Estimation of the percolation thresholds in acyclovir hydrophilic matrix tablets.

The principles of percolation theory were applied to design controlled release matrix tablets containing acyclovir. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the release and hydration rate of hydrophilic matrices allows to explain the changes in release and hydration kinetics of swellable matrix type controlled delivery systems. The objective of the present paper is to estimate the percolation threshold of HPMC K4M in matrices of acyclovir and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug. Matrix tablets have been prepared using acyclovir as drug and HPMC K4M as matrix forming material, employing five different excipient/drug percentages. Dissolution studies were carried out using the paddle method. Water uptake measurements were performed using a modified Enslin apparatus. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the excipient volumetric fraction at time zero plus initial porosity was studied. According to percolation theory, the critical points observed in dissolution and water uptake studies can be attributed to the excipient percolation threshold. This threshold was situated between between 20.76% and 26.41% v/v of excipient plus initial porosity. The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, increasing their robustness when they are prepared at Industrial scale, avoiding the formulation in the nearby of the percolation threshold.     

Lateral parabrachial lesions disrupt paraoxon-induced conditioned flavor avoidance.

Preliminary clinical evidence obtained in Gulf War veterans and patients suffering multiple chemical sensitivity points to the existence of a potential link between environmental exposure to organosphosphates (OPs) and the emergence of unspecific sickness syndromes in which associative Pavlovian conditioning might be partly involved. A laboratory animal model might be a useful tool for analyzing the involvement of conditioning in sickness syndromes potentially linked to OP poisoning. The first objective in the present study was to determine if paraoxon (PX), the neuroactive metabolite of the OP parathion, elicits a conditioned avoidance response to a novel stimulus (a taste-odor compound) in a conditioned flavor aversion procedure. Data obtained in Experiment 1 show conditioned flavor avoidance, demonstrative of the associative nature of the sickness properties of PX. The second objective was to characterize the nature of the specific physiological cue serving as the unconditioned stimulus in PX-induced conditioned avoidance. Despite PX administration did induce cholinergic hyperactivity, as measured by body hypothermia and increased jaw movements, lesions of the lateral parabrachial area (lPB) disrupted PX-elicited flavor avoidance responses, indicating that cholinergic signs were not sufficient as unconditioned stimuli supporting avoidance responses. Given that lPB neural integrity is necessary to process aversive interoceptive information, disruption of conditioned flavor avoidance as a result of lPB lesions is consistent with a central interruption of interoceptive processing in PX-poisoned animals. Data are discussed under the light of the hypothesis claiming the importance of associative processes and noncholinesterase targets in sickness syndromes potentially induced by OP exposure.     

Health-related quality of life and appropriateness of cholecystectomy

OBJECTIVE: To evaluate the relationship among appropriateness of the use of cholecystectomy and outcomes. SUMMARY BACKGROUND DATA: The use of cholecystectomy varies widely across regions and countries. Explicit appropriateness criteria may help identify suitable candidates for this commonly performed procedure. This study evaluates the relationship among appropriateness of the use of cholecystectomy and outcomes. METHODS: Prospective observational study in 6 public hospitals in Spain of all consecutive patients on waiting lists to undergo cholecystectomy for nonmalignant disease. Explicit appropriateness criteria for the use of cholecystectomy were developed by a panel of experts using the RAND appropriateness methodology and applied to recruited patients. Patients were asked to complete 2 questionnaires that measure health-related quality of life-the Short Form 36 (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI)-before the intervention and 3 months after it. RESULTS: Patients judged as being appropriate candidates for cholecystectomy, using the panel's explicit appropriateness criteria, had greater improvements in the bodily pain, vitality, and social function domains of the SF-36 than those judged to be inappropriate candidates. They also demonstrated improvements in the GIQLI's physical impairment domain. Interventions judged as inappropriate were performed primarily among patients without symptoms of cholelithiasis. Those asymptomatic had a lower improvement in the bodily pain, social functioning, and physical summary scale of the SF-36 and in the symptomatology, physical impairment, and total score domains of the GIQLI. CONCLUSIONS: These results suggest a direct relationship between the application of explicit appropriateness criteria and better outcomes, as measured by health-related quality of life. They also indicate that patients without symptoms are not good candidates for cholecystectomy.     

Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers

In this study, we analyzed the changes in biochemical markers of bone turnover in five patients with hypophosphatemic osteomalacia. The following bone markers were evaluated: among bone formation markers, total alkaline phosphatase (TAP), bone alkaline phosphatase (BAP), osteocalcin (bone Gla protein, BGP) and procollagen type I N propeptide (PINP); among bone resorption markers, serum C-terminal cross-linked telopeptide of type I collagen (s-CTx), urinary hydroxyproline (HYP), and N-terminal and and C-terminal cross-linked telopeptides of collagen (NTx and - and -CTx). In addition, the /-CTx ratio was evaluated. TAP and BAP were the markers with the highest increase in both frequency and magnitude. Conversely, BGP values were low in all patients. Collagen-related markers were slightly increased in nearly half of the patients. Among them, PINP showed the highest proportion of increased values. The /-CTx ratio was within normal values in all patients. In conclusion, TAP and BAP seem to be the best bone markers in the diagnostic evaluation of hypophosphatemic osteomalacia. In addition, their high values associated with low levels of BGP provide an even more reliable biochemical profile of this disorder, when associated with the classic mineral and skeletal homeostasis abnormalities.     

