Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation

Leukemia inhibitory factor (LIF) expression in the uterus is essential for embryo implantation in mice. Here we describe the spatial and temporal regulation of LIF signaling in vivo by using tissues isolated from uteri on different days over the implantation period. During this time, LIF receptors are expressed predominantly in the luminal epithelium (LE) of the uterus. Isolated epithelium responds to LIF by phosphorylation and nuclear translocation of signal transducer and activator of transcription (Stat) 3, but not by an increase in mitogen-activated protein kinase levels. The related cytokines Il-6, ciliary neurotrophic factor, as well as epidermal growth factor, do not activate Stat3, although epidermal growth factor stimulates mitogen-activated protein kinase. In vivo Stat3 activation is induced by LIF alone, resulting in the localization of Stat3 specifically to the nuclei of the LE coinciding with the onset of uterine receptivity. The responsiveness of the LE to LIF is regulated temporally, with Stat activation being restricted to day 4 of pregnancy despite the presence of constant levels of LIF receptor throughout the preimplantation period. Uterine receptivity is therefore under dual control and is regulated by both the onset of LIF expression in the endometrial glands and the release from inhibition of receptor function in the LE.

Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.

Transforming growth factor beta 1 (TGF beta 1)-null mice die fro complications due to an early-onset multifocal inflammatory disorder. We show here that cardiac cells are hyperproliferative and that intercellular adhesion molecule 1 (ICAM-1) is elevated. To determine which phenotypes are primarily caused by a deficiency in TGF beta 1 from those that are secondary to inflammation, we applied immunosuppressive therapy and genetic combination with the severe combined immunodeficiency (SCID) mutation to inhibit the inflammatory response. Treatment with antibodies to the leukocyte function-associated antigen 1 doubled longevity, reduced inflammation, and delayed heart cell proliferation. TGF beta 1-null SCID mice displayed no inflammation or cardiac cell proliferation, survived to adulthood, and exhibited normal major histocompatibility complex II (MHC II) and ICAM-1 levels. TGF beta 1-null pups born to a TGF beta 1-null SCID mother presented no gross congenital heart defects, indicating that TGF beta 1 alone does not play an essential role in heart development. These results indicate that lymphocytes are essential for the inflammatory response, cardiac cell proliferation, and elevated MHC II and ICAM-1 expression, revealing a vital role for TGF beta 1 in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance.

Genetic variation in vulnerability to the behavioral effects of neonatal hippocampal damage in rats.

We explored how two independent variables, one genetic (i.e., specific rat strains) and another environmental (i.e., a developmental excitotoxic hippocampal lesion), contribute to phenotypic variation. Sprague-Dawley (SD), Fischer 344 (F344), and Lewis rats underwent two grades of neonatal excitotoxic damage: small and large ventral hippocampal (SVH and LVH) lesions. Locomotion was tested before puberty [postnatal day 35 (P35)] and after puberty (P56) following exposure to a novel environment or administration of amphetamine. The behavioral effects were strain- and lesion-specific. As shown previously, SD rats with LVH lesions displayed enhanced spontaneous and amphetamine-induced locomotion as compared with controls at P56, but not at P35. SVH lesions in SD rats had no effect at any age. In F344 rats with LVH lesions, enhanced spontaneous and amphetamine-induced locomotion appeared early (P35) and was exaggerated at P56. SVH lesions in F344 rats resulted in a pattern of effects analogous to LVH lesions in SD rats--i.e., postpubertal onset of hyperlocomotion (P56). In Lewis rats, LVH lesions had no significant effect on novelty- or amphetamine-induced locomotion at any age. These data show that the degree of genetic predisposition and the extent of early induced hippocampal defect contribute to the particular pattern of behavioral outcome. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia, a disorder characterized by phenotypic heterogeneity, genetic predisposition, a developmental hippocampal abnormality, and vulnerability to environmental stress.

Onset of energy dissipation in ballistic atomic wires

Electronic transport at finite voltages in free-standing gold atomic chains of up to seven atoms in length is studied at low temperatures using a scanning tunneling microscope. The conductance vs voltage curves show that transport in these single-mode ballistic atomic wires is nondissipative up to a finite voltage threshold of the order of several mV. The onset of dissipation and resistance within the wire corresponds to the excitation of the atomic vibrations by the electrons traversing the wire and is very sensitive to strain.

