Outcome of assisted reproduction in women with congenital uterine anomalies: a prospective observational study.

OBJECTIVES: To assess the prevalence of congenital uterine anomalies, including arcuate uterus, and their effect on reproductive outcome in subfertile women undergoing assisted reproduction. METHODS: Consecutive women referred for subfertility between May 2009 and November 2015 who underwent assisted reproduction were included in the study. As part of the initial assessment, each woman underwent three-dimensional transvaginal sonography. Uterine morphology was classified using the modified American Fertility Society (AFS) classification of congenital uterine anomalies proposed by Salim et al. If the external contour of the uterus was uniformly convex or had an indentation of < 10 mm, but there was a cavity indentation, it was defined as arcuate or septate. Arcuate uterus was further defined as the presence of a concave fundal indentation with a central point of indentation at an obtuse angle. Subseptate uterus was defined as the presence of a septum, not extending to the cervix, with the central point of the septum at an acute angle; if the septum extended to the internal cervical os, the uterus was defined as septate. Reproductive outcomes, including live birth, clinical pregnancy and preterm birth, were compared between women with a normal uterus and those with a congenital uterine anomaly. Subgroup analysis by type of uterine morphology and logistic regression analysis adjusted for age, body mass index, levels of anti-Müllerian hormone, antral follicle count and number and day of embryo transfer were performed. RESULTS: A total of 2375 women were included in the study, of whom 1943 (81.8%) had a normal uterus and 432 (18.2%) had a congenital uterine anomaly. The most common anomalies were arcuate (n = 387 (16.3%)) and subseptate (n = 16 (0.7%)) uterus. The rate of live birth was similar between women with a uterine anomaly and those with a normal uterus (35% vs 37%; P = 0.47). The rates of clinical pregnancy, mode of delivery and sex of the newborn were also similar between the two groups. Preterm birth before 37 weeks' gestation was more common in women with uterine anomalies than in controls (22% vs 14%, respectively; P = 0.03). Subgroup analysis by type of anomaly showed no difference in the incidence of live birth and clinical pregnancy for women with an arcuate uterus, but indicated worse pregnancy outcome in women with other major anomalies (P = 0.042 and 0.048, respectively). CONCLUSIONS: Congenital uterine anomalies as a whole, when defined using the modified AFS classification, do not affect clinical pregnancy or live-birth rates in women following assisted reproduction, but do increase the incidence of preterm birth. The presence of uterine abnormalities more severe than arcuate uterus significantly worsens all pregnancy outcomes. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

IL-6 promotes CD4+ T-cell and B-cell activation during Plasmodium infection.

Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4+ T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6-/- mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138+ plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4+ T cells, as well as their localization close to splenic B cells, but was not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4+ T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production.

Haemarthrosis model in mice: BSS - Bleeding Severity Score assessment system.

INTRODUCTION: The prophylactic administration of clotting factor concentrate is currently the most effective strategy for the prevention of joint bleeding. As new agents with different mechanisms of action and administration schedules are developed, it will be important to study them in relevant preclinical models. AIM: The aim of this study was the standardization of a mouse haemarthrosis model in a haemophilia mouse and the development and validation of a comprehensive bleeding assessment system, the Bleeding Severity Score (BSS). METHODS AND RESULTS: Four outcome measurements were assessed, two of which, the extra-articular bleeding score and intra-articular bleeding score, were determined to be the most reliable and were summarized into a BSS which was validated using a mouse haemarthrosis variability model. CONCLUSION: Using this model, the haemostatic effect of prospective drugs can be assessed in a clinically relevant joint bleeding model and will significantly increase the value of preclinical studies.

Synovial chemokine expression and relationship with knee symptoms in patients with meniscal tears.

