Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Funding UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

A digital imaging technique to quantify the incidence of internal browning in potato (Solanum tuberosum) tubers

Internal browning disorders, including brown fleck (BF), in potato (Solanum tuberosum) tubers greatly reduce tuber quality, but the causes are not well understood. This is due, in part, to the highly variable data provided by visual value-based rating systems. A digital imaging technique was developed to quantify accurately the incidence of internal browning in potato tubers. Images of tuber sections were scanned using a flatbed scanner and digitally enhanced to highlight tuber BF lesions, and the area of affected tissue calculated using pixel quantification software. Digital imaging allowed for the determination of previously unused indices of the incidence and severity of internal browning in potato tubers. Statistical analysis of the comparison between digitally derived and visual-rating BF data from a glasshouse experiment showed that digital data greatly improved the delineation of treatment effects. The F-test probability was further improved through square root or logarithmic data transformations of the digital data, but not of the visual-rating data. Data from a field experiment showed that the area of tuber affected by BF and the number of small BF lesions increased with time and with increase in tuber size. The results from this study indicate that digital imaging of internal browning disorders of potato tubers holds much promise in determining their causes that heretofore have proved elusive.

Male eating disorders and related traits : Genetic epidemiological study in Finnish twins

The aim of this study was to deepen the understanding of eating disorders, body image dissatisfaction and related traits in males by examining the epidemiology and genetic epidemiology of these conditions in representative population-based twin samples. The sample of Study I included adolescent twins from FinnTwin12 cohorts born 1983 87 and assessed by a questionnaire at ages 14 y (N=2070 boys, N=2062 girls) and 17 y (N=1857 boys, N=1984 girls). Samples of Studies II-V consisted of young adult twins born 1974-79 from FinnTwin16 cohorts (Study II N=1245 men, Study III N=724 men, Study IV N=2122 men, Study V N=2426 women and N=1962 men), who were assessed by a questionnaire at the age 22-28 y. In addition, 49 men and 526 women were assessed by a diagnostic interview. The overall response rates for both twin cohorts in all studies were 80-90%. In boys, mainly genetic factors (82%, 95% confidence interval [CI] 72-92) explained the covariation of self-esteem between the ages 14 y and 17 y, whereas in girls, environmental factors (69%, 95% CI 43-93) were the largest contributors. Of young men, 30% experienced high muscle dissatisfaction, while 12% used or had used muscle building supplements and/or anabolic steroids on a regular basis. Muscle dissatisfaction exhibited a robust association with the indicators of mental distress and a genetic component (42%, 95% CI 23-59) for its liability in this population was found. The variation of muscle-building substance use was primarily explained by the environmental factors. The incidence rate of anorexia nervosa in males for the age of 10-24 y was 15.7 (95% CI 6.6-37.8) per 100 000 person-years, and its lifetime prevalence by the young adulthood was 0.24% (95% CI 0.03-0.44). All detected probands with anorexia nervosa had recovered from eating disorders, but suffered from substantial psychiatric comorbidity, which manifested also in their co-twins. Additionally, male co-twins of the probands displayed significant dissatisfaction with body musculature, a male-specific feature of body dysmorphic disorder. All probands were from twin pairs discordant for eating disorders. Of the five male probands with anorexia nervosa, only one was from an opposite-sex twin pair. Among women from the opposite-sex pairs, the prevalence of DSM-IV or broad anorexia nervosa was no significantly different compared to that of the women from monozygotic pairs or from dizygotic same-sex pairs. The prevalence of DSM-IV or broad bulimia nervosa did not differ in opposite- versus same-sex female twin individuals either. In both sexes, the overall profile of indicators on eating disorders was rather similar between individuals from opposite-sex and same-sex pairs. In adolescence, development of self-esteem was differently regulated in boys compared to girls: this finding may have far-reaching implications on the etiology of sex discrepancy of internalizing and externalizing disorders. In young men, muscle dissatisfaction and muscle building supplement/steroid use were relatively common. Muscle dissatisfaction was associated with marked psychological distress such as symptoms of depression and disordered eating. Both genetic and environmental factors explained muscle dissatisfaction in the population, but environmental factors appeared to best explain the use of muscle-building substances. In this study, anorexia nervosa in boys and young men from the general population was more common, transient and accompanied by more substantial co-morbidity than previously thought. Co-twins of the probands with anorexia nervosa displayed significant psychopathology such as male specific symptoms of body dysmorphic disorder, but none of them had had an eating disorder: taken together, these traits are suggestive for an endophenotype of anorexia nervosa in males. Little evidence was found on that the risk for anorexia nervosa, bulimia nervosa, disordered eating or body dissatisfaction were associated with twin zygosity. Thus, it is unlikely that in utero femininization, masculinization or postnatal socialization according to the sex of the co-twin have a major influence on the later development of eating disorders or related traits.

