Evaluation of patient's Health-Related Quality of Life using a modified and shortened version of the Living With Asthma Questionnaire (ms-LWAQ) and the medical outcomes study, Short-Form 36 (SF-36)

Objective: The specific objectives of this study were to: 1) study the effect of moderate-to-severe asthma on patient's Health-Related Quality of Life (HRQoL) as measured by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and 2) evaluate the construct validity of a modified and shortened version of the Living With Asthma Questionnaire (ms-LWAQ) using the SF-36 as a concomitant measure of HRQoL. Methods: Cross-sectional, telephone or mail surveys of asthmatic patients enrolled in two central Florida managed care organizations. Results: All subscales of the SF-36 and four subscales of the ms-LWAQ demonstrated adequate reliability in this population (Cronbach >0.72). The subscales of the SF-36 most affected by patient's asthma were: general health perceptions, vitality and physical role functioning. These three subscales were correlated with four subscales of the ms-LWAQ: consequences, seriousness, affect and leisure. Six of the eight SF-36 subscales and all of the ms-LWAQ subscales were associated with patient's emergency department and hospital utilization. Conclusion: The ms-LWAQ and SF-36 are valid as useful measures of asthma patient's HRQoL in this cross-sectional study. Severity of disease, as measured by health care utilization, was significantly associated with HRQoL.     

Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives

The widely used antiepileptic drug valproic acid (VPA), which is also used in migraine prophylaxis and the treatment of bipolar disorders, is also under trial as an anticancer agent. Despite its wide range of therapeutic applications, VPA also has two severe side effects: acute liver toxicity and teratogenicity. The mechanism of action for all these properties is unknown to date, but recently, it was shown that VPA is able to inhibit the enzyme class of histone deacetylases (HDACs), proteins with a fundamental impact on gene expression and therefore possible molecular targets of VPA-induced signaling cascades. The purpose of this study was to determine if teratogenic side effects of VPA could be linked to its HDAC inhibition ability by studying a large set of structurally diverse derivatives based on the VPA core structure. We demonstrate that only VPA derivatives with a teratogenic potential in mice are able to induce a hyperacetylation in core histone H4 in teratocarcinoma F9 cells. We also demonstrate that this marker of functional HDAC inhibition occurs almost immediately (15 min) after exposure of F9 cells to VPA, whereas no influence on the HDAC protein levels (HDAC 2 and HDAC 3) could be detected even after 24 h of treatment. Further measurement of the IC50(HDAC) values of VPA derivatives in a human HDAC enzyme test system revealed an activity range from 10 to 10 000 microM; in some derivatives, HDAC inhibition ability was 40 times that of VPA. We also show a quantitative correlation between the IC50(HDAC) and the teratogenic potential of VPA derivatives, which clearly points toward HDACs as the formerly described teratogenic receptors of VPA-induced neural tube defects (NTDs).     

Repeated topical treatment, in contrast to single oral doses, with Vitamin A-containing preparations does not affect plasma concentrations of retinol, retinyl esters or retinoic acids in female subjects of child-bearing age

BACKGROUND: Vitamin A is widely used in cosmetic preparations. Given that oral Vitamin A and its metabolites present a potential reproductive risk, the present study investigated the effect of topical Vitamin A on human endogenous plasma levels of Vitamin A and its metabolites. METHODS: Two groups of 14 female volunteers of child-bearing age were kept on a Vitamin A-poor diet and treated topically for 21 days with creams containing 0.30% retinol or 0.55% retinyl palmitate on approximately 3000 cm2 of their body surface area, amounting to a total of approximately 30,000 IU Vitamin A/subject/day. After a 12-day wash-out period, the study groups received single oral doses of 10,000 IU or 30,000 IU retinyl palmitate (RP), corresponding to the maximal EU allowance during pregnancy or three-times higher, respectively. Blood samples were collected over 24h on study days -3 (pre-study), 1, 21 (first and last days of topical treatment) and 34 (oral administration) at 0, 1, 2, 4, 6, 8, 12, 14-16 h and 24 h after treatment for determination of plasma concentrations of retinol (REL), retinyl palmitate (RP), oleate (RO) and stearate (RS), 9-cis-, 13-cis-, all-trans- (AT), 13-cis-4-oxo- or AT-4-oxo-retinoic acids (RAs). RESULTS: With the exception of transient mild (RP-group) to moderate (REL-group) local irritation on the treatment sites, no adverse local or systemic effects were noted. On days 1 or 21 of topical treatment, no changes were measured in individual or group mean plasma Cmax, AUC0-24 h or other pharmacokinetic parameters of REL, retinyl esters or RAs relative to pre-study data. In contrast, single oral doses of RP at 10,000 IU or 30,000 IU produced dose-related and sustained increases in Cmax and AUC0-24 h values of plasma RP, RO, RS, 13-cis- and 13-cis-4-oxo-RAs, as well as a transient increase in AT-RA. In conclusion, our results provide evidence that human topical exposure to retinol- or retinyl ester-containing cosmetic creams at 30,000 IU/day and maximal use concentrations do not affect plasma levels of retinol, retinyl esters or RAs, whereas single oral doses at 10,000 IU or 30,000 IU produce significant increases in plasma retinyl esters and RAs.     

