Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients.

Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity, implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving the possibilities of offering optimal care to patients. We present the results of a two-year period of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss. Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional approaches including Copy Number Variations, in silico analyses, minigene studies coupled when appropriate with complete gene sequencing, and a specific assay for STRC. This comprehensive screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the other genes (24%). Pathogenic genotypes were identified in 19 different genes, with a high prevalence of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported in 16% of the genotyped cohort. Four de novo variants were identified. This study highlights the need to develop several molecular approaches for efficient molecular diagnosis of hearing loss, as this is crucial for genetic counselling, audiological rehabilitation and the detection of syndromic forms.

Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

Social behavior and kin discrimination in a mixed group of cloned and non cloned heifers (Bos taurus).

For more than ten years, reproductive biotechnologies using somatic cell nuclear transfer have made possible the production of cloned animals in various domestic and laboratory species. The influence of the cloning process on offspring characteristics has been studied in various developmental aspects, however, it has not yet been documented in detail for behavioral traits. Behavioral studies of cloned animals have failed to show clear inter-individual differences associated with the cloning process. Preliminary results showed that clones favor each other's company. Preferential social interactions were observed among cloned heifers from the same donor in a mixed herd that also included cloned heifers and control heifers produced by artificial insemination (AI). These results suggest behavioral differences between cloned and non-cloned animals and similarities between clones from the same donor. The aim of the present study was to replicate and to extend these previous results and to study behavioral and cognitive mechanisms of this preferential grouping. We studied a group composed of five cloned heifers derived from the same donor cow, two cloned heifers derived from another donor cow, and AI heifers. Cloned heifers from the same donor were more spatially associated and interacted more between themselves than with heifers derived from another donor or with the AI individuals. This pattern indicates a possible kin discrimination in clones. To study this process, we performed an experiment (using an instrumental conditioning procedure with food reward) of visual discrimination between images of heads of familiar heifers, either related to the subjects or not. The results showed that all subjects (AI and cloned heifers) discriminated between images of familiar cloned heifers produced from the same donor and images of familiar unrelated heifers. Cattle discriminated well between images and used morphological similarities characteristic of cloned related heifers. Our results suggest similar cognitive capacities of kin and non kin discrimination in AI and cloned animals. Kinship may be a common factor in determining the social grouping within a herd.

Dairy cattle exploratory and social behaviors: is there an effect of cloning?

While an increasing number of animals are produced by means of somatic cloning, behavioral studies on cloned animals are still rare. The aim of this study was to investigate whether the somatic cloning procedure has an influence on locomotion, exploratory, vocal and social behaviors of heifers. Ten heifers were used in the present study. Five of them were cloned heifers derived from somatic cells of three different Prim'Holstein cows and five others were same-age control heifers produced by artificial insemination. In addition to observations of social behaviors in the stable group, each animal was placed individually for a short time in an unfamiliar environment. Our results failed to show any statistical differences between clones and their controls both in frequencies of agonistic and non-agonistic behaviors. However, cloned heifers showed significantly more non-agonistic and less agonistic behaviors towards other cloned partners than towards control ones. This result also stood for control heifers. As far as their Hierarchical Index was concerned, three cloned heifers were highest ranking and two others lowest ranking. In this herd, social dominance appeared to be linked to body weight and age rather than to a cloning effect. In an unfamiliar environment, cloned and control subjects exhibited the same level of locomotion and vocalization. However, cloned heifers showed more exploratory behaviors than did control ones. This difference could be due to environmental factors during the postnatal period rather than to cloning.

LRP5 gene polymorphisms and idiopathic osteoporosis in men.

Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have demonstrated the role of LRP5 in bone mass acquisition. LRP5 variants were recently reported to contribute to the population-based variance in vertebral bone mass and size in males. To investigate whether LRP5 variants are implicated in idiopathic male osteoporosis, we studied 78 men with low BMD (<2.5 T score or < -2 Z score) aged less than 70 years (mean +/- SD: 50 +/- 16 years) in whom secondary causes of osteoporosis had been excluded and 86 controls (51 +/- 10 years). Genotypes and haplotypes were based on LRP5 missense substitutions in exons 9 (c.2047G > A, p.V667M) and 18 (c.4037C > T, p.A1330V), and their association with osteoporosis evaluated after adjustment for multiple clinical and environmental variables using logistic regression. The presence of osteoporosis was significantly associated with LRP5 haplotypes (P = 0.0036) independent of age (P = 0.006), weight (P = 0.004), calcium intake (P = 0.002), alcohol (P = 0.005) and tobacco (P = 0.004) consumption. Accordingly, the odds ratio for osteoporosis was 3.78 (95% CI 1.27-11.26, P < 0.001) in male carriers of haplotype 3 (c.2047A-4037T, n = 20 cases and 12 controls) versus homozygous carriers of haplotype 1 (c.2047G-4037C, n = 42 cases and 61 controls). In conclusion, these data indicate beyond a significant role for environmental factors, an association between LRP5 variants and idiopathic osteoporosis in males, pointing to a role of LRP5 in this disease.

