Impaired musculoskeletal response to age and exercise in PPARβ(-/-) diabetic mice.

Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARβ(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARβ(-/-) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPARβ(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPARβ(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARβ(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARβ controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARβ deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPARβ appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances.

A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.

When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Development of assistive technology for the visually impaired: use of the male condom

The objectives were to develop and evaluate an assistive technology for the use of the male condom by visually impaired men. It was a technology development study with the participation of seven subjects. Three workshops were performed between April and May of 2010; they were all filmed and the statements of the participants were transcribed and analyzed by content. Three categories were established: Sexuality of the visually impaired; Utilization of the text, For avoiding STDs, condoms we will use, divided in two subcategories, Concept discussion and Text evaluation; and Construction of a simple penile prosthesis. The knowledge transmitted related to STD, the utilization of the condom on the penile prosthesis made by the subjects themselves, and the interaction during the workshops were effective factors for the study. In the context of sexual health, the necessity of developing works involving the visually impaired was noted, addressing sexually transmitted diseases and focusing on the use of the condom by this population.

Repairing the Impaired: Two Iowa Success Stories, 2005

More than 200 lakes, streams and rivers are on Iowa’s impaired waters list. Pollutants prevent these waters from supporting aquatic life, or from being used for drinking water or for full body recreational contact, like swimming. While improving Iowa’s water quality may seem a daunting task, two southern Iowa lakes show that it can be done.

Assistive technology for visually impaired women for use of the female condom: a validation study

OBJECTIVE To validate assistive technology for visually impaired women to learn how to use the female condom. METHOD a methodological development study conducted on a web page, with data collection between May and October 2012. Participants were 14 judges; seven judges in sexual and reproductive health (1st stage) and seven in special education (2nd stage). RESULTS All items have reached the adopted parameter of 70% agreement. In Stage 1 new materials were added to represent the cervix, and instructions that must be heard twice were included in the 2nd stage. CONCLUSION The technology has been validated and is appropriate for its objectives, structure / presentation and relevance. It is an innovative, low cost and valid instrument for promoting health and one which may help women with visual disabilities to use the female condom.

Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.

Iowa Drivers Manual, 2006-2207

The rules and regulations for operating a motered vechicle in Iowa

Biological markers of alcohol consumption in alcoholised drivers: Comparison of capillary electrophoresis (CZE CDT) and a direct immunoassay (N Latex CDT) with the traditional method of anion-exchange chromatography-immunoturbidimetry (%CDT TIA).

Objectives: The aim of this study was to compare specificity and sensitivity of different biological markers that can be used in a forensic field to identify potentially dangerous drivers because of their alcohol habits. Methods: We studied 280 Swiss drivers after driving while under the alcohol influence. 33 were excluded for not having CDT N results, 247 were included (218 men (88%) and 29 women (12%). Mean age was 42,4 (SD:12, min: 20 max: 76). The evaluation of the alcohol consumption concerned the month before the CDT test and was considered as such after the interview: Heavy drinkers (>3 drinks per day): 60 (32.7%), < 3 drinks per day and moderate: 127 (51.4%) 114 (46.5%), abstinent: 60 (24.3%) 51 (21%). Alcohol intake was monitored by structured interviews, self-reported drinking habits and the C-Audit questionnaire as well as information provided by their family and general practitioner. Consumption was quantified in terms of standard drinks, which contain approximately 10 grams of pure alcohol (Ref. WHO). Results: comparison between moderate (less or equal to 3 drinks per day) and excessive drinkers (more than 3 drinks) Marker ROC area 95% CI cut-off sensitivity specificity CDT TIA 0.852 0.786-0917 2.6* 0.93 LR+1.43 0.35 LR-0.192 CDT N latex 0.875 0.821-0.930 2.5* 0.66 LR+ 6.93 0.90 LR- 0.369 Asialo+disialo-tf 0.881 0.826-0.936 1.2* 0.78 LR+4.07 0.80 LR-0.268 1.7° 0.66 LR+8.9 0.93 LR-0.360 GGT 0.659 0.580-0.737 85* 0.37 LR+2.14 0.83 LR-0.764 * cut-off point suggested by the manufacturer ° cut-off point suggested by our laboratory Conclusion: With the cut-off point established by the manufacturer, CDT TIA performed poorly in term of specificity. N latex CDT and CZE CDT were better, especially if a 1.7 cut-off is used with CZE

Lack of Smad3 signaling leads to impaired skeletal muscle regeneration.

