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Background: Prior work on the link between blood-based biomarkers and cognitive status has largely been based on dichotomous classifications rather than detailed neuropsychological functioning. The current project was designed to create serum-based biomarker algorithms that predict neuropsychological test performance., Methods: A battery of neuropsychological measures was administered. Random forest analyses were utilized to create neuropsychological test-specific biomarker risk scores in a training set that were entered into linear regression models predicting the respective test scores in the test set. Serum multiplex biomarker data were analyzed on 108 proteins from 395 participants (197 Alzheimer patients and 198 controls) from the Texas Alzheimer's Research and Care Consortium., Results: The biomarker risk scores were significant predictors (p < 0.05) of scores on all neuropsychological tests. With the exception of premorbid intellectual status (6.6%), the biomarker risk scores alone accounted for a minimum of 12.9% of the variance in neuropsychological scores. Biomarker algorithms (biomarker risk scores and demographics) accounted for substantially more variance in scores. Review of the variable importance plots indicated differential patterns of biomarker significance for each test, suggesting the possibility of domain-specific biomarker algorithms., Conclusions: Our findings provide proof of concept for a novel area of scientific discovery, which we term 'molecular neuropsychology'., (Copyright © 2013 S. Karger AG, Basel.)

The vascular endothelium plays an integral part in the inflammatory response. During the acute phase of inflammation, endothelial cells (ECs) are activated by host mediators or directly by conserved microbial components or host-derived danger molecules. Activated ECs express cytokines, chemokines and adhesion molecules that mobilize, activate and retain leukocytes at the site of infection or injury. Neutrophils are the first leukocytes to arrive, and adhere to the endothelium through a variety of adhesion molecules present on the surfaces of both cells. The main functions of neutrophils are to directly eliminate microbial threats, promote the recruitment of other leukocytes through the release of additional factors, and initiate wound repair. Therefore, their recruitment and attachment to the endothelium is a critical step in the initiation of the inflammatory response. In this report, we describe an in vitro neutrophil adhesion assay using calcein AM-labeled primary human neutrophils to quantitate the extent of microvascular endothelial cell activation under static conditions. This method has the additional advantage that the same samples quantitated by fluorescence spectrophotometry can also be visualized directly using fluorescence microscopy for a more qualitative assessment of neutrophil binding.

Study Question: Do women with Turner karyotype have increased mortality and morbidity in the years after childbirth?, Summary Answer: No mortality occurred during pregnancy and follow-up in women with Turner karyotype, but a higher rate of circulatory and endocrine diseases and a high risk of aortic aneurysm were confirmed., What Is Known Already: Pregnancies in women with Turner karyotype are high-risk pregnancies with an increased risk of maternal mortality from aortic dissection and morbidity from hypertensive disorders., Study Design, Size, Duration: A retrospective Swedish population-based registry study of 124 women with Turner karyotype born between 1957 and 1987 and who gave birth between 1973 and 2010. Women with Turner karyotype without childbirth (n = 378) were selected as controls. A second control group consisted of women from the Swedish Medical Birth Register (MBR) (n = 1230) matched for maternal age, number of children and year of birth of the first child., Participants/materials, Setting and Methods: Women with Turner karyotype were identified in the Swedish Genetic Turner Register. Data were obtained by using the unique personal identification number with cross linkage to the Swedish MBR, the Cause of Death Register, the National Patient Register and the Swedish Cancer Register. Hazard ratio (HR) with 95% confidence interval (CI) was used in the analysis of morbidity., Main Results and the Role of Chance: No mortality occurred in women with Turner karyotype and childbirth. Diseases of the circulatory system occurred more often in women with Turner syndrome under the age of 40 years compared with the MBR control group (HR 4.59; 95% CI 2.75-7.66) but was similar at or above the age of 40 years. Morbidity from circulatory diseases was increased before pregnancy (HR 3.83; 95% CI 1.02-14.43) and during pregnancy or within 1 year after (HR 5.78; 95% CI 1.94-17.24), but was similar after 1 or more years after delivery (HR 1.91; 95% CI 0.74-4.96). Aortic aneurysm occurred in 11/502 (2.2%) women with Turner karyotype and in three women (2.4%) during pregnancy. The long-term follow-up showed that aortic dissection was a common cause of death in young women with Turner karyotype without childbirth. A thorough cardiac evaluation before pregnancy in women with Turner karyotype is of utmost importance., Limitations, Reasons for Caution: Although this was a population-based registry study performed over a period of more than 20 years, a much longer follow-up and larger series are needed to assess rare events. The study also lacks information on phenotype and mode of conception in women with Turner karyotype. Women who gave birth probably represent a selection of healthier women with Turner karyotype., Wider Implications of the Findings: The high risk of aortic aneurysm in young women with Turner karyotype is in agreement with the literature.

Genetic variation, both single-nucleotide variations and copy number variations (CNV), contribute to changes in gene expression. In some cases these variations are meaningfully correlated with disease states. We hypothesized that in a genetically heterogeneous disorder such as sporadic Alzheimer's disease (AD), utilizing gene expression as a quantitative trait and CNVs as a genetic marker map within the same individuals in the context of case-control status may increase the power to detect relevant loci. Using this approach an 8-kb deletion was identified that contains a PAX6-binding site on chr2q33.3 upstream of CREB1 encoding the cAMP responsive element-binding protein1 transcription factor. The association of the CNV to AD was confirmed by a case-control association study consisting of the Texas Alzheimer Research and Care Consortium and NIA-LOAD Family Study data sets.

Purpose: The purpose of the study is to compare the effect in healthy young adults of two resistance training protocols, six-repetition maximum (RM) versus 12RM on maximum strength (1RM)., Method: A single-blind, randomized controlled trial was used in the study. Sixty-two healthy physical therapy students, with age (mean [+standard deviation]) 23 (+2.6)  years, weight 67.4 (+11.7)  kg and height 171.7 (+8.4)  cm, of both genders who were recreationally active, but not training systematically, volunteered to participate in the study. They were randomized into two groups (group 1: 24 women and 8 men; group 2: 23 women and 7 men) by a block randomization procedure that ensured equal gender distribution. Sealed envelopes were used to conceal allocation to groups., Interventions: Group 1 did three sets of 6RM of each exercise, and group 2 did three sets of 12RM. Both groups performed the exercises twice per week for 8 weeks with 3 minutes rest between sets and exercises. Primary outcomes were maximum strength defined as one-repetition maximum squat (1RMSq) for lower-body strength and bench press (1RMBp) for upper-body strength. Secondary outcomes were body weight and Uro Kaleva Kekkonen (UKK) Fitness Index., Results: Both groups increased strength significantly (p < 0.001) in 1RMSq (6RM 13.6%, 12RM 13.5%) and 1RMBp (6RM 9.2%, 12RM 8.4%). There was no significant difference in the change between the two groups, no change in body weight and only a small increase in UKK Fitness Index., Conclusion: Both 6RM and 12RM training protocols improve maximum strength in recreationally active healthy young adults, with no significant difference between the protocols., (Copyright © 2011 John Wiley & Sons, Ltd.)

Endothelial cell (EC) Toll-like receptor 2 (TLR2) activation up-regulates the expression of inflammatory mediators and of TLR2 itself and modulates important endothelial functions, including coagulation and permeability. We defined TLR2 signaling pathways in EC and tested the hypothesis that TLR2 signaling differs in EC and monocytes. We found that ERK5, heretofore unrecognized as mediating TLR2 activation in any cell type, is a central mediator of TLR2-dependent inflammatory signaling in human umbilical vein endothelial cells, primary human lung microvascular EC, and human monocytes. Additionally, we observed that, although MEK1 negatively regulates TLR2 signaling in EC, MEK1 promotes TLR2 signaling in monocytes. We also noted that activation of TLR2 led to the up-regulation of intracellularly expressed TLR2 and inflammatory mediators via NF-κB, JNK, and p38-MAPK. Finally, we found that p38-MAPK, JNK, ERK5, and NF-κB promote the attachment of human neutrophils to lung microvascular EC that were pretreated with TLR2 agonists. This study newly identifies ERK5 as a key regulator of TLR2 signaling in EC and monocytes and indicates that there are fundamental differences in TLR signaling pathways between EC and monocytes.

