Search

Purpose: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing., Methods: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions., Results: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition., Conclusion: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.

Hyperparathyroidism (HPT), including normocalcaemic, vitamin D sufficient (Serum (S)-25(OH)D ≥ 50 nmol/L) hyperparathyroidism (nHPT), has increasingly been diagnosed in the last few decades due to the more common use of the serum parathyroid hormone (S-PTH) assay. We investigated if men with HPT had higher morbidity and mortality than men without HPT during 21 years' follow-up.A random population sample of 750 men, all 50 years of age, was examined in 1993. Endpoints were retrieved 21 years later at 71 years of age.Albumin-corrected serum (S) calcium, S-25-hydroxyvitamin D and S-PTH were assessed along with data on cardiovascular risk factors and medication. Outcome data on fractures, stroke, myocardial infarction, cancer and death were retrieved in 2014; 21 years after primary assessment. The prevalence of HPT at 50 years of age was 9.3%; nHPT 2.8%, primary HPT 0.4%, secondary HPT 0.4%, and HPT with vitamin D insufficiency 6%. Fracture rate, myocardial infarction, stroke, cancer and death occurred similarly in men with or without HPT, as well as in men with nHPT as compared with men without calcium/PTH aberrations during 21 years' follow-up. S-PTH was evenly distributed in the univariable analyses for each outcome. Cox regression analyses showed no increase in serious morbidity or in mortality in men with HPT, irrespective of cause, compared with men with normal S-PTH over a 21-year period. None had HPT at a S-25(OH)D level of 100 nmol/L.

Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.

Context: The factors that affect the health-related quality of life (HRQoL) of women with Turner syndrome (TS) are controversial., Objective: The aim was to describe the HRQoL of women with TS with a focus on how given GH treatment and comorbidity influence HRQoL in adulthood and to compare HRQoL of women with TS with that of women in the general population., Design: Longitudinal cohort study, up to 20 years., Setting: The Turner Center at the Section for Endocrinology and Department of Reproductive Medicine at Sahlgrenska University Hospital, Gothenburg, Sweden., Participants: Women with TS (n = 200), age range 16 to 78 years, were included consecutively and monitored every fifth year between 1995 and 2018. Women from the World Health Organization MONItoring of trends and determinants for CArdiovascular disease project were used as reference populations., Interventions and Main Outcome Measures: HRQoL was measured using the Psychological General Well-Being index and the Nottingham Health Profile. Associations with somatic variables were assessed using longitudinal linear regression models., Results: HRQoL was not associated with GH treatment in TS in spite of a mean 5.7 cm taller height. HRQoL was only associated with height per se in one of 13 subscales (P < 0.01). HRQoL was negatively affected by higher age, higher age at diagnosis, and hearing impairment in TS. Women with TS reported a similar HRQoL to the reference population., Conclusions: No association between previous GH treatment and HRQoL was found during the up to 20 years of follow-up in women with TS. HRQoL of women with TS and the reference population was similar., (Copyright © 2019 Endocrine Society.)

Background: The aim was to investigate if there were any differences in the degree of mosaicism between the left- and right-hand sides of the buccal mucosa in women with Turner syndrome., Methods: Buccal smears were taken on the left- and right-hand sides at the same time for genetic analyses with fluorescence in situ hybridization in women with Turner syndrome, n = 20; 10 with and 10 without mosaicism based on the blood karyotype, and one control. A difference in the degree of mosaicism ≥5% between the sides was considered as an actual difference and <5% as equivalent., Results: Of 20, 10 (50%) had ≥ 5% difference in the degree of mosaicism between the left- and right-hand sides of the buccal mucosa. The mean difference was 9.1% and the median was 4.5%, range 1%-38%. The control with ordinary female karyotype had no side difference., Conclusion: There was an intraorganic mosaicism of the buccal mucosa with a side difference in the degree of mosaicism of up to 38% in women with Turner syndrome. When mosaicism is strongly suspected, but not confirmed by the blood karyotype, it is recommended that buccal smears from both sides of the oral cavity should be analyzed., (© 2019 University of Gothenburg. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objective: To explore the relationship between low serum vitamin D levels and comorbidity in Somali women, immigrants to Sweden. Design and setting: Cohort study in a Primary Health Care Center and a University Hospital. Subjects: Somali women skin type V, n = 114, aged 18-56 years, from latitude 0-10 ○ N, living in Sweden, latitude 57 ○ N > 2 years were compared with women from a population sample, skin type II-III, n = 69, aged 38-56 years, the WHO MONICA study, Gothenburg, Sweden. Main outcome measures: Serum (S)-25(OH)D, S-parathyroid hormone (PTH), comorbidity and Health-Related Quality of Life (HRQoL) using the Short Form-36 (SF-36) and part of the EQ-5D questionnaires. All calculations were corrected for age. Results: Vitamin D deficiency (S-25(OH)D < 25 nmol/l) was found in 73% of the Somali women and in 1% of the controls ( p  < .0001). S-PTH was elevated (>6.9 pmol/l) in 26% and 9%, respectively ( p  < .004). Somali women used less medication, 16% vs. 55%, p  < .0001) but more allergy medication, 11% vs. 7% ( p  = .006), had fewer fractures, 2% vs. 28% ( p  < .0001) and lower HRQoL in 7 out of 9 scales ( p  < .05-.001), than native controls. There were no differences in the prevalence of diabetes mellitus, hypothyroidism, positive thyroid peroxidase antibodies, vitamin B12 deficiency, celiac disease or hypertension. Conclusions: Vitamin D deficiency was common in Somali women living in Sweden, 73%, but comorbidity was low. Both mental, and especially physical HRQoL scores were lower in the Somali women. The effects of long-lasting deficiency are unknown. Key points The aim was to explore the relationship between vitamin D deficiency (S-25(OH)D < 25 nmol/l) and comorbidity in immigrants. Vitamin D deficiency was common in Somali women living in Sweden, 73%, but comorbidity of hypothyroidism, diabetes mellitus, hypertension, fractures and use of medications was low. Both mental, and especially physical, Health-Related Quality of Life were lower in the Somali women than in native Swedish women. The effects of long-lasting deficiency are unknown.

