Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

Cognition and psychopathology in nonagenarians and centenarians living in geriatric nursing homes in Switzerland: a focus on anosognosia.

BACKGROUND: The number of nonagenarians and centenarians is rising dramatically, and many of them live in nursing homes. Very little is known about psychiatric symptoms and cognitive abilities other than memory in this population. This exploratory study focuses on anosognosia and its relationship with common psychiatric and cognitive symptoms. METHODS: Fifty-eight subjects aged 90 years or older were recruited from geriatric nursing homes and divided into five groups according to Mini-Mental State Examination scores. Assessment included the five-word test, executive clock-drawing task, lexical and categorical fluencies, Anosognosia Questionnaire-Dementia, Neuropsychiatric Inventory, and Charlson Comorbidity Index. RESULTS: Subjects had moderate cognitive impairment, with mean ± SD Mini-Mental State Examination being 15.41 ± 7.04. Anosognosia increased with cognitive impairment and was associated with all cognitive domains, as well as with apathy and agitation. Subjects with mild global cognitive decline seemed less anosognosic than subjects with the least or no impairment. Neither anosognosia nor psychopathological features were related to physical conditions. CONCLUSIONS: Anosognosia in oldest-old nursing home residents was mostly mild. It was associated with both cognitive and psychopathological changes, but whether anosognosia is causal to the observed psychopathological features requires further investigation.

Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.

Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ?3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C(tau), or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C(tau), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and raltegravir-glucuronide/raltegravir AUC(0-12) were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C(tau) with a once-daily raltegravir dose of 400 mg similar to the C(tau) with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.

Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study.

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. CONCLUSION: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

Privatization and competition in the delivery of local services: An empirical examination of the dual market hypothesis

This paper empirically analyses the hypothesis of the existence of a dual market for contracts in local services. Large firms that operate on a national basis control the contracts for delivery in the most populated and/or urban municipalities, whereas small firms that operate at a local level have the contracts in the least populated and/or rural municipalities. The dual market implies the high concentration and dominance of major firms in large municipalities, and local monopolies in the smaller ones. This market structure is harmful to competition for the market as the effective number of competitors is low across all municipalities. Thus, it damages the likelihood of obtaining cost savings from privatization.

Prevalence of nits and lice in sampls of cut hair from floors of barbershop and beauty parlors in Belo Horizonte, Minas Gerais state, Brazil

A louse survey based on samples of cut hair collected from floors of barbershops and beauty parlors was conducted in Belo Horizonte, Minas Gerais State, Brazil, from October 1984 to April 1985, as an alternative way to determine the prevalence of pediculosis capitis in the population. Of 475 samples examined for nits, nymphs, or adults of Pediculus capitis, 140 were infested (29.5%). A total of 58 lice and 3.553 nits were found in 33.632.9 g of hair collected, giving a ratio of 0.10 nit/g. Almost 29% of the nits were viable and capable of being transmitted after hatching. There was significant difference among the infestation rates by socioeconomic levels, and samples from barbershops with male customers were the most infested. based upon the number of haircuts in each sample, we estimated that 5 or 6% of the population might be infested by this species.

Economic development and changes in car ownership patterns

The contributions of this paper are twofold: On the one hand, the paper analyses the factors determining the growth in car ownership in Spain over the last two decades, and, on the other, the paper provides empirical evidence for a controversial methodological issue. From a methodological point of view, the paper compares the two alternative decision mechanisms used for modelling car ownership: ordered-response versus unordered-response mechanisms. A discrete choice model is estimated at three points in time: 1980, 1990 and 2000. The study concludes that on the basis of forecasting performance, the multinomial logit model and the ordered probit model are almost undistinguishable. As for the empirical results, it can be emphasised that income elasticity is not constant and declines as car ownership increases. Besides, households living in rural areas are less sensitive than those living in urban areas. Car ownership is also sensitive to the quality of public transport for those living in the largest cities. The results also confirmed the existence of a generation effect, which will vanish around the year 2020, a weak life-cycle effect, and a positive effect of employment on the number of cars per household. Finally, the change in the estimated coefficients over time reflects an increase in mobility needs and, consequently, an increase in car ownership.

Evaluation of different Cypermethrin formulations and concentrations in the control of Musca domestica

Cypermethrin (4 g/l, 5 g/l wettable powder and 7 ml/l, 10 ml/l emulsifiable concentrate) was tested, under laboratory conditions, against the adult Musca domestica. As a standard for comparison, a 6 ml/l concentrate suspension formulation of deltamethrin was used. One and twenty-four hours after application, mortality counts showed that the substances under test killed, respectively, more than 80% and 85% of the exposed insects. Under the conditions of the test, cypermethrin was considered effective in the control of the house fly.

