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Objective— Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals. Approach and Results— FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography–tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21–1.41), which remained significant at 1.21 (95% confidence interval, 1.11–1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% ( P =6.9×10 − 5 ) for Cer(d18:1/18:0). Conclusions— Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk.

Proper functioning wound healing strategies are sparse. Adequate vascular formation to the injured area, as well as replacement of the volume loss, is fundamental in soft tissue repair. Tissue engineering strategies have been proposed for the treatment of these injury sites. Novel cell-free substance, human adipose tissue extract (ATE), has been previously shown to induce in vitro angiogenesis and adipogenesis and in vivo soft tissue formation. This study reports the translation of ATE preparation from laboratory to the operating room (OR). ATE samples for this study were derived from adipose tissue obtained with the water-jet assisted liposuction technique from 27 healthy patients. The variables studied included incubation time (15, 30, and 45 min), temperature (room temperature vs. 37°C), and filter type to determine the optimal method yielding the most consistent total protein content, as well as consistent and high expression of adipose-derived growth factors and cytokines, including: vascular endothelial growth factor, basic fibroblast growth factor, interleukin-6, adiponectin, leptin, and insulin-like growth factor. Following the optimization, samples were produced in the OR and tested for their sterility. No significant differences were observed when comparing extract incubation time points or incubation temperature. Nonetheless, when studying the different filter types used, a syringe filter with PES membrane with larger filter area showed significantly higher protein concentration (p ≤ 0.018). When studying the different growth factor concentrations, ELISA results showed less variation in cytokine concentrations in the OR samples with the optimized protocol. All of the OR samples were tested sterile. The devised protocol is an easy and reproducible OR-ready method for ATE generation. As an attractive source of growth factors, ATE is a promising alternative in the vast field of tissue engineering. Its clinical applications include volume replacement as a complement to fillers and improvement of the permanence of fat grafts and wound healing, among other bioactive functions.

The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.

Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal—not cancer—stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression., The tumour stroma has altered stiffness and matrix architecture compared to normal tissue, which favours proliferation, and invasion. Here, the authors find that the extracellular matrix produced by normal fibroblasts inhibits cancer cell proliferation through mechanosensitive downregulation of JMJD1a.

The aim of this study was to evaluate the impact of actual rotational setup errors on dose distributions in intracranial stereotactic radiotherapy (SRT) with different alternatives for treatment position selection. A total of 38 SRT fractions from 18 patients were retrospectively evaluated with rotational setup errors obtained from actual treatments. The planning computed tomography (CT) images were rotated according to online cone‐beam CT (CBCT) images and the dose distribution was recalculated to the rotated CT images using three different patient positionings derived from: 1) an automatic 6D match neglecting rotation correction (Auto6D); 2) an automatic 3D match (Auto3D); and 3) a manual 3D match from actual treatment (Treat3D). The mean conformity index (CI) was 0.92 for the original plans and 0.91 for the Auto6D plans. The mean CI decreased significantly (p0.38) was found in the Auto3D and the Treat3D cases between the rotation error and CI, PTVmin or minimum dose of gross tumour volume. In SRT, a treatment plan of comparable quality to 6D rotation correction can be achieved by using 6D registration without a rotational correction in the selection of patient positioning. This was demonstrated for typical rotation errors seen in clinical practice. PACS number(s): 87.55, 87.57

Background. Several reports describe favorable results from frequent hemodialysis, but due to the lack of unequivocal dose measures it is not clear whether the benefits are due to more efficient toxin removal or other factors. Methods. The associations with death risk of six continuous-equivalent urea clearance measures were compared in 57 conventional in-center hemodialysis treatment periods of 51 patients, together 114 patient years. The double pool dose measures were calculated with the Solute-Solver program and separately scaled to urea distribution volume or normalized with body surface area. Results. Mortality associated significantly with equivalent renal urea clearance (EKR) scaled to urea distribution volume (V) (p=0.033) and with EKR normalized with body surface area (BSA) (p=0.044) but not with V-scaled (p=0.059) nor BSA-normalized (p=0.183) standard clearance (stdK). Women had significantly higher normalized protein catabolic rate (nPCR), EKR/V, and stdK/V than men but slightly lower BSA-normalized dose measures and lower mortality. Protein catabolic rate and dialysis dose correlated positively with each other and with survival. Conclusions. The prognostically most valid continuous-equivalent clearance in the present material was EKR/V, calculated from double pool urea generation rate, distribution volume, and time-averaged concentration.

Summary Dietary gluten present in wheat, rye and barley induces several gastrointestinal disorders, including celiac disease and non-celiac gluten sensitivity (NCGS). Celiac disease is an immune-based enteropathy triggered by ingestion of gluten in genetically susceptible individuals resulting from the interaction between genetic and environmental factors. Although gluten has been recognized as the main environmental trigger of the disease, a specific role for the intestinal microbiota in celiac disease development has been suggested. NCGS individuals develop adverse reactions after the exposure to gluten. Due to the similarities in clinical outcomes and the absence of diagnostic biomarkers, it is challenging to differentiate NCGS from celiac disease. The aetiology of NCGS remains unknown, although the involvement of innate immune mechanisms has been suggested. Since the influence of intestinal microbiota on immune cell homeostasis and on education of both innate and adaptive immune system is well known, the role of host-microbe interactions in the non-celiac gluten sensitivity have been hypothesized. This review aims to summarize the current knowledge of the contribution of microbiota to the pathogenesis and/or onset of celiac disease. In addition, a brief overview of the possible role of the microbiota components on the NCGS is presented.

Background Intermittent androgen deprivation (IAD) has received increasing attention; however, the current literature is still limited, especially in nonmetastatic prostate cancer (PCa), and the relative efficacy and safety benefits of IAD versus continuous androgen deprivation (CAD) remain unclear. Objective To add to the knowledge base regarding efficacy and potential benefits, including reduced side effects and improved quality of life (QoL), of IAD versus CAD in patients with nonmetastatic relapsing or locally advanced PCa. Design, setting, and participants A 42-mo phase 3b open-label randomised study in 933 patients from 20 European countries. Intervention Following a 6-mo induction with leuprorelin acetate (Eligard) 22.5 mg 3-mo depot, patients were randomised to CAD or IAD with leuprorelin for 36 mo. Outcome measurements and statistical analysis The primary end point was time to prostate-specific antigen (PSA) progression while receiving luteinising hormone-releasing hormone agonist, defined as three consecutive increasing PSA values ≥4 ng/ml ≥2 wk apart. Secondary end points included PSA progression-free survival (PFS), overall survival (OS), testosterone levels, performance status, and QoL. Results and limitations A total of 933 patients entered the induction phase; 701 were randomised. The median number of injections administered after randomisation was 12 (range: 1-12) for the CAD group and 3 (range: 1-10) for the IAD group. There were no statistically significant or clinically relevant differences between the groups for time to PSA progression, PSA PFS, OS, mean PSA levels over time, or QoL. A similar number of adverse events was observed in each group; the most common were hot flushes and hypertension. Study limitations include the open-label design and absence of formal testosterone recovery assessment. Conclusions IAD and CAD demonstrated similar efficacy, tolerability, and QoL in men with nonmetastatic PCa. The principal benefit of IAD compared with CAD is a potential cost reduction with comparable OS rates. There are no apparent QoL benefits. Patient summary This randomised trial showed that both intermittent and continuous hormone therapy had similar efficacy, tolerability, and quality-of-life profiles in patients with relapsing M0 or locally advanced prostate cancer. Intermittent therapy may be a valid option for selected patients. Trial registration ClinicalTrials.gov identifier NCT00378690., SCOPUS: ar.j, info:eu-repo/semantics/published