Purpose: To evaluate the feasibility of integrating vestibular rehabilitation and cognitive behaviour therapy (VR-CBT) for people with persistent dizziness in primary care., Design: Prospective single-group pre- and post-test study., Participants: Adults (aged 18-70) with acute onset of dizziness and symptoms lasting a minimum 3 months, recruited from Bergen municipality., Methods: Participants attended eight weekly group sessions of VR-CBT intervention. Feasibility outcomes consisted of recruitment and testing procedures, intervention adherence, and participant feedback, besides change in primary outcomes. The primary outcomes were Dizziness Handicap Inventory (DHI) and preferred gait velocity., Results: Seven participants were recruited for the study. All participants completed the pre-treatment tests, five participants completed the intervention and answered post-treatment questionnaires, and three completed post-treatment testing. Of the five participants, three attended at least 75% of the VR-CBT sessions, and two 50% of the sessions. Participants reported that the VR-CBT was relevant and led to improvement in function. DHI scores improved beyond minimal important change in two out of five participants, and preferred gait velocity increased beyond minimal important change in two out of three participants., Conclusion: The current tests and VR-CBT treatment protocols were feasible. Some changes are suggested to optimise the protocols, before conducting a randomised controlled trial., Trial Registration: NCT02655575. Registered 14 January 2016-retrospectively registered., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Objective: The general aim was to meet the need for empirical comparative studies of health-related quality of life (HRQoL) assessment instruments, by evaluating and comparing the psychometric properties and results of three different, widely used, generic HRQoL instruments in a population sample. The specific aims were to evaluate the subscales of the different instruments that measure the same domain and to assess the association between the HRQoL measures and a single-item self-rated health scale., Design: An observational cross-sectional study., Setting: A population-based sample from Gothenburg, Sweden, was studied in 2008 in the WHO MONItoring of trends and determinants for CArdiovascular disease., Participants: A total of 414 subjects were included, 77% women, age range 39-78 years., Interventions: The Nottingham Health Profile (NHP), the Short Form-36 questionnaire (SF-36), the Psychological General Well-Being Index (PGWB) and a self-rated health scale were used., Outcome Measures: Scores were analysed for their psychometric properties, internal consistency (Cronbach's α), construct validity (Spearman's rank correlations and R 2 coefficients) and discriminative ability for the presence of self-rated ill-health., Results: PGWB and SF-36 had higher Cronbach's α scores than NHP. All correlations calculated between the subscales that were conceptually similar were significant (p<0.01). All subscales could differentiate the presence of self-rated ill-health according to the self-rated health scale (p<0.001). The self-rated health scale correlated strongly with all of the three HRQoL instruments used., Conclusions: There was a high concordance between the instruments within each domain that was conceptually similar. All three HRQoL instruments (PGWB, SF-36 and NHP) could discriminate the presence of self-rated ill-health. The simple and quick self-rated health scale correlated strongly with the more time-consuming PGWB, SF-36 and NHP. The result supports the existence of a strong association between the self-rated health scale and HRQoL in the general population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To address the question of whether women with polycystic ovary syndrome (PCOS) reach menopause later than age-matched controls, we conducted a follow-up cohort study of women with well-characterized PCOS that was diagnosed 24 years ago. The hypothesis was that women with PCOS would reach menopause later than non-PCOS women. Parity during these 24 years was also studied., Material and Methods: Twenty-seven women diagnosed with PCOS in 1992 (mean age 29.5 years) were re-examined in 2016 (mean age 52.4 years). Randomly selected women, n = 94 (mean age 52.4 years), from the same geographic area included in the World Health Organization MONICA study, Gothenburg, Sweden, served as controls., Results: The mean menopausal age in women with PCOS was higher than in controls (53.3 ± 2.2 years vs 49.3 ± 3.5 years, P < 0.01). Serum-follicle stimulating hormone levels were lower in the PCOS women than in controls (31.0 ± 28.1 IU/L vs 52.3 ± 37.7 IU/L, P = 0.01). There was no difference in parity between women with PCOS (1.9 ± 1.3 children, range 0-4) and controls (1.7 ± 1.0, range 0-4 children)., Conclusions: Women with PCOS reached menopause 4 years later and had lower serum-follicle stimulating hormone compared with age-matched controls. Neither parity nor nulliparity differed between women with PCOS and controls., (© 2018 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Hyperfunctional dysfunction is one of the most common functional dysphonia, cha-racterized by voice insufficiency with excessive tightening of the muscles inside and outside the larynx during phonation. To make the treatment process more effective, new ways of rehabilitation are constantly being sought and developed. The aim of this work is to evaluate the effectiveness of laryngotaping - an innovative method of taping around the larynx and neck muscles., Material and Method: 10 patients with diagnosed hyperfunctional dysphonia participated in the study. Using the kinesiotaping principles, for 7 days, the suprahyoid and infrahyoid muscles, ster-nocleidomastoid muscles as well as the thyroid cartilage were taped. Before and after the therapy, the patients completed the VHI voice self-evaluation questionnaire. The evaluation of the larynx according to the L. Mathienson scale was also assessed palpation., Results: Analyzing the results of the VHI questionnaire and evaluation of palpation evaluation of the larynx before and after the therapy, statistically significant differences were observed. The results on average decreased by half, which is the desired effect of therapy., Discussion: The results confirm the positive impact of kinesiotaping around the larynx. However, more research is needed on a larger group of patients to fully evaluate the therapeutic effect., Conclusions: 1. Laryngotaping is an effective way to normalize muscle tone, and thus to improve the quality of the voice. 2. The presented studies require continuation, however, positive reception of the introduced therapy by patients encourages further research on a larger group of patients.