Objective: Hyperandrogenism is one of the characteristic features of the polycystic ovary syndrome (PCOS). Androgens are important for bone mass. Studies on bone mineral density (BMD) and fractures in postmenopausal women with PCOS are lacking. The aim of this study was to investigate whether postmenopausal women with PCOS differ from controls regarding body composition, BMD and prevalence of fractures, and to compare women with PCOS with controls regarding correlations between total BMD and sex hormones., Design: A prospective 21-year follow-up study. Anthropometry, hormonal measurements and questionnaires were performed in 1987 and in 2008. Fractures were X-ray-verified. BMD measurements were taken in 1992, using single-photon absorptiometry (SPA), and in 2008, using dual-energy X-ray absorptiometry (DXA), to also enable measurements of body composition., Patients: Twenty-five women with PCOS (Rotterdam criteria), aged 61-78 years, and 68 randomly allocated age-matched controls., Measurements: Body composition, BMD, fractures and sex steroids., Results: At follow-up, the postmenopausal women with PCOS maintained a higher free androgen index (FAI), but had similar body fat, lean mass and BMD compared with controls. The hip circumference increased only in women with PCOS (P < 0·01), during follow-up. The fracture incidence was similar to that of controls (56% vs 41%, ns). In the controls, total BMD was positively correlated with oestradiol (R = 0·322, P < 0·01) and FAI (R = 0·307, P < 0·05) and negatively correlated with SHBG (R = -0·429, P < 0·001), but not in the women with PCOS., Conclusions: Postmenopausal women with PCOS with persistently higher FAI had similar muscle mass, BMD and fracture incidence as controls during this long-term follow-up., (© 2012 Blackwell Publishing Ltd.)

The vascular endothelium is integrally involved in the host response to infection and in organ failure during acute inflammatory disorders such as sepsis. Gram-negative and Gram-positive bacterial lipoproteins circulate in sepsis and can directly activate the endothelium by binding to endothelial cell (EC) TLR2. In this report, we perform the most comprehensive analysis to date of the immune-related genes regulated after activation of endothelial TLR2 by bacterial di- and triacylated lipopeptides. We found that TLR2 activation specifically induces the expression of the genes IL-6, IL-8, CSF2, CSF3, ICAM1 and SELE by human umbilical vein ECs and human lung microvascular ECs. These proteins participate in neutrophil recruitment, adherence and activation at sites of inflammation. Significantly, our studies demonstrate that TLR2-mediated EC responses are specifically geared towards recruitment, activation, and survival of neutrophils and not mononuclear leukocytes, that ECs do not require priming by other inflammatory stimuli to respond to bacterial lipopeptides and, unlike mononuclear leukocytes, TLR2 agonists do not induce ECs to secrete TNF-α. This study suggests that endothelial TLR2 may be an important regulator of neutrophil trafficking to sites of infection in general, and that direct activation of lung endothelial TLR2 may contribute to acute lung injury during sepsis.

Background: Many studies have shown that ghrelin can down-regulate inflammatory cytokine expression via the inhibition of NF-κB activity and therefore, its administration to septic patients is considered beneficial. However, our knowledge of ghrelin's effects on the upstream activators of the NF-κB pathway, such as NOD2, is still limited. This study aimed to investigate the possible involvement of the NOD2 signaling pathway in the anti-inflammatory effects of ghrelin., Methods: Twenty-four male SD rats received cecal ligation and puncture (CLP) or sham operation, followed by infusion of saline or ghrelin. The lungs were harvested 6h after CLP or sham operation and analyzed for lung histopathology, neutrophil infiltration, inflammatory cytokines (TNF-α, and IL-6), NOD2 mRNA expression, and activation of NF-κB. Furthermore, survival was recorded for ten days in additional groups of rats., Results: Compared with sham group, neutrophil infiltration, TNF-α and IL-6 levels, NOD2 mRNA expression, as well as NF-κB activation in lungs from rats undergoing CLP were significantly increased. After the administration of ghrelin, all inflammatory parameters analyzed were lower than those without ghrelin following CLP. In addition, ghrelin improved survival after CLP., Conclusion: Our results indicate that in a CLP model of sepsis, the beneficial effects that ghrelin has on inflammatory outcomes are mediated at least in part through inhibition of NOD2 expression upstream of NF-κB., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To study secular trends in sex hormones, anthropometry, bone measures and fractures., Design: A random population sample was studied twice and subjects of similar age group were compared 13 years apart., Methods: X-ray-verified fractures were retrieved from a random population sample of 2400 men and women (participants 1616=67%) aged 25-64 years from the WHO, MONICA Project in Gothenburg, Sweden, in 1995 and 2008. Fasting serum hormones and calcaneal ultrasound were measured in every fourth subject. In fertile women, measurements were performed on cycle day interval 7-9., Results: In 2008, men had lower serum free testosterone than men of similar age in 1995 (P<0.001). Body composition, physical activity and fracture incidence were similar. In women, hormone replacement therapy (HRT) was lower in 2008, 7 vs 28% (P<0.0001), as was serum oestradiol, although use of tranquilisers and leisure time physical activity were higher. In 2008, the fracture incidence was higher in postmenopausal women, 29 vs 17% (P<0.001), and vertebral crush had increased from 8 to 19% of all fractures (P=0.031). Serum cholesterol and triglycerides were lower in all subjects in 2008 compared with that in 1995., Conclusions: Secular trends were observed with lower serum testosterone in men in 2008, but no effect was seen on the fracture incidence of these fairly young men. In postmenopausal women in 2008, there was a higher fracture incidence along with more vertebral compressions. Lower HRT use, lower serum oestradiol and higher fall risk exposure due with more tranquilisers and leisure time physical activity in 2008 may explain the results.

During wound healing, hemidesmome disassembly enables keratinocyte migration and proliferation. Hemidesmosome dynamics are altered downstream of epidermal growth factor (EGF) receptor activation, following the phosphorylation of integrin β4 residues S1356 and S1364, which reduces the interaction with plectin; however, this event is insufficient to drive complete hemidesmome disassembly. In the studies reported here, we used a fluorescence resonance energy transfer-based assay to demonstrate that the connecting segment and carboxy-terminal tail of the β4 cytoplasmic domain interact, which facilitates the formation of a binding platform for plectin. In addition, analysis of a β4 mutant containing a phosphomimicking aspartic acid residue at T1736 in the C-tail suggests that phosphorylation of this residue regulates the interaction with the plectin plakin domain. The aspartic acid mutation of β4 T1736 impaired hemidesmosome formation in junctional epidermolysis associated with pyloric atresia/β4 keratinocytes. Furthermore, we show that T1736 is phosphorylated downstream of protein kinase C and EGF receptor activation and is a substrate for protein kinase D1 in vitro and in cells, which requires its translocation to the plasma membrane and subsequent activation. In conclusion, we identify T1736 as a novel phosphorylation site that contributes to the regulation of hemidesmome disassembly, a dynamically regulated process involving the concerted phosphorylation of multiple β4 residues.

Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

Background: High-sensitivity cardiac troponin T (cTnT) assays detect small clinically important myocardial infarctions (MI) but also yield higher rates of false-positive results owing to increased concentrations sometimes present in patients without MI. Better understanding is needed of factors influencing the 99th percentile of cTnT concentrations across populations and the frequency of changes in cTnT concentrations >20% often used in combination with increased cTnT concentrations for diagnosis of MI., Methods: cTnT percentiles were determined by use of the Elecsys® hscTnT immunoassay (Modular® Analytics E170) in a random population sample, in emergency room (ER) patients, and in patients with non-ST-elevation MI (NSTEMI). Changes in cTnT concentrations were determined in hospitalized patients without MI., Results: The 99th cTnT percentile in a random population sample (median age, 65 years) was 24 ng/L. In ER patients <65 years old without obvious conditions that increase cTnT, the 99th cTnT percentile was 12 ng/L with little age dependence, whereas in those >65 years old it was 82 ng/L and highly age dependent. In hospitalized patients without MI the 97.5th percentile for change in the cTnT concentration was 51%-67%. cTnT remained below the 99th percentile (12 ng/L) in 1% of patients with NSTEMI until 8.5 h after symptom onset and 6 h after ER arrival., Conclusions: Age >65 years was the dominant factor associated with increased cTnT in ER patients. This age association was more prominent in ER patients than in a random population sample. Changes in serial cTnT concentrations >20% were common in hospitalized patients without MI.

Context: Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome and, consequently, with a potentially increased risk of cardiovascular disease (CVD) and related mortality later in life. Studies regarding CVD and mortality in PCOS women well into the postmenopausal age are lacking., Objective: Our objective was to examine whether postmenopausal PCOS women differ from controls regarding cardiovascular risk factors, myocardial infarction (MI), stroke and mortality., Design and Setting: We conducted, at a university hospital, a prospective study of 35 PCOS women (61-79 yr) and 120 age-matched controls. The study was performed 21 yr after the initial study., Participants: Twenty-five PCOS women (Rotterdam criteria) and 68 controls participated in all examinations. Data on morbidity were based on 32 of 34 PCOS women and on 95 of 119 controls., Interventions: INTERVENTIONS included reexamination, interviews, and data from the National Board of Health and Welfare and from the Hospital Discharge Registry., Main Outcome Measures: Blood pressure, glucose, insulin, triglycerides, total cholesterol, high- and low-density lipoprotein, apolipoprotein A1 and B, fibrinogen, and plasminogen activator inhibitor antigen were studied. Incidences of MI, stroke, hypertension, diabetes, cancer, cause of death, and age at death were recorded., Results: PCOS women had a higher prevalence of hypertension (P = 0.008) and higher triglyceride levels (P = 0.012) than controls. MI, stroke, diabetes, cancer, and mortality prevalence was similar in the two cohorts with similar body mass index., Conclusions: The well-described cardiovascular/metabolic risk profile in pre- and perimenopausal PCOS women does not entail an evident increase in cardiovascular events during the postmenopausal period.

Context: Women with Turner syndrome (TS) have high risk of cardiovascular complications and hypertensive disorders. Few studies have analyzed obstetric outcome in women with TS., Objective: This study compared obstetric outcome in women with TS karyotype with women in the general population., Design: The Swedish Genetic Turner Register was cross-linked with the Swedish Medical Birth Register between 1973 and 2007. Obstetric outcome in singletons was compared with a reference group of 56,000 women from the general population. Obstetric outcome in twins was described separately., Results: A total of 202 singletons and three sets of twins were born to 115 women with a TS karyotype that was unknown in 52% at time of pregnancy. At first delivery, TS women of singletons were older than controls (median 30 vs. 26 yr, P < 0.0001). Preeclampsia occurred in 6.3 vs. 3.0% (P = 0.07). Aortic dissection occurred in one woman. Compared with the general population, the gestational age was shorter in children born by TS women (-6.4 d, P = 0.0067), and median birth weight was lower (-208 g, P = 0.0012), but sd scores for weight and length at birth were similar. The cesarean section rate was 35.6% in TS women and 11.8% in controls (P < 0.0001). There was no difference in birth defects in children of TS women as compared with controls., Conclusions: Obstetric outcomes in women with a TS karyotype were mostly favorable. Singletons of TS women had shorter gestational age, but similar size at birth, adjusted for gestational age and sex. Birth defects did not differ between TS and controls.

Context: The hormonal and anthropometric profile of premenopausal women with polycystic ovary syndrome (PCOS) is well described, but there is a lack of data concerning changes in these variables into the postmenopausal period., Objective: Our objective was to examine whether PCOS women differ from normal women regarding levels of reproductive hormones, anthropometry, and presence of hirsutism/climacteric symptoms also after menopause., Design and Setting: In this prospective study, women with PCOS (61-79 yr) and age-matched controls, examined in 1987, were reinvestigated at a university hospital., Participants: Twenty-five PCOS patients (Rotterdam criteria) and 68 controls (randomly allocated from the Gothenburg WHO MONICA study) participated., Interventions: Reexamination and hormonal measurements were done 21 yr after previous visit., Main Outcome Measures: FSH, LH, TSH, thyroid peroxidase antibodies, prolactin, estrone, estradiol, SHBG, androstenedione, total testosterone, dehydroepiandrosterone sulfate, free androgen index, and anthropometry were determined. Presence of climacteric symptoms, hirsutism, and menopausal age were recorded., Results: PCOS women had higher free androgen index (P = 0.001) but lower FSH (P < 0.001) and SHBG (P < 0.01) than controls. Menopausal age, body weight, body mass index, waist to hip ratio, LH, prolactin, androstenedione, dehydroepiandrosterone sulfate, total testosterone, estradiol, and estrone were similar in PCOS and controls. Women with PCOS reported hirsutism more frequently (P < 0.001) but had fewer climacteric symptoms (P < 0.05) and hypothyroidism than controls (P < 0.05)., Conclusions: PCOS women differ from controls with regard to levels of certain reproductive hormones also after menopause, but the established premenopausal increase in waist to hip ratio in PCOS patients disappeared after menopause, mainly due to weight gain among controls. A novel finding was the lower prevalence of hypothyroidism in PCOS women.

Pregnancies occurred in 57 (12%) of 482 Swedish women with Turner syndrome with a liveborn rate of 54% in 124 pregnancies. Spontaneous pregnancies occurred in 40%, mainly in women with 45,X/46,XX mosaicism, and oocyte donation in 53% where miscarriages were less frequent, odds ratio = 0.43 (95% confidence interval 0.17-1.04)., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Summary: Risk factors for osteoporotic fractures were evaluated in 1,396 men and women for a period of 20 years. Serum total cholesterol was found to be an independent osteoporotic fracture risk factor whose predictive power improves with time., Introduction: The purpose of this study was to evaluate long-term risk factors for osteoporotic fracture., Methods: A population random sample of men and women aged 25-64 years (the Gothenburg WHO MONICA project, N = 1,396, 53% women) was studied prospectively. The 1985 baseline examination recorded physical activity at work and during leisure time, psychological stress, smoking habits, coffee consumption, BMI, waist/hip ratio, blood pressure, total, HDL and LDL cholesterol, triglycerides, and fibrinogen. Osteoporotic fractures over a period of 20 years were retrieved from the Gothenburg hospital registers. Poisson regression was used to analyze the predictive power for osteoporotic fracture of each risk factor., Results: A total number of 258 osteoporotic fractures occurred in 143 participants (10.2%). As expected, we found that previous fracture, smoking, coffee consumption, and lower BMI each increase the risk for osteoporotic fracture independently of age and sex. More unexpectedly, we found that the gradient of risk of serum total cholesterol to predict osteoporotic fracture significantly increases over time (p = 0.0377)., Conclusions: Serum total cholesterol is an independent osteoporotic fracture risk factor whose predictive power improves with time. High serum total cholesterol is a long-term cause of osteoporotic fracture.

Objectives: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD., Methods: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV., Results: The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2)., Conclusion: High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.

