Trajectories of labour market marginalisation among young adults with newly diagnosed attention-deficit/hyperactivity disorder (ADHD).

AIMS: Labour market marginalisation (LMM), i.e. severe problems in finding and keeping a job, is common among young adults with attention-deficit/hyperactivity disorder (ADHD). This study aimed to disentangle the extent of LMM as well as the heterogeneity in patterns of LMM among young adults with ADHD and what characterises those belonging to these distinct trajectories of LMM. METHODS: This population-based register study investigated all 6287 young adults, aged 22-29 years, who had their first primary or secondary diagnosis of ADHD in Sweden between 2006 and 2011. Group-based trajectory (GBT) models were used to estimate trajectories of LMM, conceptualised as both unemployment and work disability, 3 years before and 5 years after the year of an incident diagnosis of ADHD. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association between individual characteristics and the trajectory groups of LMM were estimated by multinomial logistic regression. RESULTS: Six distinct trajectories of LMM were found: 'increasing high' (21% belonged to this trajectory group) with high levels of LMM throughout the study period, 'rapidly increasing' (19%), 'moderately increasing' (21%), 'constant low' (12%) with low levels of LMM throughout the study period, 'moderately decreasing' (14%) and finally 'fluctuating' (13%), following a reversed u-shaped curve. Individuals with the following characteristics had an increased probability of belonging to trajectory groups of increasing LMM: low educational level (moderately increasing: OR: 1.4; CI: 1.2-1.8, rapidly increasing: OR: 1.7; CI: 1.3-2.1, increasing high: OR: 2.9; CI: 2.3-3.6), single parents (moderately increasing: OR: 1.6; CI: 1.1-2.4, rapidly increasing: OR: 2.0; CI: 1.3-3.0), those born outside the European Union/the Nordic countries (rapidly increasing: OR: 1.7; CI: 1.1-2.5, increasing high: OR: 2.1; CI: 1.4-3.1), persons living in small cities/villages (moderately increasing: OR: 2.4; CI: 1.9-3.0, rapidly increasing: OR: 2.1; CI: 1.6-2.7, increasing high: OR: 2.6; CI: 2.0-3.3) and those with comorbid mental disorders, most pronounced regarding schizophrenia/psychoses (rapidly increasing: OR: 6.7; CI: 2.9-19.5, increasing high: OR: 12.8; CI: 5.5-37.0), autism spectrum disorders (rapidly increasing: OR: 4.6; CI: 3.1-7.1, increasing high: OR: 9.6; CI: 6.5-14.6), anxiety/stress-related disorders (moderately increasing: OR: 1.3; CI: 1.1-1.7, rapidly increasing: OR: 2.0; CI: 1.6-2.5, increasing high: OR: 1.8; CI: 1.5-2.3) and depression/bipolar disorder (moderately increasing: OR: 1.3; CI: 1.0-1.6, rapidly increasing: OR: 1.7; CI: 1.4-2.2, increasing high: OR: 1.5; CI: 1.2-1.9). CONCLUSIONS: About 61% of young adults were characterised by increasing LMM after a diagnosis of ADHD. To avoid marginalisation, attention should especially be given to young adults diagnosed with ADHD with a low educational level, that are single parents and who are living outside big cities. Also, young adults with comorbid mental disorders should be monitored for LMM early in working life.

Interleukin 17A: a Janus-faced regulator of osteoporosis.

Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knock-out mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which is of importance for the development of new treatments of post-menopausal osteoporosis.

Use of rotational periosteal flaps in primary repair of sinofacial fractures in seven horses.