Bone mass density and risk of breast cancer and survival in older women.

STUDY OBJECTIVE: Older women with high bone mineral density (BMD) have an increased risk of breast cancer but it is not well known whether this association is associated with the stage of the tumor. The objective of the study is to determine if older women with high BMD are likely to develop a more aggressive form of breast cancer, as defined by mortality. PATIENTS: We prospectively studied 1504 women who were 75 years of age or older at the entry in the study (range, 75-90 years), between 1992 and 1994. BMD was measured by dual-photon X-ray absorptiometry at three skeletal sites (trochanter, Ward's triangle, femoral neck). The women were followed for a mean of 7 years for the occurrence of breast cancer. Cox proportional-hazards models were used to obtain estimates of the relative risk of breast cancer and relative risk of death according to the BMD. MAIN RESULTS: Forty-five incident breast cancer cases were identified. In multivariate analyses of the risk of breast cancer for women in the highest tertile of BMD was greater than for women in the lowest tertile. Indeed, the women with a trochanter BMD in the highest tertile were at 2.3-fold increased risk compared with women in the lowest tertile. The women with highest tertile BMD measured at the Ward's triangle and at the femoral neck were respectively at 2.2-and 3.3-fold increased risk compared with women at the lowest risk. The 7-year survival rates were markedly less favorable for women in the second and third tertile of the three skeletal sites compared with the lowest tertile. The risk of death was greater for women in the highest tertile of BMD than for women in the lowest tertile at every skeletal site. CONCLUSION: Elderly women with high BMD have an increased risk of breast cancer, especially advanced cancer, compared with women with low BMD.

Biological effects of drinking-water mineral composition on calcium balance and bone remodeling markers.

OBJECTIVE: To compare the effects of 2 drinking waters containing similar calcium (Ca) concentration in order to analyze the role of ions other than Ca on bone metabolism. These mineral drinking-waters differed by their mineral composition primarily concerning the concentration of bicarbonate (HCO3-), high in the HB, and sulfate, high in HS water. DESIGN: Of 60 included women, 39 completed the study. Patients were randomly assigned to an intake of 1 liter per day of mineral water HB or HS for 28 d, followed by cross-over to the alternative drinking-water for a further 28 d. At baseline and after each period of one month, Ca metabolism parameters, acid-base status, and bone remodeling markers were measured. RESULTS: Changes in Ca metabolism were significant in the HB group where the ionized Ca increased and the PTH decreased. Serum pH showed a similar increase whatever the used drinking water compared to baseline. In the HB group, significant increase in urine pH, and significant decrease in AT-HCO3- and NH4+ were observed. Bone resorption markers, urinary CTx/Cr, Pyr/Cr, and D-Pyr/Cr, significantly decreased in the HB group compared to baseline, and were not significantly modified in the HS group. CONCLUSIONS: These results showed a beneficial effect of the bicarbonaterich HB water on bone metabolism. This may account for a better bioavailability of the Ca, a greater alkalinization, and a larger decrease in PTH level secondary to a higher ionized Ca level. The higher content of silica in HB water may have also participated to the positive action on bone balance that was observed. In this short term study, these data underlined the potential role of the mineral drinking water composition on bone metabolism.

BMD is reduced in HIV-infected men irrespective of treatment.