Purpose: Women with hypopituitarism have increased morbidity and mortality, and hypogonadism has been suggested to be a contributing mechanism. The purpose of this study was to investigate the prevalence of central hypogonadism and hypoandrogenism in women with hypopituitarism at a single Swedish center., Methods: All consecutive women (n = 184) who commenced growth hormone (GH) replacement therapy at Sahlgrenska University Hospital in Gothenburg between 1995 and 2015 were included. In accordance with the Endocrine Society Clinical Practice Guidelines, strict criteria, based on menstrual history combined with laboratory measurements, were used to define central hypogonadism. Hypoandrogenism was defined as subnormal levels of dehydroepiandrosterone sulfate and/or androstenedione., Results: Central hypogonadism was present in 78% of the women, in 75% of those ≤ 52 years and in 82% of those > 52 years of age. Hypoandrogenism was found in 61% of all the women and in 92% of those with adrenocorticotropic hormone (ACTH) deficiency. The estrogen substitution rate in hypogonadal women ≤ 52 years was lower than the hormonal substitution rate in the other pituitary hormone axes (74% versus 100%, P < 0.001). The use of estrogen substitution tended to decrease between 2000 and 2016. Few women received androgen treatment., Conclusions: In this first study of hypogonadism in women with hypopituitarism, using stringent diagnostic criteria for hypogonadism, the prevalence of central hypogonadism and low androgen levels was high and estrogen substitution was insufficient. Further studies are needed to elucidate the importance of hypogonadism and insufficient sex steroid replacement for the increased morbidity in hypopituitary women.

Objective: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions., Subjects and Methods: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT 4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects., Results: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT 4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa., Conclusions: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Introduction Laryngeal paralysis deteriorates all laryngeal functions. Therefore the therapeutic process must include restoration of respiratory, defensive and vocal function. Selection of a proper rehabilitation path plays a key role. Appropriate research protocol that includes objective methods of voice evaluation is an important element of monitoring the return of vocal efficiency. Voice efficiency is important for the patient particularly due to psychological and social reasons. Aim The aim of the study was the assessment of short-term functional voice therapy (FVT) in patients with unilateral paralysis of the larynx with the usage of objective parameters describing the glottis and voice quality. Material and Method During the last 10 years 355 patients with laryngeal paralysis were hospitalized in the Audiology and Phoniatrics Clinic due to dysphonia. All patients undergone 5-day FVT. From 2015 we unified diagnostic protocol measuring parameters obtained from videostrobokymography (VSK), electroglottography (EGG), perceptual and acoustic voice analysis before and after 5 day hospitalization. Results After FVT patients improved voice quality and glottal compensation. The majority of patients achieved a statistically significant improvement in the VSK, EGG, MDVP and perceptual analysis. Group of patients with unsatisfactory voice improvement after therapy required a prolonged rehabilitation or has been qualified for laryngeal microsurgery. Potential factors that could have cause insufficient effects of FVT were analysed. Conclusions The complexity of voice rehabilitation is crucial for the success of therapy. Interdisciplinary therapeutic team plays a significant role during voice rehabilitation in patients with vocal fold paralysis.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10 -8 ), we found suggestive evidence (P<5 × 10 -6 ) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Context: Bariatric surgery can lead to nutrient deficiencies. Gastric by-pass (GBP) entails restriction and malabsorption, whereas, vertical banded gastroplasty (VBG) is only restrictive., Objective: The objective of this study is to study whether GBP-patients develop iodine deficiency from malabsorption, and if GBP- and VBG-patients develop lower 24-h urinary iodine excretion (24-UIE) than obese non-operated controls (OB-controls) due to lower iodine intake., Design: The Swedish Obese Subjects (SOS) study is a prospective, non-randomized study of 4047 obese patients included 1987-2001, who chose bariatric surgery or non-surgical treatment. SOS-groups were compared at baseline, after 2 and 10 years and with population-based subsamples (MONICA-controls)., Patients: One hundred eighty-eight GBP-patients were matched with 188 VBG-patients and 188 OB-controls and with three subgroups from 412 MONICA-controls., Main Outcome Measurements: Primary outcome was 24-UIE. Secondary outcomes were iodine intake, iodine supplementation, TSH, FT4, and thyroid morbidity., Results: At baseline, median 24-UIE was higher in GBP-patients, VBG-patients and OB-controls than in MONICA-controls (214, 201, 203 and 137 μg/day, p < 0.001). At 10 years, 24-UIE in GBP-patients (161 μg/day) and VBG-patients (149 μg/day) was lower compared with baseline (p < 0.01) and OB-controls (189 μg/day, p < 0.01), but similar to 24-UIE in MONICA-controls (137 μg/day). The 10-year-dietary iodine intake was similar in GPB-patients and OB-controls, but higher in VBG-patients. Iodine supplementation was taken by 0-9% in SOS-groups., Conclusion: After surgery, GBP- and VBG-patients did not suffer from iodine deficiency, but both groups had lower iodine status than OB-controls. Dietary supplements recommended after bariatric surgery do not need to include iodine, in iodine sufficient countries., Trial Registration: clinicaltrials.gov : NCT01479452.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10 -8 ), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

PurposeWe investigated the diagnostic and clinical performance of exome sequencing in fetuses with sonographic abnormalities with normal karyotype and microarray and, in some cases, normal gene-specific sequencing.MethodsExome sequencing was performed on DNA from 15 anomalous fetuses and from the peripheral blood of their parents. Parents provided consent to be informed of diagnostic results in the fetus, medically actionable findings in the parents, and their identification as carrier couples for significant autosomal recessive conditions. We assessed the perceptions and understanding of exome sequencing using mixed methods in 15 mother-father dyads.ResultsIn seven (47%) of 15 fetuses, exome sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1 and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that exome sequencing would explain the results (5.2 on a 10-point scale) was higher than the approximately 30% diagnostic yield discussed in pretest counseling.ConclusionExome sequencing had diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy and variant interpretation must be addressed by highly tailored pre- and posttest genetic counseling.

N -Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA's anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation., (Copyright © 2017 by The American Association of Immunologists, Inc.)

