Circulating fractures-related microRNAs distinguish primary hyperparathyroidism-related from estrogen withdrawal-related osteoporosis in postmenopausal osteoporotic women: A pilot study.

Primary hyperparathyroidism (PHPT) represents a common cause of secondary osteoporosis in postmenopausal women, where the negative effect of estrogen withdrawal and that of hyperparathyroidism on bone mineralization coexist. Circulating microRNAs (miRNAs) expression profile has been correlated to both osteoporosis and fragility fractures. The study aimed to profile a set of miRNAs associated with osteoporotic fractures, namely miR-21-5p, miR-23a-5p, miR-24-2-5p, miR-24-3p, miR-93-5p, miR-100-5p, miR-122-5p, miR-124-3p, miR-125b-5p and miR-148-3p, in the plasma of 20 postmenopausal PHPT women. PHPT miRNAs profiles were compared with those detected in 10 age-matched postmenopausal non-PHPT osteoporotic women (OP). All the 10 miRNAs were detected in the plasma samples of both PHPT and OP women. The miRNA profiles clearly distinguished PHPT from OP samples, and identified within the PHPT group, two clusters differing for the PHPT severity, in term of ionized calcium and bone mineralization. In particular, miR-93-5p was significantly downregulated in PHPT samples, while miR-24-3p negatively correlated with the T-score at lumbar, femur neck and total hip sites. PHPT women who experienced osteoporotic fractures had plasma miR-24-3p levels higher than those detected in unfractured PHPT women. In conclusion, PHPT may modulate circulating fractures-related miRNAs, in particular, miR-93-5p, which may distinguish estrogen-related from PHPT-related osteoporosis.

Ultrasound elastography is useful to distinguish acute and chronic deep vein thrombosis.

Essentials Ultrasound elastography uses tissue deformation to assess the relative quantification of its elasticity. Compression and duplex ultrasonography may be unable to correctly determine the thrombus age. Ultrasound elastography may be useful to distinguish between acute and chronic deep vein thrombosis. The exact determination of the thrombus age could have both therapeutic and prognostic implications. BACKGROUND: Background Ultrasound elastography (UE) imaging is a novel sonographic technique that is commonly employed for relative quantification of tissue elasticity. Its applicability to venous thromboembolic events has not yet been fully established; in particular, it is unclear whether this technique may be useful in determining the age of deep vein thrombosis (DVT). Thus, the aim of this study was to assess the role of UE in distinguishing acute from chronic DVT. Methods Consecutive patients with a first unprovoked acute and chronic (3 months old) DVT of the lower limbs were analyzed. Patients with recurrent DVT or with a suspected recurrence were excluded. The mean elasticity index (EI) values of acute and chronic popliteal and femoral vein thrombosis were compared. The accuracy of the EI in distinguishing acute from chronic DVT was also assessed by measuring the sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Results One-hundred and forty-nine patients (mean age 63.9 years, standard deviation 13.6; 73 males) with acute and chronic DVT were included. The mean EI of acute femoral DVT was higher than that of chronic femoral DVT (5.09 versus 2.46), and the mean EI of acute popliteal DVT was higher than that of chronic popliteal DVT (4.96 versus 2.48). An EI value of > 4 resulted in a sensitivity of 98.9% (95% confidence interval [CI] 93.3-99.9), a specificity of 99.1% (95% CI 94.8-99.9), a positive predictive value of 91.1% (95% CI 77.9-97.1), a negative predictive value of 98.6% (95% CI 91.3-99.9), a positive likelihood ratio of 13.23 (95% CI 93-653) and a negative likelihood ratio of 0.001 (95% CI 0.008-0.05) for acute DVT. Conclusions UE appears to be a promising technique for distinguishing between acute and chronic DVT. Larger prospective studies are warranted to confirm our preliminary findings.

Effect of aerobic exercise intervention on markers of insulin resistance in breast cancer women.

Insulin may affect breast cancer (BC) risk and prognosis. Exercise reduces insulin in obese BC survivors. We designed a randomised controlled trial to test the effect of an aerobic exercise intervention (AEI) on insulin parameters and body composition in non-obese BC women without insulin resistance. Thirty-eight BC women were randomised into an intervention group (IG = 18) or control group (CG = 20). IG participated in a structured AEI for 3 months, while CG received only the Word Cancer Research Fund/American Institute Cancer Research (WCRF/AICR) recommendation to be physically active. Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, metabolic parameters and body composition were collected at baseline and after the AEI. IG reduced insulin and HOMA-IR index by 15% and 14%, while CG increased these parameters (+12% and +16%). Insulin changed differently over time in the two randomised groups (pinteraction  = .04). The between-group differences in the change of insulin (IG = -1.2 µU/ml versus CG = +0.8 µU/ml) and HOMA-IR index (IG = -0.26 versus CG = +0.25) were respectively significant (p = .04) and non-significant (p = .06). IG significantly improved lower limb muscle mass in comparison with CG (p = .03). A structured AEI may improve insulin, HOMA-IR index and body composition in non-obese BC survivors without insulin resistance.