UNLABELLED: Osteoporosis has be reported to be a complication of active antiretroviral therapy of HIV infection. We studied 148 HIV-infected men stratified according to their treatment. Our data show that these patients have an average 9% decreased BMD, irrespective of their treatment. Low body mass index and high resorption markers were associated with low bone density. INTRODUCTION: Osteoporosis has been reported in HIV-infected (HIV+) patients, and it has been suggested that it may be linked to protease-inhibitor treatments (PI). MATERIALS AND METHODS: To assess this risk and to investigate its putative link with treatments, we compared the bone density of HIV+ men, who were either receiving treatment (including PI [PI+], n = 49; without PI [PI-], n = 51) or untreated (UT, n = 48). We included 81 age-matched control HIV-negative (HIV-) males (age, 40 +/- 8 years). RESULTS: BMD adjusted for age (Z-score) was lower in the HIV+ patients at the lumbar spine (HIV+: -1.08 +/- 1.21, HIV-: -0.06 +/- 1.26, p < 0.001) and the femoral neck (HIV+: -0.39 +/- 1.05, HIV-: 0.25 +/- 0.87, p < 0.001). The prevalence of osteoporosis was 16% in HIV+ and 4% in HIV- subjects (p < 0.01). In the HIV+ subjects, the Z-score was correlated only to body mass index (r = 0.27 at lumbar spine and 0.35 at femoral neck). Untreated HIV+ patients had a negative Z-score (-0.82 +/- 1.15 for the lumbar spine), which was not different from the one of treated HIV+ patients. In the PI+ and PI- groups, the Z-score did not depend on the presence of lipodystrophy or the proportion of fat in the abdomen and legs measured by DXA. Markers of bone remodeling were measured in the 132 HIV+ and 35 HIV- subjects. Compared with controls, HIV+ patients had lower bone alkaline phosphatase and higher urinary cross-laps/Cr, which was negatively correlated with the Z-score at both the femoral neck (r = -0.22) and lumbar spine (r = -0.21). TNFalpha was increased in untreated compared with treated HIV+ subjects and was not correlated to the Z-score. CONCLUSION: Our cross-sectional study does not show any deleterious effect of the treatment but does indicate a decrease in bone density in HIV+ patients irrespective of the treatment. This low bone density is in part related to the low body weight and is associated with increased bone resorption.

Osteoporosis in patients on long-term home parenteral nutrition: a longitudinal study.

UNLABELLED: The prevalence of osteoporosis was investigated in 88 patients with intestinal failure (IF). Osteoporosis was found in 67%, dependent of body mass index and age when IF occurred. In 56 patients on HPN, followed prospectively, changes in bone density were dependent on the duration of HPN; older patients had a higher increase. INTRODUCTION: It has been suggested that low bone mass and negative bone balance may occur in adult patients receiving home parenteral nutrition (HPN). The aim of this study was to assess prospectively the prevalence of osteoporosis in intestinal failure (IF) patients and the changes in bone mineral density in those on long-term HPN and to analyze the factors that may influence the occurrence and evolution of osteoporosis. MATERIALS AND METHODS: Bone mineral density was measured at the lumbar spine and femoral neck in 88 IF patients. RESULTS: At the first bone mineral density determination (baseline), the prevalence of osteoporosis was 67% in this population (median age, 52 years). Ten percent of the patients with osteoporosis experienced fragility fractures. Osteoporosis was independent of age and gender but occurred earlier in patients who had received corticosteroids. At baseline, the lumbar Z-score was positively correlated mainly to body mass index and age when IF occurred; these two parameters explained 34% of the Z-score. Repeated measurements were performed in 56 patients during long-term HPN (mean duration, 5.5 +/- 1.2 years). The changes in Z-score at the lumbar spine were dependent on the age when IF occurred and on the duration of HPN, with a synergistic effect between them. The older the patients, the higher the increase in Z-score during HPN. CONCLUSION: HPN had no deleterious effect on cortical bone and actually improved trabecular bone in patients whose intestinal disease started after the age of 21 years.

Reduced bone mineral density in postmenopausal women self-reporting premenopausal wrist fractures.