Case history: Medical records were reviewed of horses (n = 7) undergoing surgery for fracture of one or more facial bones extending into the paranasal sinuses that was repaired primarily within 24 hours of the time of injury using a rotational periosteal flap, between April 2009 and May 2017. A kick from another horse was the cause of the injury of three horses, and one horse was injured when it collided with a tree. The cause of the injury of three horses was unknown.Clinical findings and treatment: Fractures were of the right maxillary bone in two horses, the left maxillary bone in two horses, the left frontal and left nasal bones in two horses, and the right frontal bones in one horse. The fracture of all but one horse was accompanied by an open wound. The fracture of all seven horses was reduced, stabilised, and covered with a rotational, periosteal flap. Surgery was carried out while standing in six horses, and while anesthetised in one horse. All horses had a deficit in the fractured facial bones after the fracture was reduced. Four horses had complications following surgery, but all horses were reported to have excellent cosmetic outcomes and had retuned to their previous level of activity, as reported by their owners.Clinical relevance: Covering a primarily repaired sinofacial fracture of a horse with a rotational periosteal flap resulted in good cosmetic outcomes, and may be especially beneficial if the fracture is accompanied by loss of bone.

Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients.

BACKGROUND: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. METHODS: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. RESULTS: The percentage of CD3-positive T-cells was lower (p = 0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p = 0.2) nor the T-cell/monocyte ratio (p = 0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7+/CD3-/CD56bright/CD16dim/-) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p = 0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p = 0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p = 0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p = 0.04). CONCLUSIONS: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton.

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

Increased bone mass in a mouse model with low fat mass.

Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex, the receptor internalization and degradation (RID) complex that inhibits proinflammatory signaling, under the control of the aP2 promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than littermate wild-type control mice. Contrary to our hypothesis, RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass due to impaired adipose tissue inflammation have increased bone mass.

ERα expression in T lymphocytes is dispensable for estrogenic effects in bone.

Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERα) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERα expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERα expression specifically in T lymphocytes (Lck-ERα-/-) and ERαflox/flox littermate (control) mice. Deletion of ERα expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERα-/- compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERα-/- mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERα-/- led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERα in T lymphocytes. In conclusion, ERα expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.

Human cytomegalovirus replication induces endothelial cell interleukin-11.

Endothelial cells (EC) are critical sites of human cytomegalovirus (hCMV) infection in vivo. Infection can induce the production of various EC cytokines, such as interleukin (IL-)6, which can have autocrine and/or paracrine effector functions. Here, we report that hCMV induces the production of EC IL-11, a relatively understudied member of the IL-6-type cytokine family. We detail temporal EC IL-11 translation and protein secretion dynamics in response to hCMV infection, and reveal distinct differences compared to EC IL-6. Viral replication had markedly opposing effects on the regulation of these closely related cytokines, representing a major driving force behind IL-11 production, whilst concurrently suppressing IL-6 expression. This is the first report of any biological agent that stimulates EC IL-11 production.

E. coli promotes human Vγ9Vδ2 T cell transition from cytokine-producing bactericidal effectors to professional phagocytic killers in a TCR-dependent manner.

γδT cells provide immune-surveillance and host defense against infection and cancer. Surprisingly, functional details of γδT cell antimicrobial immunity to infection remain largely unexplored. Limited data suggests that γδT cells can phagocytose particles and act as professional antigen-presenting cells (pAPC). These potential functions, however, remain controversial. To better understand γδT cell-bacterial interactions, an ex vivo co-culture model of human peripheral blood mononuclear cell (PBMC) responses to Escherichia coli was employed. Vγ9Vδ2 cells underwent rapid T cell receptor (TCR)-dependent proliferation and functional transition from cytotoxic, inflammatory cytokine immunity, to cell expansion with diminished cytokine but increased costimulatory molecule expression, and capacity for professional phagocytosis. Phagocytosis was augmented by IgG opsonization, and inhibited by TCR-blockade, suggesting a licensing interaction involving the TCR and FcγR. Vγ9Vδ2 cells displayed potent cytotoxicity through TCR-dependent and independent mechanisms. We conclude that γδT cells transition from early inflammatory cytotoxic killers to myeloid-like APC in response to infectious stimuli.

