Clinical Skin Mildness Evaluations of Direct and Indirect Exposure to Two Commercial Laundry Detergents with Markedly Different pH Designed for Sensitive Skin Using a Hand-Laundering Model.

The skin mildness of two commercial laundry detergents designed for sensitive skin, Tide Free and Gentle® (TFG) versus All Free Clear® (AFC), was compared in clinical studies, and the role of marked product pH differences was assessed. Two double-blind randomized human studies were conducted. Study 1 was a 1-day repeat insult forearm test, in which four exposures to solutions of TFG or AFC were performed to mimic direct exposure to dilute detergent during hand-laundering. Corneometer, erythema and dryness grading, transepidermal water loss (TEWL), and skin surface pH evaluations were carried out. Study 2 was a 21-day arm patch test of fabrics washed with TFG or AFC to mimic indirect contact to skin of detergent residues, with erythema grading. Separately, pH and reserve alkalinity were determined for each detergent. In Study 1, TFG was significantly milder than AFC in all measures except TEWL (no significant difference). In Study 2, the detergents were approximately equivalent in erythema grading. Analysis showed AFC was substantially more alkaline (pH 10.8) than TFG (pH 7.9) with higher reserve alkalinity. TFG was significantly milder than AFC in Study 1, which may be due in part to the increased skin surface pH seen with direct exposure to AFC's high alkalinity.

A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation­contraction coupling together with additional muscle alterations.

INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.

Patterns of gene expression in muscle and fat in tumor-bearing rats: effects of CRF2R agonist on cachexia.

The hypothesis we tested was that administering corticotropin-releasing factor receptor agonists preserves muscle mass during cancer that is related to changes in tissue gene expression. cDNA microarrays were used to compare mRNAs from muscle and adipose tissues of non-treated and agonist-treated tumor-bearing rats. In muscle of non-tumor-bearing agonist-treated animals we observed decreased expression of genes associated with fatty acid uptake and esterification. In tumor-bearing animals, CRF2R agonist administration produced decreased mRNA content of the atrogene lipin-1. In white adipose tissue, agonist treatment of non-tumor-bearing animals induced genes typically related to muscle structure and function. The fact that this treatment decreased expression of atrogenes could have clinical application. In addition, agonist treatment changed the gene pattern of adipose tissue to render it similar to that of skeletal muscle; thus, treatment with this agonist alters the gene pattern to what could be called "muscularization of white adipose tissue."

Sex differences in global mRNA content of human skeletal muscle.

Women oxidize more fat as compared to men during endurance exercise and several groups have shown that the mRNA content of selected genes related to fat oxidation are higher in women (e.g. hormone sensitive lipase, beta-hydroxyacyl-CoA dehydrogenase, CD36). One of the possible mechanisms is that women tend to have a higher area percentage of type I skeletal muscle fibers as compared with men. Consequently, we hypothesized that sex would influence the basal mRNA and protein content for genes involved in metabolism and the determination of muscle fiber type. Muscle biopsies from the vastus lateralis were collected from healthy men and women. We examined mRNA content globally using Affymetrix GeneChips, and selected genes were examined and/or confirmed by RT-PCR. Furthermore, we examined protein content by Western blot analysis. Stringent gene array analysis revealed 66 differentially expressed genes representing metabolism, mitochondrial function, transport, protein biosynthesis, cell proliferation, signal transduction pathways, transcription and translation. Stringent gene array analysis and RT-PCR confirmed that mRNA for; acyl-coenzyme A acyltransferase 2 (ACAA2), trifunctional protein beta (HADHB), catalase, lipoprotein lipase (LPL), and uncoupling protein-2 (UCP-2) were higher in women. Targeted gene analysis revealed that myosin heavy chain I (MHCI), peroxisome proliferator-activated receptor (PPAR)delta were higher in women compared with men. Surprisingly, there were no significant sex based differences in protein content for HADHB, ACAA2, catalase, PPARdelta, and MHC1. In conclusion, the differences in the basal mRNA content in resting skeletal muscle suggest that men and women are transcriptionally "primed" for known physiological differences in metabolism however the mechanism behind sex differences in fiber type remains to be determined.

Functional grouping of osteoclast genes revealed through microarray analysis.

We describe for the first time functional clusters of genes that are modulated during the differentiation of osteoclasts. Pathway analysis was applied to gene array data generated from affymetrix chips hybridized to RNA isolated from RAW264.7 cells exposed to RANK-ligand (RANK-L) for 5 days. This analysis revealed major functional gene clusters that were either up- or down-regulated during osteoclastogenesis. Some of the genes within the clusters have known functions, while others do not. We discuss herein the relevance of these functional gene clusters and their modulation to biological processes underlying the formation, function, and fate of osteoclasts.

Gene expression, fiber type, and strength are similar between left and right legs in older adults.

Methodological issues relevant to studies using microarrays and reverse transcription-polymerase chain reaction (RT-PCR) in human aging have rarely been evaluated. Because aging may accentuate biological differences between muscles, we compared transcriptome expression patterns, targeted messenger RNA (mRNA) abundance, strength, and muscle fiber type in the right and left legs of older adults. Muscle biopsies were taken from each Vastus lateralis in eight older (71 +/- 2 years) men, and isometric strength was determined. Samples were analyzed using an Affymetrix gene array, ATPase histochemistry, and RT-PCR for mRNA species involved in metabolism, apoptosis, vascular growth, and antioxidant status. Microarray analysis found that 31 of 5499 genes (0.6%) were significantly different between legs (negative log of the p value [NLOGP] >/= 2.0, but fold < 1.5), with only one gene, jumonji domain containing 1C (JMJD1C), being significantly different by >/= 1.50-fold. None of the mRNA species, or muscle fiber type, size, or strength, was different between legs. These findings are important for the design and analysis of studies using muscle data in older adults.

Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice.

BACKGROUND: Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy. METHODS: Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression. RESULTS: We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression. CONCLUSION: Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.

Assessment of non-vertebral fracture risk in postmenopausal women.

BACKGROUND: Non-vertebral (NV) fractures are responsible for a great amount of morbidity, mortality and cost attributable to osteoporosis. OBJECTIVES: To identify risk factors for NV fractures in postmenopausal women with osteoporosis, and to design an assessment tool for prediction of these fractures. METHODS: 2546 postmenopausal women with osteoporosis included in the placebo groups of three risedronate controlled trials were included (mean age 72 years, mean femoral T-score -2.5; 60% and 53% of patients with prevalent vertebral and NV fractures, respectively). Over 3 years, 222 NV fractures were observed. Baseline data on 14 risk factors were included in a logistic regression analysis. RESULTS: 6 risk factors were associated with NV fracture risk: prevalent NV fracture (p = 0.004), number of prevalent vertebral fractures (p<0.001), femoral T-score (p = 0.031), serum level of 25-hydroxyvitamin D (p<0.001), age (p = 0.012) and height (p = 0.037). An NV risk index was developed by converting the multivariate logistic equation into an additive score. In the group of women with a score > or =2.1, the incidence of NV fracture was 13.2% (95% CI 11.1 to 15.3), 1.5 times higher than that of the general population. CONCLUSIONS: The NV risk index is a convenient tool for selection of patients with osteoporosis with a high risk for NV fractures, and may help to choose from available treatments those with a proven efficacy for reduction of NV fracture risk.

Efficacy of systemic administration of SDF-1 in a model of vascular insufficiency: support for an endothelium-dependent mechanism.

OBJECTIVE: Studies have reported that administration of stromal cell-derived factor-1 (SDF-1), the ligand for the G-protein coupled receptor CXCR4, increased collateral blood flow in a mouse model of vascular insufficiency via recruitment of endothelial precursor cells (EPC). The present study investigated the contribution of mature endothelial cells in the actions of SDF-1. METHODS: The regulation of SDF-1 and CXCR4 was examined in the rat cornea cauterization (CC) and aortic ring (AR) model. The functional significance of the SDF-1/CXCR4 pathway was explored in cultured endothelial cells, the AR model, and on collateral blood flow in a rat model of vascular insufficiency. RESULTS: In the present study, the CXCR4 transcript was dramatically upregulated in the rat CC and AR explants, systems containing and lacking bone marrow-derived EPCs, respectively. Addition of AMD3100, a selective CXCR4 antagonist, had no effect on vessel growth in the AR alone, but completely inhibited SDF-1 mediated increases in vascular sprouting. In cultured endothelial cells, SDF-1 alone or in combination with vascular endothelial growth factor (VEGF) significantly enhanced cell survival and migration. Finally, systemic administration of SDF-1 in a rat model of arterial insufficiency enhanced collateral blood flow above vehicle control and equal to that of VEGF after 2 weeks of treatment. CONCLUSION: These studies support activation of the SDF-1/CXCR4 axis as a means to promote blood vessel growth and enhance collateral blood flow, at least in part, via direct effects on vascular endothelial cells.

European women's preference for osteoporosis treatment: influence of clinical effectiveness and dosing frequency.

OBJECTIVE: To determine participant preference for weekly versus monthly bisphosphonate therapy for osteoporosis after being informed about differences in fracture efficacy. DESIGN: 20-minute, semi-structured, face-to-face or telephone interviews. Two bisphosphonate choices were presented on the basis of block randomization: weekly therapy with proven efficacy to reduce fracture risk at the spine and hip, or monthly therapy with proven efficacy to reduce fracture risk at the spine but not the hip. SUBJECTS: Women from the UK, Germany, France, Spain and Italy, with postmenopausal osteoporosis and aged > or = 55 years. Fifty percent were currently taking a weekly bisphosphonate; 50% had no history of taking any bisphosphonate. MEASURES: An efficacy rating scale and an intention-to-use rating scale were developed for this study. The primary endpoint was preference for weekly or monthly therapy. Reasons for preference were recorded. RESULTS: A preference was recorded for 1248 women (1253 were recruited). More women preferred weekly to monthly therapy (82% vs. 18%, respectively; p < 0.001). Among women who preferred weekly therapy, efficacy was the most commonly cited reason (65%). Ninety-two percent of the total cohort rated the efficacy of the weekly therapy as 'excellent/good' versus 38% for monthly (p < 0.001). Sixty-nine percent intended to use weekly bisphosphonates compared with 34% for monthly (p < 0.001). CONCLUSIONS: When informed about differences in fracture efficacy in weekly and monthly bisphosphonates, a significantly greater proportion (82%) of women preferred a weekly bisphosphonate with proven fracture efficacy at the spine and hip over a monthly bisphosphonate with proven fracture efficacy only at the spine.

Bayesian analysis of quantitative antimicrobial assays.

Quantitative antimicrobial assays are used to assess the efficacy of chemical germicides. Standard methods for statistical analysis use log reduction (LR), the difference on the log scale between average surviving microbes for control and test carriers, as an efficacy measure. These methods have several deficiencies. The LR parameter is not on the original response scale, which complicates its interpretation. The presence of two different definitions of LR makes the statistical inference even more difficult. Current statistical methods for antimicrobial assay analysis rely on asymptotic normal theory, which might not work well for small samples. In addition, they do not appropriately incorporate censored ('too numerous to be counted') observations in the analysis. To overcome those problems, a new Bayesian approach is introduced here. It has also the advantages of more flexible statistical inference, and incorporated prior information in the model.