Response perseveration in psychopathic women.

Recent attempts to validate the Psychopathy Checklist-Revised (PCL-R) as a measure of psychopathy in female offenders have been limited by a failure to examine laboratory correlates of the syndrome. We assessed 112 incarcerated women by using the PCL-R and examined their performance on a card perseveration task that has been used to demonstrate response perseveration in psychopathic men. Contrary to prediction, psychopathic women did not perseverate responding when the PCL-R was used either dimensionally or categorically. The authors discuss the implications of the results for the PCL-R and for female psychopathy more generally.

The mahogany protein is a receptor involved in suppression of obesity.

Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.

Hyperinsulinaemia and normal glucose tolerance tests in pregnancy

Hyperinsulinaemia is a condition present during late pregnancy, returning to normal after delivery. Since some pregnant women are not able to adapt themselves to this high insulin secretion they could become gestational diabetics. We attempt here to describe the insulin metabolism during late pregnancy according to the women's levels of fasting insulin at six months postpartum. Sixty-seven pregnant women underwent a glucose tolerance test at weeks 20, 30 and 36 of pregnancy and at 6 months postpartum. Glucose and insulin values were measured. The women were classified as follows: group one, women who at 6 months postpartum had fasting insulin levels above the mean (13.5/dl) and group two, who fasting levels were below the mean. The significant difference between the groups was found at all points of the insulin curve at six months postpartum, but not for the glucose curve. During pregnancy, a difference in insulin was also found for weeks 20;30 and 36 but not for the glucose. Group one, whose insulin level were higher since week 20, presented with hyperinsulinaemia, while group two behaved as described in the literature, i.e., secreting more insulin as the pregnancy advanced. Women of group one are at major risk to develop diabetes mellitus, type II later in life (AU)

Pancreatic cancer among workers processing synthetic resins.

A nested case-control study was conducted to investigate whether an excess of pancreatic cancer, identified in a cohort mortality study with follow-up from 1946 through 1988, was associated with potential workplace exposures at a New Jersey plastics manufacturing and research and development facility. The study population included 28 male pancreatic cancer cases and 140 randomly selected controls, matched on year of birth and at risk (alive) at the time of the case death. Using plant work history records, department assignments for the two groups were compared according to duration and time since first assignment. Workers assigned to a work area that processed vinyl resins and polyethylene (PE) were shown to be at increased risk. Men assigned more than 16 years to this department had a significantly increased risk ratio of 7.15 (95% confidence intervals [CI]: 1.28-40.1). No excess was seen with shorter duration assignments. Seven of the nine cases began working in this area in the 1940s. Average latency was 32 years, and all but three cases worked 20 years or more in this unit. Over the study period, significant exposure-related process changes occurred, in addition to the use of numerous chemical additives. Although vinyl and PE processing operations could not be analyzed separately, the pancreatic cancer excess is more likely to be related to vinyl processing. Identification of a causative agent or combination of agents would require investigations with more detailed exposure information.

Developmental and tissue-specific expression of human CD4 in transgenic rabbits.

A major obstacle to understanding AIDS is the lack of a suitable small animal model for studying HIV-1 infection and the subsequent development of AIDS, and for testing diagnostic, therapeutic, and preventive modalities. Our goal is to produce a rabbit model for the study of AIDS. Here we report on the generation of transgenic rabbits that express the human CD4 (hCD4) gene. The transgene, which contains the coding region for hCD4 and approximately 23 kb of sequence upstream of the translation start site, was used previously to direct hcD4 expression on the surface of CD4+ T cells of transgenic mice (Gillespie et al., 1993: Mol Cell Biol 13:2952-2958). The hCD4 transgene was detected in five males and two females derived from the microinjection in five males and two females derived from the microinjection of 271 rabbit embryos. Both hCD4 RNA and protein were expressed in peripheral blood lymphocytes (PBLs) from all five males but neither of the females. Human CD4 was expressed on PBLs from F1 offspring of all founder males. T-cell subset analysis revealed that hCD4 expression was restricted to rabbit CD4 (rCD4) expressing lymphocytes; mature rCD4- rCD8+ lymphocytes did not express hCD4. In preliminary studies, PBLs from hCD4 transgenic rabbits produced greater amounts of HIV-1 p24 core protein following HIV-1 infection in vitro than HIV-1 p24 antigen in nontransgenic rabbit infected cultures. These results extend to rabbits our previous observation that this transgene contains the sequence elements required for high-level expression in the appropriate cells of transgenic mice. Furthermore, these and previous studies demonstrating that expression of hCD4 protein enhances HIV-1 infection of rabbit T cells in vitro, coupled with reports that normal, nontransgenic rabbits are susceptible to HIV-1 infection, suggests that the hCD4 transgenic rabbits described herein will have an increased susceptibility to HIV-1 infection. In vivo HIV-1 infection studies with these rabbits are under way.