On the Radial Onset of Clumping in the Wind of the B0I Massive Star QV Nor

We present an analysis of a 78 ks Chandra high-energy transmission gratings observation of the B0I star QV Nor, the massive donor of the wind-accreting pulsar 4U1538−52. The neutron star (NS) orbits its companion in a very close orbit (r < 1.4R*, in units of the stellar radii), thereby allowing probing of the innermost wind regions. The flux of the Fe Kα line during eclipse reduces to only ∼30% of the flux measured out of eclipse. This indicates that the majority of Fe fluorescence must be produced in regions close to the NS, at distances smaller than 1R* from its surface. The fact that the flux of the continuum decreases to only ∼3% during eclipse allows for a high contrast of the Fe Kα line fluorescence during eclipse. The line is not resolved and centered at 1.9368 0.0018 l = 0.0032 - + Å. From the inferred plasma speed limit of v < c l < 800 l D km s−1 and range of ionization parameters of log 1, 2 x = [- ], together with the stellar density profile, we constrain the location of the cold, dense material in the stellar wind of QV Nor using simple geometrical considerations. We then use the Fe Kα line fluorescence as a tracer of wind clumps and determine that these clumps in the stellar wind of QV Nor (B0I) must already be present at radii r < 1.25R*, close to the photosphere of the star.

Diabetic vascular disease and Maturity-onset diabetes of the young

Aim: Vascular disease such as cardiovascular and cerebrovascular diseases, or retinopathy, nephropathy and neuropathy are common in diabetes. Maturity - onset diabetes of the young (MODY) describes a clinically heterogeneous group of familial diabetes characterized by monogenic, autosomal dominant inheritance that generally results from beta cell dysfunction. This study aims to assess the presence of vascular complications on Portuguese patients with a clinical diagnosis of MODY.

Prospective longitudinal study of subcortical brain volumes in individuals at high familial risk of mood disorders with or without subsequent onset of depression

Subcortical volumetric brain abnormalities have been observed in mood disorders. However, it is unknown whether these reflect adverse effects predisposing to mood disorders or emerge at illness onset. Magnetic resonance imaging was conducted at baseline and after two years in 111 initially unaffected young adults at increased risk of mood disorders because of a close family history of bipolar disorder and 93 healthy controls (HC). During the follow-up, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the others remaining well (HR-well). Volumes of the lateral ventricles, caudate, putamen, pallidum, thalamus, hippocampus and amygdala were extracted for each hemisphere. Using linear mixed-effects models, differences and longitudinal changes in subcortical volumes were investigated between groups (HC, HR-MDD, HR-well). There were no significant differences for any subcortical volume between groups controlling for multiple testing. Additionally, no significant differences emerged between groups over time. Our results indicate that volumetric subcortical brain abnormalities of these regions using the current method appear not to form familial trait markers for vulnerability to mood disorders in close relatives of bipolar disorder patients over the two-year time period studied. Moreover, they do not appear to reduce in response to illness onset at least for the time period studied.

Identifying Areas of Needed Support for Young Girls with Central Precocious Puberty (CPP)

Thesis (Master's)--University of Washington, 2016-06

Analysis of Melanoma Onset: Assessing Familial Aggregation by Using Estimating Equations and Fitting Variance Components via Bayesian Random Effects Models

We investigate whether relative contributions of genetic and shared environmental factors are associated with an increased risk in melanoma. Data from the Queensland Familial Melanoma Project comprising 15,907 subjects arising from 1912 families were analyzed to estimate the additive genetic, common and unique environmental contributions to variation in the age at onset of melanoma. Two complementary approaches for analyzing correlated time-to-onset family data were considered: the generalized estimating equations (GEE) method in which one can estimate relationship-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modeled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov Chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the free ware package BUGS. In addition, we also used a Bayesian model to investigate the relative contribution of genetic and environmental effects on the expression of naevi and freckles, which are known risk factors for melanoma.

Impairment in the cervical flexors: a comparison of whiplash and insidious onset neck pain patients

There has been little investigation into whether or not differences exist in the nature of physical impairment associated with neck pain of whiplash and insidious origin. This study examined the neck flexor synergy during performance of the cranio-cervical flexion test, a test targeting the action of the deep neck flexors. Seventy-five volunteer subjects participated in this study and were equally divided between Group 1, asymptomatic control subjects, Group 2, subjects with insidious onset neck pain and Group 3, subjects with neck pain following a whiplash injury. The cranio-cervical flexion test was performed in five progressive stages of increasing cranio-cervical flexion range. Subjects' performance was guided by feedback from a pressure sensor inserted behind the neck which monitored the slight flattening of the cervical lordosis which occurs with the contraction of longus colli. Myoelectric signals (EMG) were detected from the muscles during performance of the test. The results indicated that both the insidious onset neck pain and whiplash groups had higher measures of EMG signal amplitude (normalized root mean square) in the sternocleidomastoid during each stage of the test compared to the control subjects (all P

Major Depressive Disorder, Suicidal Ideation, and Suicide Attempt in Twins Discordant for Cannabis Dependence and Early-Onset Cannabis Use