Modelling Breaks and Clusters in the Steady States of Macroeconomic Variables

Macroeconomists working with multivariate models typically face uncertainty over which (if any) of their variables have long run steady states which are subject to breaks. Furthermore, the nature of the break process is often unknown. In this paper, we draw on methods from the Bayesian clustering literature to develop an econometric methodology which: i) finds groups of variables which have the same number of breaks; and ii) determines the nature of the break process within each group. We present an application involving a five-variate steady-state VAR.

Matching and Sorting in a Global Economy

We develop a neoclassical trade model with heterogeneous factors of production. We consider a world with two factors, labor and .managers., each with a distribution of ability levels. Production combines a manager of some type with a group of workers. The output of a unit depends on the types of the two factors, with complementarity between them, while exhibiting diminishing returns to the number of workers. We examine the sorting of factors to sectors and the matching of factors within sectors, and we use the model to study the determinants of the trade pattern and the effects of trade on the wage and salary distributions. Finally, we extend the model to include search frictions and consider the distribution of employment rates.

Characterisation of heteromers and oligomers in the TNF family of ligands and receptors

TNF family ligands and receptors fulfill a number of functions, mainly in the immune system. For example, the ligands BAFF and APRIL control growth and survival of mature Β cells at various stages of differentiation. TNF family ligands usually form homotrimers, but heteromers have also been described for lymphotoxin α1β2 and for BAFF and APRIL. Interestingly, twenty BAFF homotrimers can assemble into virus-like particles coined BAFF 60-mer, which are superior to BAFF 3-mer regarding their ability to signal in primary Β cells. A screen was performed in 293T cells, by co-transfecting differently tagged ligands, to identify six novel heteromers. The specificity of these novel heteromers, however, did not correspond to that of orphan receptors in the TNFR family. Little is known about heteromers of BAFF and APRIL, in particular their receptor-binding specificity and their ability to signal. A method to produce and purify heteromers of defined stoechiometry was developed, and the resulting reagents were used to demonstrate that BAFF2APRIL, like BAFF, binds to all BAFF receptors - namely BAFFR, TACI and Β CM A -, while APRIL2BAFF and APRIL only binds to TACI and BCMA. Heteromers could signal via their cognate receptors, sometimes as potently and sometimes less potently than homomers, depending on the receptors. A promising system to measure the activity of single-chain homo- and heteromers in vivo was set up: it measures mature Β cell rescue upon administration of single-chain ligands into BAFF-ko mice. To tackle the question of the physiological importance of BAFF 60-mer, a point mutation that prevents assembly of mouse BAFF into 60-mer while retaining its ability to form trimers was identified. This mutation (E247K) was introduced by homologous recombination into mouse embryonic stem cells that are now being used to generate knock-in mice. Results obtained in this work will help to better understand the role of various BAFF and APRIL forms that are elevated in a several autoimmune diseases. - Les ligands et récepteurs de la famille du TNF joue un rôle prédominant dans le système immunitaire. Par exemple, les ligands BAFF et APRIL contrôlent la croissance et la survie des cellules Β matures à différents stades de différenciation. Ces ligands existent souvent sous forme d'homotrimères (3-mer), bien que des héteromères aient été décrits pour la lymphotoxine α1β2 et pour BAFF et APRIL. Dans le cas de BAFF, vingt trimères peuvent, telle une particule virale, s'assembler en 60-mer qui surpasse le 3-mer pour signaler dans des cellules Β primaires. Un crible effectué dans des cellules 293T, par co-transfection de ligands différemment marqués, a permis d'identifier six nouveaux heteromères dont la spécificité n'a, hélas, pas correspondu à celle d'un récepteur orphelin de la famille du TNFR. Les connaissances sur la spécificité de liaison aux récepteurs et la capacité à signaler des heteromères de BAFF et d'APRIL sont fragmentaires. Une méthode pour produire et purifier des heteromères "simple chaîne" de stoechiométrie déterminée a été mise au point, et les réactifs ainsi obtenus utilisés pour démontrer que BAFF2APRIL, comme BAFF, lie tous les récepteurs de BAFF - c'est-à-dire BAFFR, TACI et BCMA -, alors qu'APRIL2BAFF et APRIL ne lient que TACI et BCMA. Les héteromères peuvent transmettre des signaux, parfois aussi bien et parfois plus faiblement que les homomères, selon les récepteurs. Un système prometteur pour mesurer l'activité des ligands simple chaîne in vivo a été mis au point. Il mesure la réapparition de cellules Β matures dans des souris déficientes pour BAFF après administration des ligands. Pour s'attaquer à la question de l'importance physiologique du 60-mer de BAFF, ime mutation empêchant l'assemblage en 60-mer sans affecter la capacité à former des trimères a été identifiée. Cette mutation (E247K) a été introduite par recombinaison homologue dans des cellules souches embryonnaires de souris qui sont utilisées pour obtenir des souris déficientes en BAFF 60-mer. Les résultats de ces travaux contribueront à mieux cerner le rôle des différentes formes de BAFF et d'APRIL produites en excès dans plusieurs maladies auto-immunes.