Health impact evaluation of particle air pollution in five Spanish cities. European APHEIS project

BACKGROUND: The health effects of air pollution have been analyzed in numerous studies over recent years, thus having made it possible to quantify the relationship between the two. This study is aimed at analyzing the theoretical benefits which would be achieved by meeting the air quality objectives set forth under EC Directive 1999/30/EC with regard to suspended particles. METHODS: The exposure measurement was taken for Black Smoke (Barcelona, Bilbao, Valencia) and suspended particles under 10 microm (PM10) (Bilbao, Madrid y Sevilla). The health indicators calculated were the mortality due to all causes and respiratory and cardiovascular causes, and emergency hospital admissions and mortality due to respiratory and cardiovascular causes. In the case of PM10 the impact has been calculated because its effects to short-term, within a period of up to 40 days following exposure, and to long-term. For Black Smoke the effects only has been calculated to short-term. RESULTS: The daily levels of PM10 from exceeding 50 microg/m3 in Bilbao, Madrid and Sevilla cause the earlier death of 1.4/100,000 individuals per year because its effects. The effect within a period of up to 40 days following exposure is of 2.8 deaths/100,000. The total number of deaths per year which may be later due to long-term exposure if the yearly average is lowered to 20 microg/m3 is 68/100,000. CONCLUSIONS: The health impact of the current air pollution levels is quantifiable and is not insignificant. APHEIS and the impact evaluations may be of aid in healthcare planning and environmental policies.     

Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation

BACKGROUND: Despite high cardiovascular mortality in rheumatoid arthritis (RA), few studies of body mass index (BMI) and obesity as risk factors for death in RA have been published. METHODS: We estimated the effect of BMI on survival in a cohort of 779 patients with RA adjusting for comorbidity, RA disease severity, erythrocyte sedimentation rate (ESR), and other potential confounders. RESULTS: The cohort accrued 123 deaths in 3460 person-years (3.6 deaths per 100 person-years; 95% confidence interval [CI], 3.0-4.2). The BMI was inversely associated with mortality. Patients with BMIs of 30 or higher had the lowest mortality, 1.7 deaths per 100 person-years (95% CI, 1.1-2.5). Mortality was higher in each lower BMI category, reaching its highest rate among patients with BMIs lower than 20 with 15.0 deaths per 100 person-years (95% CI, 9.9-23.0). The survival advantage of high BMI was independent of RA onset age, RA duration, sex, ethnic group, socioeconomic status, smoking status, and use of methotrexate but was lost on adjusting for comorbidity and RA severity. We observed an interaction between BMI and ESR, where the BMI protective influence occurred only if the ESR was low. The BMI x ESR interaction was independent of all covariates, including comorbidity and RA severity. CONCLUSIONS: Body mass has a paradoxical effect on mortality in RA. Patients with high BMI have lower mortality than thinner patients. This effect is mediated in part by comorbidity. The effect of body mass on survival seems to be modified by the level of systemic inflammation.     

Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis

OBJECTIVE: To estimate the contribution of cardiovascular (CV) risk factors and rheumatoid arthritis (RA) disease manifestations to atherosclerosis in RA. METHODS: We used high-resolution carotid ultrasound to measure the carotid intima-media thickness (IMT) and plaque in 631 RA patients. Using R(2) measures from multivariable models, we estimated the contribution of demographic characteristics (age, sex, and ethnic group), CV risk factors (diabetes mellitus, hypercholesterolemia, cigarette smoking, hypertension, and body mass index, and RA manifestations (joint tenderness, swelling, and deformity, nodules, erythrocyte sedimentation rate [ESR], C-reactive protein, rheumatoid factor, the HLA-DRB1 shared epitope, and cumulative glucocorticoid dose) to each of the outcomes. Estimates were obtained in the full sample, and within strata defined by age, sex, and ethnic group. We tested for interaction between CV risk factors and RA manifestations. RESULTS: The contribution of demographic factors, CV risk factors, and RA manifestations to IMT and plaque R(2) varied depending on the patients' age stratum. Demographic features explained 11-16% of IMT variance, CV risk factors explained 4%-12%, and RA manifestations explained 1-6%. The greatest contribution of RA manifestations occurred in the youngest age group, while that of CV risk factors occurred in the older age groups. Results for carotid plaque were similar. There was a significant interaction between the number of CV risk factors present and the ESR, suggesting that the ESR's effect on IMT varied according to the number of CV risk factors. CONCLUSION: Both established CV risk factors and manifestations of RA inflammation contribute significantly to carotid atherosclerosis in RA, and may modify one another's effects. These findings may have implications regarding the prevention of atherosclerosis in RA.