Novel insights on functions of myotilin/palladin family members

Poikkijuovaisen luuranko- ja sydänlihaksen supistumisyksikkö, sarkomeeri, koostuu tarkoin järjestyneistä aktiini- ja myosiinisäikeistä. Rakenne eroaa muista solutyypeistä, joissa aktiinisäikeistö muovautuu jatkuvasti ja sen järjestyminen säätelee solun muotoa, solujakautumista, soluliikettä ja solunsisäisten organellien kuljetusta. Myotilin, palladin ja myopalladin kuuluvat proteiiniperheeseen, jonka yhteispiirteenä ovat immunoglobuliinin kaltaiset (Igl) domeenit. Proteiinit liittyvät aktiinitukirankaan ja niiden arvellaan toimivan solutukirangan rakenne-elementteinä ja säätelijöinä. Myotilinia ja myopalladinia ilmennetään poikkijuovaisessa lihaksessa. Sen sijaan palladinin eri silmukointimuotoja tavataan monissa kudostyypeissä kuten hermostossa, ja eri muodoilla saattaa olla solutyypistä riippuvia tehtäviä. Poikkijuovaisessa lihaksessa kaikki perheen jäsenet sijaitsevat aktiinisäikeitä yhdistävässä Z-levyssä ja ne sitovat Z-levyn rakenneproteiinia, -aktiniinia. Myotilingeenin pistemutaatiot johtavat periytyviin lihastauteihin, kun taas palladinin mutaatioiden on kuvattu liittyvän periytyvään haimasyöpään ja lisääntyneeseen sydäninfarktin riskiin. Tässä tutkimuksessa selvitettin myotilinin ja pallainin toimintaa. Kokeissa löydettiin uusia palladinin 90-92kDa alatyyppiin sitoutuvia proteiineja. Yksi niistä on aktiinidynamiikkaa säätelevä profilin. Profilinilla on kahdenlaisia tehtäviä; se edesauttaa aktiinisäikeiden muodostumista, mutta se voi myös eristää yksittäisiä aktiinimolekyylejä ja edistää säikeiden hajoamista. Solutasolla palladinin ja profilinin sijainti on yhtenevä runsaasti aktiinia sisältävillä solujen reuna-alueilla. Palladinin ja profilinin sidos on heikko ja hyvin dynaaminen, joka sopii palladinin tehtävään aktiinisäideiden muodostumisen koordinoijana. Toinen palladinin sitoutumiskumppani on aktiinisäikeitä yhteensitova -aktiniini. -Aktiniini liittää solutukirangan solukalvon proteiineihin ja ankkuroi solunsisäisiä viestintämolekyylejä. Sitoutumista välittävä alue on hyvin samankaltainen palladinissa ja myotilinissa. Luurankolihaksen liiallinen toistuva venytys muuttaa Z-levyjen rakennetta ja muotoa. Prosessin aikana syntyy uusia aktiinifilamenttejä sisältäviä tiivistymiä ja lopulta uusia sarkomeereja. Löydöstemme perusteella myotilinin uudelleenjärjestyminen noudattaa aktiinin muutoksia. Tämä viittaa siihen, että myotilin liittää yhteen uudismuodostuvia aktiinisäikeitä ja vakauttaa niitä. Myotilin saattaa myös ankkuroida viesti- tai rakennemolekyylejä, joiden tehtävänä on edesauttaa Z-levyjen uudismuodostusta. Tulostemme perusteella arvelemme, että myotilin toimii Z-levyjen rakenteen vakaajana ja aktiinisäikeiden säätelijänä. Palladinin puute johtaa sikiöaikaiseen kuolemaan hiirillä, mutta myotilinin puutoksella ei ole samanlaisia vaikutuksia. Tuotettujen myotilin poistogeenisten hiirten todetiin syntyvän ja kehittyvän normaalisti eikä niillä esiintynyt rakenteellisia tai toiminnallisia häiriöitä. Toisaalta aiemmissa kokeissa, joissa hiirille on siirretty ihmisen lihastautia aikaansaava myotilingeeni, nähdään samankaltaisia kuin sairailla ihmisillä. Näin ollen muuntunut myotilin näyttä olevan lihaksen toiminnalle haitallisempi kuin myotilinin puute. Myotilinin ja palladinin yhteisvaikutusta selvittääksemme risteytimme myotilin poistegeenisen hiiren ja hiirilinjan, joka ilmentää puutteellisesti palladinin 200 kDa muotoa. Puutteellisesti 200 kDa palladinia ilmentävien hiirten sydänlihaksessa todettiin vähäisiä hienorakenteen muutoksia, mutta risteytetyillä hiirillä tavattiin rakenteellisia ja toiminnallisia muutoksia myös luurankolihaksessa. Tulosten perusteella voidaan todeta, että palladinin 200 kDa muoto säätelee sydänlihassolujen rakennetta. Luurankolihaksessa sen sijaan myotilinilla ja palladinilla näyttäisi olevan päällekkäisiä tehtäviä.