Objectives: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of fertile age. The aim was to study whether PCOS has an effect on sexual functioning., Study Design: Women meeting the Rotterdam criteria for PCOS (n=49), and 49 age-matched controls identified from the population registry, were recruited. Sexual functioning was assessed by means of (i) an in-person, structured interview covering various aspects of sexuality, and (ii) the nine-item McCoy questionnaire of female sexual satisfaction. Participants also completed the Psychological General Well-Being Index., Results: Almost half the women with PCOS reported that the disorder had a great impact on their sex life. Despite having the same number of partners and about the same frequency of sexual intercourse, women with PCOS were generally less satisfied with their sex lives compared to the population-based controls. Within the group of women with PCOS, high body mass index had only a minor effect on sexual functioning, while the total serum level of testosterone correlated positively to sexual satisfaction. PCOS women scored numerically lower than controls on the McCoy total score, but this difference was not statistically significant., Conclusion: Women with PCOS reported decreased satisfaction with their sex life. Sexual function should be taken into account in treatment trials of PCOS, which traditionally target only symptoms related to insulin resistance, overweight, and hirsutism., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated., Method: In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses., Results: A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence., Conclusions: The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.

The National Ignition Facility (NIF) is the world's largest optical instrument, comprising 192 37 cm square beams, each generating up to 9.6 kJ of 351 nm laser light in a 20 ns beam precisely tailored in time and spectrum. The Facility houses a massive (10 m diameter) target chamber within which the beams converge onto an ∼1 cm size target for the purpose of creating the conditions needed for deuterium/tritium nuclear fusion in a laboratory setting. A formidable challenge was building NIF to the precise requirements for beam propagation, commissioning the beam lines, and engineering systems to reliably and safely align 192 beams within the confines of a multihour shot cycle. Designing the facility to minimize drift and vibration, placing the optical components in their design locations, commissioning beam alignment, and performing precise system alignment are the key alignment accomplishments over the decade of work described herein. The design and positioning phases placed more than 3000 large (2.5 m×2 m×1 m) line-replaceable optics assemblies to within ±1 mm of design requirement. The commissioning and alignment phases validated clear apertures (no clipping) for all beam lines, and demonstrated automated laser alignment within 10 min and alignment to target chamber center within 44 min. Pointing validation system shots to flat gold-plated x-ray emitting targets showed NIF met its design requirement of ±50 μm rms beam pointing to target chamber. Finally, this paper describes the major alignment challenges faced by the NIF Project from inception to present, and how these challenges were met and solved by the NIF design and commissioning teams.

TLR2 activation induces cellular and organ inflammation and affects lung function. Because deranged endothelial function and coagulation pathways contribute to sepsis-induced organ failure, we studied the effects of bacterial lipoprotein TLR2 agonists, including peptidoglycan-associated lipoprotein, Pam3Cys, and murein lipoprotein, on endothelial function and coagulation pathways in vitro and in vivo. TLR2 agonist treatment induced diverse human endothelial cells to produce IL-6 and IL-8 and to express E-selectin on their surface, including HUVEC, human lung microvascular endothelial cells, and human coronary artery endothelial cells. Treatment of HUVEC with TLR2 agonists caused increased monolayer permeability and had multiple coagulation effects, including increased production of plasminogen activator inhibitor-1 (PAI-1) and tissue factor, as well as decreased production of tissue plasminogen activator and tissue factor pathway inhibitor. TLR2 agonist treatment also increased HUVEC expression of TLR2 itself. Peptidoglycan-associated lipoprotein induced IL-6 production by endothelial cells from wild-type mice but not from TLR2 knockout mice, indicating TLR2 specificity. Mice were challenged with TLR2 agonists, and lungs and plasmas were assessed for markers of leukocyte trafficking and coagulopathy. Wild-type mice, but not TLR2 mice, that were challenged i.v. with TLR2 agonists had increased lung levels of myeloperoxidase and mRNAs for E-selectin, P-selectin, and MCP-1, and they had increased plasma PAI-1 and E-selectin levels. Intratracheally administered TLR2 agonist caused increased lung fibrin levels. These studies show that TLR2 activation by bacterial lipoproteins broadly affects endothelial function and coagulation pathways, suggesting that TLR2 activation contributes in multiple ways to endothelial activation, coagulopathy, and vascular leakage in sepsis.

Background: We previously created a serum-based algorithm that yielded excellent diagnostic accuracy in Alzheimer's disease. The current project was designed to refine that algorithm by reducing the number of serum proteins and by including clinical labs. The link between the biomarker risk score and neuropsychological performance was also examined., Methods: Serum-protein multiplex biomarker data from 197 patients diagnosed with Alzheimer's disease and 203 cognitively normal controls from the Texas Alzheimer's Research Consortium were analyzed. The 30 markers identified as the most important from our initial analyses and clinical labs were utilized to create the algorithm., Results: The 30-protein risk score yielded a sensitivity, specificity, and AUC of 0.88, 0.82, and 0.91, respectively. When combined with demographic data and clinical labs, the algorithm yielded a sensitivity, specificity, and AUC of 0.89, 0.85, and 0.94, respectively. In linear regression models, the biomarker risk score was most strongly related to neuropsychological tests of language and memory., Conclusions: Our previously published diagnostic algorithm can be restricted to only 30 serum proteins and still retain excellent diagnostic accuracy. Additionally, the revised biomarker risk score is significantly related to neuropsychological test performance., (2011 S. Karger AG, Basel.)

Background: A low level of response to alcohol during an individual's early experience with alcohol is associated with an increase risk of alcoholism. A family-based genome-wide linkage analysis using sibling pairs that underwent an alcohol challenge where the level of response to alcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q terminal (10qter) region. CYP2E1, a gene known for its involvement with ethanol metabolism, maps to this region., Methods: Variance component multipoint linkage analysis was performed on a combined map of single-nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogeneity evident in the dataset, a calculation assuming locus heterogeneity was made using the Heterogeneity Log of Odds (HLOD) score. Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a logistic regression model., Results: Linkage analysis detected significant linkage to CYP2E1, which was diminished because of apparent locus heterogeneity traced to a single family with extreme phenotypes. In retrospect, circumstances recorded during testing for this family suggest that their phenotype data are likely to be unreliable. Significant allelic associations were detected for several CYP2E1 polymorphisms and the SHAS score. DNA sequencing from families that contributed the greatest evidence for linkage did not detect any changes directly affecting the primary amino acid sequence. With the removal of a single family, combined evidence from microsatellites and SNPs offers significant linkage between the level of response to alcohol and the region on the end of chromosome 10., Conclusion: Combined linkage and association indicate that sequence changes in or near CYP2E1 affect the level of response to alcohol providing a predictor of risk of alcoholism. The absence of coding sequence changes indicates that regulatory sequences are responsible. Implicating CYP2E1 in the level of response to alcohol allows inferences to be made about how the brain perceives alcohol., (Copyright © 2010 by the Research Society on Alcoholism.)

Context: There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level., Objective: To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma., Design, Setting, Participants: Analysis of serum biomarker proteins were conducted on 197 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data., Major Outcome Measures: Alzheimer's disease., Results: 11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49-14.47), the likelihood ratio of not having AD based on the algorithm (LR-) = 3.55 (SE = 1.15; 2.22-5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86-69.47)., Conclusions: It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.

Migration of keratinocytes requires a regulated and dynamic turnover of hemidesmosomes (HDs). We and others have previously identified three serine residues on the integrin β4 cytoplasmic domain that play a critical role in the regulation of HD disassembly. In this study we show that only two of these residues (Ser-1356 and Ser-1364) are phosphorylated in keratinocytes after stimulation with either PMA or EGF. Furthermore, in direct contrast to previous studies performed in vitro, we found that the PMA- and EGF-stimulated phosphorylation of β4 is not mediated by PKC, but by ERK1/2 and its downstream effector kinase p90RSK1/2. EGF-stimulated phosphorylation of β4 increased keratinocyte migration, and reduced the number of stable HDs. Furthermore, mutation of the two serines in β4 to phospho-mimicking aspartic acid decreased its interaction with the cytoskeletal linker protein plectin, as well as the strength of α6β4-mediated adhesion to laminin-332. During mitotic cell rounding, when the overall cell-substrate area is decreased and the number of HDs is reduced, β4 was only phosphorylated on Ser-1356 by a distinct, yet unidentified, kinase. Collectively, these data demonstrate an important role of β4 phosphorylation on residues Ser-1356 and Ser-1364 in the formation and/or stability of HDs.