Article, Motivation A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. Results We introduce metaCCA , a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness. Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA , using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies., published version, peerReviewed

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) andα-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asnmutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asngene mutation in their cellular size, Ca2+handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying eitherMYBPC3-Gln1061XorTPM1-Asp175Asngene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well.

Background: After the failure of medical treatment, the surgery of chronic rhinosinusitis (CRS) is planned according to endoscopic and paranasal sinus computed tomography (CT) findings. Objective: The aim of this prospective study was to evaluate whether this study method might be eligible in studies aiming at radiation dose reduction. Sinus CT scans were chosen as a model because of the high variation of the radiological anatomy of surgically important sinonasal structures. We hypothesized that 3 mm-slice-thick reconstruction CT had poor reproducibility. Methods: 59 CRS patients underwent routine multi-detector sinus CT (CTMD). CT3mm was reconstructed from CTMD data-sets. Lund-Mackay (LM) scores and 43 other structural parameters were analyzed blinded. Agreement was studied between CTMD and CT3mm (intra-observer reproducibility), and between three observers (inter-observer reproducibility) by using Cohen’s kappa. Results: The inter-observer agreement was moderate (kappa 0.4 - 0.6, p < 0.01) in the majority of structures of CT3mm scans. The intra-observer reproducibility of CT3mm scans was very good in most structures, however, it was poor in important structures such as frontal and spheno-ethmoid recess, lamina pa-pyracae, and location of optic nerve or anterior ethmoidal artery. The grade of surgeon’s confidence of CT3mm in comparison to CTMD was lower (kappa 0.2 - 0.4, P < 0.05). Conclusion: This methodology might have some use in studies aiming at radiation dose reduction. As was expected, 3 mm-slice-thick reconstruction CT had poor reproducibility and surgeon’s confidence. More recent methods such as cone beam computed tomography scans have nowadays more relevant dose reduction potential

glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response. METHODS: We conducted a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults. RESULTS: A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P

Background and purpose Background and purpose — Perioperative hyperglycemia has been associated with adverse outcomes in several fields of surgery. In this observational study, we identified factors associated with an increased risk of hyperglycemia following hip and knee replacement. Patients and methods Patients and methods — We prospectively monitored changes in glucose following primary hip and knee replacements in 191 patients with osteoarthritis. Possible associations of patient characteristics and operation-related factors with hyperglycemia (defined as glucose > 7.8 mmol/L in 2 consecutive measurements) and severe hyperglycemia (glucose > 10 mmol/L) were analyzed using binary logistic regression with adjustment for age, sex, operated joint, and anesthesiological risk score. Results Results — 76 patients (40%) developed hyperglycemia, and 48 of them (25% of the whole cohort) had severe hyperglycemia. Glycemic responses were similar following hip replacement and knee replacement. Previously diagnosed diabetes was associated with an increased risk of hyperglycemia and severe hyperglycemia, compared to patients with normal glucose metabolism, whereas newly diagnosed diabetes and milder glucose metabolism disorders had no effect. In patients without previously diagnosed diabetes, increased values of preoperative glycosylated hemoglobin (HbA1c) and fasting glucose on the day of operation were associated with hyperglycemia. Higher anesthesiological risk score—but none of the operation-related factors analyzed—was associated with an increased risk of hyperglycemia. Interpretation Interpretation — Perioperative hyperglycemia is common in primary hip and knee replacements. Previously diagnosed diabetes is the strongest risk factor for hyperglycemia. In patients with no history of diabetes, preoperative HbA1c and fasting glucose on the day of operation can be used to stratify the risk of hyperglycemia.

Prostate cancer is the third most common cause of male cancer death in developed countries, and one of the most comprehensively characterized human cancers. Roughly 60% of prostate cancers harbor gene fusions that juxtapose ETS-family transcription factors with androgen regulated promoters. A second subtype, characterized by SPINK1 overexpression, accounts for 15% of prostate cancers. Here we report the discovery of a new prostate cancer subtype characterized by rearrangements juxtaposing the SMAD inhibitor SKIL with androgen regulated promoters, leading to increased SKIL expression. SKIL fusions were found in 6 of 540 (1.1%) prostate cancers and 1 of 27 (3.7%) cell lines and xenografts. 6 of 7 SKIL-positive cancers were negative for ETS overexpression, suggesting mutual exclusivity with ETS fusions. SKIL knockdown led to growth arrest in PC-3 and LNCaP cell line models of prostate cancer, and its overexpression led to increased invasiveness in RWPE-1 cells. The role of SKIL as a prostate cancer oncogene lends support to recent studies on the role of TGF-β signaling as a rate-limiting step in prostate cancer progression. Our findings highlight SKIL as an oncogene and potential therapeutic target in 1-2% of prostate cancers, amounting to an estimated 10,000 cancer diagnoses per year worldwide. This article has supplementary files, which can be found here:http://dx.doi.org/10.18632/oncotarget.3359

Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhoodonset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms andmediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors.We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. Copyright © 2015 Pinja Ilmarinen et al. This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In addition to vaccines, noninfectious virus-like particles (VLPs) that mimic the viral capsid show an attractive possibility of presenting immunogenic epitopes or targeting molecules on their surface. Here, functionalization of norovirus-derived VLPs by simple non-covalent conjugation of various molecules is shown. By using the affinity between a surface-exposed polyhistidine-tag and multivalent tris-nitrilotriacetic acid (trisNTA), fluorescent dye molecules and streptavidin–biotin conjugated to trisNTA are displayed on the VLPs to demonstrate the use of these VLPs as easily modifiable nanocarriers as well as a versatile vaccine platform. The VLPs are able to enter and deliver surface-displayed fluorescent dye into HEK293T cells via a surface-attached cell internalization peptide (VSV-G). The ease of manufacturing, the robust structure of these VLPs, and the straightforward conjugation provide a technology, which can be adapted to various applications in biomedicine.

