Characterization of a receptor for human chorionic gonadotrophin in luteinized rat ovaries

Radioiodine-labeled human chorionic gonadotrophin (HCG) binds in a highly specific manner to sedimentable components from luteinized ovaries of rats in which pseudopregnancy has been induced by treatment with pregnant mare's serum gonadotropin and HCG, but not to similar fractions from parotid or adrenal glands. Of the other iodinated compounds tested (asialo HCG, oxidized HCG, the [alpha] and [beta] subunits of HCG and bovine serum albumin) only asialo HCG was bound to a significant extent to subcellular fractions from ovarian homogenates. Binding [131I]HCG to the crude 800 x g pellet from ovarian homogenates was inhibited by non-labeled HCG. Ovine follicle stimulating hormone, human growth hormone, ovine prolactin, human thyroid stimulating hormone and the [alpha] and [beta] subunits of HCG were virtually ineffective as competitors for HCG binding sites. The possibility that at least a portion of the binding to sedimentable components may be due to plasma membrane contamination of the fractions is not excluded.The amount of hormone bound to receptor increased with increasing duration of incubation, temperature of incubation, and hormone concentration. Kinetic studies indicated that the concentration of binding sites is approximately 2 [middle dot] 10-14 M and that the Kd for the radioiodinated hormone was on the order of 10-10 M. This simple, specific, high affinity binding system may provide a tool for investigating initial steps in the action of HCG.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33892/1/0000157.pd

Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs

Isolation of plasma membranes from bovine corpus luteum possessing adenylate cyclase, 125I-hCG binding and Na---K-ATPase activities

Plasma membranes from bovine corpora lutea have been purified by sucrose density gradient centrifugation. The purified membranes, in addition to binding 125I-hCG, also possess hCG-stimulated adenylate cyclase and Na---K-ATPase. The relative purification of 125I-hCG binding, adenylate cyclase and Na---K-ATPase on the basis of the specific activities in the whole homogenate were 7.8, 6.4 and 2.6, respectively. The presence of both the hormone sensitive adenylate cyclase and 125I-hCG binding activities suggest that these plasma membranes might possess the `receptor' for gonadotropin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22423/1/0000873.pd

MRI Digital Artery Volume Index (DAVIX) as a surrogate outcome measure of digital ulcer disease in patients with systemic sclerosis: a prospective cohort study