Mortality study of ethylene oxide workers in chemical manufacturing: a 10 year update.

Men assigned to units producing ethylene oxide by the chlorohydrin or direct oxidation processes and to other departments using ethylene oxide in two chemical plants were followed up for mortality from 1940 to 1988 (n = 1896). Based on findings from a previous study of these workers to the end of 1978, which identified confounding exposures, workers assigned to one unit with low ethylene oxide exposure potential were excluded (n = 278). Average duration of exposure was over five years and average follow up was 27 years, with all subjects at least 10 years from first exposure. The data did not support associations of ethylene oxide with all cancer types combined, leukaemia, non-Hodgkin's lymphoma, or brain, pancreatic, or stomach cancers. There were also no duration-response trends. The standardised mortality ratio (SMR) for total cancer was 86 (95% confidence interval 71-104) and did not increase for those hired the earliest and with long duration assignments. The results of this 10 year update and those of other recent studies of ethylene oxide workers do not confirm findings from animal studies and are not consistent with the earliest results reported among ethylene oxide workers.

Tissue-specific expression of human CD4 in transgenic mice.

The gene for the human CD4 glycoprotein, which serves as the receptor for human immunodeficiency virus type 1, along with approximately 23 kb of sequence upstream of the translational start site, was cloned. The ability of 5' flanking sequences to direct tissue-specific expression was tested in cell culture and in transgenic mice. A 5' flanking region of 6 kb was able to direct transcription of the CD4 gene in NIH 3T3 cells but did not result in detectable expression in the murine T-cell line EL4 or in four lines of transgenic mice. A larger 5' flanking region of approximately 23 kb directed high-level CD4 transcription in the murine T-cell line EL4 and in three independent lines of transgenic mice. Human CD4 expression in all tissues analyzed was tightly correlated with murine CD4 expression; the highest levels of human CD4 RNA expression were found in the thymus and spleen, with relatively low levels detected in other tissues. Expression of human CD4 protein in peripheral blood mononuclear cells was examined by flow cytometry in these transgenic animals and found to be restricted to the murine CD4+ subset of lymphocytes. Human CD4 protein, detected with an anti-human CD4 monoclonal antibody, was present on the surface of 45 to 50% of the peripheral blood mononuclear cells from all transgenic lines.

Cloning of the goat beta-casein-encoding gene and expression in transgenic mice.

The goat beta-casein-encoding gene (CSN2), which encodes the most abundant protein of goat milk, has been cloned and sequenced. The intron/exon organization of the 9.0-kb goat CSN2 gene is similar to that of other CSN2 genes. Expression of the goat gene was principally restricted to the mammary gland of lactating transgenic animals. A low level of expression was also observed in skeletal muscle and skin. In contrast to a rat CSN2 transgene [Lee et al., Nucleic Acids Res. 16 (1988) 1027-1041], the goat gene was expressed to a high degree in the lactating mammary gland. Differences in the content or context of regulatory elements may account for the enhanced performance of the goat relative to the rat CSN2 gene in transgenic mice.

Effects of oral soy phosphatidylcholine on phagocytosis, arachidonate concentrations, and killing by human polymorphonuclear leukocytes.

A dietary supplement of linoleic acid (LA) as soy phosphatidylcholine (PC) or as triglyceride on polymorphonuclear leukocyte (PMNL) functions, arachidonate (AA) concentrations, AA release, and leukotriene B4 (LTB4) generation was studied in normal adults. Study 1: Eight subjects were fed PC (27 g) or placebo for 3 d in a blinded crossover experiment with PMNL assays at baseline and 4, 7, and 14 d. Study 2: Subjects were fed equal quantities of LA as PC (18 g, n = 8), safflower (SF, n = 4), or soybean oil (SY, n = 4) with PMNL assays at baseline and 48 h. Study 1: PC increased PMNL phagocytosis and killing of Candida albicans twofold (P less than 0.001) and PMNL phospholipid AA content threefold (P less than 0.001); AA release after Candida albicans stimulation increased 5.3-fold, correlating with PMNL killing (r = 0.932) and phagocytosis (r = 0.872). Study 2: PC, but not SF or SY, produced changes similar to those of study 1. With PMNL exposure to calcium ionophore A23187 or N-formyl-methionyl-leucyl-phenylalanine, PC increased LTB4 generation. Phospholipid LA, in contrast to triglyceride LA, enhanced PMNL phospholipid AA, phagocytosis, and killing.