Decorin (DCN) is the best characterized member of the extracellular small leucine-rich proteoglycan family present in connective tissues, typically in association with or “decorating” collagen fibrils. It has substantial interest to clinical medicine owing to its antifibrotic, anti-inflammatory, and anticancer effects. Studies on DCN knockout mice have established that a lack of DCN is permissive for tumor development and it is regarded as a tumor suppressor gene. A reduced expression or a total disappearance of DCN has been reported to take place in various forms of human cancers during tumor progression. Furthermore, when used as a therapeutic molecule, DCN has been shown to inhibit tumor progression and metastases in experimental cancer models. DCN affects the biology of various types of cancer by targeting a number of crucial signaling molecules involved in cell growth, survival, metastasis, and angiogenesis. The active sites for the neutralization of different growth factors all reside in different parts of the DCN molecule. An emerging concept that multiple proteases, especially those produced by inflammatory cells, are capable of cleaving DCN suggests that native DCN could be inactivated in a number of pathological inflammatory conditions. In this paper, we review the role of DCN in cancer. Copyright © 2015 Tero A. H. Järvinen and Stuart Prince. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Tausta. Iho- ja pehmytkudosinfektiot, kuten leikkaushaavojen infektiot, ovat suhteellisen yleisiä ja aiheuttavat yhteiskunnalle merkittävää kuormitusta. Nopeaa ja kustannustehokasta menetelmää infektion aiheuttajan tunnistamiseen ei ole kehitetty. Bakteeriviljely on edullinen menetelmä, mutta tulosten valmistuminen kestää usein päiviä. Nopeampien menetelmien, kuten PCR:n ongelmana on niiden vaatimat kalliit laitteistot ja se, että ne vaativat erikoiskoulutettua henkilökuntaa. Nopean ja edullisen menetelmän puuttuessa antibioottihoito joudutaan usein aloittamaan ilman tarkempaa tietoa infektion aiheuttajasta. Menetelmät. Tutkimuksessa käytettiin elektronista nenää (eNose) yleisimpien haavainfektioita aiheuttavien bakteerien tunnistamisessa. Tutkittavat bakteerit viljeltiin petrimaljoille, ja niiden erittämää kaasuseosta analysoitiin eNosella. Tulokset. Enose kykeni erottelemaan Staphylococcus aureuksen, Streptococcus pyogeneksen, Escherichia colin, Pseudomonas aeruginosan ja Clostridium perfringensin 78 % täsmällisyydellä minuuteissa ilman edeltävää näytteiden valmistelua. Laite erotti myös metisilliiniresistentin ja metisilliinisensitiivisen S. aureuksen 83 %:n herkkyydellä ja 100 %:n tarkkuudella. Johtopäätös. Tulokset osoittavat, että eNosea voidaan käyttää bakteerien nopeaan tunnistamiseen viljelmistä. Lisäksi laite kykeni erottelemaan MRSA:n ja MSSA:n toisistaan, joten sitä voisi käyttää myös antibioottiherkkyyden määrittämiseen.

Social phobia and depression are common and highly comorbid disorders in adolescence. There is a lack of studies on possible psychosocial shared risk factors for these disorders. The current study examined if low social support is a shared risk factor for both disorders among adolescent girls and boys. This study is a part of the Adolescent Mental Health Cohort Study's two-year follow-up. We studied cross-sectional and longitudinal associations of perceived social support with social phobia, depression, and comorbid social phobia and depression among girls and boys. The study sample consisted of 2070 15-year-old adolescents at baseline. Depression was measured by the 13-item Beck Depression Inventory, social phobia by the Social Phobia Inventory (SPIN), and perceived social support by the Perceived Social Support Scale-Revised (PSSS-R). Girls reported higher scores on the PSSS-R than boys in total scores and in friend and significant other subscales. Cross-sectional PSSS-R scores were lower among adolescents with social phobia, depression, and comorbid disorder than among those without these disorders. Low PSSS-R total score and significant other subscale were risk factors for depression among both genders, and low support from friends among girls only. Low perceived social support from any source was not a risk factor for social phobia or comorbid social phobia and depression. As conclusion of the study, low perceived social support was a risk factor for depression, but not a shared risk factor for depression and social phobia. Interventions enhancing perceived social support should be an important issue in treatment of depression. This is an open-access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted

Our aim was to compare the effects of calcium carbonate and sevelamer-HCl treatments on calcium-phosphate metabolism and renal function in 5/6 nephrectomized (NX) rats so that long-term disease progression preceded the treatment. After 15-week progression, calcium carbonate (3.0%), sevelamer-HCl (3.0%), or control diets (0.3% calcium) were given for 9 weeks. Subtotal nephrectomy reduced creatinine clearance (−40%), plasma calcidiol (−25%), and calcitriol (−70%) and increased phosphate (+37%), parathyroid hormone (PTH) (11-fold), and fibroblast growth factor-23 (FGF-23) (4-fold). In NX rats, calcium carbonate diet increased plasma (+20%) and urinary calcium (6-fold), reduced plasma phosphate (−50%) and calcidiol (−30%), decreased creatinine clearance (−35%) and FGF 23 (−85%), and suppressed PTH without influencing blood pH. In NX rats, sevelamer-HCl increased urinary calcium (4-fold) and decreased creatinine clearance (−45%), PTH (−75%), blood pH (by 0.20 units), plasma calcidiol (−40%), and calcitriol (−65%). Plasma phosphate and FGF-23 were unchanged. In conclusion, when initiated after long-term progression of experimental renal insufficiency, calcium carbonate diet reduced plasma phosphate and FGF-23 while sevelamer-HCl did not. The former induced hypercalcemia, the latter induced acidosis, while both treatments reduced vitamin D metabolites and deteriorated renal function.Thus, delayed initiation influences the effects of these phosphate binders in remnant kidney rats. Copyright © 2014 Suvi Törmänen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals. Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes ( XRCC4 and MTHFD2L ) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study. Availability and implementation: R-code freely available for download at http://users.ics.aalto.fi/pemartti/gene_metabolome/ . Contact: samuli.ripatti@helsinki.fi ; samuel.kaski@aalto.fi Supplementary information: Supplementary data are available at Bioinformatics online.