This case report describes a 38-year-old woman, who presented with bilateral femoral stress fractures and osteoporosis after years of excessive levothyroxine treatment. Her bone health was restored rapidly and long-lasting with the reduction of levothyroxine dosage. No bone-active treatment was warranted., Introduction: Hyperthyroidism is a known risk factor for osteoporosis and fractures. Recent studies on patients with serum thyrotropin-suppressive therapy have not, however, indicated adverse effects on bone during long-term follow-up., Methods: This case report describes long-term follow-up data of a clinically euthyreoid patient, who developed symptomatic osteoporosis due to excessive levothyroxine treatment., Results: After correction of levothyroxine dosage, her bone mineral density (BMD) and previously elevated serum osteocalcin levels normalized rapidly and she remained free from fractures during 23 years of follow-up over menopause., Conclusion: Excessive TSH suppression contributed to the secondary osteoporosis in this patient; BMD normalized after dose reduction of levothyroxine and no fractures occurred during 23 years' follow-up. Some patients develop severe osteoporosis if they are over-substituted with levothyroxine, and decent follow-up of patients with levothyroxine supplementation is mandatory.

Background: Increased Serum insulin-like growth factor-1 (S-IGF-1) has been noted after physical activity in healthy subjects, while the acute release of S-IGF-1 in relation to exercise has not previously been studied in women with fibromyalgia (FM). S-IGF-1 and its binding protein (S-IGFBP-3) are mediated by growth hormone and have anabolic effects on the skeletal muscle. Aim of the study was to investigate acute release of IGF-1 after aerobic exercise in women with FM., Methods: The acute effect of physical exercise on S-IGF-1 and S-IGFBP-3 were studied in 22 women with FM and in 27 healthy controls during moderate and high-intensity cycling (i.e. ratings 12-13 and 15-17, on Borg's perceived exertion scale (RPE), respectively). Self-reported pain and fatigue were recorded. Differences within and between the two groups were analyzed., Results: After 15 min of bicycling, S-IGF-1 and S-IGFBP-3 increased both within the group with FM and in the healthy controls (p < 0.01). The increases in S-IGF-1 did not significantly differ between the women with FM and the healthy control group (mean increase 11 ± 10 vs. 11 ± 15 ng/ml and 13 ± 10 vs. 19 ± 22 ng/ml) when bicycling at moderate or high intensity, respectively. Self-reported pain and fatigue during exercise, irrespective of intensity, were higher in women with FM compared with healthy controls (p < 0.001)., Conclusions: Fifteen minutes bicycling at moderate intensity was sufficient to acutely mobilise S-IGF-1 in women with FM similarly to healthy controls in spite of higher score of fatigue and pain in women with FM. Hence, patients with FM were able to activate their skeletal muscle metabolism during a short, moderate bout of exercise and were not resistant to training effects. The result is important for encouraging clinical rehabilitation of patients with FM who commonly exercise at a moderate, rather than at a high-intensity level., Trial Registration: ClinicalTrials.govNCT01592916 , May 4, 2012.

Introduction: Hypothyroidism is a common disorder, appearing mainly in women although less frequently found in women with polycystic ovary syndrome (PCOS). The objective was to test the hypothesis that hyperandrogenism might protect against hypothyroidism., Material and Methods: The data from three prospective follow-up studies (up to 21 years) and one register study were compared: women with PCOS (Rotterdam criteria), n = 25, women with Turner syndrome, n = 217, a random population sample of women, n = 315, and men, n = 95 (the WHO MONICA study). Findings were to be verified or rejected in all females, n = 553 716, from the same region. The proportion of hypothyroidism was calculated and thyroid peroxidase antibodies (TPO) in serum were measured., Results: Hypothyroidism at >50 years of age was found in 8% of women with PCOS, 4% in men (PCOS vs. men; ns), 43% of women with Turner syndrome, irrespective of karyotype (p < 0.001 vs. PCOS), and in 17% of postmenopausal women in the population (p < 0.01 vs. PCOS). Elevated TPO were similar in PCOS and women and men in the population but higher in Turner syndrome. Hypothyroidism increased with age in all groups except PCOS women and men. In the register study, hypothyroidism was less common in women with PCOS >25 years (5.5%) than in women without PCOS (6.8%) from the same region (p < 0.01)., Conclusions: Hypothyroidism was less frequently seen in women with PCOS and in men compared with women in the general population and among women with Turner syndrome. This was not explained by altered autoimmunity or the Y-chromosome. Androgens seem to protect against hypothyroidism., (© 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Upper respiratory tract infections are common childhood diseases. Children are more susceptible to middle ear infections because their Eustachian tube is short, straight and wide. As a consequence of these inflammatory changes while impaired patency of the Eustachian tube often arises conductive hearing., Objective: The aim of this study was to Assessment effectiveness of treatment Eustachian tube dysfunction using inhaler AMSA., Material and Methods: The study group comprised 30 patients. Same was in the control group. All patients reported conductive hearing loss. Test group was treated as an inhaler AMSA. The control group was treated pharmacologically. Patients were examined with the use of pure-tone audiometry, and impedance at baseline, after one week and four weeks., Results: Statistical analysis showed improvement in the studied parameters in patients treated with inhaler AMSA in a much shorter time than patients treated with pharmacotherapy.

Objective: Abnormal secretion of thyroid hormones, growth hormone, cortisol and androgens influences body composition. We hypothesised that higher cortisol excretion, in combination with higher androgen and IGF-I concentrations, had a synergistic, favourable effect on body mass and bone., Design, Patients and Methods: This was a cross-sectional study on a population sample of 290 women and 93men. The mean age was 65.4±7.2yearsinwomen and 59.7±10.0yearsinmen. Body composition was assessed with bioimpedance, and skeletal health with calcaneal quantitative ultrasound and fracture rate. The influence of urinary free cortisol (UFC), serum DHEAs (women), testosterone (men), free T4andIGF-I on the outcome was studied with regression analyses adjusted for age and body mass index., Results: In women, higher concentrations of UFC, DHEAs, IGF-I and lower free T4, were associated with higher fat-free mass. Only a higher UFC concentration was associated with favourable calcaneal measurements. In men, higher testosterone was associated with higher fat-free mass and lower fat mass. Higher IGF-I concentration, but not UFC, was independently associated with higher fat-free mass in men. Interaction analyses did not reveal any additive effects of hormones on body composition or bone in either sex. In both men and women, only age was associated with osteoporotic fractures., Conclusion: Serum concentrations of androgens together with IGF-I were positively associated with body composition in both sexes. Urinary cortisol was positively associated with fat-free mass and bone status in women only. Increasing age, but not hormones, was the major determinant of osteoporotic fractures in this population sample., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: There is limited information about the prevalence of vitamin D deficiency and the effects of treatment on immigrants. The effects of oral vitamin D intake and UVB treatment on vitamin D status in healthy Somali women living in Sweden were analysed., Design: Two studies were carried out; a randomized, double-blind, placebo-controlled study, with oral drops of 800 IU and 1600 IU cholecalciferol and similar amounts of placebo given daily during 12 weeks and a single-blind, placebo-controlled study, using UVB (4·3-8·7 J/cm(2) ) or Woods lamp (placebo) on the upper body, or the face and hands., Patients: One-hundred fourteen Somali women, mean age 34 years, latitude 0-10°N, living in Sweden >2 years, latitude 57°N, participated., Measurements: Serum 25-hydroxyvitamin D (S-25(OH)D) was monitored before, every 6 weeks and at 3 months after treatment., Results: The majority of the women (n = 83, 73%) were vitamin D-deficient, S-25(OH)D < 25 nmol/l at start. There was a dose-dependent increase in S-25(OH)D levels (P = 0·001, stratified Jonckheere-Terpstra test) with a mean increase after twelve weeks in women treated with 800 IU/day and women treated with 1600 IU/day of 18 nmol/l (95% CI: 6-29, median = 17) and 29 nmol/l (95% CI: 17-42, median = 34), respectively. S-25(OH)D decreased during follow-up but remained above baseline levels. The placebo group remained unchanged throughout the study. UVB treatment increased S-25(OH)D dose-dependently after 6 weeks (P = 0·03, Jonckheere-Terpstra test)., Conclusions: Vitamin D deficiency was common in immigrants living at higher latitudes. Vitamin D treatment increased S-25(OH)D levels dose-dependently during 3 months. The effect was maintained for another 3 months. At least 1600 IU/day is recommended. The dropout rate was high., (© 2016 John Wiley & Sons Ltd.)

Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans (NA) experience some of the highest rates of substance abuse of all the US ethnic groups. The described analyses used data from a low-coverage whole genome sequence scan to conduct a genome-wide association study (GWAS) of an impulsivity phenotype in an American Indian community sample (n = 658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using emmax. Simulations were conducted to calculate empirical P-values. Genome-wide significant findings were observed for a variant 50-kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal-specific catenin, in the REG gene cluster. A meta-analysis of GWAS had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of nei endonuclease VIII-like 3 (NEIL3) on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population., (© 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Intravenous Ig is used to treat autoimmune or autoinflammatory disorders, but the mechanism by which it exerts its immunosuppressive activity is not understood completely. To examine the impact of intravenous Ig on macrophages, we compared cytokine production by LPS-activated macrophages in the presence and absence of intravenous Ig. Intravenous Ig treatment induced robust production of IL-10 in response to LPS, relative to LPS stimulation alone, and reduced production of proinflammatory cytokines. This anti-inflammatory, intravenous Ig-induced activation was sustained for 24 h but could only be induced if intravenous Ig were provided within 1 h of LPS stimulation. Intravenous Ig activation led to enhanced and prolonged activation of MAPKs, Erk1/2, p38, and Erk5, and inhibition of each reduced intravenous Ig-induced IL-10 production and suppression of IL-12/23p40. IL-10 production occurred rapidly in response to intravenous Ig + LPS and was sufficient to reduce proinflammatory IL-12/23p40 production in response to LPS. IL-10 induction and reduced IL-12/23p40 production were transcriptionally regulated. IL-10 played a direct role in reducing proinflammatory cytokine production by macrophages treated with intravenous Ig + LPS, as macrophages from mice deficient in the IL-10R β chain or in IL-10 were compromised in their ability to reduce proinflammatory cytokine production. Finally, intraperitoneal injection of intravenous Ig or intravenous Ig + LPS into mice activated macrophages to produce high levels of IL-10 during subsequent or concurrent LPS challenge, respectively. These findings identify IL-10 as a key anti-inflammatory mediator produced by intravenous Ig-treated macrophages and provide insight into a novel mechanism by which intravenous Ig may dampen down inflammatory responses in patients with autoimmune or autoinflammatory diseases., (© Society for Leukocyte Biology.)

Background: Hypopituitarism has been reported in patients with idiopathic normal pressure hydrocephalus (iNPH), which could enhance characteristic symptoms like impaired wakefulness, gait, body balance, and subcortical cognitive deterioration., Purpose: To compare basal serum levels of pituitary and sex hormones and serum insulin-like growth factor-1 (S-IGF-1) in patients with iNPH and an age-matched control population, and to correlate the preoperative hormone levels with symptoms and signs pre-operatively and three months after surgery., Methods: A cross-sectional case control design was used. Patients diagnosed with iNPH, n=108 (65 men and 43 women, mean age 72.3 years), were consecutively included during 2006-2011 at Sahlgrenska University Hospital, Gothenburg, Sweden. S-TSH, S-free T4, S-FSH, S-LH, S-prolactin, plasma ACTH, S-testosterone, S-oestradiol and S-IGF-1 were examined. Symptoms and signs were scored using the iNPH scale score. Population controls, n=146, were recruited from the WHO MONICA project, Gothenburg in 2008., Results: Men and women with iNPH had higher S-IGF-1 than controls (p<0.001). Women with iNPH had lower S-TSH (p=0.016) than controls, but the frequency of levothyroxine substitution was similar. Among men, a higher level of S-IGF-1 was associated with milder symptoms, while higher levels of S-FSH and S-LH were associated with more severe symptoms., Conclusions: Patients with iNPH did not have lower levels of pituitary or sex hormones but presented with higher levels of S-IGF-1, compared with healthy, age-matched controls. Higher S-IGF-1 in men was related to milder mental and physical symptoms and signs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The endothelium forms a vast network that dynamically regulates vascular barrier function, coagulation pathways and vasomotor tone. Microvascular endothelial cells are uniquely situated to play key roles during infection and injury, owing to their widespread distribution throughout the body and their constant interaction with circulating blood. While not viewed as classical immune cells, endothelial cells express innate immune receptors, including the Toll-like receptors (TLRs), which activate intracellular inflammatory pathways mediated through NF-κB and the MAP kinases. TLR agonists, including LPS and bacterial lipopeptides, directly upregulate microvascular endothelial cell expression of inflammatory mediators. Intriguingly, TLR activation also modulates microvascular endothelial cell permeability and the expression of coagulation pathway intermediaries. Microvascular thrombi have been hypothesized to trap microorganisms thereby limiting the spread of infection. However, dysregulated activation of endothelial inflammatory pathways is also believed to lead to coagulopathy and increased vascular permeability, which together promote sepsis-induced organ failure. This article reviews vascular endothelial cell innate immune pathways mediated through the TLRs as they pertain to sepsis, highlighting links between TLRs and coagulation and permeability pathways, and their role in healthy and pathologic responses to infection and sepsis., (© The Author(s) 2015.)