Le nombre de reines chez les fourmis et sa conséquence sur l'organisations sociale

Nearly half of all ant species form polygyne societies (cohabitation of more than a single egg-laying queen). These queens are generally smaller and store fewer fat reserves than queens from monogyne colonies. Most queens in polygyne colonies (70-100 pour 100) are inseminated, although this proportion varies among species, and even among populations of the same species. They exhibit mutual tolerance and they all contribute to the reproductive effort of the colony. Nevertheless, their individual fecundity is considerably reduced compared with that of queens from monogyne colonies. This reduction in fecundity seems to be due to some form of mutual inhibition, in some cases the secretion by each female of a substance suppressing egg production in other queens has been implicated. In a few species, queens are organized into a hierarchy such that certain queens lay more eggs than others or even monopolize egg-laying (functional monogyny). Polygyny is linked to a particular life history. It rarely results from the association of several foundresses (primary polygyny). Usually, it is due to the adoption of young queens by an established nest just after a nuptial flight. This secondary polygyny means that the dispersal of the species is limited and is achieved by the budding of a mother nest. Thus colony founding is dependent; with workers accompanying young queens in establishing new colonies. Observation of closely related species exhibiting different social organizations, some monogyne and others polygyne, shows a possible link between queen number and ecological conditions: polygyne forms are more frequent in unstable habitats susceptible to rapid change, such as that caused by human activity. The existence of polygyne societies is an intriguing evolutionary mystery. Research into the origin and maintenance of polygyny focuses on patterns of speciation in relation to queen number and the different theories put forth for the evolution of eusociality, mainly kin selection and mutualism.

Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects

The last several years have seen an increasing number of studies that describe effects of oxytocin and vasopressin on the behavior of animals or humans. Studies in humans have reported behavioral changes and, through fMRI, effects on brain function. These studies are paralleled by a large number of reports, mostly in rodents, that have also demonstrated neuromodulatory effects by oxytocin and vasopressin at the circuit level in specific brain regions. It is the scope of this review to give a summary of the most recent neuromodulatory findings in rodents with the aim of providing a potential neurophysiological basis for their behavioral effects. At the same time, these findings may point to promising areas for further translational research towards human applications.

Reading Ng Kim Chew: Malaysian-Chineseness and memory in contemporary Malaysian Chinese literature in taiwan

The idea of Chineseness as a geographic, cultural-specific and ethnically-charged concept, and the pivotal role assumed by memory linger throughout the writings of most authors hailing from Chinese community in Southeast Asia. Among these communities, being the Malaysian Chinese the more prolific in terms of number of writers and pieces of literature produced, this paper deals specifically with it. Its focus is put on the literature produced by Malaysian Chinese authors residing in Taiwan, which topic constitutes an important part of the first chapter, and on one of its main representatives, Ng Kim Chew, to whom chapter two and three are fully dedicated. A literary analysis of one of his short stories, Huo yu tu, will allow the reader to have a first-hand experience, through excerpts from the original text, of the importance of Chineseness and memory in the literary production of Ng and of many authors sharing with him similar life and literary experiences. I started this research from the assumption that these authors make large use of their own memories and memories from their own community in their writing as a way to re-tie themselves to the Chineseness they left in their places of origin. However in the case of Ng Kim Chew, the analysis of his works led be to theorizing that the identity he is imbued with, if there is one, is not Chinese, nor Malaysian, but purely and distinctively Malaysian-Chinese. This paper can also serve as an introduction for the general public to the field of Sinophone literature from Southeast Asia and to promote wider and innovative paths of research within the realm of Chinese studies that go beyond China proper.

Health care utilization among immigrants and native-born populations in 11 European countries. Results from the Survey of Health, Ageing and Retirement in Europe

Objective: This study examines health care utilization of immigrants relative to the native-born populations aged 50 years and older in eleven European countries. Methods. We analyzed data from the Survey of Health Aging and Retirement in Europe (SHARE) from 2004 for a sample of 27,444 individuals in 11 European countries. Negative Binomial regression was conducted to examine the difference in number of doctor visits, visits to General Practitioners (GPs), and hospital stays between immigrants and the native-born individuals. Results: We find evidence those immigrants above age 50 use health services on average more than the native-born populations with the same characteristics. Our models show immigrants have between 6% and 27% more expected visits to the doctor, GP or hospital stays when compared to native-born populations in a number of European countries. Discussion: Elderly immigrant populations might be using health services more intensively due to cultural reasons.