Temporal trends in age at menarche and age at menopause: a population study of 312 656 women in Norway.

STUDY QUESTION: Have mean age at menarche or mean age at natural menopause changed from the 1939 birth cohort to the 1964 birth cohort? SUMMARY ANSWER: We estimated a minor decrease in mean age at menarche and an increase by nearly 3 years in mean age at natural menopause. WHAT IS KNOWN ALREADY: In the Western world, age at menarche decreased across birth cohorts from the early 1800s until the 1950s. Whether mean age at menarche has continued to decrease in birth cohorts after the 1950s remains uncertain. It is also uncertain whether mean age at natural menopause has changed across birth cohorts. STUDY DESIGN, SIZE, DURATION: We performed a retrospective population study of 312 656 women who were born in Norway during the years 1936-1964. PARTICIPANTS/MATERIALS, SETTING, METHODS: The data were obtained by two self-administered questionnaires from women who participated in the Norwegian breast cancer screening program (BreastScreen Norway) during the years 2006-2014. We used flexible parametric survival models with restricted cubic splines to estimate mean age at menarche, mean age at menopause and mean number of years between menarche and menopause according to the women's year of birth. The women who were still having menstrual periods contributed with follow-up time until the time of data collection, and the women who had reported surgical removal of the uterus and/or both ovaries prior to natural menopause contributed with follow-up time until the time of surgery. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age at menarche was 13.42 years (95% CI: 13.40-13.44 years) among women born during 1936-1939, and it was 13.24 years (95% CI: 13.22-13.25 years) among women born during 1960-1964. The mean age at natural menopause increased from 50.31 years (95% CI: 50.25-50.37 years) among women born during 1936-1939 to 52.73 years (95% CI: 52.64-52.82 years) among women born during 1960-1964. The mean number of years between menarche and menopause increased from 36.83 years (95% CI: 36.77-36.89 years) to 40.22 years (95% CI: 40.11-40.34 years). LIMITATIONS, REASONS FOR CAUTION: Information about age at menarche and age at menopause was based on self-reports. WIDER IMPLICATIONS OF THE FINDINGS: Late menopause is associated with increased risk of breast cancer but also with increased life expectancy. Thus, higher mean age at menopause may partly explain the increase in breast cancer incidence after menopause and the increase in life expectancy in recent time. Also, a longer interval between menarche and menopause could suggest that the number of years of female fecundity has increased. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the South-Eastern Norway Regional Health Authority [grant number 2016112 to M.S.G.] and by the Norwegian Cancer Society [grant number 6863294-2015 to E.K.B.]. The authors declare no conflicts of interest.

A robust PCR for the differentiation of potential virulent strains of Haemophilus parasuis.

BACKGROUND: Haemophilus parasuis is the etiological agent of Glässer's disease in swine. H. parasuis comprises strains with heterogeneous virulence capacity, from non-virulent to highly virulent. Determination of the pathogenic potential of the strains is important for diagnosis and disease control. The virulence-associated trimeric autotransporters (vtaA) genes have been used to predict H. parasuis virulence by PCR amplification of their translocator domains. Here, we report a new and improved PCR designed to detect a different domain of the vtaA genes, the leader sequence (LS) as a diagnostic tool to predict virulence. METHODS: A collection of 360 H. parasuis strains was tested by PCR with LS specific primers. Results of the PCR were compared with the clinical origin of the strains and, for a subset of strains, with their phagocytosis and serum resistance using a Chi-square test. RESULTS: LS-PCR was specific to H. parasuis, and allowed the differential detection of the leader sequences found in clinical and non-clinical isolates. Significant correlation was observed between the results of the LS-PCR and the clinical origin (organ of isolation) of the strains, as well as with their phagocytosis and serum susceptibility, indicating that this PCR is a good predictor of the virulence of the strains. In addition, this new PCR showed a full correlation with the previously validated PCR based on the translocator domain. LS-PCR could be performed in a wide range of annealing temperatures without losing specificity. CONCLUSION: This newly described PCR based on the leader sequence of the vtaA genes, LS-PCR, is a robust test for the prediction of the virulence potential of H. parasuis strains.