OBJECTIVE: In patients with knee OA, synovitis is associated with knee pain and symptoms. We previously identified synovial mRNA expression of a set of chemokines (CCL19, IL-8, CCL5, XCL-1, CCR7) associated with synovitis in patients with meniscal tears but without radiographic OA. CCL19 and CCR7 were also associated with knee symptoms. This study sought to validate expression of these chemokines and association with knee symptoms in more typical patients presenting for meniscal arthroscopy, many who have pre-existing OA. DESIGN: Synovial fluid (SF) and biopsies were collected from patients undergoing meniscal arthroscopy. Synovial mRNA expression was measured using quantitative RT-PCR. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was administered preoperatively. Regression analyses determined if associations between chemokine mRNA levels and KOOS scores were independent of other factors including radiographic OA. CCL19 in SF was measured by ELISA, and compared to patients with advanced knee OA and asymptomatic organ donors. RESULTS: 90% of patients had intra-operative evidence of early cartilage degeneration. CCL19, IL-8, CCL5, XCL1, CCR7 transcripts were detected in all patients. Synovial CCL19 mRNA levels independently correlated with KOOS Activities of Daily Living (ADL) scores (95% CI [-8.071, -0.331], P = 0.036), indicating higher expression was associated with more knee-related dysfunction. SF CCL19 was detected in 7 of 10 patients, compared to 4 of 10 asymptomatic donors. CONCLUSION: In typical patients presenting for meniscal arthroscopy, synovial CCL19 mRNA expression was associated with knee-related difficulty with ADL, independent of other factors including presence of radiographic knee OA.

Outbreak of zoonotic cutaneous leishmaniasis with local dissemination in Balkh, Afghanistan.

OBJECTIVES: In Afghanistan zoonotic cutaneous leishmaniasis (CL) due to Leishmania major has been less widely reported than anthroponotic CL due to L. tropica. However, an outbreak of zoonotic CL occurred amongst a group of British soldiers at a military camp near Mazar-e-Sharif in the Balkh province of northern Afghanistan in 2004. METHODS: A study was performed to assess the epidemiology, clinical features, parasitology results, treatment outcomes and environmental health measures associated with this incident. RESULTS: Twenty (17%) of 120 soldiers developed CL due to L. major and the risk of infection increased with the proximity of their accommodation to an area of recently cleared scrub, where many wild rodents were observed. Most cases had features of local dissemination, including secondary lesions from the pseudo-Koebner phenomenon, sporotrichoid lymphatic spread, lymphadenopathy and satellite papules or milia formation around healing lesions. Several cases responded poorly to fluconazole and low dose (10 mg/kg) sodium stibogluconate, which were considered suitable treatments at the time. Environmental health measures at the military camp were found to be deficient. CONCLUSIONS: Zoonotic CL due to L. major is a significant threat for foreign troops based in Balkh, Afghanistan and may present with unusually severe clinical features and be resistant to previously recommended treatments.

Lupus-specific health outcome measure for US patients: the LupusQoL-US version.

BACKGROUND: Patient-reported outcomes are valuable for the management of chronic diseases like systematic lupus erythematosus (SLE), but no measures have been validated for use in US-based patients with SLE. OBJECTIVES: To adapt and assess the validity and reliability of an SLE-specific quality of life (QoL) measure developed in the United Kingdom, the LupusQoL, for use in US-based patients with SLE. METHODS: Debriefing interviews of subjects with SLE guided the language modifications of the tool. The LupusQoL-US, SF-36 and EQ5D were administered. Internal consistency (ICR) and test-retest (TRT) reliability, convergent and discriminative validity were examined. Factor analyses were performed. RESULTS: The mean (SD) age of the 185 subjects with SLE was 42.5 (12.9) years. ICR and TRT of the eight domains ranged from 0.85 to 0.94 and 0.68 to 0.92, respectively. Related domains on the SF-36 correlated with the LupusQoL domains (physical health and physical function r = 0.73, physical health and role physical r = 0.57, emotional health and mental health r = 0.72, emotional health and role emotional r = 0.48, pain and bodily pain r = 0.66, fatigue and vitality r = 0.70, planning and social functioning r = 0.58). Most LupusQoL-US domains could discriminate between subjects with varied disease activity and damage. Principal component analysis disclosed five factors in the US version, with physical function, pain and planning items loading on one factor. CONCLUSIONS: These data provide evidence to support the psychometric properties of the LupusQoL-US, suggesting its utility as an assessment tool for patients with SLE in the USA.

Bright light treatment of winter depression: a placebo-controlled trial.