A case of true hermaphroditism reveals an unusual mechanism of twinning

Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.

Pathogenic Mechanisms of Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL)

PATHOGENIC MECHANISMS OF PLOSL Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease, is a recessively inherited disease of brain and bone. PLOSL manifests as early-onset progressive dementia and bone fractures. Mutations in the TYROBP (DAP12) and TREM2 genes have been identified as the primary cause of PLOSL. DAP12 and TREM2 encode important signalling molecules in cells of the innate immune system. The mechanism by which loss-of-function of the DAP12/TREM2 signalling complex leads to PLOSL is currently unknown. The aim of this thesis work was to gain insight into the pathogenic mechanisms behind PLOSL. To first identify the central nervous system (CNS) cell types that express both Dap12 and Trem2, the expression patterns of Dap12 and Trem2 in mouse CNS were analyzed. Dap12 and Trem2 expression was seen from embryonic stage to adulthood and microglial cells and oligodendrocytes were identified as the major Dap12/Trem2 producing cells of the CNS. To subsequently identify the pathways and biological processes associated with DAP12/TREM2 mediated signalling in human cells, genome wide transcript analysis of in vitro differentiated dendritic cells (DCs) of PLOSL patients representing functional knockouts of either DAP12 or TREM2 was performed. Both DAP12 and TREM2 deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Transcript profiles of the patient DCs showed differential expression of genes involved in immune response and for genes earlier associated with other disorders of the CNS as well as genes involved in the remodeling of bone, linking the findings with the tissue phenotype of PLOSL patients. To analyze the effect of Dap12 deficiency in the CNS, genome wide expression analysis of Dap12 deficient mouse brain and Dap12 deficient microglia as well as functional analysis of Dap12 deficient microglia was performed. Regulation of several pathways involved in synaptic function and transcripts coding for the myelin components was seen in Dap12 knockout mice. Decreased migration, morphological changes and shortened lifespan of the Dap12 knockout microglia was further observed. Taken together, this thesis work showed that both Dap12 and Trem2 are expressed by CNS microglia and that Dap12 deficiency results in functional defects of these cells. Lack of Dap12 in the CNS also leads to synaptic abnormalities even before pathological changes are seen in the tissue level.This work further showed that loss-of-function of DAP12 or TREM2 leads to changes in morphology and gene expression in human dendritic cells. These data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia.