Background: Phototherapy (broadband UVB (BUVB), narrowband UVB (NBUVB) and heliotherapy) is commonly used treatment modalities for widespread psoriasis. Vitamin D3, cholecalciferol, is produced in the epidermis by ultraviolet radiation (290-315 nm) of 7-dehydrocholesterol. 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] are the major circulating metabolites. Sun exposure is the strongest factor influencing 25(OH)D. The similar wavelength spectrum of UVB responsible for D vitamin synthesis (BUVB, 280-315 nm) has been successfully used for years to treat psoriasis., Purpose: The aim was: (1) To increase the knowledge about the effects of phototherapy on vitamin D production during treatment of psoriasis. (2) To examine if there were differences between the effect of BUVB, NBUVB and heliotherapy on vitamin D synthesis in psoriasis patients., Methods: Serum concentrations of 25(OH)D, 1,25(OH)(2)D, PTH, calcium and creatinine, measured before and after phototherapy in white Caucasian patients with moderate to severe active plaque psoriasis, were aggregated from three studies., Results: Psoriasis improved in all patients, with a reduction in PASI ((Psoriasis Area and Severity Index) score of about 75% on all regimes. Serum 25(OH)D increased and PTH decreased after the phototherapy. The increase in 25(OH)D was higher in the BUVB treated patients compared with NBUVB. There was no correlation between the dose of UVB and the increase of 25(OH)D., Conclusion: UVB and heliotherapy improved the psoriasis score, increased the serum 25(OH)D levels and reduced the serum PTH concentrations. Vitamin D production in psoriasis patients increased less with NBUVB than with BUVB phototherapy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: The aim was to identify maternal risk factors in women giving birth to girls with Turner syndrome (TS) and to describe the characteristics of newborns with TS., Methods: The Swedish Genetic Turner Register was cross-linked with the Swedish Medical Birth Register. Between 1973 and 2005, 494 children with TS were born. Maternal age, parity, height, smoking habits and neonatal characteristics; mode of delivery, gestational age, size at birth and Apgar score, were compared with women in the general population who gave birth to girls during the same period., Results: More women with advanced maternal age (40+) delivered girls with TS, 3.2% when compared with 1.8% in the general population [OR 1.83, 95% confidence interval (CI) 1.09-3.08, after adjustment for year of birth]. Maternal height was inversely associated with TS pregnancies (P = 0.005). Late preterm birth occurred in newborns with TS in 10.5% when compared with 4.8% in the general population (OR 2.23; 95% CI: 1.67-2.97, after adjustment for year of birth and maternal age). Newborns with TS had birthweight less than -2SD in 17.8% and birth length less than -2SD in 21.0% when compared with 3.5 and 3.4%, in the general population (OR 6.55; 95% CI: 5.12-8.38 and OR 8.69; 95% CI: 6.89-10.97, after adjustment for year of birth and maternal age)., Conclusion: Advanced maternal age and short stature were risk factors for giving birth to a girl with TS. More TS girls were born late preterm and were smaller for gestational age than non-TS girls in the general population.

Context: GH and/or oxandrolone are used to promote growth in Turner syndrome (TS)., Objective: The aim of this study was to compare quality of life (QoL) in TS women with controls and determine the impact of growth promoting therapy on QoL in TS women., Design: This was a cross-sectional, case-control study., Setting: The study was conducted at an outpatient clinic at Sahlgrenska University Hospital, Göteborg, Sweden., Patients: PATIENTS included 111 TS women (age range 18-59 yr) and 111 randomly selected, age-matched women (25-54 yr) from the World Health Organization Monitoring Trends and Determinants for Cardiovascular Disease project (Göteborg, Sweden) served as controls., Main Outcome Measures: QoL was estimated by the Psychological General Well-Being scale (anxiety, depressed mood, positive well-being, self-control, general health and vitality) and the Nottingham Health Profile (physical mobility, pain, sleep, energy, social isolation, and emotional reactions)., Results: TS women reported more social isolation than controls (P < 0.001). After age adjustment, significantly less pain (<0.05) was reported attributable to GH treatment within TS. No significant difference in any other subscales used could be shown. In TS, QoL was negatively affected by higher current age and age at diagnosis and positively affected by better body balance, fine motor function, and higher bone mineral density., Conclusions: Social isolation was more commonly reported in the whole TS cohort than in the population. Except for less pain, no significant impact on QoL attributable to GH treatment could be found, despite the mean +5.1 cm final height.

Summary: Risk factors for hip fracture were studied in 7,495 randomly selected men during 30 years; 451 men had a hip fracture. High degree of leisure-time, but not work-related, physical activity, high occupational class, and high body mass index (BMI) protected against hip fracture. Smoking, tall stature, interim stroke, and dementia increased the risk., Purpose: The purpose was to prospectively study risk factors for hip fracture in men., Methods: We studied midlife determinants of future hip fractures in 7,495 randomly selected men aged 46-56 years in Gothenburg, Sweden. The subjects were investigated in 1970-1973 and followed for over 30 years. Questionnaires were used regarding lifestyle factors, psychological stress, occupational class, and previous myocardial infarction, stroke, and diabetes mellitus. Alcohol problems were assessed with the aid of registers. Using the Swedish hospital discharge register, data were collected on intercurrent stroke and dementia diagnoses and on first hip fractures (X-ray-verified)., Results: Four hundred fifty-one men (6%) had a hip fracture. Age, tall stature, low occupational class, tobacco smoking, alcoholic intemperance, and interim stroke or dementia were independently associated with the risk of hip fracture. There were inverse associations with leisure-time physical activity, BMI, and coffee consumption. The gradient of risk for one standard deviation of multivariable risk decreased with time since measurement yet was a good alternative to dual energy X-ray absorptiometry measurements., Conclusions: High degree of leisure-time physical activity, high occupational class, and high BMI protected against hip fracture. However, work-related physical activity was not protective. Smoking, tall stature, and interim stroke or dementia increased the risk.

Ultrasound is a quick, cheap and non-radiating device for assessing bone quality. We wanted to validate the method for clinical and epidemiological use. Eighty women, aged 53-73 years, with osteoporosis and/or fractures were followed repeatedly during 7 years. Quantitative ultrasound (QUS) measurements (LUNAR Achilles) were compared with bone mineral density (BMD) and bone mineral content (BMC) estimated by DXA (LUNAR) in regions of interest. Changes in the speed of sound, broadband ultrasound attenuation and stiffness were positively correlated with changes in BMD and BMC in all regions measured with DXA (r=0.20-0.53; p=0.09 to <0.0001). The QUS t-score at the left heel was positively correlated with the t-score at the right heel (r=0.90, p<0.0001). The DXA t-score of the left vs. the right femur was also positively correlated (r=0.72-0.86; p<0.0001). A t-score<-2.5 S.D. was found in 70% and 56% at baseline, and 74% and 65% at follow-up measured with QUS and DXA, respectively. The mean sensitivity of QUS vs. DXA was 79% and the mean specificity 45% over a 7-year period. A QUS t-score of <-3.65 S.D. was consistent with a DXA t-score of <-2.5 S.D. In conclusion, QUS was well correlated with DXA in all regions over the 7-year period. QUS can be used in settings without access to DXA and in epidemiological studies. The sensitivity was high but the specificity was low, implicating that DXA, if available, is recommended before treatment for osteoporosis. However, treatment can be started without DXA at a QUS t-score<-3.65 S.D., and especially in the presence of fractures., (Copyright (c) 2008 Elsevier Ireland Ltd. All rights reserved.)