BACKGROUND: Bright light therapy is the recommended treatment for winter seasonal affective disorder (SAD). However, the studies with the best placebo controls have not been able to demonstrate that light treatment has a benefit beyond its placebo effect. METHODS: Ninety-six patients with SAD completed the study. Patients were randomly assigned to 1 of 3 treatments for 4 weeks, each 1.5 hours per day: morning light (average start time about 6 AM), evening light (average start about 9 PM), or morning placebo (average start about 6 AM). The bright light (approximately 6000 lux) was produced by light boxes, and the placebos were sham negative-ion generators. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD) were performed weekly. RESULTS: There were no differences among the 3 groups in expectation ratings or mean depression scores after 4 weeks of treatment. However, strict response criteria revealed statistically significant differences; after 3 weeks of treatment morning light produced more of the complete or almost complete remissions than placebo. By 1 criterion (24-item SIGH-SAD score <50% of baseline and < or =8), 61% of the patients responded to morning light, 50% to evening light, and 32% to placebo after 4 weeks of treatment. CONCLUSIONS: Bright light therapy had a specific antidepressant effect beyond its placebo effect, but it took at least 3 weeks for a significant effect to develop. The benefit of light over placebo was in producing more of the full remissions.

Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Relation to duration of illness and depressive symptoms.

The responses of serum prolactin (PRL) and growth hormone (GH) to the dopamine agonist apomorphine hydrochloride (0.75 mg subcutaneously) were studied in a large group of unmedicated hospitalized patients with functional psychoses. There were no differences in the GH response in various diagnostic groups. The PRL response was greater in patients with affective disorders. The GH response was inversely related to total duration of illness in the entire sample of patients, but this correlation was independent of age effect only in the group of patients with major depression. In schizophrenics, the effect of the two factors, age and duration of the illness, could not be separated. The apomorphine-induced GH response was significantly correlated with psychosis ratings and negative symptom scale scores. The apomorphine-induced PRL suppression correlated significantly with various measures of depression across diagnostic groups.

Conflicting bright light exposure during night shifts impedes circadian adaptation.

This simulated night shift field study compared high-intensity ("bright") light exposures designed to either facilitate or conflict with adaptation to a 9-h phase shift of the sleep/dark schedule. There were 7 days of baseline with night sleep followed by 8 night shifts with day sleep in a 2 x 2 design with factors bright light (facilitating vs. conflicting) and direction of shifted sleep/dark (delayed vs. advanced). A total of 32 subjects (8 in each group) were exposed to 3 h of bright light (about 5,000 lux) and 5 h of ordinary indoor room light of "dim" light (< 500 lux) during each 8-h night shift. The bright light was timed according to the light phase-response curve (PRC) to delay or advance rhythms; it was timed to occur either before or after the baseline body temperature minimum, which served as an estimate of the PRC crossover point between delays and advances. Core body temperature was measured continuously and demasked to determine daily temperature minima. Significantly more subjects showed large temperature rhythm phase shifts (> or = 6 h during the last 4 night shifts relative to baseline) with facilitating bright light compared to conflicting bright light as well as with delayed sleep/dark compared to advanced sleep/dark. The combination of facilitating bright light and delayed sleep/dark produced large phase delay shifts in all subjects tested. By contrast, the combination of conflicting bright light and advanced sleep/dark resulted in very small phase shifts in most subjects. Because bright light timed to delay usually was not able to phase shift rhythms when sleep/dark was advanced, it appears that the timing of sleep/dark was as important as the timing of the bright light. There was a relationship between the amount of phase shift and the individual's baseline phase when sleep/dark was delayed. Larger phase delays were achieved by subjects with later baseline temperature minima and greater eveningness on the Morningness-Eveningness Questionnaire. These results show that it is important to time bright light appropriately to achieve circadian adaptation to the night shift and that individual differences play an important role in the ability of the circadian system to phase shift.

The circadian rhythm of temperature during light treatment for winter depression.