Background Vascular fibrosis is a key manifestation of systemic sclerosis that leads to the narrowing of small and medium arteries, causing vascular clinical manifestations including digital ulcers and pulmonary arterial hypertension. We investigated the potential of the MRI-based Digital Artery Volume Index (DAVIX) as a surrogate outcome measure of vascular fibrosis by using it to quantify and predict the burden of digital ulcer disease in patients with systemic sclerosis. Methods Two independent cohorts of patients participating in the prospective observational study STRIKE were consecutively enrolled from the Scleroderma Clinic of the Leeds Teaching Hospitals Trust, Leeds, UK. Eligible patients were aged 18 years or older and fulfilled the very early diagnosis of systemic sclerosis (VEDOSS) or the 2013 American College of Rheumatology (ACR)–European Alliance of Associations for Rheumatology (EULAR) systemic sclerosis classification criteria. DAVIX was calculated as the percentage mean of the ratio of digital artery volume to finger volume in the four fingers of the dominant hand. Data were collected at baseline and 12-month follow-up, and the primary outcome was the presence of digital ulcers at 12-month follow-up. Findings Between Feb 7, 2018, and April 11, 2022, we included 85 patients in the exploratory cohort and 150 in the validation cohort. In the exploratory cohort, the mean age was 54·5 years (SD 11·6), 75 (88%) of 85 patients were women, ten (12%) were men, and 69 (82%) were White. In the validation cohort, the mean age was 53·5 years (SD 13·8), 136 (91%) of 150 patients were women, 14 (9%) were men, and 127 (85%) were White. In the exploratory cohort, DAVIX was significantly lower in patients with previous or active digital ulcers (0·34% [IQR 0·16–0·69]) than in those without digital ulcer disease (0·65% [0·42–0·88]; p=0·015); this finding was substantiated in the validation cohort (0·43% [0·20–0·73] vs 0·73% [0·53–0·97]; p<0·0001). Patients who developed new digital ulcers during 12-month follow-up had a lower DAVIX (0·23% [0·10–0·66]) than those who did not (0·65% [0·45–0·91]; p=0·0039). DAVIX was negatively correlated with disease duration (r=−0·415; p<0·0001), the ratio of forced vital capacity to the diffusing capacity of the lungs for carbon monoxide (r=−0·334; p=0·0091), nailfold capillaroscopy pattern (r=−0·447; p<0·0001), and baseline modified Rodnan skin score (r=−0·305; p=0·014) and was positively correlated with the diffusing capacity of carbon monoxide (r=0·368; p=0·0041). DAVIX was negatively correlated with change in score on the Scleroderma Health Assessment Questionnaire-Disability Index (r=−0·308; p=0·024), Visual Analogue Scale (VAS) Raynaud's (r=−0·271; p=0·044), and VAS digital ulcers (r=−0·291; p=0·044). Interpretation DAVIX is a promising surrogate outcome measure of digital ulcer disease in patients with systemic sclerosis. The ability of DAVIX to non-invasively predict future digital ulcers and worsening of patient-reported outcomes could aid patient enrichment and stratification in clinical trials. Clinically, DAVIX could offer insights into the assessment of vascular activity. The sensitivity of DAVIX to change over time and with treatment will establish its value as an imaging outcome measure of vascular disease. Funding National Institute for Health Research Biomedical Research Centre and University of Leeds Industry Engagement Accelerator Fund

Inter-population variations in concentrations, determinants of and correlations between 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE): a cross-sectional study of 3161 men and women from Inuit and European populations

BACKGROUND: The study is part of a collaborative project (Inuendo), aiming to assess the impact of dietary persistent organochlorine pollutants (POPs) on human fertility. The aims with the present study are to analyze inter-population variations in serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE), to assess inter-population variations in biomarker correlations, and to evaluate the relative impact of different determinants for the inter-individual variations in POP-biomarkers. METHOD: In study populations of 3161 adults, comprising Greenlandic Inuits, Swedish fishermen and their wives, and inhabitants from Warsaw, Poland and Kharkiv, Ukraine, serum concentrations of CB-153 and p,p'-DDE, were analysed by gas chromatography-mass spectrometry. RESULTS: The median serum concentrations of CB-153 were for male and female Inuits 200 and 110, for Swedish fishermen 190 and their wives 84, for Kharkiv men and women 44 and 27, and for Warsaw men and women 17 and 11 ng/g lipids, respectively. The median serum concentrations of p,p'-DDE were for Kharkiv men and women 930 and 650, for male and female Inuits 560 and 300, for Warsaw men and women 530 and 380, and for Swedish fishermen 240 and their wives 140 ng/g lipids, respectively. The correlation coefficients between CB-153 and p,p'-DDE varied between 0.19 and 0.92, with the highest correlation among Inuits and the lowest among men from Warsaw. Men had averagely higher serum concentrations of CB-153 and p,p'-DDE, and there were positive associations between age and the POP-biomarkers, whereas the associations with BMI and smoking were inconsistent. Dietary seafood was of importance only in the Inuit and Swedish populations. CONCLUSION: CB-153 concentrations were much higher in Inuits and Swedish fishermen's populations than in the populations from Eastern Europe, whereas the pattern was different for p,p'-DDE showing highest concentrations in the Kharkiv population. The correlations between the POP-biomarkers varied considerably between the populations, underlining that exposure sources differ and that the choice of representative biomarkers of overall POP exposure has to be based on an analysis of the specific exposure situation for each population. Age and gender were consistent determinants of serum POPs; seafood was of importance only in the Inuit and Swedish populations