Off-time pubertal maturation is associated with mental disorders, presumably due to stress caused by deviation from peers that could also attract negative attention and result in being bullied. Stress related to off-time maturation could be acted out by involving oneself in bullying behavior. The associations between pubertal timing and involvement in bullying have so far not been a focus of research. The objective is to explore associations between off-time pubertal maturation and involvement in bullying. Cross-sectional and longitudinal associations between self-reported pubertal timing and involvement in bullying as victims and perpetrators were studied in a sample of 2070 Finnish adolescents aged 15–17 who participated in the Adolescent Mental Health Cohort Study. Internalizing (depression) and externalizing (conduct disorder) symptoms were controlled for. The adolescents were recruited to response the baseline survey in 2002–2003 (T1) and follow-up two years later (T2). In T1, response rate was 94.4% of all eligible students. The 2070 participants in T2 comprised 63.1% of the T1 participants. Early maturation among boys was cross-sectionally associated with being a bully, and late maturation with exclusion from peer group. After two years, the associations had disappeared. Among girls, no associations were detected between pubertal timing and involvement in bullying. Off-time pubertal maturation places boys at risk for involvement in bullying. The influence is transient and supports the stressful change hypothesis of pubertal timing. This is an open-access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

Object. Gender and disease course specific incidences were studied in high- and medium-risk regions of MS in Finland.Methods. Age- and gender-specific incidences with 95% CIs were calculated in 10-year periods from 1981 to 2010. Poser diagnostic criteria were used and compared with the McDonald criteria from 2001 to 2010. Association between age and diagnostic delay over time was assessed by using the Kruskal-Wallis test.Results. 1419 (89%) RRMS and 198 (11%) PPMS cases were included. RRMS incidence increased with the female to male ratio (F/M) from 4,2/105(F/M 1.9) to 9,7 (2.3), while that of PPMS decreased from 1,2 (1.6) to 0,7 (1.2). The use of McDonald criteria did not change the conclusion. The decreasing diagnostic delay and age at diagnosis in RRMS were associated within the 10-year periods and contrasted those in PPMS. Increasing female risk in RRMS was observed in the high-risk region.Conclusion. Increasing RRMS incidence and high female ratios shown in each age group indicate gender-specific influences acting already from childhood. A more precise definition of the risk factors and their action in MS is needed to provide a better understanding of underlying pathological processes and a rationale for the development of new preventive and treatment strategies.

Background and Aims. Assessing young children’s mental health is a crucial and challenging task. The aim of the study was to evaluate the clinical relevance of asking parents, nurses, and young children themselves to identify children’s mental health problems by only one or two questions.Methods. In regular health check-ups of 4- to 9-year-old children(n=2682), parents and public health nurses assessed by one question whether the child had any emotional or behavioral difficulties. The child completed a self-evaluation enquiry on his/her emotional well-being. A stratified proportion of the participating parents were invited to a diagnostic interview.Results. Sensitivities were fairly good for the parents’ (68%), nurses’ (65%), and their combined (79%) one-question screens. Difficulties identified by parents and nurses were major risks (OR 10–14) for any child psychiatric disorders(P<0.001). The child’s self-evaluation was related to 2-fold to 3-fold risks(P<0.05)for any psychiatric diagnosis, for any emotional diagnosis, and for negative situational factors.Conclusion. The one-question screen for parents and public health nurses together quite adequately identified the young children with mental health problems. The child’s self-evaluation provided relevant and complementary information on his/her mental health and especially emotional problems.

COPD (chronic obstructive pulmonary disease) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, adipose tissue mediated inflammation has gathered increasing interest in the pathogenesis of the disease. In this study, we investigated the role of novel adipocytokines nesfatin-1 and visfatin in COPD by measuring if they are associated with the inflammatory activity, lung function, or symptoms. Plasma levels of NUCB2/nesfatin-1 and visfatin were measured together with IL-6, IL-8, TNF-α, and MMP-9, lung function, exhaled nitric oxide, and symptoms in 43 male patients with emphysematous COPD. The measurements were repeated in a subgroup of the patients after four weeks’ treatment with inhaled fluticasone. Both visfatin and NUCB2/nesfatin-1 correlated positively with plasma levels of IL-6 (r=0.341,P=0.027andrho=0.401,P=0.008, resp.) and TNF-α(r=0.305,P=0.052andrho=0.329,P=0.033, resp.) and NUCB2/nesfatin-1 also with IL-8 (rho=0.321,P=0.036) in patients with COPD. Further, the plasma levels of visfatin correlated negatively with pulmonary diffusing capacity (r=-0.369,P=0.016). Neither of the adipokines was affected by fluticasone treatment and they were not related to steroid-responsiveness. The present results introduce adipocytokines NUCB2/nesfatin-1 and visfatin as novel factors associated with systemic inflammation in COPD and suggest that visfatin may mediate impaired pulmonary diffusing capacity.

Participating in competitive sport increases the risk for injuries and musculoskeletal pain among adolescent athletes. There is also evidence that the use of prescription drugs has increased among sport club athletes. The purpose of this study was to evaluate the use of painkillers among young male ice hockey players (IHP) in comparison to schoolboys (controls) and its relation to the prevalence of musculoskeletal pain and problems during activities and sleeping. Information was gathered through a questionnaire, completed by 121 IHP and compared to the responses of 618 age-matched controls. Results showed that monthly existing pain was at 82% for IHP, and 72% for controls, though IHP had statistically more musculoskeletal pain in their lower limbs (56% vs. 44%), lower back (54% vs. 35%), and buttocks (26% vs. 11%). There were no group differences in the neck, upper back, upper limb, or chest areas. The disability index was statistically similar for both groups, as musculoskeletal pain causing difficulties in daily activities and sleeping was reported by a minority of subjects. Despite this similarity, IHP used more painkillers than controls (18% vs. 10%). Further nuanced research is encouraged to compare athletes and non-athletes in relation to painkillers. This is an open-access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

MicroRNAs are involved in disease development and may be utilized as biomarkers. We investigated the association of blood miRNA levels and a) fatty liver (FL), b) lipoprotein and lipid pathways involved in liver lipid accumulation and c) levels of predicted mRNA targets in general population based cohort. Blood microRNA profiling (TaqMan OpenArray), genome-wide gene expression arrays and nuclear magnetic resonance metabolomics were performed for Young Finns Study participants aged 34–49 years (n = 871). Liver fat status was assessed ultrasonographically. Levels of hsa-miR-122-5p and -885-5p were up-regulated in individuals with FL (fold change (FC) = 1.55, p = 1.36 * 10−14 and FC = 1.25, p = 4.86 * 10−4, respectively). In regression model adjusted with age, sex and BMI, hsa-miR-122-5p and -885-5p predicted FL (OR = 2.07, p = 1.29 * 10−8 and OR = 1.41, p = 0.002, respectively). Together hsa-miR-122-5p and -885-5p slightly improved the detection of FL beyond established risk factors. These miRNAs may be associated with FL formation through the regulation of lipoprotein metabolism as hsa-miR-122-5p levels associated with small VLDL, IDL, and large LDL lipoprotein subclass components, while hsa-miR-885-5p levels associated inversely with XL HDL cholesterol levels. Hsa-miR-885-5p levels correlated inversely with oxysterol-binding protein 2 (OSBPL2) expression (r = −0.143, p = 1.00 * 10−4) and suppressing the expression of this lipid receptor and sterol transporter could link hsa-miR-885-5p with HDL cholesterol levels., published version, peerReviewed