Objective: Head stability, central for balance control during locomotion, is associated with attenuation of trunk oscillations. The study aimed at exploring trunk attenuation in patients with unilateral vestibular disorder (UVD) assuming it was compromised, and to see if attenuation could be influenced by vestibular rehabilitation therapy., Methods: Patients with UVD (N= 21), mean age (SD): 50.7 (11.5) years, women: 57%, were tested before and after intervention. Patients walked at different velocities with triaxial accelerometers over the lower and upper trunk. Normalization of data allowed comparison across patients over time. Self-reported symptoms and perception of handicap were registered., Results: Acceleration was significantly higher at the lower compared to the upper trunk on both occasions. Increased accelerations at the lower and decreased accelerations at the upper trunk following intervention caused attenuation to increase along the antero-posterior (p=0.05) and medio-lateral axes (p< 0.01). Cadence was reduced (p=0.01), step-length increased (p= 0.01), and self-reported balance (p=0.05) and handicap (p<0.01) improved., Conclusion: More effective attenuation of trunk oscillations was found during walking following intervention. The observed increased stability of the upper trunk is compatible with improved head control, and this was associated with increased mobility of the lower trunk facilitating balance control during ambulation. Trunk accelerations may be useful for identification of balance control in UVD patients.

Background: Climate therapy (heliotherapy) of psoriasis is an effective and natural treatment. Ultraviolet radiation (UVB) from the sun improves psoriasis and induces vitamin D(3) synthesis., Objective: The aim of the study was to investigate the effect of climate therapy on vitamin D(3) synthesis, blood glucose, lipids and vitamin B12 in psoriasis patients., Methods: Twenty Caucasian patients (6 women and 14 men; mean age, 47.2 years; range, 24-65) with moderate to severe psoriasis [mean Psoriasis Area and Severity Index (PASI) score 9.8; range, 3.8-18.8] received climate therapy at the Gran Canarias for 3 weeks. Blood samples were drawn before and after 15 days of sun exposure. In addition, the patients' individual skin UV doses based on UV measurements were estimated., Results: Sun exposure for 15 days lead to a 72.8% (+/- 18.0 SD) reduction in the PASI score in psoriasis patients. Although no direct correlation was observed between PASI score improvement and UVB dose, the sun exposure improved the vitamin D, lipid and carbohydrate status of the patients. The serum concentrations of 25-hydroxyvitamin D [25(OH)D] increased from 57.2 +/- 14.9 nmol/L before therapy to 104.5 +/- 15.8 nmol/L (P < 0.0001) after 15 days of sun exposure; the serum levels of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] increased from 146.5 +/- 42.0 to 182.7 +/- 59.1 pmol/L (P = 0.01); the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol decreased from 2.4 to 1.9 (P < 0.001); and the haemoglobin A(1)c (HbA(1)c) levels decreased from 5.6 +/- 1.7% to 5.1 +/- 0.3% (P < 0.0001)., Conclusion: Climate therapy with sun exposure had a positive effect on psoriasis, vitamin D production, lipid and carbohydrate status.

Objective: Fractures are related to falling. Turner syndrome (TS) is associated with hypogonadism, osteoporosis and fractures and has been considered as a syndrome of early ageing. The aim was to study whether fine motor function (FM) and body balance (BB) were impaired and related to genotype, fractures, metabolic variables and hearing., Design: Cross-sectional study., Patients: TS women, n = 75, mean age 30 years (range 16-59) and treated with oestrogen hormone replacement therapy (HRT) at the out-patient clinic, Sahlgrenska University Hospital, Göteborg, Sweden, and 31 healthy controls, mean age 37 years (range 24-63)., Measurements: Six FM and eight BB tests with open and closed eyes, respectively, were done. Bone mineral density was estimated with Dual energy X-ray Absorptiometry. Presence/absence of fractures was noted, blood samples were taken and audiometry was done in the TS women., Results: TS women had poorer FM (27.4 +/- 6.0 vs. 32.8 +/- 2.2; P < 0.0001) and BB (28.0 +/- 8.1 vs. 34.7 +/- 2.4; P < 0.0001) than controls. FM was poorer in TS women with hearing aids compared to those without (P < 0.05). FM and BB were negatively correlated with age, waist : hip ratio and positively correlated with hearing, and bone mineral density, and BB was negatively correlated with physical activity in TS women. BB correlated negatively with age in controls. FM, BB and hearing function were poorer in 45,X, nonmosaics, than in 45,X/46,XX, mosaics., Conclusions: FM and BB were poorer in adult TS women on HRT than in controls. Higher age, hearing impairment, osteoporosis, abdominal obesity, a sedentary lifestyle and the TS per se were strong determinants, and mosaicism mitigated both fine motor function and BB in TS.

Background: Phototherapy of psoriasis is an effective treatment. In addition to standard broadband ultraviolet radiation B (UVB), (280-320 nm), narrowband phototherapy (NBUVB) (monochromatic UV between 311 and 312 nm) has become an important treatment for psoriasis. The same wavelength range of UVB (290-315 nm) induces synthesis of vitamin D. The aim was to compare the effect of broadband with NBUVB therapy on vitamin D synthesis in patients with psoriasis., Methods: Sixty-eight Caucasian patients (17 women and 51 men) mean age 54.1 +/- 16.0 years, with active plaque psoriasis, were treated with broadband UVB (n=26) or NBUVB (n=42) two to three times/week for 8-12 weeks. The serum concentrations of 25-hydroxyvitamin D (25(OH)D3), 1,25-dihydroxyvitamin D (1,25(OH)(2)D3), intact parathyroid hormone (PTH), calcium and creatinine were measured before the first exposure and after the last dose of radiation., Results: In broadband UVB treated patients, 25(OH)D3 increased from 37.9 +/- 16.9 to 69.4 +/- 19.7 ng/ml (P<0.0001) and in patients treated with NBUVB from 34.8 +/- 11.9 to 55.3 +/- 17.6 ng/ml (P<0.0001) and P=0.008 between the treatment groups. PTH decreased on broadband UVB (P<0.05). The serum concentrations of 1,25(OH)(2)D3, calcium or creatinine remained unaltered., Conclusion: Serum 25(OH)D3 in psoriasis patients increased less with NBUVB than with broadband UVB phototherapy. Psoriasis improved on both regimens.

Background: The long-term course of dizziness was investigated combining medical chart and survey data. The survey was undertaken median (interquartile range (IQR)) 4.6 (4.3) years after the initial medical examination., Methods: Chart data comprised sex, age, diagnosis, symptom duration, postural sway and neck pain. Survey data comprised symptom severity assessed by the Vertigo Symptom Scale - Short Form (VSS-SF), and data regarding current state of dizziness, medication, neck pain and other chronic conditions., Results: The sample consisted of 503 patients, the mean (standard deviation (SD)) age was 50.0 (11.6) years, women being slightly overrepresented (60%). Severe problems with dizziness (VSS-SF mean (SD) 13.9, (10.8)) were indicated in the total group and in 5 of 6 diagnostic sub-groups. Vertigo/balance- and autonomic/anxiety-related symptoms were present in all groups. Current dizziness was confirmed by 73% who had significantly more severe problems than the non-dizzy (VSS-SF mean (SD): 17.2 (10.1) versus 5.0 (7.3)). Symptoms were related to vertigo/balance more than to autonomic/anxiety (test of interaction p < 0.001).Based on simple logistic regression analysis, sex, symptom duration, neck pain, sway and diagnoses predicted dizziness. Symptom duration and neck pain remained predictors in the adjusted analysis. Age, symptom duration, neck pain, sway and diagnoses predicted vertigo/balance-related dizziness in both regression analyses. Sex, neck pain and sway predicted development of autonomic/anxiety-related dizziness according to simple regression analysis, while only neck pain remained a significant predictor in the adjusted analysis. With respect to diagnosis, simple regression analysis showed significant reduced likelihood for development of dizziness in all vestibular sub-groups when compared to the non-otogenic dizziness group. With respect to vertigo/balance- and autonomic/anxiety-related symptoms, the implication of diagnostic belonging varied. No effect of diagnoses was seen in adjusted analyses., Conclusion: The majority of patients had persistent and severe problems with dizziness. The wait-and-see attitude before referral to specialist institutions may be questioned. Early, active movements seem necessary, and attention should be paid to the presence of neck pain. Diagnoses had limited prognostic value. Questionnaire-based evaluations could assist in classification and identification of type of dizziness and thereby provide a better basis for specific rehabilitation.