Postmenopausal fractures are associated with low bone mass; however, the role of low peak bone mass in young adults in determining subsequent osteoporosis suggests that premenopausal fractures may also be relevant. We therefore sought to determine whether a self-reported previous history of premenopausal wrist and nonwrist fractures could also be associated with bone density and therefore be used to predict osteoporosis. We recruited 453 volunteer women with a median age of 64 years (range 50-83 years), with no metabolic bone disease, previous femoral neck fracture, or prevalent vertebral fracture. Bone density at the femoral neck (FN) and lumbar spine (LS) was measured using a Lunar DPX-L. As expected, the 319 women who did not report any fracture had a higher T score at LS (-0.93 +/- 1.44) than the 134 women who reported a previous fracture at any site and at any age (T score -1.60 +/- 1.21, p < 0.001). The findings for the FN were similar. Compared with fracture-free women, the women who reported a first wrist fracture before menopause now had a lower LS T score (-1.77 +/- 1.20, n = 15, p < 0.05), whereas those who reported a nonwrist fracture showed no significant decrease in their LS T score (-1.26 +/- 1.00, n = 36). When both wrist and nonwrist fractures had occurred after menopause, the T score was significantly lower. Twenty percent of the fracture-free women were osteoporosis patients. After adjusting for body weight, age, hormonal replacement therapy (HRT), and hip fracture in the family, the relative risk (RR) of osteoporosis for premenopausal wrist fractures was 2.7 (95% confidence interval 1.4-4.3) vs. 1.2 (0.7-2.4) for women with premenopausal nonwrist fractures. We conclude that self-reported premenopausal wrist fractures, but no other fractures occurring before menopause, are likely to be associated with osteoporosis at 65 years of age, and therefore constitute strong grounds for screening.

Foraging behavioural changes induced by conspecific and heterosubspecific odours in two strains of wild mice.

Mice in wild populations of the two subspecies Mus musculus domesticus and Mus musculus musculus may potentially compete for food. Because of the importance of olfaction in mice, we hypothesised that the presence of unfamiliar conspecific or heterosubspecific chemical cues could play a role in access to and use of food resources. We used an experimental design that tested this assumption with males from two strains, originated from wild populations of these subspecies, as subjects. Exploratory activity, latency of food approach, time and frequency on the food area, number of seeds eaten and foraging rate (number of seeds eaten/time on the food areax100) were compared for three different categories of odours (own, same strain and other strain odours) in both strains. In a foraging context, unfamiliar odours induced behavioural changes in male mice, especially an increase in exploratory activity from the more (same strain) to the less similar odour (different strain), and a reduction of time spent in the food area. Odour similarity related to genetic proximity in Mus and the cost-benefit ratio of an encounter are two possible explanations for the different processes involved in the treatment of odours in these two strains of mice.

Genetic and environmental factors affect bone density variances of families of men and women with osteoporosis.

Our aim was to assess the relative impacts of genetics and environment in the families of osteoporotic patients and identify the best subgroup of patients to investigate the genes associated with osteoporosis. We recruited 36 men and 47 women with osteoporosis (probands), median age of 52 and 68 yr, and all their siblings (90) and offspring (83). The families were classified as young or old on the basis of the median age of the probands. We measured the bone mineral density at the femoral neck (FN) and lumbar spine (LS) adjusted for age and weight and standardized (Z-score). Physical activity, nutritional calcium, and alcohol and tobacco consumption were investigated. We compared the mean Z-score using linear mixed model and assessed the familial resemblance using intraclass correlation. The mean Z-scores of the families of osteoporotic patients were significantly negative at FN and LS, with no intergeneration or intergender differences. At FN, but not at LS, the mean Z-score was independently lower in the families of male probands (mean +/- SD: -0.57 +/- 0.96, female: -0.18 +/- 0.85, P = 0.012) and in young families (-0.58 +/- 0.94, old families: -0.11 +/- 0.83, P = 0.006). This suggested that the lower Z-score in the families of men with osteoporosis was related to their younger age. There was significant phenotypic resemblance among members in the families. In the families of female probands, the correlation between the probands and her siblings was weak and disappeared after adjustment on environment, and a resemblance appeared within their children (FN: r = 0.61) suggesting that different environment had masked the resemblance in this subgroup. In the families of male probands, a strong resemblance persisted after adjusting for environment, (proband-offspring at FN: r = 0.46 and within offspring at FN: r = 0.66, at LS: r = 0.61). This showed that resemblance was independent of a common measurable environment in these families of men with osteoporosis. In conclusion, mainly young osteoporotic patients, most of whom were male in our study, are affected by the genetic component.

Alcohol consumption by non-institutionalised elderly women: the EPIDOS Study.

The prevalence of alcohol use declines with age, but studies suggest that between 2% and 4% of the elderly population have a particularly high alcohol consumption. The objective of this study was to verify or refute this finding and identify clinical or social characteristics associated with alcohol consumption. We measured alcohol consumption by autoquestionnaire in 7575 women, aged 75 or older, recruited at five centers in France. The alcohol consumption was computed taking account of the number of beer, wine or liquor (or spirits) drinks consumed per day. The mean age of the respondents was 80+/-6 y. Forty percent used some alcohol and 2.5% drank more than 30 grams per day. Smoking, good health status, higher socioeconomic status or single marital status were factors whose percentages increased significantly with increasing alcohol use. Despite the advanced age of this population, regular alcohol intake was prevalent but not heavy and abusive consumption drinking. Drinking appears to be associated with some medical or social characteristics and possibly with better health status.