Summary Puumala hantavirus (PUUV) infection causes nephropathia epidemica (NE), a relatively mild form of haemorrhagic fever with renal syndrome (HFRS). Hypophyseal haemorrhage and hypopituitarism have been described in case reports on patients with acute NE. Chronic hypopituitarism diagnosed months or years after the acute illness has also been reported, without any signs of a haemorrhagic aetiology. The mechanisms leading to the late-onset hormonal defects remain unknown. Here, we present a case of NE-associated autoimmune polyendocrinopathy and hypopituitarism presumably due to autoimmune hypophysitis. Thyroid peroxidase antibody seroconversion occurred between 6 and 12 months, and ovarian as well as glutamate decarboxylase antibodies were found 18 months after acute NE. Brain MRI revealed an atrophic adenohypophysis with a heterogeneous, low signal intensity compatible with a sequela of hypophysitis. The patient developed central (or mixed central and peripheral) hypothyroidism, hypogonadism and diabetes insipidus, all requiring hormonal replacement therapy. This case report suggests that late-onset hormonal defects after PUUV infection may develop by an autoimmune mechanism. This hypothesis needs to be confirmed by prospective studies with sufficient numbers of patients. Learning points: Pituitary haemorrhage resulting in hypopituitarism has been reported during acute HFRS caused by PUUV and other hantaviruses. Central and peripheral hormone deficiencies developing months or years after HFRS have also been found, with an incidence higher than that in the general population. The pathogenesis of these late-onset hormonal defects remains unknown. This case report suggests that the late-onset hypopituitarism and peripheral endocrine defects after HFRS could evolve via autoimmune mechanisms. The sensitivity of current anti-pituitary antibody (APA) tests is low. A characteristic clinical course, together with typical brain MRI and endocrine findings may be sufficient for a non-invasive diagnosis of autoimmune hypophysitis, despite negative APAs.

BACKGROUND: Mortality from coronary heart disease (CHD) remains at quite notable levels. Research on the risk factors and the treatment of CHD has focused on physiological factors, but there is an increasing amount of evidence connecting mental health and personality traits to CHD, too. The data concerning the connection of CHD and dispositional optimism and pessimism as personality traits is relatively scarce. The aim of this study was to investigate the connection between optimism, pessimism, and CHD mortality. METHODS: This was an 11-year prospective cohort study on a regional sample of three cohorts, aged 52-56, 62-66, and 72-76 years at baseline (N = 2815). The levels of dispositional optimism and pessimism of the study subjects were determined at baseline using a revised version of the Life Orientation Test (LOT-R). Eleven years later, those results and follow-up data about CHD as a cause of death were used to calculate odds. Adjustments were made for cardiovascular disease risk. RESULTS: Those who died because of CHD were significantly more pessimistic at baseline than the others. This finding applies to both men and women. Among the study subjects in the highest quartile of pessimism, the adjusted risk of death caused by CHD was approximately 2.2-fold (OR 2.17, 95 % CI 1.21-3.89) compared to the subjects in the lowest quartile. Optimism did not seem to have any connection with the risk of CHD-induced mortality. CONCLUSIONS: Pessimism seems to be a substantial risk factor for death from CHD. As an easily measured variable, it might be a very useful tool together with the other known risk factors to determine the risk of CHD-induced mortality. BioMed Central open access

Key Clinical Message Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare disorder outside Quebec causing childhood-onset cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. A Finnish family with milder form of ARSACS was found to harbor three mutations, p.E1100K, p.N1489S, and p.M1359T, in SACS gene. The mutations segregated with the disease.

BACKGROUND: The safety of vaginal breech delivery has been debated for decades. Although it has been shown to predispose infants to immediate depression, several observational studies have also shown that attempting vaginal breech delivery does not increase perinatal morbidity or low Apgar score at the age of five minutes. Cardiotocography monitoring is recommended during vaginal breech delivery, but comparative data describing differences between cardiotocography tracings in breech and vertex deliveries is scarce. This study aims to evaluate differences in intrapartum cardiotocography tracings between breech and vertex deliveries in the final 60 min of delivery. A secondary goal is to identify risk factors for suboptimal neonatal outcome in the study population. METHODS: One hundred eight breech and 108 vertex singleton, intended vaginal deliveries at term from a tertiary hospital with 5000 annual deliveries were included. Two experienced obstetricians, blinded to fetal presentation, neonatal outcome and actual mode of delivery, evaluated traces recorded 60 min before delivery. They provided a three-tier classification and evaluated different trace features according to FIGO (1987) guidelines. Factors associated with acidemia and low Apgar scores were identified by univariate and multivariable analyses performed with binary logistic regression. Student's T-test and chi-square test were used, as appropriate. RESULTS: Late decelerations were seen in 13.9 % of breech and 2.8 % of vertex deliveries (p = 0.003) and decreased variability in 26.9 % of breech and 8.3 % of vertex deliveries (p

Norovirus (NoV) is a leading cause of acute gastroenteritis in people of all ages worldwide. NoV specific serum antibodies which block the binding of NoV virus-like particles (VLPs) to the cell receptors have been thoroughly investigated. In contrast, only a few publications are available on the NoV capsid VP1 protein-specific T cell responses in humans naturally infected with the virus. Freshly isolated peripheral blood mononuclear cells of eight healthy adult human donors previously exposed to NoV were stimulated with purified VLPs derived from NoV GII.4-1999, GII.4-2012 (Sydney), and GI.3, and IFN-g production was measured by an ELISPOT assay. In addition, 76 overlapping synthetic peptides spanning the entire 539 amino acid sequence of GII.4 VP1 were pooled into two-dimensional matrices and used to identify putative T cell epitopes. Seven of the eight subjects produced IFN-g in response to the peptides and five subjects produced IFN-g in response to the VLPs of the same origin. In general, stronger T cell responses were induced with the peptides in each donor compared to the VLPs. A CD8+ T cell epitope in the shell domain of the VP1 (134SPSQVTMFPHIIVDVRQL151) was identified in two subjects, both having human leukocyte antigen (HLA)-A*02:01 allele. To our knowledge, this is the first report using synthetic peptides to study NoV-specific T cell responses in human subjects and identify T cell epitopes.