Differentiation of neural stem cells in fragile X syndrome

Multipotent stem cells can self-renew and give rise to multiple cell types. One type of mammalian multipotent stem cells are neural stem cells (NSC)s, which can generate neurons, astrocytes and oligodendrocytes. NSCs are likely involved in learning and memory, but their exact role in cognitive function in the developing and adult brain is unclear. We have studied properties of NSCs in fragile X syndrome (FXS), which is the most common form of inherited mental retardation. FXS is caused by the lack of functional fragile X mental retardation protein (FMRP). FMRP is involved in the regulation of postsynaptic protein synthesis in a group I metabotropic glutamate receptor 5 (mGluR5)-dependent manner. In the absence of functional FMRP, the formation of functional synapses is impaired in the forebrain which results in alterations in synaptic plasticity. In our studies, we found that FMRP-deficient NSCs generated more neurons and less glia than control NSCs. The newborn neurons derived from FMRP-deficient NSCs showed an abnormally immature morphology. Furthermore, FMRP-deficient NSCs exhibited aberrant oscillatory Ca2+ responses to glutamate, which were specifically abolished by an antagonist of the mGluR5 receptor. The data suggested alterations in glutamatergic differentiation of FMRP-deficient NSCs and were further supported by an accumulation of cells committed to glutamatergic lineage in the subventricular zone of the embryonic Fmr1-knockout (Fmr1-KO) neocortex. Postnatally, the aberrant cells likely contributed to abnormal formation of the neocortex. The findings suggested a defect in the differentiation of distinct glutamatergic mGluR5 responsive cells in the absence of functional FMRP. Furthermore, we found that in the early postnatal Fmr1-KO mouse brain, the expression of mRNA for regulator of G-protein signalling-4 (RGS4) was decreased which was in line with disturbed G-protein signalling in NSCs lacking FMRP. Brain derived neurotrophic factor (BDNF) promotes neuronal differentiation of NSCs as the absence of FMRP was shown to do. This led us to study the effect of impaired BDNF/TrkB receptor signaling on NSCs by overexpression of TrkB.T1 receptor isoform. We showed that changes in the relative expression levels of the full-length and truncated TrkB isoforms influenced the replication capacity of NSCs. After the differentiation, the overexpression of TrkB.T1 increased neuronal turnover. To summarize, FMRP and TrkB signaling are involved in normal differentiation of NSCs in the developing brain. Since NSCs might have potential for therapeutic interventions in a variety of neurological disorders, our findings may be useful in the design of pharmacological interventions in neurological disorders of learning and memory.

Anterior cruciate ligament reconstruction with special reference to magnetic resonance imaging of the postoperative outcome

Anterior cruciate ligament (ACL) tear is a common sports injury of the knee. Arthroscopic reconstruction using autogenous graft material is widely used for patients with ACL instability. The grafts most commonly used are the patellar and the hamstring tendons, by various fixation techniques. Although clinical evaluation and conventional radiography are routinely used in follow-up after ACL surgery, magnetic resonance imaging (MRI) plays an important role in the diagnosis of complications after ACL surgery. The aim of this thesis was to study the clinical outcome of patellar and hamstring tendon ACL reconstruction techniques. In addition, the postoperative appearance of the ACL graft was evaluated using several MRI sequences. Of the 175 patients who underwent an arthroscopically assisted ACL reconstruction, 99 patients were randomized into patellar tendon (n=51) or hamstring tendon (n=48) groups. In addition, 62 patients with hamstring graft ACL reconstruction were randomized into either cross-pin (n=31) or interference screw (n=31) fixation groups. Follow-up evaluation determined knee laxity, isokinetic muscle performance and several knee scores. Lateral and anteroposterior view radiographs were obtained. Several MRI sequences were obtained with a 1.5-T imager. The appearance and enhancement pattern of the graft and periligamentous tissue, and the location of bone tunnels were evaluated. After MRI, arthroscopy was performed on 14 symptomatic knees. The results revealed no significant differences in the 2-year outcome between the groups. In the hamstring tendon group, the average femoral and tibial bone tunnel diameter increased during 2 years follow-up by 33% and 23%, respectively. In the asymptomatic knees, the graft showed homogeneous and low signal intensity with periligamentous streaks of intermediate signal intensity on T2-weighted MR images. In the symptomatic knees, arthroscopy revealed 12 abnormal grafts and two meniscal tears, each with an intact graft. Among 3 lax grafts visible on arthroscopy, MRI showed an intact graft and improper bone tunnel placement. For diagnosing graft failure, all MRI findings combined gave a specificity of 90% and a sensitivity of 81%. In conclusion, all techniques appeared to improve patients' performance, and were therefore considered as good choices for ACL reconstruction. In follow-up, MRI permits direct evaluation of the ACL graft, the bone tunnels, and additional disorders of the knee. Bone tunnel enlargement and periligamentous tissue showing contrast enhancement were non-specific MRI findings that did not signify ACL deficiency. With an intact graft and optimal femoral bone tunnel placement, graft deficiency is unlikely, and the MRI examination should be carefully scrutinized for possible other causes for the patients symptoms.