Hydroxamic acid and fluorinated derivatives of valproic acid: anticonvulsant activity, neurotoxicity and teratogenicity

PURPOSE: Fluorinated and non-fluorinated valproic acid (VPA) analogues with hydroxamic acid moieties were tested for their teratogenic, anticonvulsant and neurotoxic potencies in mice. METHODS: Compounds were synthesized from their corresponding acids. The induction of neural tube defects (exencephaly) of the resulting hydroxamates (applied on day 8.25 of gestation) was tested in the offspring of pregnant animals (Han:NMRI mice). The anticonvulsant activity was evaluated in the subcutaneous pentylenetetrazole (PTZ) seizure threshold test and neurotoxicity in the rotorod neurotoxicity test. RESULTS: All tested hydroxamates showed no or greatly reduced teratogenic potency in mice compared to the free acids. Furthermore all compounds exhibited anticonvulsant activity with ED(50) doses ranging from 0.16 mmol/kg to 0.59 mmol/kg (VPA 0.57 mmol/kg). Neurotoxicity of the hydroxamates was increased compared to VPA. TD(50) doses range from 0.70 mmol/kg to 1.42 mmol/kg (VPA 1.83 mmol/kg). CONCLUSION: Hydroxamic acid derivatives of VPA with improved protective index and little or undetectable teratogenic potency compared to the free acids are described. alpha-fluorination of VPA also resulted in loss of teratogenic activity. Such fluorination of the hydroxamic acids also led to compounds with an improved anticonvulsant profile compared to non-fluorinated hydroxamates. The non-chiral 2-Fluoro-VPA-hydroxamic acid was the most promising compound with a protective index (ratio of TD(50) to ED(50)) of 4.4 compared to 3.2 for VPA. This compound combines an improved ratio of anticonvulsant potency/neurotoxicity with the advantage of not being teratogenic in the mouse neural tube defect model used.     

PGD9 Outcomes and Cost-Benefit of Inhaled Corticosteroid Therapy Introduction in Medicaid-Enrolled Asthmatic Children

OBJECTIVE: The purpose of this study was to assess the clinical and economic impact of the introduction of inhaled corticosteroid therapy for asthma in a cohort of children 12 years and younger who were North Carolina Medicaid enrollees.
METHODS: The North Carolina Medicaid claims database was used to retrieve clinical and economic variables for the purpose of this study. The case group, which was comprised of 84 children who started corticosteroid inhaler therapy between March 1994 and March 1995, was followed up for 1 year before and 1 year after the start of the therapy. The control group was comprised of 72 children with similar severity of asthma who remained on any other therapy other than corticosteroids for a continuous 2-year period. Paired t-tests were used to compare differences, and multiple regression analysis was used to adjust for potential confounders.
RESULTS: There was a 58% reduction in hospital visits, and a 19% reduction in physician visits in the case group after initiation of inhaled corticosteroids. In the control group, an increase of 34% in the number of outpatient visits occurred in the second year. All the decreases and increases were statistically significant. Children with regular patterns of inhaled corticosteroid refills were found to be significantly lower costing for Medicaid. However, after adjusting for potential confounders, no significant change in health care costs per asthmatic child occurred as a result of the introduction of inhaled corticosteroid therapy.
CONCLUSION: Overall, the study found that introduction of inhaled corticosteroids in a cohort of asthmatic children enrolled in Medicaid was beneficial to Medicaid because it brought about dramatic decreases in health care utilization without additionally increasing costs.     

Anti-diabetic effects including diabetic nephropathy of anti-osteoporotic trace minerals on diabetic mice

Objective

In our previous study to evaluate the effects of soluble silicon (Si) on bone metabolism, Si and coral sand (CS) as a natural Si-containing material suppressed peroxisome proliferator-activated receptor γ (PPARγ), which regulates both glucose and bone metabolism and increases adipogenesis at the expense of osteogenesis, leading to bone loss. In this study, we investigated the anti-diabetic effects of bone-seeking elements, Si and stable strontium (Sr), and CS as a natural material containing these elements using obese diabetic KKAy mice.

Methods

Weanling male mice were fed diets containing 1% Ca supplemented with CaCO₃ as the control and CS, and diets supplemented with 50 ppm Si or 750 ppm Sr to control diet for 56 d. The mRNA expressions related to energy expenditure in the pancreas and kidney were quantified by real-time polymerase chain reaction.

Results

At the end of feeding, plasma glucose, insulin, leptin, and adiponectin levels decreased significantly in three test groups, while pancreatic PPARγ and adiponectin mRNA expression levels increased significantly toward the normal level, improving the glucose sensitivity of β-cells and inducing a significant decrease in insulin expression. The renal PPARγ, PPARα, and adiponectin expression levels, histologic indices of diabetic glomerulopathy, and plasma indices of renal function were also improved significantly in the test groups.

Conclusion

Taken together, anti-osteoporotic trace minerals, Si and Sr, and CS containing them showed novel anti-diabetic effects of lowering blood glucose level, improving the tolerance to insulin, leptin, and adiponectin, and reducing the risk of glomerulopathy through modulation of related gene expression in the pancreas and kidney.     

Mortality and failure among tuberculosis patients who did not complete treatment in Vietnam: a cohort study

Background  

Tuberculosis treatment failure and death rates are low in the Western Pacific Region, including Vietnam. However, failure or death may also occur among patients who did not complete treatment, i.e. reported as default or transfer-out. We aimed to assess the proportion failures and deaths among new smear-positive pulmonary tuberculosis patients with reported default or transfer-out.     

苄基四氢巴马汀对表达于非洲爪蟾卵母细胞及中华大蟾蜍卵母细胞的延迟整流钾电流的抑制作用

苄基四氢巴马汀对表达于非洲爪蟾卵母细胞及中华大蟾蜍卵母细胞的延迟整流钾电流的抑制作用童秋生，夏国瑾，姚伟星，江明性，白小川，包永德（同济医科大学基础医学院药理学教研室，武汉４３００３０；中国科学院上海生理学研究所，上海２０００３１）苄基四氢巴马汀（ｂ...