines (66.7%; 87.0%; 74.4%).

Although the Drugwipe 5 successfully detected amphetamine-type stimulant drugs and the police officers were quite pleased with the current features of the Drugwipe tests, improvements must still be made regarding the detection of cannabis and benzodiazepines.

Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue

Pohjanvirta, R., Boutros, P. C., Moffat, I. D., Linden, J., Wendelin, D. and Okey, A. B.

Toxicol Appl Pharmacol. 2008. IF 4.722

Acute progressive feed restriction (APFR) represents a specific form of caloric restriction in which feed availability is increasingly curtailed over a period of a few days to a few weeks. It is often used for control animals in toxicological and pharmacological studies on compounds causing body weight loss to equalize weight changes between experimental and control groups and thereby, intuitively, to also set their metabolic states to the same phase. However, scientific justification for this procedure is lacking.

In the present study, we analyzed by microarrays the impact on hepatic gene expression in rats of two APFR regimens that caused identical diminution of body weight (19%) but differed slightly in duration (4 vs. 10 days). In addition, white adipose tissue (WAT) was also subjected to the transcriptomic analysis on day-4. The data revealed that the two regimens led to distinct patterns of differentially expressed genes in liver, albeit some major pathways of energy metabolism were similarly affected (particularly fatty acid and amino acid catabolism). The reason for the divergence appeared to be entrainment by the longer APFR protocol of peripheral oscillator genes, which resulted in derailment of circadian rhythms and consequent interaction of altered diurnal fluctuations with metabolic adjustments in gene expression activities. WAT proved to be highly unresponsive to the 4-day APFR as only 17 mRNA levels were influenced by the treatment.

This study demonstrates that body weight is a poor proxy of metabolic state and that the customary protocols of feed restriction can lead to rhythm entrainment.

The mediating role of C-reactive protein and handgrip strength between obesity and walking limitation

Stenholm, S., Rantanen, T., Heliovaara, M. and Koskinen, S.

J Am Geriatr Soc. 2008; 56(3): 462-9. IF 3.331

OBJECTIVES: To study the association between different obesity indicators and walking limitation and to examine the role of C-reactive protein (CRP) and handgrip strength in that association.

DESIGN: A cross-sectional, population-based study.

SETTING: The Health 2000 Survey with a representative sample of the Finnish population.

PARTICIPANTS: Subjects aged 55 and older with complete data on body composition, CRP, handgrip strength, and walking limitation (N=2,208).

MEASUREMENTS: Body composition, anthropometrics, CRP, medical conditions, handgrip strength, and maximal walking speed were measured in the health examination. Walking limitation was defined as maximal walking speed less than 1.2 m/s or difficulty walking half a kilometer.

RESULTS: The two highest quartiles of body fat percentage and CRP and the two lowest quartiles of handgrip strength were all significantly associated with greater risk of walking limitation when chronic diseases and other covariates were taken into account. In addition, high CRP and low handgrip strength partially explained the association between high body fat percentage and walking limitation, but the risk of walking limitation remained significantly greater in persons in the two highest quartiles than in those in the lowest quartile of body fat percentage (odds ratio (OR)=1.75, 95% confidence interval (CI)=1.19-2.57 and OR=2.80, 95% CI 1.89-4.16). The prevalence of walking limitation was much higher in persons who simultaneously had high body fat percentage and low handgrip strength (61%) than in those with a combination of low body fat percentage and high handgrip strength (7%). Using body mass index and waist circumference as indicators of obesity yielded similar results as body fat percentage.

CONCLUSION: Low-grade inflammation and muscle strength may partially mediate the association between obesity and walking limitation. Longitudinal studies and intervention trials are needed to verify this pathway.

Streptococcus pyogenes activates human plasmacytoid and myeloid dendritic cells

Veckman, V. and Julkunen, I.

J Leukoc Biol. 2008; 83(2): 296-304. IF 4.572

Human peripheral blood contains two major dendritic cell (DC) populations, namely CD11c(-)CD123+ plasmacytoid DCs (PDCs) and CD11c+CD123(-) myeloid DCs (MDCs). Although the activation of these DC types by various TLR ligands has been relatively well-characterized, less is known about the ability of whole live bacteria to induce PDC and MDC activation.

In the present report, we have compared the activation of human PDCs and MDCs in response to major human bacterial pathogen Streptococcus pyogenes (group A streptococci) and influenza A virus. S. pyogenes stimulation resulted in the maturation of both DC types, as evidenced by enhanced expression of costimulatory molecules and production of proinflammatory cytokines and chemokines. Furthermore, S. pyogenes-stimulated PDCs and MDCs activated naive CD4+ T cells and enhanced their Th1 cytokine production. Influenza A virus infection induced rapid PDC activation, whereas MDCs were extremely sensitive to influenza A virus-induced cell death. The most significant differences between DC types were seen in the production of IL-10 and IL-12, which were only produced by S. pyogenes-stimulated MDCs. Although S. pyogenes was able to induce PDC activation, only influenza A virus infection resulted in detectable IFN-alpha production.

Our results show that depending on the infecting microbe, the functions of PDCs and MDCs may be partially overlapping, suggesting a considerable flexibility of the human DC system.

Characteristics of oxysterol binding proteins

Yan, D. and Olkkonen, V. M.

Int Rev Cytol. 2008; 265: 253-85. IF 5.988

Protein families characterized by a ligand binding domain related to that of oxysterol binding protein (OSBP) have been identified in eukaryotic species from yeast to humans. These proteins, designated OSBP-related (ORP) or OSBP-like (OSBPL) proteins, have been implicated in various cellular functions. However, the detailed mechanisms of their action have remained elusive.

Data from our and other laboratories suggest that binding of sterol ligands may be a unifying theme. Work with Saccharomyces cerevisiae ORPs suggests a function of these proteins in the nonvesicular intracellular transport of sterols, in secretory vesicle transport from the Golgi complex, and in the establishment of cell polarity. Mammals have more ORP genes, and differential splicing substantially increases the complexity of the encoded protein family. Functional studies on mammalian ORPs point in different directions: integration of sterol and sphingomyelin metabolism, sterol transport, regulation of neutral lipid metabolism, control of the microtubule-dependent motility of endosomes/lysosomes, and regulation of signaling cascades.

We envision that during evolution, the functions of ORPs have diverged from an ancestral one in sterol transport, to meet the increasing demand of the regulatory potential in multicellular organisms.

Our working hypothesis is that mammalian ORPs mainly act as sterol sensors that relay information to a spectrum of different cellular processes.