This prospective, community-based study examined trajectories of physical activity from childhood to adulthood and whether these trajectories contributed to depressive symptoms in adulthood to a greater degree than adulthood physical activity. Participants (n=3596) were from the ongoing Cardiovascular Risk in Young Finns Study which started in 1980. Depressive symptoms were measured with Beck Depression Inventory (BDI-II) in 2012, and physical activity was assessed from 1980 to 2011 with self-reports. Analyses were adjusted for age, sex, childhood negative emotionality, socioeconomic factors, previous depressive symptoms, social support, body mass index, and smoking status (1980–2007). Highly, moderately, and lightly physically active trajectory groups were identified. Highly active participants reported lower levels of depressive symptoms compared to lightly active ones (p<0.001) and compared to moderately active ones (p=0.001). Moderately active participants had less symptoms than lightly active ones (p<0.001). High levels of adulthood physical activity associated with lower levels of depressive symptoms (p<0.001). The findings did not withstand adjustment for previous depressive symptoms (p>0.05). Lifelong physical activity trajectories or adulthood physical activity was not associated with the progression of depressive symptoms in adulthood. Thus, physical activity history does not contribute to the progression of the depressive symptoms to a greater degree than adulthood physical activity.

The European Food Safety Authority (EFSA) states that young child formulae (YCFs) “cannot be considered as a necessity to satisfy the nutritional requirements” of children aged 12–36 months. This study quantifies the dietary changes needed to ensure nutritional adequacy in U.K. young children who consume YCFs and/or supplements and in those who do not. Dietary data from 1147 young children (aged 12–18 months) were used to identify, using linear programming models, the minimum changes needed to ensure nutritional adequacy: (i) by changing the quantities of foods initially consumed by each child (repertoire-foods); and (ii) by introducing new foods (non-repertoire-foods). Most of the children consumed neither YCFs, nor supplements (61.6%). Nutritional adequacy with repertoire-foods alone was ensured for only one child in this group, against 74.4% of the children consuming YCFs and supplement. When access to all foods was allowed, smaller food changes were required when YCFs and supplements were initially consumed than when they were not. In the total sample, the main dietary shifts needed to ensure nutritional adequacy were an increase in YCF and a decrease in cow’s milk (+226 g/day and −181 g/day, respectively). Increasing YCF and supplement consumption was the shortest way to cover the EFSA nutrient requirements of U.K. children.

Ethyl pyruvate (EP) is a simple derivative of pyruvic acid, which is an important endogenous metabolite that can scavenge reactive oxygen species (ROS). Treatment with EP is able to ameliorate systemic inflammation and multiple organ dysfunctions in multiple animal models, such as acute pancreatitis, alcoholic liver injury, acute respiratory distress syndrome (ARDS), acute viral myocarditis, acute kidney injury and sepsis. Recent studies have demonstrated that prolonged treatment with EP can ameliorate experimental ulcerative colitis and slow multiple tumor growth. It has become evident that EP has pharmacological anti-inflammatory effect to inhibit multiple early inflammatory cytokines and the late inflammatory cytokine HMGB1 release, and the anti-tumor activity is likely associated with its anti-inflammatory effect. EP has been tested in human volunteers and in a clinical trial of patients undergoing cardiac surgery in USA and shown to be safe at clinical relevant doses, even though EP fails to improve outcome of the heart surgery, EP is still a promising agent to treat patients with multiple inflammatory organ injuries and the other clinical trials are on the way. This review focuses on how EP is able to ameliorate multiple organ injuries and summarize recently published EP investigations. Graphical Abstract The targets of the anti-inflammatory agent EP

Innate immunity receptors play a critical role in host defence, as well as in allergy and asthma. The aim of this exploratory study was to evaluate whether there are associations between TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084 or TLR10 rs4129009 polymorphisms and viral findings, clinical characteristics or subsequent wheezing in infants with bronchiolitis. In all, 135 full-term infants were hospitalized for bronchiolitis at age less than 6 months: 129 of them were followed-up until the age of 1.5 years. The outcome measures were repeated wheezing, use of inhaled corticosteroids, atopic dermatitis during the first 1.5 years of life and total serum immunoglobulin E (IgE). There were no significant associations between the genotypes or allele frequencies of TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084 or TLR10 rs4129009 polymorphisms and clinical characteristics or the severity of bronchiolitis during hospitalization. During follow-up, repeated wheezing was more common in children with TLR9 rs187084 variant genotype CC (30.5%) than in children with TLR9 wild-type genotype TT (12.2%) (p = 0.02, aOR 2.73, 95% CI 1.02–7.29). The TLR10 rs4129009 minor allele G was associated with elevated total serum IgE. TLR9 rs187084 gene polymorphism may be associated with post-bronchiolitis wheezing and TLR10 rs4129009 gene polymorphism may be associated with atopy.

Objective Chronic rhinosinusitis (CRS) is a variable multifactorial disease. It can be divided into forms with nasal polyps (CRSwNP) and without (CRSsNP). Sinus and/or nasal polypectomy surgery are considered if maximal conservative treatment is insufficient. The predictive factors of the need of revision surgery comprise mostly the CRSwNP phenotype and are not fully understood. Study Design The aim of this follow-up study was to evaluate the factors associated with the revision surgery rate in CRS patients with variable extent of disease. Methods Data of CRS patients (N = 178) undergoing sinus surgery and/or nasal polypectomy in 2001 to 2010 were used. Patient characteristics and follow-up data were collected from patient records and questionnaires. Associations were analyzed by Fisher's exact, Mann Whitney U, and the Kaplan-Meier method with log-rank test. Unadjusted Cox's proportional hazard models were used for 12 variables and were fitted for the need for revision sinus surgery and/or nasal polypectomy during follow-up of in average 9 years. Results The proportion of CRS patients who had undergone revision in 5 years was 9.6%. After adjustment, the following factors associated significantly with the need for recurrent CRS surgery: allergic rhinitis, corticosteroid treatment, previous surgery of CRS, and recurrent NP. Conclusion Increased risk of progressive CRS phenotypes with the need for revision surgery would putatively be recognized by relatively simple clinical questions. Further studies with increased sample size are needed to evaluate whether these predictive factors would be relevant for developing better detection and management of progressive CRS. Level of Evidence 2b.