Objective: To study the prevalence and profile of thyroid disease in a cohort of referred patients with oral lichen planus (OLP) in comparison with a random population sample and to examine the clinical characteristics of OLP patients with and without thyroid disease., Study Design: Data from 1611 patients with OLP and 1615 patients from the general population were collected by using a standardized registration method. Patients with OLP using levothyroxine (OLP/levothyroxine+) were re-examined to collect information about existing OLP lesions and to confirm the thyroid disease diagnosis. The clinical characteristics of OLP lesions in this group were compared with those in an age- and gender-matched population of patients with OLP without a history of thyroid disease or levothyroxine medication (OLP/levothyroxine-)., Results: Nearly 11% (n=170) of the patients with OLP were taking levothyroxine compared with 2.5% (n=40) of the controls (multivariate odds ratio 2.99, 95% confidence interval 2.03-4.44; P<.0001). No difference was found in the thyroid disease profile between the groups. At the time of re-examination, patients with OLP/levothyroxine- displayed more erythematous OLP lesions and complained of more severe symptoms compared with the OLP/levothyroxine+ group (P<.001)., Conclusions: The prevalence of thyroid disease in patients with OLP was significantly higher than in the general population. The OLP lesions of patients with concomitant thyroid disease have a different presentation over time, which indicates a specific subgroup of OLP., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: Growth hormone (GH) treatment increases bone mineral density (BMD) in women with postmenopausal osteoporosis., Objective: The objective was to report bone data, fractures, and quality of life (QoL) in a 10-year follow-up of women who had received GH for 3 years and compared with controls followed in parallel., Design and Setting: A follow-up of a double-blind, placebo-controlled study conducted at Sahlgrenska University Hospital was performed., Patients: Eighty women aged between 50 and 70 years with osteoporosis and estrogen hormone replacement were studied and compared with an age-matched random population sample of women (n = 120) from the World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease project (Gothenburg, Sweden)., Interventions: Patients were randomized to GH 1.0 U or GH 2.5 U recombinant human GH or placebo sc daily during 3 years. All received calcium 750 mg and vitamin D 400 U and were followed up during 10 years., Main Outcome Measures: BMD and bone mineral content were measured with dual-energy X-ray absorptiometry. QoL was estimated with the 36-item Short Form., Results: GH increased BMD and bone mineral content dose dependently in all regions (P = .01, GH 1.0 U, and P = .0006, GH 2.5 U vs placebo). After 10 years the number of fractures decreased from 56% to 28% (P = .0003) in patients evenly distributed between groups. In controls, fractures increased from 8% to 32% (P = .0008). QoL did not change during GH treatment or during the 10-year follow-up and did not differ compared with controls., Conclusion: GH treatment was beneficial for bone and fracture outcome after 10 years but did not affect the QoL of the women with postmenopausal osteoporosis.