Sterol-binding proteins in late endosomes : Regulation of endosome motility and lipid metabolism

Despite its bad reputation in the mass media, cholesterol is an indispensable constituent of cellular membranes and vertebrate life. It is, however, also potentially lethal as it may accumulate in the arterial intima causing atherosclerosis or elsewhere in the body due to inherited conditions. Studying cholesterol in cells, and research on how the cell biology of cholesterol affects on system level is essential for a better understanding of the disease states associated with cholesterol and for the development of new therapies for these conditions. On its way to the cell, exogenous cholesterol traverses through endosomes, transport vesicles involved in internalizing material to cells, and needs to be transported out of this compartment. This endosomal pool of cholesterol is important for understanding both the common disorders of metabolism and the more rare hereditary disorders of cholesterol metabolism. The study of cholesterol in cells has been hampered by the lack of bright fluorescent sterol analogs that would resemble cholesterol enough to be used in cellular studies. In the first study of my thesis, we present a new sterol analog, Boron-Dipyrromethene (BODIPY)-cholesterol for visualizing sterols in living cells and organism. This fluorescent cholesterol derivative is shown to behave similarly to cholesterol both by atomic scale computer simulations and biochemical experiments. We characterize its localization inside different types of living cells and show that it can be used to study sterol trafficking in living organisms. Two sterol binding proteins associated with the endosomal membrane; the Niemann-Pick type C disease protein 1 (NPC1) and the Oxysterol Binding Protein Related Protein 1 (ORP1) are the subjects of the rest of this study. Sensing cholesterol on endosomes, transporting lipids away from this compartment and the effects these lipids play on cellular metabolism are considered. In the second study we characterize how the NPC1 protein affects lipid metabolism. We show that this cholesterol binding protein affects synthesis of triglycerides and that genetic polymorphisms or a genetic defect in the NPC1 gene affect triglyceride on the whole body level. These effects take place via regulation of carbon fluxes to different lipid classes in cells. In the third part we characterize the effects of another endosomal sterol binding protein, ORP1L on the function and motility of endosomes. Specifically we elucidate how a mutation in the ability of ORP1L to bind sterols affects its behavior in cells, and how a change in ORP1L levels in cells affects the localization, degradative capacity and motility of endosomes. In addition we show that ORP1L manipulations affect cholesterol balance also in macrophages, a cell type important for the development of atherosclerosis.