Hemidesmosomes (HDs) promote the stable adhesion of basal epithelial cells to the underlying basement membrane (BM). Critical for the mechanical stability of the HD is the interaction between integrin alpha6beta4 and plectin, which is destabilized when HD disassembly is required, for instance, to allow keratinocyte migration during wound healing. Growth factors such as epidermal growth factor (EGF) can trigger HD disassembly and induce phosphorylation of the beta4 intracellular domain. Whereas tyrosine phosphorylation appears to mediate cooperation with growth factor signaling pathways and invasion in carcinoma cells, serine phosphorylation seems the predominant mechanism for regulating HD destabilization. Here, we discuss recent advances that shed light on the residues involved, the identity of the kinases that phosphorylate them, and the interactions that become disrupted by these phosphorylations.

Background: The causes of subclinical hyperthyroidism have only been reported from clinical studies., Aim: To determine the prevalence and pathological causes of reduced serum TSH levels in subjects recruited from an epidemiological survey., Material/subjects and Methods: Serum TSH was measured in 7954 subjects in the 5th Tromsø study. Subjects with serum TSH<0.50 mIU/l, not using T4, without a previous diagnosis of thyroid disease, without serious concomitant disease, and younger than 80 yr, were invited for a re-examination. If low serum TSH was persistent, thyroid scintigraphy was performed., Results: Among the 4962 subjects that met the inclusion criteria, serum TSH was <0.50 mIU/l in 105 subjects. Twelve subjects had a suppressed serum TSH level (<0.05 mIU/l). Two of these were lost to follow-up, 4 had Graves' disease, 4 had adenoma, and 2 had multinodular goiter. In the 93 subjects with serum TSH 0.05-0.5 mIU/l, 55 were re-examined, of whom 35 had normalized their serum TSH level. In the remaining 20 subjects, 1 had Graves' disease, 6 had adenoma (of which 2 were toxic adenomas), 7 had multinodular goiter, and 6 were considered normal. Among the 521 subjects using T4, 70 (13.4%) had a suppressed serum TSH level., Conclusions: Most of the subjects with a suppressed serum TSH level will be on T4 medication. Otherwise, if the suppressed serum TSH level is found by chance, this probably represents a clinically important thyroid pathology. Also, in subjects with a persistently low serum TSH level (0.05-0.5 mIU/l) most will have a pathological thyroid scan.

Background and Purpose: Although there have been studies on patients with persistent dizziness, physical findings have not been formerly focused. The aim of this study was to investigate localization and extent of physical dysfunctions in patients with long-lasting dizziness. To investigate physical change, we re-examined patients who had completed a vestibular rehabilitation (VR) programme., Methods: A longitudinal design was used. Patients with peripheral vestibular dysfunction were examined with the Global Physiotherapy Examination (GPE-52) and the Vertigo Symptom Scale-short form (VSS-SF). The GPE-52 consists of 52 standardized items within posture, respiration, movement, muscle and skin. Initially, 32 patients were included; 20 completed the VR programme. The programme, based upon traditional VR exercises combined with a body awareness approach, was administered as group sessions taking place once weekly for nine weeks., Results: The majority of patients had a flexed head posture, and their respiration was restricted. Reduced flexibility, reduced ability to relax, measured with passive movements, and restricted range of motion (ROM) were found in about half of the patients in the neck, jaw, shoulder girdle and thorax. On palpation of muscles, 70-94% of the patients had reduced stretch in the abdominals/diaphragm, upper trapezius, sternocleidomastoid and medial gastrocnemius muscles. After the VR programme, significant improvements (p < 0.05) were shown in the following areas: respiration, flexibility and passive movement tests in the shoulder and cervical region, and ROM in the neck and jaw. Significant improvement (p < 0.05) was also reported in the balance subscale of the VSS-SF., Conclusions: This study documents that postural changes, restricted respiration, lack of flexibility, ability to relax and reduced muscular stretch seem quite common in patients with dizziness. A modified VR comprising body awareness significantly improved respiration and movements in the upper body as well as self-reported balance., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Objective: Polycystic ovary syndrome (PCOS) is a common hyperandrogenic endocrine disorder affecting women of fertile age. The aim of this study was to survey whether the rate of clinical psychiatric disorders in PCOS differs from the normal population., Method: Women with PCOS (n=49) meeting the Rotterdam criteria for PCOS, and 49 age-matched controls identified from the population registry, were recruited. Trained clinicians used the MINI International Neuropsychiatric Interview to establish lifetime occurrence of Axis I DSM diagnoses. Serum-testosterone and sex hormone binding globulin were analyzed., Results: Women with PCOS had higher lifetime incidence of depressive episodes, social phobia, and eating disorders than controls. Suicide attempts were seven times more common in the PCOS group than in the controls. Current as well as lifetime use of antidepressants and anxiolytic drugs were more common in the PCOS group., Conclusions: Previous studies have found that PCOS is associated with decreased quality of life and self-rated mental symptoms. This study demonstrates that PCOS is also linked to psychiatric syndromes as verified by structured clinical assessments. The clinical implication of this study is that clinicians treating women with PCOS should be aware that these women are a high risk group for common affective and anxiety disorders as well as suicide attempts.

Background: The aim of the study was to examine the psychometric properties of the Vertigo symptom scale - short form (VSS-SF), a condition-specific measure of dizziness, following translation of the scale into Norwegian., Methods: A cross-sectional survey design was used to examine the factor structure, internal consistency and discriminative ability (sample I, n = 503). A cross-sectional pre-intervention design was used to examine the construct validity (sample II, n = 36) of the measure and a test-retest design was used to examine reliability (sub-sample of sample II, n = 28)., Results: The scree plot indicated a two factor structure accounting respectively for 41% and 12% of the variance prior to rotation. The factors were related to vertigo-balance (VSS-V) and autonomic-anxiety (VSS-A). Twelve of the items loaded clearly on either of the two dimensions, while three items cross-loaded. Internal consistency of the VSS-SF was high (alpha = 0.90). Construct validity was indicated by correlation between path length registered by platform posturography and the VSS-V (r = 0.52), but not with the VSS-A. The ability to discriminate between dizzy and not dizzy patients was excellent for the VSS-SF and sub-dimension VSS-V (area under the curve 0.87 and 0.91, respectively), and acceptable for the sub-dimension VSS-A (area under the curve 0.77). High test-retest reliability was demonstrated (ICC VSS-SF: 0.88, VSS-V: 0.90, VSS-A: 0.90) and no systematic change was observed in the scores from test to retest after 2 days., Conclusion: Using a Norwegian translated version of the VSS-SF, this is the first study to provide evidence of the construct validity of this instrument demonstrating a stable two factor structure of the scale, and the identified sub-dimensions of dizziness were related to vertigo-balance and autonomic-anxiety, respectively. Evidence regarding a physical construct underlying the vertigo-balance sub-scale was provided. Satisfactory internal consistency was indicated, and the discriminative ability of the instruments was demonstrated. The instrument showed satisfactory test-retest reliability.