Background: Previous research has reported both a moderate degree of comorbidity between cannabis dependence and major depressive disorder (MDD) and that early-onset cannabis use is associated with increased risks for MDD. Objective: To examine whether associations between both lifetime cannabis dependence and early cannabis use and measures of MDD, suicidal ideation, and suicide attempt persist after controlling for genetic and/or shared environmental influences. Design: Cross-sectional survey of twin pairs discordant for lifetime cannabis dependence and those discordant for early cannabis use. Setting: General population sample of twins (median age, 30 years). Participants: Two hundred seventy-seven same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17 years). Main Outcome Measures: Self-report measures of DSM-IV-defined lifetime MDD, suicidal ideation, and suicide attempt. Results: Individuals who were cannabis dependent had odds of suicidal ideation and suicide attempt that were 2.5 to 2.9 times higher than those of their non-cannabis-dependent co-twin. Additionally, cannabis dependence was associated with elevated risks of MDD in dizygotic but not in monozygotic twins. Those who initiated cannabis use before age 17 years had elevated rates of subsequent suicide attempt (odds ratio, 3.5 [95% confidence interval, 1.4-8.6]) but not of MDD or suicidal ideation. Early MDD and suicidal ideation were significantly associated with subsequent risks of cannabis dependence in discordant dizygotic pairs but not in discordant monozygotic pairs. Conclusions: Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.

Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease

We recently reported that a linkage disequilibrium (LD) block on chromosome 10q encompassing the gene encoding insulin-degrading enzyme (IDE) harbors sequence variants that associate with Alzheimer disease (AD). Evidence also indicated effects upon a number of quantitative indices of AD severity, including age-at-onset (AAO). Since linkage of this immediate region to AAO has been shown in both AD and Parkinson disease (PD), we have explored the possibility that polymorphism within this LD block might also influence PD. Utilizing single nucleotide polymorphisms that delineate common haplotypes from this region, we observed significant evidence of association with AAO in an Australian PD case-control sample. Analyses were complemented with AAO data from two independent Swedish AD case samples, for which previously reported findings were replicated. Results were consistent between AD and PD, suggesting the presence of equivalent detrimental and protective alleles. These data highlight a genomic region in the proximity of IDE that may contribute to AD and PD in a similar manner.

Molecular tools for studying puberty in the grey mullet, Mugil cephalus: cloning of cDNAs that regulate reproductive function

The cDNAs coding for the brain GnRHs (AY373449-51), pituitary GH, SL and PRL, and liver IGFs (AY427954-5) were isolated. Partial cDNA sequences of the brain (Cyp19b) and gonadal (Cyp19a) aromatases have also been obtained. These tools would be utilized to study the endocrine regulation of puberty in the grey mullet.

Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam

Background: In many developing countries vitamin K prophylaxis is not routinely administered at birth. There are insufficient data to assess the cost effectiveness of its implementation in such countries. Objective: To estimate the burden of intracranial haemorrhage caused by late onset vitamin K deficiency bleeding in Hanoi, Vietnam. Methods: Cases of intracranial haemorrhage in infants aged 1 - 13 weeks were identified in Hanoi province for 5 years ( 1995 - 1999), and evidence for vitamin K deficiency was sought. The data were compared with those on vitamin K deficiency bleeding in developed countries and used to obtain an approximation to the incidence of intracranial haemorrhage caused by vitamin K deficiency bleeding in Hanoi. Results: The estimated incidence of late onset vitamin K deficiency bleeding in infants who received no prophylaxis was unexpectedly high ( 116 per 100 000 births) with 142 and 81 per 100 000 births in rural and urban areas respectively. Mortality was 9%. Of the surviving infants, 42% were neurologically abnormal at the time of hospital discharge. Identified associations were rural residence, male sex, and low birth weight. A significant reduction in the incidence was observed in urban Hanoi during 1998 and 1999, after vitamin K prophylaxis was introduced at one urban obstetric hospital. Conclusions: Vitamin K deficiency bleeding is a major public health problem in Hanoi. The results indicate that routine vitamin K prophylaxis would significantly reduce infant morbidity and mortality in Vietnam and, costing an estimated US$87 (pound48, E72) per disability adjusted life year saved, is a highly cost effective intervention.

A brief motivational intervention for substance misuse in recent-onset psychosis

Substance misuse is common in early psychosis, and impacts negatively on outcomes. Little is known about effective interventions for this population. We report a pilot study of brief intervention for substance misuse in early psychosis ( Start Over and Survive: SOS), comparing it with Standard Care(SC). Twenty-five in-patients aged 18 - 35 years with early psychosis and current misuse of non-opioid drugs were allocated randomly to conditions. Substance use and related problems were assessed at baseline, 6 weeks and 3, 6 and 12 months. Final assessments were blind to condition. All 13 SOS participants who proceeded to motivational interviewing reported less substance use at 6 months, compared with 58% (7/12) in SC alone. Effects were well maintained to 12 months. However, more SOS participants lived with a relative or partner, and this also was associated with better outcomes. Engagement remained challenging: 39% (16/41) declined participation and 38% (5/13) in SOS only received rapport building. Further research will increase sample size, and address both engagement and potential confounds.