Process of burnout: structure, antecedents, and consequences

The major changes that have been witnessed in today's workplaces are challenging the mental well-being of employed people. Stress and burnout are considered to be modern epidemics, and their importance to physical health and work ability has been acknowledged world-wide. The aim of the thesis was to study the concept of burnout as a process proceeding from its antecedents, through the development of the syndrome, and to its outcomes. Several work-related factors considered antecedents of burnout were studied in different occupational groups. The syndrome of burnout is seen as consisting of three dimensions - exhaustion, cynicism and lack of professional efficacy - and different alternatives for the sequential development of these dimensions were tested. Furthermore, several indicators of the severely detrimental health and work ability outcomes of burnout were investigated in a longitudinal study design. The research questions were as follows. 1) Is burnout, as measured with the Maslach Burnout Inventory - General Survey (MBI-GS), a three-dimensional construct and how invariant is the factorial structure across occupations (Finnish) and national samples (Finnish, Swedish and Dutch)? How persistent is exhaustion over time? 2) What is the sequential process of burnout? Is it similar across occupations? How do work stressors relate to the process? 3) How does burnout relate to severe health consequences as well as temporary and chronic work disability according to hospitalization periods, sick-leave episodes and receiving disability pensions? The data were collected between 1986 and 2005. The population of the study consisted of respondents to a company-wide questionnaire survey carried out in 1996-1997 (N=9705, response rate 63%). The participants comprised 6025 blue-collar workers and 3680 white-collar workers. The majority were men (N=7494) and the average age was 43.7 years. In addition, a sample from the population had responded to a questionnaire survey in 1988, which was combined with the 1996 data to form panel data on 713 respondents. The register-based data were collected between 1986 and 2005 from 1) the company's occupational health services' records for a sample of respondents from the 1996 questionnaire survey (sick-leave data), 2) hospitalization records from the Hospital discharge register, and 3) disability pension records from the Finnish Centre for Pensions. These data were combined person by person with the 1996 questionnaire survey data with the help of personal identification numbers which were saved with the study numbers by the researchers. The results showed that burnout consists of three separate but correlating symptoms: exhaustion, cynicism and lack of professional efficacy. As a syndrome, burnout was strongly related to job stressors at work, and seemed to develop from exhaustion through cynicism to lack of professional efficacy in a similar manner among white-collar and blue-collar employees. The results also showed that exhaustion persisted even after eight years of follow-up but did not predict cynicism or lack of professional efficacy after that amount of time. Nor were job stressors longitudinally related to burnout. Longitudinal results were obtained for the severe health-related consequences of burnout. The investigated outcomes represented different phases of health deterioration ranging from sick-leaves and hospitalization periods to receiving work disability pensions. The results showed that burnout syndrome, and its elements of exhaustion and cynicism, were related to future mental and cardiovascular disorders as indicated by hospitalization periods. Burnout was also related to future sick-leave periods due to mental, cardiovascular and musculoskeletal disorders. Of the separate elements, exhaustion was related to the same three categories of disorder, cynicism to mental, musculoskeletal and digestive disorders, and lack of professional efficacy to mental and musculoskeletal disorders. Burnout also predicted receiving disability pensions due to mental and musculoskeletal disorders among initially healthy subjects. Exhaustion was related to receiving disability pensions even when self-reported chronic illness was taken into account. The results suggest that burnout is a multidimensional, chronic, work-related syndrome, which may have serious consequences for health and work ability.

Antioxidant and antihepatotoxic effect of Spirulina laxissima against carbon tetrachloride induced hepatotoxicity in rats

The vast biodiversity of nature provides bioactive compounds that may be useful in the fight against chronic diseases. This study was designed to investigate the protective effects of the ethanol extract of Spirulina laxissima West (Pseudanabaenaceae) (EESL) against carbon tetrachloride (CCl4) induced hepatotoxicities in rats. Male albino rats of Sprague-Dawley strain were treated orally with the ethanol extract of S. laxissima (50, 100 mg kg(-1) body wt.) 1 h before each CCl4 administration. The ethanol extract of S. laxissima showed the maximum antioxidant property in vitro. There were statistically significant losses in the activities of antioxidant enzymes and an increase in TBARS and liver function marker enzymes in the serum of the CCl4-treated group compared with the control group. However, all the tested groups were able to counteract these effects. The antioxidant activity of the extracts might be attributable to its proton-donating ability, as evidenced by DPPH. In the present study, the decline in the level of antioxidant observed in CCl4-treated rats is a clear manifestation of excessive formation of radicals and activation of the lipid peroxidation system resulting in tissue damage. The significant increases in the concentration of antioxidant enzymes in tissues of animals treated with CCl4 + EESL indicate the antioxidant effect of EESL. This study suggests that EESL can protect the liver against CCl4-induced oxidative damage in rats, and the hepatoprotective effect might be correlated with its antioxidant and radical-scavenging effects.

Non-viral ex vivo hepatic gene transfer by in situ lipofection of liver and intraperitoneal transplantation of hepatocytes

Perfusion of liver with plasmid DNA-lipofectin complexes via the portal vein results in efficient accumulation of the vector in hepatocytes. Such hepatocytes, when administered intraperitoneally into a hepatectomized rat, repopulate the liver and express the transgene efficiently. This procedure obviates the need for large-scale hepatocyte culture for ex vivo gene transfer. Further, intraperitoneal transplantation is a simple and cost-effective strategy of introducing genetically modified hepatocytes into liver. Thus, in situ lipofection of liver and intraperitoneal transfer of hepatocytes can be developed into a novel method of non-viral ex vivo gene transfer technique that has applications in the treatment of metabolic disorders of liver and hepatic gene therapy.