Association between celiac disease and type 1 diabetes in adults is still somewhat unclear, and that between celiac disease and type 2 diabetes even less known. We studied these issues in a large cohort of adult celiac disease patients. METHODS: The prevalence of type 1 and type 2 diabetes in 1358 celiac patients was compared with the population-based values. Furthermore, patients with celiac disease and concomitant type 1 or type 2 diabetes and those with celiac disease only underwent comparisons of clinical and histological features and adherence to gluten-free diet. RESULTS: The prevalence of type 1 diabetes (men/women) was 8.0 % /1.8 % in celiac patients and 0.7 % /0.3 % in the population, and that of type 2 diabetes 4.3 % /2.5 % and 4.4 % /3.0 %, respectively. Celiac patients with concomitant type 1 diabetes were younger (45 years vs 65 years and 52 years, P

BACKGROUND: In low-resource settings, malaria and macronutrient undernutrition are major health problems in pregnancy, contributing significantly to adverse pregnancy outcomes such as preterm birth and fetal growth restriction. Affected pregnancies may result in stillbirth and neonatal death, and surviving children are at risk of poor growth and infection in infancy, and of non-communicable diseases in adulthood. Populations exposed to macronutrient undernutrition frequently reside in malaria-endemic areas, and seasonal peaks of low food supply and malaria transmission tend to coincide. Despite these geographic and temporal overlaps, integrated approaches to these twin challenges are infrequent. DISCUSSION: This opinion article examines the current evidence for malaria-macronutrition interactions and discusses possible mechanisms whereby macronutrient undernutrition and malaria may interact to worsen pregnancy outcomes. Macronutrient undernutrition dysregulates the immune response. In pregnant women, undernutrition may worsen the already increased susceptibility to malarial infection and could impair development of protective immunity to malaria, and is likely to exacerbate the impact of placental malaria on fetal growth. Malarial infection, in turn, can drive nutritional depletion; poor gestational weight gain and weight loss in pregnancy increases the risk of adverse pregnancy outcomes. Despite a commendable number of studies and trials that, in isolation, attempt to address the challenges of malaria and undernutrition in pregnancy, few dare to venture beyond the 'single disease - single solution' paradigm. We believe that this may be a lost opportunity: researching malaria-nutrition interactions, and designing and implementing integrated interventions to prevent and treat these commonly co-existing and intertwining conditions, may markedly reduce the high burden of preterm birth and fetal growth restriction in affected areas. CONCLUSION: We call for more collaboration between researchers studying malaria and nutrition in pregnancy, and propose a research agenda to address this important twin health problem. BioMed Central open access

Acute abdominal pain is one of the most frequent complaints evaluated at emergency departments. Approximately 25 % of abdominal pain patients discharged from emergency departments are diagnosed with undifferentiated abdominal pain. One possible reason for acute abdominal pain is renal infarction. Diagnosis is difficult and often late. CASE PRESENTATION: A white, 33-year-old, previously healthy Finnish man came to our emergency department because of acute abdominal pain. After evaluation and follow-up he was discharged the next day with a diagnosis of undifferentiated abdominal pain. He returned a day later and was diagnosed with renal infarction. Appropriate therapy was initiated in the nephrology ward. Further tests confirmed a diagnosis of renal infarction as a result of fibromuscular dysplasia. He recovered well and was discharged on the tenth day of hospitalization. His renal function was normal. CONCLUSIONS: Renal infarction is rare and should be considered if a patient with intense flank pain has no sign of urolithiasis or pyelonephritis. Contrast-enhanced computer tomography and assay of lactate dehydrogenase are recommended. The optimal treatment is still uncertain. Every patient discharged with undifferentiated abdominal pain should be given clear instructions as to when it is necessary to return to the emergency department. BioMed Central open access

Background Traumatic brain injury (TBI) is one of the leading causes of death and permanent disability. Emergency Medical Services (EMS) personnel are often the first healthcare providers attending patients with TBI. The level of available care varies, which may have an impact on the patient’s outcome. The aim of this study was to evaluate mortality and neurological outcome of TBI patients in two regions with differently structured EMS systems. Methods A 6-year period (2005 – 2010) observational data on pre-hospital TBI management in paramedic-staffed EMS and physician-staffed EMS systems were retrospectively analysed. Inclusion criteria for the study were severe isolated TBI presenting with unconsciousness defined as Glasgow coma scale (GCS) score ≤ 8 occurring either on-scene, during transportation or verified by an on-call neurosurgeon at admission to the hospital. For assessment of one-year neurological outcome, a modified Glasgow Outcome Score (GOS) was used. Results During the 6-year study period a total of 458 patients met the inclusion criteria. One-year mortality was higher in the paramedic-staffed EMS group: 57 % vs. 42 %. Also good neurological outcome was less common in patients treated in the paramedic-staffed EMS group. Discussion We found no significant difference between the study groups when considering the secondary brain injury associated vital signs on-scene. Also on arrival to ED, the proportion of hypotensive patients was similar in both groups. However, hypoxia was common in the patients treated by the paramedic-staffed EMS on arrival to the ED, while in the physician-staffed EMS almost none of the patients were hypoxic. Pre-hospital intubation by EMS physicians probably explains this finding. Conclusion The results suggest to an outcome benefit from physician-staffed EMS treating TBI patients. Trial registration ClinicalTrials.gov ID NCT01454648

Article, Introduction: Glaucoma patients frequently exhibit ocular surface side effects during treatment with prostaglandin eye drops. The present work investigated whether glaucoma patients suffering from signs and symptoms of ocular surface disease while using preserved latanoprost eye drops benefited from switching to preservative-free tafluprost eye drops. Patients and methods: The analysis was based on 339 glaucoma patients enrolled in two Phase IIIb trials. The patients were required to have two symptoms, or one sign and one symptom of ocular surface disease at baseline, and at least 6 months preceding treatment with latanoprost eye drops preserved with benzalkonium chloride. All eligible patients were switched from latanoprost to preservative-free tafluprost for a total of 12 weeks. Ocular symptoms and ocular signs were evaluated at baseline and at 2 weeks, 6 weeks, and 12 weeks after commencing treatment with tafluprost. Intraocular pressure (IOP), drop discomfort, and treatment preference were evaluated to investigate the clinical efficacy and patient-related outcomes. Results: After 12 weeks of treatment with preservative-free tafluprost, the incidences of irritation/burning/stinging, foreign body sensation, tearing, itching, and dry eye sensation had diminished to one-third of those reported for preserved latanoprost at baseline. The incidences of blepharitis and corneal/conjunctival fluorescein staining had in turn decreased to one-half of those reported for preserved latanoprost. Severity of conjunctival hyperemia was halved during treatment with preservative-free tafluprost, and there was significant improvement in tear break-up time and tear production. A further reduction in IOP (~1 mmHg) was seen with preservative-free tafluprost compared with preserved latanoprost. Drop discomfort was alleviated during preservative-free tafluprost treatment, and an outstanding majority of patients (72%) preferred preservative-free tafluprost over preserved latanoprost. Conclusion: This meta-analysis confirmed that IOP remained at the same level after replacing benzalkonium chloride-preserved latanoprost eye drops with preservative-free tafluprost eye drops. Preservative-free tafluprost significantly decreased the symptoms and signs of ocular surface disease and outrated latanoprost in drop comfort and treatment preference., published version, http://purl.org/eprint/status/PeerReviewed