Smad3 is a key intracellular signaling mediator for both transforming growth factor-β and myostatin, two major regulators of skeletal muscle growth. Previous published work has revealed pronounced muscle atrophy together with impaired satellite cell functionality in Smad3-null muscles. In the present study, we have further validated a role for Smad3 signaling in skeletal muscle regeneration. Here, we show that Smad3-null mice had incomplete recovery of muscle weight and myofiber size after muscle injury. Histological/immunohistochemical analysis suggested impaired inflammatory response and reduced number of activated myoblasts during the early stages of muscle regeneration in the tibialis anterior muscle of Smad3-null mice. Nascent myofibers formed after muscle injury were also reduced in number. Moreover, Smad3-null regenerated muscle had decreased oxidative enzyme activity and impaired mitochondrial biogenesis, evident by the downregulation of the gene encoding mitochondrial transcription factor A, a master regulator of mitochondrial biogenesis. Consistent with known Smad3 function, reduced fibrotic tissue formation was also seen in regenerated Smad3-null muscle. In conclusion, Smad3 deficiency leads to impaired muscle regeneration, which underscores an essential role of Smad3 in postnatal myogenesis. Given the negative role of myostatin during muscle regeneration, the increased expression of myostatin observed in Smad3-null muscle may contribute to the regeneration defects.

On the drivers of commodity co-movement: Evidence from biofuels

We use the recent introduction of biofuels to study the effect of industry factors on the relationshipsbetween wholesale commodity prices. Correlations between agricultural products and oilare strongest in the 2005-09 period, coinciding with the boom of biofuels, and remain substantialuntil 2011. We disentangle three possible drivers for the linkage: substitution, energy costs, andfinancialization. The timing and magnitude of the biofuels-to-oil relationships are different to thoseof other commodities, and far higher than can be justified by costs and financialization. Substitutionand costs drive the monthly correlations of long-term futures, and each of the three contributeequally to the daily co-movement of the short-term ones. The findings survive many robustnesschecks and appear in the stock market.

Drivers and sources of supply flexibility: An exploratory study

Purpose - There has been much research on manufacturing flexibility, but supply chain flexibility is still an under-investigated area. This paper focuses on supply flexibility, the aspects of flexibility related to the upstream supply chain. Our purpose is to investigate why and how firms increase supply flexibility.Methodology/Approach An exploratory multiple case study was conducted. We analyzed seven Spanish manufacturers from different sectors (automotive, apparel, electronics and electrical equipment).Findings - The results show that there are some major reasons why firms need supply flexibility (manufacturing schedule fluctuations, JIT purchasing, manufacturing slack capacity, low level of parts commonality, demand volatility, demand seasonality and forecast accuracy), and that companies increase this type of flexibility by implementing two main strategies: to increase suppliers responsiveness capability and flexible sourcing . The results also suggest that the supply flexibility strategy selected depends on two factors: the supplier searching and switching costs and the type of uncertainty (mix, volume or delivery).Research limitations - This paper has some limitations common to all case studies, such as the subjectivity of the analysis, and the questionable generalizability of results (since the sample of firms is not statistically significant).Implications - Our study contributes to the existing literature by empirically investigating which are the main reasons for companies needing to increase supply flexibility, how they increase this flexibility, and suggesting some factors that could influence the selection of a particular supply flexibility strategy.

Gazelle companies: Growth drivers and an evolution analysis

Gazelle companies are relevant because they generate much more employment than other companies and deliver high returns to their shareholders. This paper analyzes their behavior in the years of high growth and their evolution in the following years. The main factors that explain their success are competitive advantages based on human resources, innovation, internationalization, the excellence in processes and a conservative financial policy. Nevertheless, as time goes by they can be divided in two groups: a group which continues having growth, but most of them with lower growth rates; and the rest which face great problems or even disappear. The present study identifies several key factors that explain this different evolution.