Objectives: To study the prevalence and incidence of elevated liver enzymes and their relationship with body weight, metabolic factors and other diseases in Turner syndrome (TS)., Design: Five-year follow-up., Patients: Women with TS (n = 218, mean age 33 +/- 13, range 16-71 years) from outpatient clinics at university hospitals in Sweden., Measurements: Fasting blood samples for aspartate (AST) and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transferase (GT), viral hepatitis serology and hepatic auto-antibodies, vitamin B12, blood glucose, lipids and hormones., Results: Seventy-nine subjects (36%) had one or more liver enzyme levels higher than the reference level, the most prevalent being GT. Karyotype 45,X was present in 51% of all TS women and in 48% of those with elevated liver enzymes. Body weight, body mass index (BMI), total cholesterol, triglycerides, and apolipoproteins A and B at start were higher in TS women with elevated liver enzymes than in TS women with normal levels. At 5 years, AST, ALT and GT were increased and another 23% of patients had developed elevated liver enzymes, that is, 59% in total (36% + 23%), while in 6%, the elevated liver enzymes had been normalized and all 6% also had lowered cholesterol levels. Multivariate analysis showed that GT was correlated with total cholesterol; P = 0.0032 at start and P = 0.0005 at 5 years, independently of other factors. Liver biopsy in six TS women showed one cholangitis, one hepatitis C, two steatosis and two normal biopsies. Withdrawal of oestrogen substitution did not influence the liver enzymes., Conclusions: Pathological liver enzymes were common in TS women, with a prevalence of 36% at 33 years of age, an annual incidence over 5 years of 3.4%. There was no relation to karyotype, alcohol, viral hepatitis, E(2) or autoimmunity, but a connection with total serum cholesterol.

The major PKC substrates MARCKS and MacMARCKS (MRP) are membrane-binding proteins implicated in cell spreading, integrin activation and exocytosis. According to the myristoyl-electrostatic switch model the co-operation between the myristoyl moiety and the positively charged effector domain (ED) is an essential mechanism by which proteins bind to membranes. Loss of the electrostatic interaction between the ED and phospholipids, such as Ptdins(4,5)P2, results in the translocation of such proteins to the cytoplasm. While this model has been extensively tested for the binding of MARCKS far less is known about the mechanisms regulating MRP localization. We demonstrate that after phosphorylation, MRP is relocated to the intracellular membranes of late endosomes and lysosomes. MRP binds to all membranes via its myristoyl moiety, but for its localization at the plasma membrane the ED is also required. Although the ED of MRP can bind to Ptdins(4,5)P2 in vitro, this binding is not essential for its retention at or targeting to the plasma membrane. We conclude that the co-operation between the myristoyl moiety and the ED is not required for the binding to membranes in general but that it is essential for the targeting of MRP to the plasma membrane in a Ptdins(4,5)P2-independent manner.

The aims of this study were to examine whether postmenopausal women with psoriasis who were exposed to regular ultraviolet light B (UVB) therapy had greater bone mineral density than women of similar age from the same region, and to estimate the influence of risk factors on bone status. A total of 35 randomly selected women, age (mean +/- SD) 69.3 +/- 6.29 years (age range 60-82 years), with active psoriasis, mean onset at 37.0 years (+/- 23.5 SD) were studied. The patients had been previously exposed to broadband or narrowband UVB. Age-matched, women (n = 2448) from Göteborg, examined at the Geriatric out-patient clinic during the years 2001 and 2002, were used as controls. Bone mineral density was examined by Dual-Energy X-ray Absorptiometry (Hologic Delphi A) at the hip and the lumbar spine. Medical history and lifestyle factors were assessed with a questionnaire. Postmenopausal women with psoriasis were found to have higher bone mineral density than age-matched controls. Higher body weight, physical activity and UVB exposure could explain this finding.

Protein Phosphatase type 2A (PP2A) represents a family of holoenzyme complexes with diverse biological activities. Specific holoenzyme complexes are thought to be deregulated during oncogenic transformation and oncogene-induced signaling. Since most studies on the role of this phosphatase family have relied on the use of generic PP2A inhibitors, the contribution of individual PP2A holoenzyme complexes in PP2A-controlled signaling pathways is largely unclear. To gain insight into this, we have constructed a set of shRNA vectors targeting the individual PP2A regulatory subunits for suppression by RNA interference. Here, we identify PR55gamma and PR55delta as inhibitors of c-Jun NH(2)-terminal kinase (JNK) activation by UV irradiation. We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC. We also find that the physical interaction between PR55gamma and c-SRC is sensitive to UV irradiation. Our data reveal a novel mechanism of c-SRC regulation whereby in response to stress c-SRC activity is regulated, at least in part, through loss of the interaction with its inhibitor, PR55gamma., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

The outer nuclear membrane proteins nesprin-1 and nesprin-2 are retained at the nuclear envelope through an interaction of their klarsicht/ANC-1/syne homology (KASH) domain with Sun proteins present at the inner nuclear membrane. We investigated the requirements for the localization of nesprin-3alpha at the outer nuclear membrane and show that the mechanism by which its localization is mediated is similar to that reported for the localization of nesprin-1 and nesprin-2: the last four amino acids of the nesprin-3alpha KASH domain are essential for its interaction with Sun1 and Sun2. Moreover, deletion of these amino acids or knockdown of the Sun proteins results in a redistribution of nesprin-3alpha away from the nuclear envelope and into the endoplasmic reticulum (ER), where it becomes colocalized with the cytoskeletal crosslinker protein plectin. Both nesprin-3alpha and plectin can form dimers, and dimerization of plectin is required for its interaction with nesprin-3alpha at the nuclear envelope, which is mediated by its N-terminal actin-binding domain. Additionally, overexpression of the plectin actin-binding domain stabilizes the actin cytoskeleton and prevents the recruitment of endogenous plectin to the nuclear envelope. Our studies support a model in which the actin cytoskeleton influences the binding of plectin dimers to dimers of nesprin-3alpha, which in turn are retained at the nuclear envelope through an interaction with Sun proteins.

Background: Vitamin D3 is produced in the epidermis by ultraviolet (UV) radiation (290-315 nm) of 7-dehydrocholesterol. A similar range of 290-320 nm (broadband UVB) has been successfully used for years to treat psoriasis. The aim of this study was to investigate whether UVB therapy was able to influence vitamin D synthesis in psoriasis patients., Methods: Twenty-four postmenopausal, white Caucasian women, aged 69 +/- 5.9 (mean +/- SD), with active plaque psoriasis, were treated with broadband UVB two to three times per week for 8-12 weeks. The serum concentrations of calcidiol (25(OH)D3), calcitriol (1,25(OH)2D3), intact parathyroid hormone (PTH), thyroid hormones, osteocalcin, calcium and creatinine were measured before the first and after the last dose of radiation. Bone density was measured using Dual-Energy X-ray Absorptiometry (Hologic Delphi A) at the hip and lumbar spine., Results: Serum levels of 25(OH)D3 increased from 36.8 +/- 17 ng/ml (mean +/- SD) to 59.6 +/- 18.7 ng/ml (P<0.001) after the UVB treatment period. Serum PTH decreased from 62.8 +/- 25.7 ng/l to 48.2 +/- 17.4 ng/l (P<0.001). Secondary hyperparathyroidism (PTH>65 ng/l) was revealed in seven patients (29%) in whom PTH values were suppressed by the UVB therapy. The serum levels of calcitriol, calcium, osteocalcin, thyroid hormones and creatinine were unaltered., Conclusion: UVB therapy in elderly psoriatic women improved psoriasis, increased serum 25(OH)D3 synthesis and reduced serum PTH concentrations.