Background Sensory discrimination training (SDT) for people with chronic low back pain (CLBP) is a novel approach based on theories of the cortical reorganization of the neural system. SDT aims to reverse cortical reorganization, which is observed in chronic pain patients. SDT is still a developing therapeutic approach and its effects have not been systematically reviewed. The aim of this systematic review was to evaluate if SDT decreases pain and improves function in people with CLBP. Methods A systematic review was performed on the available literature to evaluate the effects of SDT. Randomised controlled trials compared the effectiveness of SDT on pain and function in people with CLBP with the effectiveness of other physiotherapy interventions, no treatment, or sham therapy. The methodological quality of the included studies and the clinical relevance of reported treatment effects were investigated. Results The original search revealed 42 records of which 6 fulfilled the inclusion criteria. The majority of studies showed that SDT caused statistically significant improvements in pain and function, but only two studies reported clinically relevant improvements. The applied SDT varied considerably with regard to dosage and content. The methodological quality of the included studies also varied, which hampered the comparability of results. Conclusions Although SDT seems to improve pain and function in people with CLBP, study limitations render firm conclusions unsafe. Future studies should pay closer attention to power and sample selection as well as to the content and dosage of the SDT intervention. We recommend a large, well-powered, prospective randomized control study that uses a standardized SDT approach to address the hypothesis that SDT causes clinically relevant improvements in pain and function. Electronic supplementary material The online version of this article (doi:10.1186/s12891-016-0997-8) contains supplementary material, which is available to authorized users.

Objectives: A lesion in the spinal accessory nerve is typically iatrogenic: related to lymph node biopsy or excision. This injury may cause paralysis of the trapezius muscle and thus result in a characteristic group of symptoms and signs, including depression and winging of the scapula, drooped shoulder, reduced shoulder abduction, and pain. The elements evaluated in this long-term follow-up study include range of shoulder motion, pain, patients’ satisfaction, delay of surgery, surgical procedure, occupational status, functional outcome, and other clinical findings. Methods: We reviewed the medical records of a consecutive 37 patients (11 men and 26 women) having surgery to correct spinal accessory nerve injury. Neurolysis was the procedure in 24 cases, direct nerve repair for 9 patients, and nerve grafting for 4. Time elapsed between the injury and the surgical operation ranged from 2 to 120 months. The patients were interviewed and clinically examined after an average of 10.2 years postoperatively. Results: The mean active range of movement of the shoulder improved at abduction 44° (43%) in neurolysis, 59° (71%) in direct nerve repair, and 30° (22%) in nerve-grafting patients. No or only slight atrophy of the trapezius muscle was observable in 75%, 44%, and 50%, and no or controllable pain was observable in 63%, 56%, and 50%. Restriction of shoulder abduction preceded deterioration of shoulder flexion. Patients’ overall dissatisfaction with the state of their upper extremity was associated with pain, lower strength in shoulder movements, and occupational problems. Conclusion: We recommend avoiding unnecessary delay in the exploration of the spinal accessory nerve, if a neural lesion is suspected.

Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-β induced protein (TGFβIp). The 4th_FAS1 domain of TGFβIp harbors ~80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4th_FAS1 domains of TGFβIp carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from αβ conformation to β-sheet oligomers. The β-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that β-oligomers of H572R were larger compared to R555W. The β-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The β-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities.

Background Horizontal gene transfer (HGT) is a movement of genetic information occurring outside of normal mating activities. It is especially common between prokaryotic endosymbionts and their protozoan, insect, and nematode hosts. Although beta carbonic anhydrase (β-CA) plays a crucial role in metabolic functions of many living organisms, the origin of β-CA genes in eukaryotic species remains unclear. Methods This study was conducted using phylogenetics, prediction of subcellular localization, and identification of β-CA, transposase, integrase, and resolvase genes on the MGEs of bacteria. We also structurally analyzed β-CAs from protozoans, insects, and nematodes and their putative prokaryotic common ancestors, by homology modelling. Results Our investigations of a number of target genomes revealed that genes coding for transposase, integrase, resolvase, and conjugation complex proteins have been integrated with β-CA gene sequences on mobile genetic elements (MGEs) which have facilitated the mobility of β-CA genes from bacteria to protozoan, insect, and nematode species. The prokaryotic origin of protozoan, insect, and nematode β-CA enzymes is supported by phylogenetic analyses, prediction of subcellular localization, and homology modelling. Conclusion MGEs form a complete set of enzymatic tools, which are relevant to HGT of β-CA gene sequences from prokaryotes to protozoans, insects, and nematodes. Electronic supplementary material The online version of this article (doi:10.1186/s13071-016-1415-7) contains supplementary material, which is available to authorized users.

Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders. Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia. Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease. Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.

Background Augmentation index, a marker of central wave reflection, is influenced by age, sex, height, blood pressure, heart rate, and arterial stiffness. However, the detailed haemodynamic determinants of augmentation index, and their relations, remain uncertain. We examined the association of augmentation index with vascular resistance and other haemodynamic and non-haemodynamic factors. Methods Background information, laboratory values, and haemodynamics of 488 subjects (239 men, 249 women) without antihypertensive medication were obtained. Indices of central wave reflection, systemic vascular resistance, cardiac function, and pulse wave velocity were measured using continuous radial pulse wave analysis and whole-body impedance cardiography. Results In a regression model including only haemodynamic variables, augmentation index in males and female subjects, respectively, was associated with systemic vascular resistance (β = 0.425, β = 0.336), pulse wave velocity (β = 0.409, β = 0.400) (P

Anne Huhtala,1 Juhani Pietilä,1,2 Petri Mäkinen,1,2 Hannu Uusitalo1–3 1Silmäasema Eye Hospital, 2SILK, Department of Ophthalmology, School of Medicine, University of Tampere, 3TAUH Eye Center, Tampere University Hospital, Tampere, Finland Purpose: The aim of this study was to review and meta-analyze whether there are differences between reported femtosecond (FS) lasers for laser-assisted in situ keratomileusis (LASIK) in terms of efficacy, predictability, and safety as primary outcomes and corneal flap thickness measurements and pre- and postoperative complications as secondary outcomes.Methods: A comprehensive literature search of PubMed, Science Direct, Scopus, and Cochrane CENTRAL Trials Library databases was conducted to identify the relevant prospective randomized controlled trials of FS lasers for LASIK. Thirty-one articles describing a total of 5,404eyes were included.Results: Based on efficacy, IntraLase FS 10 and 30kHz gave the best results. Based on predictability and safety, there were no differences between various FS lasers. FEMTO LDV and IntraLase FS 60kHz produced the most accurate flap thicknesses. IntraLase and Wavelight SF200 had the fewest intraoperative complications. IntraLase, Visumax, and Wavelight FS200 had the most seldom postoperative complications.Conclusion: There were dissimilarities between different FS lasers based on efficacy and intraoperative and postoperative complications. All FS lasers were predictable and safe for making corneal flaps in LASIK. Keywords: femtosecond laser, laser in situ keratomileusis, LASIK, meta-analysis