Indomethacin increases 15-PGDH mRNA expression in HL60 cells differentiated by PMA.

We previously reported an induction of 15-hydroxyprostaglandin dehydrogenase type I mRNA (15-PGDH) expression accompanied by a decrease in prostaglandin E2(PGE2) levels during cord blood monocytes differentiation into preosteoclastic cells by 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3). These results suggested a role of prostaglandin (PG) enzymes in adhesion and/or differentiation of monocytes. In the present work, we studied modulation of gene expression of PG metabolism enzymes mRNAs in HL60 cells differentiated by phorbol myristate acetate (PMA) into the monocyte/macrophage lineage. We showed that adhesion of HL60 induced by PMA causes an increase of cyclooxygenase 2 (COX 2) and 15-PGDH mRNAs. When adding indomethacin, a non steroidal antiinflammatory drug known to inhibit COX activity, the cells remained attached and expressed large amounts of 15-PGDH mRNA while COX 2 mRNA expression remained unchanged. Indomethacin, in association with PMA can consequently exert a dual control on key enzymes of PGE2 metabolism without modifying adhesion of the cells.

Defects in adhesion and migration, but not in proliferation and differentiation, of embryonic stem cells upon replacement of integrin subunit beta1A by beta1D.

Beta1D is a skeletal muscle-specific splice variant of the beta1 integrin subunit, while beta1A integrin subunit has a wide tissue distribution. We have previously shown that replacement of beta1A by beta1D by homologous recombination (knockin) in all mouse tissues was embryonic lethal. Through two successive rounds of homologous recombination, we have now produced embryonic stem (ES) cells expressing beta1D instead of beta1A, and analyzed the ability of beta1D to support ES cell differentiation in vitro and in teratomas in vivo. Beta1D knockin (KI) ES cells grew at a similar rate but as more compact colonies than the beta1A-expressing cells. Increased cell cohesiveness, however, did not appear to involve changes in cadherin activity. Although in both beta1A and beta1D-KI ES cells only one beta1 allele is active; the expression of beta1 integrins in the beta1D-KI ES cells was reduced by 50%, compared with that in the beta1A-expressing cells; this correlated with impaired adhesive and migratory capacities. It appeared that during in vitro cardiac differentiation, in spite of a slight delay in the induction of two cardiac-specific transcripts, the alpha- and beta-myosin heavy chains, contracting cardiomyocytes were detected in similar numbers and at the same time in embryoid bodies (EB) derived from beta1D-KI and from beta1A cells. Furthermore, replacement of beta1A by beta1D in ES cells did not affect neurite differentiation in embryoid bodies in the presence of retinoic acid suggesting that beta1D supports neurogenesis. However, the impaired migration of other cells from the EB, including endodermal cells, prevented the normal outgrowth of neurites in beta1D-KI EB. Finally, injection of beta1D-KI ES cells in the flank of syngeneic mice gave rise to fully developed teratomas containing simple and pluristratified epithelia, muscle, cartilage, blood vessels, and tissues from the neural lineage. These results show that the muscle-specific splice variant beta1D, in spite of its specific cytoplasmic domain, supports the differentiation of many cell types. This further suggests that the embryonic lethality in the beta1D-KI embryos was mainly due to the different ability of beta1 A and beta1D to mediate cell adhesion and migration.

A comparative study of parental care between two rodent species: implications for the mating system of the mound-building mouse Mus spicilegus.

Paternal care is uncommon in mammals where males are more often involved in sexual competition than in providing care for their own offspring. However some species present some form of paternal care and, most of the time, this phenomenon is associated with a monogamous mating system. Mice of the genus Mus, such as the house mouse Mus musculus domesticus, are commonly considered to be polygamous-polygynous species. In Mus spicilegus, the mound-building mouse, previous results on female sexual preferences have suggested the existence of pair bonding more compatible with a monogamous mating system than with a polygamous one. We therefore tested the hypothesis that male M. spicilegus present a higher level of paternal care than males of the polygynous house mouse. Results showed that male M. spicilegus spent significantly more time covering the young during the first week after birth than male M. m. domesticus, particularly when the female was exploring, and retrieved stray pups significantly more frequently and more rapidly than male M. m. domesticus. There were practically no differences between the females of these two species. M. spicilegus parents also more significantly alternated their protection of the pups than M. m. domesticus parents. We discuss the evolution of paternal care in M. spicilegus in relation to monogamy.