Discovery of serum biomarkers predicting development of a subsequent depressive episode in social anxiety disorder.

Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention.

[Biomarker research in neuropsychiatry: challenges and potential]. / Biomarkerforschung in der Neuropsychiatrie: Herausforderung und Potenzial.

The introduction of blood-based biomarkers for psychiatric disorders faces numerous challenges. The goal of research efforts is the improvement of the current more or less subjective diagnosis, treatment and patient management. So far attempts to introduce molecular analyses have faced considerable resistance. There is an urgent need for a paradigm shift so that peripheral markers may also deliver insights into pathological states of the brain. Health regulators have called for a reform of research and development approaches, with the goal to enhance the safety and efficiency of future antipsychotic drugs using biomarker-based methods. Here we discuss the potential of the biomarker sector in this context, as exemplified by the recent introduction of Veripsych™, the first blood test aiding the diagnosis of schizophrenia.

Severe cochlear inflammation and vestibular syndrome in an experimental model of Streptococcus suis infection in mice.

Hearing impairment is a common and frequently permanent sequel of Streptococcus suis meningitis in humans. Nevertheless, mechanisms underlying the development of cochlear damage have not been addressed so far. In the present work, we characterized a mouse model of suppurative labyrinthitis and meningitis induced by a systemic infection with S. suis and studied the impact of the injected bacterial dosage on the progression of such inflammatory events. We observed that high infection doses of bacteria lead to sustained bacteremia, with an increase in the permeability of the blood-labyrinth and blood-brain barriers, causing suppurative labyrinthitis and meningitis, respectively. However, in mice infected with a low dose of S. suis, bacteria disappeared quickly from blood, hence, cochlear inflammation and meningitis were not consistent features. This model of S. suis infection seems ideal to evaluate novel drugs that may help alleviate the negative consequences of such important sequelae of S. suis-induced meningitis and labyrinthitis.

Artificial neural networks for classification in metabolomic studies of whole cells using 1H nuclear magnetic resonance.

We report the successful classification, by artificial neural networks (ANNs), of (1)H NMR spectroscopic data recorded on whole-cell culture samples of four different lung carcinoma cell lines, which display different drug resistance patterns. The robustness of the approach was demonstrated by its ability to classify the cell line correctly in 100% of cases, despite the demonstrated presence of operator-induced sources of variation, and irrespective of which spectra are used for training and for validation. The study demonstrates the potential of ANN for lung carcinoma classification in realistic situations.

Redescription of Sibling Species of Rhinoleucophenga (Diptera: Drosophilidae): R. brasiliensis and R. fluminensis.

Rhinoleucophenga Hendel comprises an unusual Drosophilidae (Diptera) genus with predaceous larvae, currently compounded by 29 nominal species with New World distribution. In the present study, Rhinoleucophenga brasiliensis (Costa Lima) and R. fluminensis (Costa Lima) are redescribed. These two species are commonly misidentified in Drosophilidae species inventories, mainly by the few morphological character details presented in the original taxonomic description. Thus, by the morphological review performed here, lectotype and paralectotypes designed to R. brasiliensis and R. fluminensis, as well as new morphological characters, drawings and photos (for the first time) are presented in order to avoid further taxonomic mistakes with those referred sibling species of Rhinoleucophenga.

Insulator-metal transition induced by electric voltage in a ruthenate Mott insulator.

We report the observation of electric-voltage induced insulator-metal phase transition in a ruthenate Mott insulator Ca3(Ru0.9Ti0.1)2O7. We show that the electric field effect dominates and leads to a sharp phase transition at measurement temperatures far below the Mott transition, whereas the thermal effect becomes more significant and broadens the phase transition as the measurement temperature approaches the insulator-metal transition. The electric field induced insulator-metal transition is presumably attributed to the avalanche breakdown of the correlated insulating state when driven out of equilibrium. This work highlights the strategy of using electric voltage to control the phase transition of this system in addition to other nonthermal parameters such as magnetic field and pressure reported previously.

Mitogenic effect contributes to increased virulence of Streptococcus suis sequence type 7 to cause streptococcal toxic shock-like syndrome.

Streptococcus suis serotype 2 sequence type 7 strains emerged in 1996 and caused a streptococcal toxic shock-like syndrome in 1998 and 2005 in China. Evidence indicated that the virulence of S. suis sequence type 7 had increased, but the mechanism was unknown. The sequence type 7 strain SC84, isolated from a patient with streptococcal toxic shock-like syndrome during the Sichuan outbreak, and the sequence type 1 strain 31533, a typical highly pathogenic strain isolated from a diseased pig, were used in comparative studies. In this study we show the mechanisms underlying cytokine production differed between the two types of strains. The S. suis sequence type 7 strain SC84 possesses a stronger capacity to stimulate T cells, naive T cells and peripheral blood mononuclear cell proliferation than does S. suis sequence type 1 strain 31533. The T cell response to both strains was dependent upon the presence of antigen-presenting cells. Histo-incompatible antigen-presenting cells were sufficient to provide the accessory signals to naive T cell stimulated by the two strains, indicating that both sequence type 7 and 1 strains possess mitogens; however, the mitogenic effect was different. Therefore, we propose that the difference in the mitogenic effect of sequence type 7 strain SC84 compared with the sequence type 1 strain 31533 of S. suis may be associated with the clinical, epidemiological and microbiological difference, where the ST 7 strains have a larger mitogenic effect.

Disruption of srtA gene in Streptococcus suis results in decreased interactions with endothelial cells and extracellular matrix proteins.

Streptococcus suis, a major pathogen of swine, is an emerging zoonotic agent which causes meningitis and septic shock. In this study, we investigated the ability of S. suis mutant strain (SRTDeltaA) lacking the sortase A gene (srtA) to interact with host cells and extracellular matrix (ECM) proteins, as well as its virulence in a mouse infection model. We demonstrated that mutant SRTDeltaA had reduced capacity to adhere to and invade porcine brain microvascular endothelial cells compared to the wild-type strain. In addition, mutant SRTDeltaA also showed significantly less adherence to plasma fibronectin, cellular fibronectin and collagen type I. However, disruption of srtA had little effect on the virulence of S. suis in a mouse intraperitoneal model of infection. These results indicate that surface proteins anchored by sortase A are required for a normal level of bacterial binding. However, other factors may also be important for S. suis virulence and interaction with host tissues.

Fluoxetine, not donepezil, reverses anhedonia, cognitive dysfunctions and hippocampal proteome changes during repeated social defeat exposure.

While anhedonia is considered a core symptom of major depressive disorder (MDD), less attention has been paid to cognitive dysfunctions. We evaluated the behavioural and molecular effects of a selective serotonin re-uptake inhibitor (SSRI, fluoxetine) and an acetylcholinesterase inhibitor (AChEI, donepezil) on emotional-cognitive endophenotypes of depression and the hippocampal proteome. A chronic social defeat (SD) procedure was followed up by "reminder" sessions of direct and indirect SD. Anhedonia-related behaviour was assessed longitudinally by intracranial self-stimulation (ICSS). Cognitive dysfunction was analysed by an object recognition test (ORT) and extinction of fear memory. Tandem mass spectrometry (MSE) and protein-protein-interaction (PPI) network modelling were used to characterise the underlying biological processes of SD and SSRI/AChEI treatment. Independent selected reaction monitoring (SRM) was conducted for molecular validation. Repeated SD resulted in a stable increase of anhedonia-like behaviour as measured by ICSS. Fluoxetine treatment reversed this phenotype, whereas donepezil showed no effect. Fluoxetine improved recognition memory and inhibitory learning in a stressor-related context, whereas donepezil only improved fear extinction. MSE and PPI network analysis highlighted functional SD stress-related hippocampal proteome changes including reduced glutamatergic neurotransmission and learning processes, which were reversed by fluoxetine, but not by donepezil. SRM validation of molecular key players involved in these pathways confirmed the hypothesis that fluoxetine acts via increased AMPA receptor signalling and Ca2+-mediated neuroplasticity in the amelioration of stress-impaired reward processing and memory consolidation. Our study highlights molecular mediators of SD stress reversed by SSRI treatment, identifying potential viable future targets to improve cognitive dysfunctions in MDD patients.