The role of androgens in fetal growth: observational study in two genetic models of disordered androgen signalling.

OBJECTIVE: To examine the role of androgens on birth weight in genetic models of altered androgen signalling. SETTING: Cambridge Disorders of Sex Development (DSD) database and the Swedish national screening programme for congenital adrenal hyperplasia (CAH). PATIENTS: (1) 29 girls with XY karyotype and mutation positive complete androgen insensitivity syndrome (CAIS); (2) 43 girls and 30 boys with genotype confirmed CAH. MAIN OUTCOME MEASURES: Birth weight, birth weight-for-gestational-age (birth weight standard deviation score (SDS)) calculated by comparison with national references. RESULTS: Mean birth weight SDS in CAIS XY infants was higher than the reference for girls (mean, 95% CI: 0.4, 0.1 to 0.7; p=0.02) and was similar to the national reference for boys (0.1, -0.2 to 0.4). Birth weight SDS in CAH girls was similar to the national reference for girls (0.0, -0.2 to 0.2) and did not vary by severity of gene mutation. Birth weight SDS in CAH boys was also similar to the national reference for boys (0.2, -0.2 to 0.6). CONCLUSION: CAIS XY infants have a birth weight distribution similar to normal male infants and birth weight is not increased in infants with CAH. Alterations in androgen signalling have little impact on birth weight. Sex dimorphism in birth size is unrelated to prenatal androgen exposure.

Evaluation of macrophyte control in 38 Florida lakes using triploid grass carp

Florida’s large number of shallow lakes, warm climate and long growing season have contributed to the development of excessive growths of aquatic macrophytes that have seriously interfered with many water use activities. The introduction of exotic aquatic macrophyte species such as hydrilla ( Hydrilla verticillata ) have added significantly to aquatic plant problems in Florida lakes. The use of grass carp ( Ctenopharyngodon idella ) can be an effective and economical control for aquatic vegetation such as hydrilla. Early stocking rates (24 to 74 grass carp per hectare of lake area) resulted in grass carp consumption rates that vastly exceeded the growth rates of the aquatic plants and often resulted in the total loss of all submersed vegetation. This study looked at 38 Florida lakes that had been stocked with grass carp for 3 to 10 years with stocking rates ranging from < 1 to 59 grass carp per hectare of lake and 1 to 207 grass carp per hectare of vegetation to determine the long term effects of grass carp on aquatic macrophyte communities. The median PAC (percent area coverage) value of aquatic macrophytes for the study lakes after they were stocked with grass carp was 14% and the median PVI (percent volume infested) value of aquatic macrophytes was 2%. Only lakes stocked with less than 25 to 30 fish per hectare of vegetation tended to have higher than median PAC and PVI values. When grass carp are stocked at levels of > 25 to 30 fish per hectare of vegetation the complete control of aquatic vegetation can be achieved, with the exception of a few species of plants that grass carp have extreme difficulty consuming. If the management goal for a lake is to control some of the problem aquatic plants while maintaining a small population of predominately unpalatable aquatic plants, grass carp can be stocked at approximately 25 to 30 fish per hectare of vegetation.

Management of inland capture fisheries and challenges in fish production in Nigeria

The paper critically examines the trend in fish production in Nigeria. The problem of excessive mismanagement and lack of attention by relevant agencies are still common place in inland water bodies. The paper discusses these mismanagement practices which are non compliance with the existing rules and regulations on good fishing methods, uncontrollable, unorthodox and obnoxious fishing practices, destruction of the natural breeding grounds and the collapse of the fishery due to massive over fishing. The challenges posed by the fishing methods as well as the effect of different gears and mechanization of fishing crafts on fish production are discussed. The paper recommends ways to increase domestic fish production in inland water bodies, which include a well planned strategy of restocking the existing reservoirs after careful scientific study, enforcement of the existing laws and regulation based on community participation. Training of stakeholders on the code of practice for responsible fisheries (CPRF), extension of subsidies to fisher folks, the traditional practices, which encourage the adherence to close season and other fish conservation and utilization strategies, are also advocated