Effect of alcohol intake on bone mineral density in elderly women: The EPIDOS Study. Epidémiologie de l'Ostéoporose.

To study potential associations between alcohol consumption and bone mineral density in women aged 75 years or older, the authors analyzed 7,598 ambulatory women (mean age, 79.9 years; standard deviation, 3.8 years) recruited at five centers in France between 1992 and 1994. The current alcohol intake was assessed using a self-questionnaire. Bone mineral density was measured by dual-photon X-ray absorptiometry of the proximal femur and total body and adjusted for age, weight, and height (Z score). Compared with nonusers, women who drank 11-29 g of alcohol per day (g/day) had higher bone mineral density values at the trochanteric site (p = 0.0017). Neither 1-10 g/day nor >30 g/day users had increased bone mineral density levels. These results were unrelated to estrogen replacement therapy use, dietary calcium intake, current smoking status, usual physical activity, educational attainment, household monthly income, and general health status. Alcohol intake was not associated with bone mineral density at the femoral neck. Total body bone mineral density was lower in subjects with alcohol intakes >30 g/day (p = 0.047). Our data suggest that moderate drinking (e.g., 1-3 glasses of wine per day) is associated with an increase in trochanteric bone mineral density in elderly ambulatory women. However, higher intakes may have detrimental effects on bone mass.

Calcitonin receptor mRNA in mononuclear leucocytes from postmenopausal women: decrease during osteoporosis and link to bone markers with specific isoform involvement.

Calcitonin inhibits bone resorption via its receptor (CTR) on osteoclasts. Two hCTR isoforms, hCTR1 and hCTR2, give proteins that differ in their structure and signaling pathways. We investigated whether specific isoforms or quantitative changes in total hCTR mRNA were associated with high bone resorption and turnover in menopause or osteoporosis. The hCTR mRNA in mononuclear blood cells of premenopausal (PreM), healthy (PostM), and osteoporotic (OsteoP) postmenopausal women was assessed using reverse-transcriptase polymerase chain reaction. hCTR1 and hCTR2 were investigated for 59 total RNA samples, and semiquantitative analysis of total hCTR mRNA was performed for 71. Serum calcitonin, free urinary deoxypyridinoline (D-Pyr), serum bone alkaline phosphatase (SBAP), and osteocalcin (SOC) were also evaluated. Serum calcitonin levels did not differ in PostM and OsteoP. The prevalence of each isoform was similar in the three groups. Healthy postmenopausal women and OsteoP with hCTR2 had lower bone turnover (D-Pyr: 6.79 +/- 0.54, n = 25; SBAP: 11.63 +/- 1.47, n = 26; SOC: 8.31 +/- 0.58, n = 26) than those without hCTR2 (D-Pyr: 9.90 +/- 1.95, n = 5; SBAP: 21 +/- 5.19, n = 5; SOC: 11.9 +/- 2.10, n = 5; p < 0.05). Total hCTR mRNA levels were not different in PreM and PostM. By contrast, values were strikingly lower in OsteoP (0.57 +/- 0.17, n = 28) than in PostM (2. 25 +/- 0.61, n = 19, p < 0.05) and negatively correlated with bone markers values in both. We suggest that a specific isoform and amounts of total hCTR mRNA are linked to increased bone resorption in postmenopausal osteoporosis.

Discrimination of olfactory sexual cues in staggerer mutant male mice.

Generally, staggerer male mice do not express any preference between oestrous and anoestrous female odours in a choice test situation. The staggerer ability to discriminate between these olfactory sexual cues was evaluated in an habituation-dishabituation paradigm. In this situation it was found that the staggerer mice discriminate between these two odours. The lack of sexual odour preference in staggerer male mice is discussed through hormonal and neurological interpretation.

Olfactory learning abilities in staggerer mutant mice.

Staggerer mutant mice were compared to non-mutant mice in two olfactory learning tasks. It was found that, in spite of a delayed acquisition compared to non-mutants, staggerer mice were able to learn an olfactory habituation task. On the other hand, staggerer presented deficits in an associative olfactory task and, contrary to non-mutants, did not learn this task. Perturbations in olfactory bulbs of staggerer mice could explain their olfactory learning deficits.