Update on Actinobacillus pleuropneumoniae-knowledge, gaps and challenges.

Porcine pleuropneumonia, caused by the bacterial porcine respiratory tract pathogen Actinobacillus pleuropneumoniae, leads to high economic losses in affected swine herds in most countries of the world. Pigs affected by peracute and acute disease suffer from severe respiratory distress with high lethality. The agent was first described in 1957 and, since then, knowledge about the pathogen itself, and its interactions with the host, has increased continuously. This is, in part, due to the fact that experimental infections can be studied in the natural host. However, the fact that most commercial pigs are colonized by this pathogen has hampered the applicability of knowledge gained under experimental conditions. In addition, several factors are involved in development of disease, and these have often been studied individually. In a DISCONTOOLS initiative, members from science, industry and clinics exchanged their expertise and empirical observations and identified the major gaps in knowledge. This review sums up published results and expert opinions, within the fields of pathogenesis, epidemiology, transmission, immune response to infection, as well as the main means of prevention, detection and control. The gaps that still remain to be filled are highlighted, and present as well as future challenges in the control of this disease are addressed.

A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.

The 9-23 amino acid region of the insulin B chain (B9-23) is a dominant epitope recognized by pathogenic T lymphocytes in nonobese diabetic mice, the animal model for type 1 diabetes. We describe herein similar (B9-23)-specific T-cell responses in peripheral lymphocytes obtained from patients with recent-onset type 1 diabetes and from prediabetic subjects at high risk for disease. Short-term T-cell lines generated from patient peripheral lymphocytes showed significant proliferative responses to (B9-23), whereas lymphocytes isolated from HLA and/or age-matched nondiabetic normal controls were unresponsive. Antibody-mediated blockade demonstrated that the response was HLA class II restricted. Use of the highly sensitive cytokine-detection ELISPOT assay revealed that these (B9-23)-specific cells were present in freshly isolated lymphocytes from only the type 1 diabetics and prediabetics and produced the proinflammatory cytokine IFN-gamma. This study is, to our knowledge, the first demonstration of a cellular response to the (B9-23) insulin epitope in human type 1 diabetes and suggests that the mouse and human diseases have strikingly similar autoantigenic targets, a feature that should facilitate development of antigen-based therapeutics.

Bone mass and the risk of breast cancer: the influence of cumulative exposure to oestrogen and reproductive correlates. Results of the Marburg breast cancer and osteoporosis trial (MABOT).

BACKGROUND: Recent studies suggest an inverse relation between breast cancer and osteoporosis. Oestrogen is important in the pathophysiology of both breast and bone, and although cumulative exposure to oestrogen may explain the link between breast cancer and bone mass, this has never been proved. The Marburg breast cancer and osteoporosis trial (MABOT) aimed to elucidate the relation between breast cancer and bone mass ascertained by ultrasonometry measurement and to investigate whether endogenous and exogenous exposure to oestrogen and reproductive correlates has a role in this association. METHODS: We performed a case-control study including 2492 women (mean age+/-S.D., 54.4+/-10.3 years) in whom diseases and drug treatments known to affect bone metabolism, except for HT, had been excluded. All women underwent ultrasonometry measurement at the heel; 242 of the women had an incident breast cancer without a prior, specific pharmacological breast cancer treatment. The ultrasonometry variables - speed of sound (SOS), broadband ultrasound attenuation (BUA) and the stiffness index (SI) - were calculated and compared in women with and without breast cancer. Because of significant intergroup differences in factors such as age, body mass index and exposure to oestrogen, a multiple linear regression analysis as well as a second analysis of ultrasonometry variables was undertaken using a randomly selected sample of 242 healthy women post-matched with the breast cancer group for possible confounding variables. Odds ratios were used to compare the relation between breast cancer risk and ultrasonometry heel measurements. RESULTS: Women with breast cancer were significantly older, weighed more, had a higher body mass index, were more likely to be parous and to have breast fed, were older at the menopause and had been exposed to oestrogen for longer than control women. In addition, the ultrasonometry variables speed of sound and the stiffness index T- and Z-score were significantly higher in women with breast cancer even after a matched pair analysis was performed (p<0.001). Additionally, results of a multiple linear regression showed that women with breast cancer had a significantly higher SOS (p<0.001), body weight (p<0.05) and duration of breast feeding (p<0.05) while osteoporotic fracture were reduced (p<0.001). When women with breast cancer and their matched controls were finally grouped according to SOS and T-score quartiles, the odds ratios (95% confidence intervals) for breast cancer risk in the second, third and fourth quartiles compared with the lowest quartile were 2.5 (1.4-4.3), 3.1 (1.8-5.3) and 4.7 (2.7-8.2) as well as 1.9 (1.1-3.2), 2.3 (1.3-3.9) and 2.9 (1.7-5.0), respectively. CONCLUSIONS: The ultrasonometry variables speed of sound, stiffness index, T- and Z-score are higher in women with an incident breast cancer than in healthy controls, even after post-matching for possible confounding variables. This association was confirmed in a multiple linear regression model. Women with SOS and T-score values in the higher quartiles have a greater risk of breast cancer than women in the lowest quartile. We found no association between the higher ultrasonometry variables and cancer specific characteristics or reproductive correlates such as age at menarche and menopause or cumulative oestrogen exposure. Although the biological mechanisms linking bone mass and the risk of breast cancer are not fully understood, factors other than reproductive correlates, endogenous and exogenous exposure to oestrogen must play a part.

[Vaccine development: strategies for coping with the antigenic diversity of bacteria]. / Les vaccins face à la diversité antigénique des bactéries.

Bacterial pathogens have evolved a whole range of anti-immune strategies to overcome both the innate and acquired immunity of their hosts. These strategies play a crucial role in the capacity of pathogens to trigger disease and also explain why it is so difficult to develop vaccines and to control these microorganisms. One of the main problems is that bacteria are highly antigenically diverse. The vaccination strategies for coping with this variability, which we are starting to understand more fully as a result of sequencing bacterial genomes, consist of using either several variants of one or more proteins capable of inducing protective antibodies, or else proteins (or protein fragments) or epitopes that have been relatively well preserved notably because they are involved in the pathogen's metabolism. The most sophisticated approach calls upon 'pan genomic' inverse vaccinology which compares the protein profiles of a large number of isolates from various strains of a single species in order to reveal the surface-expressed proteins present in all the isolates. Of these proteins, the ones which are expressed when the host is infected are then evaluated in order to determine their capacity to induce a protective immune response. So far this approach has been successful in controlling bacteria in humans and the way is now open for its application in veterinary medicine, thanks to progress with the genomic sequencing of pathogens of veterinary importance.

Serotypes of Streptococcus suis isolated from healthy pigs in Phayao Province, Thailand.