Objective: Patients with glucocorticoid excess have increased cardiovascular risk, decreased bone mineral density and impaired quality of life (QoL). The aim of this study was to evaluate the association between urinary cortisol excretion and cardiovascular risk factors, bone status and QoL in the population. We hypothesized that higher cortisol excretion was associated with adverse cardiovascular risk profile, worse skeletal health and QoL., Design, Patients and Methods: This was a cross-sectional study including a population sample (n=348), aged 38-77years. The mean age in women was 64.0±8.5years (n=276) and 60.3±10.2years in men (n=72). The metabolic syndrome, body composition measured with bioimpedance, calcaneal quantitative ultrasound, fractures and QoL evaluated with the Nottingham Health Profile, Psychological General Well-Being (PGWB) and the Short Form 36 (SF-36) were studied. Urinary free cortisol (UFC) was measured using radioimmunoassay., Results: UFC was higher in men (230±120nmol/L) compared to women (153±71; P<0.001) and decreased with increasing age (P<0.001). In a regression analysis, after adjustment for gender, age and body mass index, higher UFC was associated with higher fat-free mass (P<0.01), favourable calcaneal bone measurements (P<0.05), better general health measured with PGWB (P<0.01) and SF-36 (P=0.001) and tended to be negatively associated with the metabolic syndrome (P=0.07)., Conclusion: In contrast to our hypothesis, UFC in the upper physiological range was associated with a favourable cardiovascular risk profile, bone measures and QoL., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2). We inhibited the kinase activities and reduced the abundances of ERK5 and MEK5, a MAPK kinase directly upstream of ERK5, in primary human vascular endothelial cells and monocytes, and found that ERK5 promoted inflammation induced by a broad range of microbial TLR agonists and by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, we found that inhibitors of MEK5 or ERK5 reduced the plasma concentrations of proinflammatory cytokines in mice challenged with TLR ligands or heat-killed Staphylococcus aureus, as well as in mice that underwent sterile lung ischemia-reperfusion injury. Finally, we found that inhibition of ERK5 protected endotoxemic mice from death. Together, our studies support a proinflammatory role for ERK5 in primary human endothelial cells and monocytes, and suggest that ERK5 is a potential therapeutic target in diverse disorders that cause inflammatory critical illness., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Cholecalciferol (vitamin D3), produced in the skin by UVB irradiation (290-315nm) of 7-dehydrocholesterol, is metabolized in the liver into 25-hydroxyvitamin D [25(OH)D] which is a major circulating metabolite., Aim: To examine changes in serum concentrations of cholecalciferol and its metabolites after UVB exposure of different skin areas., Methods: 21 healthy Caucasians (skin type II and III, aged 23-47years) were exposed to broadband UVB (290-320nm) and randomized to either exposure to one minimal erythema dose given as a single dose, or a suberythemic dose given for 3 subsequent days. The following areas were exposed: face and back of hands, upper half of the body and the whole body, respectively. Serum cholecalciferol and 25(OH)D were measured immediately before start and 24h after the 1st and last exposure, respectively., Results: Subjects with whole body exposure had an average S-cholecalciferol increase per dose unit of 0.18ngml(-1)mJ(-1)cm(2), 0.95 CI: (0.16, 0.20), upper body treatment 0.13ngml(-1)mJ(-1)cm(2), 0.95 CI: (0.10, 0.15) and face and hands exposure 0.013ngml(-1)mJ(-1)cm(2), 0.95 CI: (-0.012, 0.037). The increase in cholecalciferol correlated positively to the UVB dose and skin erythema and negatively to body mass index (BMI) when controlling for other factors. Exposure of face and hands induces smaller cholecalciferol production in comparison with exposure of larger skin areas., Conclusion: Size of the exposed skin area, UVB dose, skin erythema and BMI were the major determinants for serum levels of skin synthesized cholecalciferol. Exposure of hands and face induces smaller cholecalciferol production in comparison with exposure of larger skin areas., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: There is limited knowledge about the natural history of normocalcaemic, vitamin D-sufficient hyperparathyroidism (nHPT). The aim was to study the prevalence of nHPT and its relation to morbidity., Design: Cross-sectional and retrospective study at the Sahlgrenska University Hospital, Gothenburg, Sweden., Subjects: A random population of 608 men and women, age 25-64 years, was studied in 1995 as part of the WHO MONICA study and reinvestigated in 2008 (n = 410, of whom 277 were vitamin D sufficient)., Measurements: A serum intact parathyroid hormone (S-PTH) ≥60 ng/l was considered as HPT, S-calcium 2·15-2·49 mmol/l as normocalcaemia and S-25(OH)D ≥ 50 nmol/l as vitamin D sufficiency. Data on fractures, stroke and myocardial infarction were retrieved until 2013, that is a 17-year follow-up., Results: The prevalence of nHPT was 2·0% in 1995 (age 25-64) and 11·0% in 2008 (age 38-79). S-PTH was positively correlated with age and BMI. After adjustment for these variables, a high S-PTH level (≥60 ng/l) at follow-up was associated with previously low S-25(OH)D, high osteocalcin, S-PTH and both past and presently treated hypertension. No relation was seen with creatinine, cystatin C, malabsorption markers, thyroid function, glucose, insulin, lipids, calcaneal quantitative ultrasound, fractures, myocardial infarction, stroke or death at follow-up., Conclusions: This small random population study showed that nHPT was common, 11% at follow-up. Only one individual developed mild hypercalcaemia in 13 years. Previous S-PTH was predictive of nHPT and hypertension was prevalent, but no increase in hard end-points was seen over a 17-year period., (© 2015 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

In the normal population, loss of one of the sex chromosomes leading to monosomy (45,X) is a part of the aging process. In Turner syndrome (TS), the classic karyotype 45,X is found in up to 50% at birth, and others have a second cell line; mosaicism. The aim was to study if the chromosomal pattern in TS women changes over time. Fluorescence in situ hybridization was performed on buccal smear cells obtained twice, 10 years apart, from 42 women with TS aged 26-66 years (mean±standard deviation: 42.0±11.6). DNA probes specific for chromosomes X (DXZ1) and Y (DYZ3) were used and >100 cells were analyzed/patient. Nineteen women had monosomy (45,X) (<10% 46,XX), nine had 45,X/46,XX mosaicism, and 14 had iso, ring, or a marker chromosome at baseline. At 10 years, the percentage of diploid cells had increased in 29 of 42 women (69%), with an average increase of 5.7±13.0%. There was a positive correlation between age and % change in diploid 46,XX or 46,XY cells (r=0.38, p=0.023). This new finding might have relevance for the life expectancy in TS.