Circadian rhythm abnormalities have been implicated in winter seasonal affective disorder. We examined the circadian temperature rhythm of 22 patients with winter depression and 10 normal controls who had participated in various high-intensity light treatment experiments. We did not find abnormalities in the baseline phase or amplitude of the temperature rhythm in patients compared to controls. Nor did we find abnormalities in the phase-shifting response to morning light. There was some evidence that the "phase-delayed" half of the patients responded poorly to phase advances produced by morning light, whereas the "phase-advanced" half of the patients responded poorly when their rhythms delayed. However, the antidepressant responses during the best week (week of lowest depression score) were unrelated to temperature rhythm phase shifts. In general, there was not strong support for a relationship between circadian rhythms changes and antidepressant response.

Interactions of risk factors in predicting suicide.

The authors examined interactions among risk factors for suicide, a strategy not typically followed in suicide research. Their results suggest an explanation for gender differences in suicide rates and qualifications in the relationship between hopelessness and suicide based on history of drug and alcohol abuse.

A field test of Motto's risk estimator for suicide.

The authors undertook a field test of Motto and colleagues' Risk Estimator for Suicide by selecting a subset (N = 593) of psychiatric patients with major or chronic affective disorder that corresponded to Motto's sample. They rated each subject on Motto's scale, using standardized data collected at hospital admission. Fourteen patients (2.4%) in their sample and 136 (4.9%) in Motto's sample died by suicide within 2 years. The authors tested the null hypothesis of a uniform suicide risk across all 10 deciles of risk scores by comparing observed and expected frequencies of suicide using the variance test for homogeneity of the binomial distribution. Their findings raise questions about Motto's risk scale but do not definitively invalidate it.

Time-related predictors of suicide in major affective disorder.

The authors studied 954 psychiatric patients with major affective disorders and found that nine clinical features were associated with suicide. Six of these--panic attacks, severe psychic anxiety, diminished concentration, global insomnia, moderate alcohol abuse, and severe loss of interest or pleasure (anhedonia)--were associated with suicide within 1 year, and three others--severe hopelessness, suicidal ideation, and history of previous suicide attempts--were associated with suicide occurring after 1 year. These findings draw attention to the importance of 1) standardized prospective data for studies of suicide, 2) assessment of short-term suicide risk factors, and 3) anxiety symptoms as modifiable suicide risk factors within a clinically relevant period.

Circadian rhythm adaptation to simulated night shift work: effect of nocturnal bright-light duration.

We compared bright-light durations of 6, 3 and 0 hours (i.e. dim light) during simulated night shifts for phase shifting the circadian rectal temperature rhythm to align with a 12-hour shift of the sleep schedule. After 10 baseline days there were 8 consecutive night-work, day-sleep days, with 8-hour sleep (dark) periods. The bright light (about 5,000 lux, around the baseline temperature minimum) was used during all 8 night shifts, and dim light was < 500 lux. This was a field study in which subjects (n = 46) went outside after the night shifts and slept at home. Substantial circadian adaptation (i.e. a large cumulative temperature rhythm phase shift) was produced in many subjects in the bright light groups, but not in the dim light group. Six and 3 hours of bright light were each significantly better than dim light for phase shifting the temperature rhythm, but there was no significant difference between 6 and 3 hours. Thus, durations > 3 hours are probably not necessary in similar shift-work situations. Larger temperature rhythm phase shifts were associated with better subjective daytime sleep, less subjective fatigue and better overall mood.

Dark goggles and bright light improve circadian rhythm adaptation to night-shift work.

We compared the contributions of bright light during the night shift and dark goggles during daylight for phase shifting the circadian rhythm of temperature to realign with a 12-hour shift of sleep. After 10 baseline days there were 8 night-work/day-sleep days. Temperature was continuously recorded from 50 subjects. There were four groups in a 2 x 2 design: light (bright, dim), goggles (yes, no). Subjects were exposed to bright light (about 5,000 lux) for 6 hours on the first 2 night shifts. Dim light was < 500 lux. Both bright light and goggles were significant factors for producing circadian rhythm phase shifts. The combination of bright light plus goggles was the most effective, whereas the combination of dim light and no goggles was the least effective. The temperature rhythm either phase advanced or phase delayed when it aligned with daytime sleep. However, when subjects did not have goggles only phase advances occurred. Goggles were necessary for producing phase delays. The most likely explanation is that daylight during the travel-home window after a night shift inhibits phase-delay shifts, and goggles can prevent this inhibition. Larger temperature-rhythm phase shifts were associated with better subjective daytime sleep, less subjective fatigue and better mood.

Suicide: a four-pathway clinical-biochemical model.

This chapter, based on a review of recent research as well as data presented in this report, proposes four hypothetical pathways leading to suicide in clinical depression: (1) an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor (CRF or CRH) levels, (2) trait baseline and reactivity hopelessness, (3) severe anhedonia, and (4) trait impulsiveness associated with low brain serotonin turnover and low total cholesterol as a possible peripheral correlate. Clinical research showing evidence for acute versus chronic high-risk suicide factors and other studies linking severe anxiety/agitation to high CRF levels will be presented as associated with acute suicidal risk, which is potentially reversible with recognition and treatment. Evidence for anhedonia severity as a risk factor and trait, as well as evidence that baseline hopelessness and sensitivity are traits related to chronic suicide risk, will be presented. Finally, evidence relating low serum cholesterol to suicide in depressed inpatients will be presented in the context of literature suggesting a relationship between low serum cholesterol and violent death and suicide in population studies. Data suggesting a relationship between low serum cholesterol and decreased CSF 5-HIAA, suggesting reduced serotonin turnover, will be presented, in light of prior studies relating low CSF 5-HIAA and violent suicide. These data taken together suggest four pathways to suicide that are worth investigating in order to better understand the mechanisms leading to this behavior. Future possibilities and applications of these findings are discussed.

Two types of thought disorder and lateralized neuropsychological dysfunction.

This report examined positive and negative thought disorder in relation to medication status and cerebral lateralization measures obtained from the Halstead-Reitan Neuropsychological Battery and Wechsler Adult Intelligence Scale in a sample of 59 patients with schizophrenia, schizoaffective and manic disorders, and unspecified functional psychoses. Discriminant function analyses of comparable left- and right-hemisphere variables from the neuropsychological tests were examined for both types of thought disorder, in which presence or absence of psychotropic medications was included as a variable in each analysis. Results indicated a relationship between positive thought disorder and left- but not right-hemisphere variables. Both the left- and right-hemisphere variables were related to negative thought disorder, and these relationships were influenced by the global measures of verbal and performance IQ as well as by medication status. These findings provide qualified support for the left-hemisphere-dysfunction hypothesis, insofar as it is associated specifically with positive thought disorder. Diffuse or bilateral cerebral impairment is more characteristic of negative thought disorder; however, medication status is also equivalent to neuropsychological variables in influencing this relationship.

Assessment of negative and positive symptoms in schizophrenia.

Reliable, convenient rating scales to assess negative and positive symptoms in schizophrenia are necessary to evaluate further the theoretical and clinical importance of this division of symptoms and signs. The authors describe the application of the Rasch model, a probabilistic, item-independent, and sample-independent test construction procedure to the development of scales for both types of symptoms. The scales for negative and positive symptoms, which are based separately on the Schedule for Affective Disorders and Schizophrenia-Current (SADS-C) and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE), demonstrated excellent reliability and temporal stability (i.e., yielded a rank order of patients that remained stable over time). The pattern of interscale correlations supports the view that positive symptoms, cognitive-affective negative symptoms, and social withdrawal are independent of one another.

Stable trait components of hopelessness: baseline and sensitivity to depression.

Hopelessness (H) plays an important theoretical and practical role in depression. The authors hypothesized that a patient's H is comprised of (a) a baseline level of H when not depressed and (b) an increment in H related to the severity of depression at the time and the person's rate of increase in H as a function of severity of depression (sensitivity). Baseline and sensitivity are explanatory stable traits; H and depression are observed, time-varying states. The corresponding statistical model described well the longitudinal data of 316 participants. Baseline and sensitivity were uncorrelated and correlated with different clinical and demographic variables. Baseline predicted a future suicide attempt; sensitivity and H when depressed did not. It may be useful to ask "How hopeless is this person when not depressed and how much more hopeless is he or she when depressed?", rather than simply "How hopeless is this depressed person?"