Sex differences in the presentation of stroke.

Stroke affects both men and women of all ages, although the condition is more common among the elderly. Stroke occurs at an older age among women than among men; although the incidence is lower among women than among men, as women have a longer life expectancy their lifetime risk is slightly higher. Ischemic stroke is the most common type of stroke; and reperfusion treatment is possible if the patient reaches hospital early enough. Thrombolysis and thrombectomy are time-sensitive treatments - the earlier they are initiated the better is the chance of a positive outcome. It is therefore important to identify a stroke as soon as possible. Medical personnel can readily identify typical stroke symptoms but the presentation of non-traditional stroke symptoms, such as impaired consciousness and altered mental status, is often associated with a significant delay in the identification of stroke and thus delay in or inability to provide treatment. Non-traditional stroke symptoms are reported to be more common in women, who are thereby at risk of delayed recognition of stroke and treatment delay.

Extra-nuclear effects of estrogen on cortical bone in males require ERαAF-1.

Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects not only by translocating to the nucleus and affecting gene transcription but also by extra-nuclear actions e.g., triggering cytoplasmic signaling cascades. ERα contains various domains, and the role of activation function 1 (ERαAF-1) is known to be tissue specific. The aim of this study was to determine the importance of extra-nuclear estrogen effects for the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. Five-month-old male wild-type (WT) and ERαAF-1-inactivated (ERαAF-10) mice were orchidectomized and treated with equimolar doses of 17ß-estradiol (E2) or an estrogen dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only initiates extra-nuclear ER actions or their corresponding vehicles for 3.5 weeks. As expected, E2 treatment increased cortical thickness and trabecular bone volume per total volume (BV/TV) in WT males. EDC treatment increased cortical thickness in WT males, whereas no effect was detected in trabecular bone. In ERαAF-10 males, E2 treatment increased cortical thickness, but did not affect trabecular bone. Interestingly, the effect of EDC on cortical bone was abolished in ERαAF-10 mice. In conclusion, extra-nuclear estrogen signaling affects cortical bone mass in males, and this effect is dependent on a functional ERαAF-1. Increased knowledge regarding estrogen signaling mechanisms in the regulation of the male skeleton may aid the development of new treatment options for male osteoporosis.

The role of membrane ERα signaling in bone and other major estrogen responsive tissues.

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles.

Shb deficiency in endothelium but not in leucocytes is responsible for impaired vascular performance during hindlimb ischaemia.

AIM: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischaemia. This study was conducted in order to assess the contribution of Shb deficiency in myeloid cells to impaired vascular function in ischaemia. METHODS: Wild type and Shb-deficient mice were subjected to peritoneal vascular endothelial growth factor A (VEGFA) followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leucocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. RESULTS: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not lipopolysaccharide (LPS) in the absence of Shb. Furthermore, the macrophage population in ischaemic muscle was unaffected by Shb deficiency after 2 days but reduced 7 days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leucocyte genotype. CONCLUSION: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.

Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays.

INTRODUCTION: Apixaban is an oral direct factor Xa inhibitor developed for the prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary, but the effects on common coagulation reagents and assays constitute clinically valuable information. OBJECTIVES: To investigate the effects of apixaban on commonly used coagulation methods, and to evaluate anti-FXa assays for specific determination of the drug concentration. MATERIALS AND METHODS: Apixaban was added to plasma from healthy subjects in the concentration range 0-1000 µg L(-1) , and analyses were performed with different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, protein C, and protein S. A lupus anticoagulant assay and an APTT assay with varying phospholipid concentrations were used to study the phospholipid dependence. RESULTS: In general, apixaban showed fewer effects in vitro than have been shown for rivaroxaban, another direct FXa inhibitor. The concentration needed to double the APTT varied between 2200 and 4700 µg L(-1) , and the concentration needed to double the PT varied between 700 and 3900 µg L(-1) . The effects on antithrombin, protein C and protein S assays were dependent on the type of reagent. Apixaban did not cause false-positive lupus anticoagulant results. Chromogenic anti-FXa assays showed linear dose-response curves with apixaban. CONCLUSIONS: Therapeutic concentrations of apixaban variably affect different assay groups, and even different reagents within an assay group. The effects were much smaller than with rivaroxaban. The use of APTT and/or PT assays to screen the anticoagulant activity of apixaban cannot be recommended. A chromogenic anti-FXa assay can be used for reliable measurements of apixaban concentration.