Background: Cholecalciferol is an essential steroid produced in the skin by solar ultraviolet B radiation (UVB 290-315nm). Skin production of cholecalciferol depends on factors affecting UVB flux, age and exposed skin area., Purpose: Serum cholecalciferol and 25-hydroxyvitamin D3 [25(OH)D3] concentrations were measured after UVB irradiation of 3 different skin areas to compare the skin capacity to produce vitamin D in different anatomic sites in the same individuals., Method: Ten voluntary Caucasians (skin photo type II & III, aged 48±12years (±SD)) were exposed to broadband UVB (280-320nm) between February and April. Hands and face, upper body and whole body were exposed to a suberythemic dose of UVB (median 101mJ/cm(2) (min 66, max 143)) (for 3 subsequent days 24h apart with a wash out period of about 3weeks (median 18days (min 11, max 25)) between the exposures of respective area. Serum concentrations of cholecalciferol and 25(OH)D3, were measured immediately before the first and 24h after the last dose of radiation., Results: There was a significantly higher increase in serum cholecalciferol after UVB exposure of the two larger skin areas compared to face and hands, but no difference in increase was found between upper body and whole body exposures., Conclusion: Exposure of a larger skin area was superior to small areas and gave greater increase in both serum cholecalciferol and serum 25(OH)D3 concentrations. However, exposure of face and hands, i.e. only 5% of the body surface area, was capable of increasing serum concentrations of 25(OH)D3., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Vitamin D deficiency can lead to osteomalacia. Bone mineral density was lower in Somali women, living in Sweden, in relation to both the American and the African-American reference populations. The majority, 73 %, had vitamin D deficiency, and supplementation should be considered to prevent from osteomalacia, osteoporosis and future fractures., Purpose: Low vitamin D can lead to osteomalacia. The hypothesis was that bone mineral density (BMD) in Somali women living in Sweden was lower in comparison with different ethnic reference populations., Methods: Women from Somalia, n = 67, median age 35.8 years (range 18 to 56), latitude 0-10° North living in Gothenburg, Sweden, latitude 57° North, >2 years were studied. All wore traditional Islamic clothing and had skin photo type V. BMD was recorded as the Z-score and compared with white American and African-American women, respectively, using standard data from the dual energy X-ray absorptiometry (DXA) manufacturer (Lunar Prodigy enCORETM, GE Healthcare, LU44663). A fasting blood test was drawn for analysis of serum 25(OH)D., Results: The median Z-score compared with the American white population was -0.9 SD of the lumbar spine (p < 0.00001), 0.1 SD of the left hip and 0.0 SD of the right hip (ns). The median Z-score compared with the African-American population was -1.6 SD of the lumbar spine (p < 0.00001), -0.9 SD of the left hip and -0.9 SD of the right hip (p < 0.001). The majority, 73 %, had vitamin D deficiency, serum 25(OH)D <25 nmol/l (<10 ng/ml). BMD did not correlate to vitamin D levels or to the number of years in Sweden. One wrist fracture was reported., Conclusions: BMD was lower in these fairly young immigrant women from Somalia, living in Sweden, in relation to both the American and the African-American reference populations. Vitamin D supplementation should be considered to prevent from osteomalacia, osteoporosis and future fractures.

Background and Purpose: Persistent dizziness and balance problems have been reported in some patients with unilateral vestibular pathology. The purpose of this case series was to address the examination and treatment of musculoskeletal dysfunction in patients with unilateral vestibular hypofunction., Case Description: The musculoskeletal system was evaluated with the Global Physiotherapy Examination, dynamic balance was measured during walking with triaxial accelerometers positioned on the lower and upper trunk, and symptoms and functional limitations were assessed with standardized self-report measures. The 4 included patients had symptoms of severe dizziness that had lasted more than 1 year after the onset of vestibular dysfunction and a moderate level of perceived disability. Musculoskeletal abnormalities typically included postural misalignment, restricted abdominal respiration, restricted trunk movements, and tense muscles of the upper trunk and neck. The patients attended a modified vestibular rehabilitation program consisting of body awareness exercises addressing posture, movements, and respiration., Outcomes: After the intervention, self-reported symptoms and perceived disability improved. Improvements in mobility and positive physical changes were found in the upper trunk and respiratory movements. The attenuation of mediolateral accelerations (ie, body oscillations) in the upper trunk changed; a relatively more stable upper trunk and a concomitantly more flexible lower trunk were identified during walking in 3 patients., Discussion: The recovery process may be influenced by self-inflicted rigid body movements and behavior strategies that prevent compensation. Addressing physical dysfunction and enhancing body awareness directly and dizziness indirectly may help patients with unilateral vestibular hypofunction break a self-sustaining cycle of dizziness and musculoskeletal problems. Considering the body as a functional unit and including both musculoskeletal and vestibular systems in examination and treatment may be important., (© 2014 American Physical Therapy Association.)

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

Objectives: Arachnoid cysts (AC) are benign, congenital malformations of the leptomeninges, with a predilection for the temporal fossa. In our clinical experience, patients with temporal AC often complain of dizziness and imbalance. However, these symptoms and the effect of surgery on them have not been studied before., Materials and Methods: Dizziness and imbalance in patients with temporal AC were quantified before and after surgical cyst decompression, using the Dizziness Handicap Inventory (DHI), Vertigo Symptom Scale - Short-Form (VSS-SF) and computerized dynamic posturography (CDP). The study includes 16 patients with temporal AC and 15 control subjects undergoing surgery for benign lesions of the larynx (n = 10) or the parotid glands (n = 5). All participants answered the DHI and VSS-SF and underwent CDP the day before and 3-6 months after surgery. The patients with AC also graded their dizziness through the use of a visual analogue scale (VAS)., Results: Preoperatively, cyst patients scored higher than controls on subjective symptoms (DHI, VSS-SF A and VSS-SF V), but not on postural sway (CDP). Symptom scores decreased after surgery; the cyst patients improved significantly in the subjective tests (DHI, VAS and VSS-SF), while CDP scores did not. In the controls, symptom and CDP scores were unchanged after surgery., Conclusions: Patients with temporal AC have a significant preoperative impairment and post-operative improvement in their subjective dizziness, but not in postural sway as measured by CDP., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to investigate whether the regulation of 5-hydroxytryptamine-7 (5-HT7) receptors in the bilateral basolateral amygdala (BLA) could alter the amnesic effects of sevoflurane and change the hippocampal expression of Arc and neural apoptosis. Male Sprague-Dawley rats were randomized into ten groups. First, the animals received bilateral injection of SB269970 (20, 50, or 100 pmol/0.2 μl) or saline (0.2 μl) or AS-19 (2, 10, or 50 pmol/0.2 μl), followed by inhalation of 2% sevoflurane or air for 2h. Then, fear conditioning training was carried out, and the percentage of freezing was detected 24h later. Furthermore, hippocampal Arc protein level and neural apoptosis were measured. Pre-training inhalation of sevoflurane reduced the extent of freezing, and hippocampal Arc expression. The largest dose of SB269970 (100 pmol) could block sevoflurane-induced amnesia and reverse the inhibitive effect of sevoflurane on Arc expression, while the maximal dose of AS-19 could exacerbate the amnesic effect, and further inhibit Arc expression. Furthermore, pre-training inhalation of 2% sevoflurane for 6h could not induce neural apoptosis in the hippocampus. The amnesic effect of sevoflurane might partly attribute to its impairment of memory formation in the hippocampus via activation of 5-HT7 receptors in the BLA., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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.