BACKGROUND: Streptococcus suis (S. suis) is an important swine and human pathogen. There are 33 serotypes that have been described. Zoonotic cases are very common the Northern part of Thailand, especially in Phayao Province. However, the prevalence of S. suis and, more particularly the different serotypes, in pigs in this region is poorly known and needed to be addressed. THE CONTEXT AND PURPOSE OF THE STUDY: Distribution of S. suis serotypes varies depending on the geographical area. Knowledge of the serotype distribution is important for epidemiological studies. Consequently, 180 tonsil samples from slaughterhouse pigs in Phayao Province had been collected for surveillance, from which 196 S. suis isolates were recovered. Each isolate was subcultured and its serotype identified using multiplex PCR. Slide agglutination combined with precipitation tests were used following multiplex PCR to differentiate the isolates showing similar sizes of amplified products specific to either serotype 1 or 14 and 2 or 1/2. Non-typable isolates by multiplex PCR were serotyped by the coagglutination test. RESULTS: Of the 196 isolates, 123 (62.8%) were typable and 73 (37.2%) were non-typable. This study revealed the presence of serotypes 1, 1/2, 2, 3, 4, 5, 7, 9, 11, 12, 13, 14, 21, 22, 23, 24, 25, 29, and 30. Serotype 23 was the most prevalent (20/196, 10.2%), followed by serotype 9 (16/196, 8.2%), serotype 7 (16/196, 8.2%), and serotype 2 (11/196, 5.6%). The latter is the serotype responsible for most human cases. CONCLUSION: Almost all serotypes previously described are present in Northern Thailand. Therefore, this report provides useful data for future bacteriological studies.

Primary Care Provider Management of Congenital Hypothyroidism Identified Through Newborn Screening.

OBJECTIVE: To assess Primary Congenital Hypothyroidism (CH) management patterns and feasibility of providing long-term care for patients with CH identified through newborn screening by Primary Care Providers (PCPs) in California and Hawaii. STUDY DESIGN: A survey was mailed to all physicians (N=823) listed as the referral doctor for confirmed patients with CH identified through newborn screening programs in both states between 01/01/2009-12/31/2013. Information was collected on CH management patterns, barriers to providing care, and knowledge on CH treatment. Descriptive statistics and bivariate logistic regression results were reported. RESULTS: 206 PCPs completed the survey. Among these, 78% currently have patients with CH and 91% indicated willingness to provide long-term care to new patients with CH. Among PCPs currently caring for patients with CH, 17% managed CH by themselves with limited assistance from endocrinologists; 63% were involved in managing CH but endocrinologists played a larger role than PCPs; 19% were not involved in CH care. Only 49% of PCPs correctly answered questions regarding recommended follow-up frequencies and 23% knew the correct age for a trial off levothyroxine for suspected transient CH. Top two perceived barriers to providing long-term care included "need guidance or support from endocrinologists" (61%) and "not familiar with CH treatment guidelines" (28%). CONCLUSION: The majority of PCPs surveyed are willing to provide long-term care to patients with CH, but need support from endocrinologists and increased knowledge about current treatment guidelines.

Heritability of semen traits in German Warmblood stallions.

The objectives of the present study were to evaluate genetic parameters for semen quality traits of 241 fertile German Warmblood stallions regularly employed in artificial insemination (AI). Stallions were owned by the National Studs Celle and Warendorf in Germany. Semen traits analyzed were gel-free volume, sperm concentration, total number of sperm, progressive motility and total number of progressively motile sperm. Semen protocols from a total of 63,972 ejaculates were collected between the years 2001 and 2014 for the present analysis. A multivariate linear animal model was employed for estimation of additive genetic and permanent environmental variances among stallions and breeding values (EBVs) for semen traits. Heritabilities estimated for all German Warmblood stallions were highest for gel-free volume (h(2)=0.28) and lowest for total number of progressively motile sperm (h(2)=0.13). The additive genetic correlation among gel-free volume and sperm concentration was highly negative (rg=-0.76). Average reliabilities of EBVs were at 0.37-0.68 for the 241 stallions with own records. The inter-stallion variance explained between 33 and 61% of the trait variance, underlining the major impact of the individual stallion on semen quality traits analyzed here. Recording of semen traits from stallions employed in AI may be recommended because EBVs achieve sufficient accuracies to improve semen quality in future generations. Due to favorable genetic correlations, sperm concentration, total number of sperm and total number of progressively motile sperm may be increased simultaneously.