Separated response function ratios in exclusive, forward π(±) electroproduction.

The study of exclusive π(±) electroproduction on the nucleon, including separation of the various structure functions, is of interest for a number of reasons. The ratio RL=σL(π-)/σL(π+) is sensitive to isoscalar contamination to the dominant isovector pion exchange amplitude, which is the basis for the determination of the charged pion form factor from electroproduction data. A change in the value of RT=σT(π-)/σT(π+) from unity at small -t, to 1/4 at large -t, would suggest a transition from coupling to a (virtual) pion to coupling to individual quarks. Furthermore, the mentioned ratios may show an earlier approach to perturbative QCD than the individual cross sections. We have performed the first complete separation of the four unpolarized electromagnetic structure functions above the dominant resonances in forward, exclusive π(±) electroproduction on the deuteron at central Q(2) values of 0.6, 1.0, 1.6 GeV(2) at W=1.95 GeV, and Q(2)=2.45 GeV(2) at W=2.22 GeV. Here, we present the L and T cross sections, with emphasis on RL and RT, and compare them with theoretical calculations. Results for the separated ratio RL indicate dominance of the pion-pole diagram at low -t, while results for RT are consistent with a transition between pion knockout and quark knockout mechanisms.

Associations between health and combinations of sickness presence and absence.

BACKGROUND: The association between sickness presence (SP), sickness absence (SA) and health is not well known although research on these phenomena has grown in recent years. AIMS: To identify the health outcomes of different combinations of self-reported SP and SA while controlling for background and work-related factors. METHODS: The study group was a representative three-wave sample of 1886 employed individuals from the Swedish Working Life Cohort, gathered in 2004-2006. Block-wise multiple logistic regression analyses were conducted for combinations of self-reported SP and SA, using controls for background, work-related and previous health factors. RESULTS: The crude odds ratios showed that health and mental well-being were most negatively affected in the group with high SP and SA in the preceding year. When differences in individual background, health and work-related factors were controlled for, distinct significant odds ratios remained. The odds ratios for negative health outcomes were between 1.49 (95% CI: 1.02-2.18) and 2.64 (95% CI: 1.81-3.85) higher among those with both high SP and high SA than those with both low SP and low SA. However, the study also indicated that individuals with high SP and low SA showed the highest odds ratios for poor mental well-being. CONCLUSIONS: The results showed that combinations of frequent self-rated SP and SA are related to negative values in the four measured aspects of self-reported health 1 year later. Occupational medicine practitioners should therefore be concerned particularly with employees who report frequently occurring SP and SA.

Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle.

STUDY QUESTION: Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle? SUMMARY ANSWER: Total thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle. WHAT IS KNOWN ALREADY: The coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results. STUDY DESIGN, SIZE, DURATION: Thrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods. MAIN RESULTS AND THE ROLE OF CHANCE: It was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P = 0.027). Factor X was significantly higher during the follicular phase (P = 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P = 0.043 and P = 0.033, respectively) and with factors II and VII during the luteal phase (P = 0.034 and P = 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level >0.8). LIMITATIONS, REASONS FOR CAUTION: The wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified. WIDER IMPLICATIONS OF THE FINDINGS: The associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use.

Type 2 diabetes and cardiovascular disease in women.

Cardiovascular disease is the leading cause of death in both men and women. This is also true for patients with diabetes. In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed. Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities. However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes. Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors. This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes. Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular. The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed.