The effect of beta-alanine supplementation on neuromuscular fatigue in elderly (55–92 Years): a double-blind randomized study

<p>Abstract</p> <p>Background</p> <p>Ageing is associated with a significant reduction in skeletal muscle carnosine which has been linked with a reduction in the buffering capacity of muscle and in theory, may increase the rate of fatigue during exercise. Supplementing beta-alanine has been shown to significantly increase skeletal muscle carnosine. The purpose of this study, therefore, was to examine the effects of ninety days of beta-alanine supplementation on the physical working capacity at the fatigue threshold (PWC_FT) in elderly men and women.</p> <p>Methods</p> <p>Using a double-blind placebo controlled design, twenty-six men (n = 9) and women (n = 17) (age ± SD = 72.8 ± 11.1 yrs) were randomly assigned to either beta-alanine (BA: 800 mg × 3 per day; n = 12; CarnoSyn™) or Placebo (PL; n = 14) group. Before (pre) and after (post) the supplementation period, participants performed a discontinuous cycle ergometry test to determine the PWC_FT.</p> <p>Results</p> <p>Significant increases in PWC_FT(28.6%) from pre- to post-supplementation were found for the BA treatment group (p < 0.05), but no change was observed with PL treatment. These findings suggest that ninety days of BA supplementation may increase physical working capacity by delaying the onset of neuromuscular fatigue in elderly men and women.</p> <p>Conclusion</p> <p>We suggest that BA supplementation, by improving intracellular pH control, improves muscle endurance in the elderly. This, we believe, could have importance in the prevention of falls, and the maintenance of health and independent living in elderly men and women.</p

Innovation and growth in the UK pharmaceuticals: the case of product and marketing introductions

New drug introductions are key to growth for pharmaceutical firms. However, not all innovations are the same and they may have differential effects that vary by firm size. We use quarterly sales data on UK pharmaceuticals in a dynamic panel model to estimate the impact of product (new drugs) and marketing (additional pack varieties) innovations within a therapeutic class on a firm’s business unit growth. We find that product innovations lead to substantial growth in both the short and long run, whereas a new pack variety only produces short-term effects. The strategies are substitutes but the marginal effects are larger for product innovations relative to additional packs, and the effects are larger for smaller business units. Nonetheless, pack introductions offer a viable short-term growth strategy, especially for small- and medium-sized businesses

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes

<p>Abstract</p> <p>Background</p> <p>The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively. While otherwise widespread in systems with heteromorphic sex chromosomes, the case of dosage compensation in birds (males ZZ, females ZW) remains an unsolved enigma.</p> <p>Results</p> <p>Here, we use a microarray approach to show that male chicken embryos generally express higher levels of Z-linked genes than female birds, both in soma and in gonads. The distribution of male-to-female fold-change values for Z chromosome genes is wide and has a mean of 1.4–1.6, which is consistent with absence of dosage compensation and sex-specific feedback regulation of gene expression at individual loci. Intriguingly, without global dosage compensation, the female chicken has significantly lower expression levels of Z-linked compared to autosomal genes, which is not the case in male birds.</p> <p>Conclusion</p> <p>The pronounced sex difference in gene expression is likely to contribute to sexual dimorphism among birds, and potentially has implication to avian sex determination. Importantly, this report, together with a recent study of sex-biased expression in somatic tissue of chicken, demonstrates the first example of an organism with a lack of global dosage compensation, providing an unexpected case of a viable system with large-scale imbalance in gene expression between sexes.</p

Interactions between Casein Kinase Iε (CKIε) and Two Substrates from Disparate Signaling Pathways Reveal Mechanisms for Substrate-Kinase Specificity

Members of the Casein Kinase I (CKI) family of serine/threonine kinases regulate diverse biological pathways. The seven mammalian CKI isoforms contain a highly conserved kinase domain and divergent amino- and carboxy-termini. Although they share a preferred target recognition sequence and have overlapping expression patterns, individual isoforms often have specific substrates. In an effort to determine how substrates recognize differences between CKI isoforms, we have examined the interaction between CKIepsilon and two substrates from different signaling pathways.CKIepsilon, but not CKIalpha, binds to and phosphorylates two proteins: Period, a transcriptional regulator of the circadian rhythms pathway, and Disheveled, an activator of the planar cell polarity pathway. We use GST-pull-down assays data to show that two key residues in CKIalpha's kinase domain prevent Disheveled and Period from binding. We also show that the unique C-terminus of CKIepsilon does not determine Dishevelled's and Period's preference for CKIepsilon nor is it essential for binding, but instead plays an auxillary role in stabilizing the interactions of CKIepsilon with its substrates. We demonstrate that autophosphorylation of CKIepsilon's C-terminal tail prevents substrate binding, and use mass spectrometry and chemical crosslinking to reveal how a phosphorylation-dependent interaction between the C-terminal tail and the kinase domain prevents substrate phosphorylation and binding.The biochemical interactions between CKIepsilon and Disheveled, Period, and its own C-terminus lead to models that explain CKIepsilon's specificity and regulation

Are one or two simple questions sufficient to detect depression in cancer and palliative care? A Bayesian meta-analysis

The purpose of this study is to examine the value of one or two simple verbal questions in the detection of depression in cancer settings. This study is a systematic literature search of abstract and full text databases to January 2008. Key authors were contacted for unpublished studies. Seventeen analyses were found. Of these, 13 were conducted in late stage palliative settings. (1) Single depression question: across nine studies, the prevalence of depression was 16%. A single ‘depression' question enabled the detection of depression in 160 out of 223 true cases, a sensitivity of 72%, and correctly reassured 964 out of 1166 non-depressed cancer sufferers, a specificity of 83%. The positive predictive value (PPV) was 44% and the negative predictive value (NPV) 94%. (2) Single interest question: there were only three studies examining the ‘loss-of-interest' question, with a combined prevalence of 14%. This question allowed the detection of 60 out of 72 cases (sensitivity 83%) and excluded 394 from 459 non-depressed cases (specificity of 86%). The PPV was 48% and the NPV 97%. (3) Two questions (low mood and low interest): five studies examined two questions with a combined prevalence of 17%. The two-question combination facilitated a diagnosis of depression in 138 of 151 true cases (sensitivity 91%) and gave correct reassurance to 645 of 749 non-cases (specificity 86%). The PPV was 57% and the NPV 98%. Simple verbal methods perform well at excluding depression in the non-depressed but perform poorly at confirming depression. The ‘two question' method is significantly more accurate than either single question but clinicians should not rely on these simple questions alone and should be prepared to assess the patient more thoroughly

Efficacy and safety of vertebroplasty for treatment of painful osteoporotic vertebral fractures: a randomised controlled trial [ACTRN012605000079640]

Background. Vertebroplasty is a promising but as yet unproven treatment for painful osteoporotic vertebral fractures. It involves radiographic-guided injection of various types of bone cement directly into the vertebral fracture site. Uncontrolled studies and two controlled quasi-experimental before-after studies comparing volunteers who were offered treatment to those who refused it, have suggested an early benefit including rapid pain relief and improved function. Conversely, several uncontrolled studies and one of the controlled before-after studies have also suggested that vertebroplasty may increase the risk of subsequent vertebral fractures, particularly in vertebrae adjacent to treated levels or if cement leakage into the adjacent disc has occurred. As yet, there are no completed randomised controlled trials of vertebroplasty for osteoporotic vertebral fractures. The aims of this participant and outcome assessor-blinded randomised placebo-controlled trial are to i) determine the short-term efficacy and safety (3 months) of vertebroplasty for alleviating pain and improving function for painful osteoporotic vertebral fractures; and ii) determine its medium to longer-term efficacy and safety, particularly the risk of further fracture over 2 years. Design. A double-blind randomised controlled trial of 200 participants with one or two recent painful osteoporotic vertebral fractures. Participants will be stratified by duration of symptoms (< and ≥ 6 weeks), gender and treating radiologist and randomly allocated to either the treatment or placebo. Outcomes will be assessed at baseline, 1 week, 1, 3, 6, 12 and 24 months. Outcome measures include overall, night and rest pain on 10 cm visual analogue scales, quality of life measured by the Assessment of Quality of Life, Osteoporosis Quality of Life and EQ-5D questionnaires; participant perceived recovery on a 7-point ordinal scale ranging from 'a great deal worse' to 'a great deal better'; disability measured by the Roland-Morris Disability Questionnaire; timed 'Up and Go' test; and adverse effects. The presence of new fractures will be assessed by radiographs of the thoracic and lumbar spine performed at 12 and 24 months. Discussion. The results of this trial will be of major international importance and findings will be immediately translatable into clinical practice. Trial registration. Australian Clinical Trial Register # [ACTRN012605000079640]. © 2008 Buchbinder et al; licensee BioMed Central Ltd.Rachelle Buchbinder, Richard H Osborne, Peter R Ebeling, John D Wark, Peter Mitchell, Chris J Wriedt, Lainie Wengier, David Connell, Stephen E Graves, Margaret P Staples and Bridie Murph

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances