Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: A novel mechanism of action

Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss, inability to perform the activities of daily living and personality changes. Unfortunately, drugs effective for this disease are limited to acetylcholinesterase inhibitors that do not impact disease pathogenesis. Statins, which belong to the class of cholesterol-reducing drugs, were proposed as novel agents useful in AD therapy, but the mechanism underlying their neuroprotective effect is still unknown. In this study, we show that atorvastatin may have antioxidant effects, in aged beagles, that represent a natural higher mammalian model of AD. Atorvastatin (80 mg/day for 14.5 months) significantly reduced lipoperoxidation, protein oxidation and nitration, and increased GSH levels in parietal cortex of aged beagles. This effect was specific for brain because it was not paralleled by a concomitant reduction in all these parameters in serum. In addition, atorvastatin slightly reduced the formation of cholesterol oxidation products in cortex but increased the 7-ketocholesterol/total cholesterol ratio in serum. We also found that increased oxidative damage in the parietal cortex was associated with poorer learning (visual discrimination task). Thus, a novel pharmacological effect of atorvastatin mediated by reducing oxidative damage may be one mechanism underlying benefits of this drug in AD.     

Folinic acid protects against suppression of growth by methotrexate in mice.

The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.     

Formation of acetaldehyde adducts of glutathione S-transferase A3 in the liver of rats administered alcohol chronically.

Hepatic tissue damage induced by chronic exposure to alcohol is mediated through acetaldehyde and associated with reactive oxygen species, which impair cellular defense mechanisms. Because glutathione S-transferases (GSTs) play an important role in the detoxification of xenobiotics and reactive oxygen species, the current study was undertaken to test the effect of alcohol administration on structural and functional characteristics of rat (r) liver Alpha class rGSTs. Western blot analysis revealed an appreciable change in the expression of rGSTA3 subunit levels, whereas no change was observed in activity after chronic alcohol treatment. Reverse-phase high performance liquid chromatographic analysis of rat liver GSTs that were affinity purified with glutathione showed a 1.07-fold increase in rGSTA3 subunit levels in rats treated with alcohol chronically. In addition, liquid chromatographic-electrospray ionization mass spectrometric analysis of GSTs that were affinity purified with glutathione showed the formation of acetaldehyde adducts to the rGSTA3 subunit. Given the abundant expression of rGSTA3 subunit and acetaldehyde adduct formation, results of the current study support the suggestion that modification of rGSTA3 subunit, and thus its impaired function, in alcohol-exposed rats may contribute to the progression of alcohol-induced liver damage.     

Dyspnea reproducibility in a rural Bangladesh population

Background and Aims: Dyspnea may signal serious disease with increased morbidity/mortality. Dyspnea screening would only be valid if reproducible. The study aim was to determine the reliability (reproducibility) of assessing dyspnea through a simple questionnaire among a rural population. Methods: Participants were recruited from a Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Dyspnea assessment used a questionnaire among 129 participants at two time points: at baseline and after 2 weeks to 9 months by trained physicians. All subjects were asked about the presence/absence of dyspnea in the last 6 months. At the second interview, a physician (blinded to questionnaire) conducted a clinical heart/lung examination and obtained a pulse oximeter reading. Results: Dyspnea prevalence by baseline questionnaire was 2.4%. Overall dyspnea reliability was 94% (121 out of 129). If the initial response was ‘yes’ for the presence of dyspnea, reliability was 91% (49 out of 54). For an initial response of ‘no’ for the presence of dyspnea, reliability was 96% (72 out of 75). The pulmonary examination and pulse oximeter readings were significantly more likely to be abnormal in those with dyspnea (P < 0.01). Conclusions: The reliability of a simple question on dyspnea is very high when obtained by physicians. Although validity was not the primary outcome, the increased likelihood of an abnormal chest examination or low pulse oximeter saturation for those reporting ‘yes’ to the dyspnea question suggests more significant underlying cardiopulmonary disease in those reporting recent dyspnea. Please cite this paper as: Pesola GR, Parvez F, Jasmin S, Hasan AKM R and Ahsan H. Dyspnea reproducibility in a rural Bangladesh population. The Clinical Respiratory Journal 2009; 3: 222–228.     

Changes of placental diameter thickness and cotyledon in eclampsia

The study was done to see the changes of placental diameter, thickness and number of cotyledons in eclapmsia. A total 45 placenta, 25 from eclamptic mother and 20 from normal pregnant mother were collected from Gynaecology and Obstetric department of Mymensingh Medical College and Hospital (MMCH). Study was done in Anatomy department of Mymensingh Medical College (MMC). Macroscopic study of the formol saline fixed placentas revealed that, compared to the controls there was trend of less placental diameter in eclamptic group(p=0.0004). Cotyledon number was found to be significantly less in eclampsia (p=0.0001). However there was no significant difference in placental thickness in eclamptic placenta than that of normal group. Statistical significance of difference between two groups was calculated by using Students "t" test. A difference between the two groups was considered to be significant when p<0.005. The morphological changes in placenta are possibly due to reduced uteroplacental blood flow in eclampsia.     

Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.     

Biological Responses in Brook Trout (<Emphasis Type="Italic">Salvelinus fontinalis</Emphasis>) Caged Downstream from Municipal Wastewater Treatment Plants in the Credit River,ON, Canada

To determine whether discharges of contaminants from municipal wastewater treatment plants (WWTPs) may be contributing to the decline in populations of brook trout (Salvelinus fontinalis) in the watershed of the Credit River in ON, Canada, we caged juvenile brook trout upstream and downstream of the WWTPs of the small communities of Acton and Orangeville. Levels of vitellogenin were significantly elevated in liver tissue of trout caged downstream of both WWTPs, indicating exposure to estrogenic substances. Levels of thiobarbituric acid reactive substances indicative of oxidation of lipids were elevated in the gill tissue of brook trout caged downstream of the Orangeville WWTP, and levels of total glutathione were significantly lower in the gills of brook trout caged downstream of the Acton WWTP. Both biomarkers are indicative of oxidative stress, although many constituents of wastewater could be responsible for these responses. More work is needed to determine whether discharges of wastewater are contributing to the decline of brook trout in the Credit River and other cold-water streams in the Lake Ontario catchment basin.     

Asthma education for school staff in Riyadh city: effectiveness of pamphlets as an educational tool

Teachers and support staff are often called upon to manage asthma at school but may have little knowledge and understanding of the condition. The objectives of this study were to develop educational package (pamphlets) about asthma, and assess its effectiveness as an educational tool for schools' staff through evaluation of its impact on the staff's asthma-related knowledge, attitudes and management practices on their pupils. A pre-post experimental research design was used in Riyadh city with distribution of self-administered questionnaires and asthma package to 4 randomly selected girls schools compounds. Participants were school staff (n = 297) of primary, intermediate and secondary schools. Results showed that only 5.7% of the staff had received previous training in asthma education. Lack of knowledge and misconceptions about asthma medication were evident among a considerable proportion of the staff specifically for use of antibiotics, steroids, side effect of ventolin, and addicting effect of inhalers. At pretest, only 35% and 40.1% of the staff had good level of knowledge and management practices. At posttest, the corresponding percentages increased significantly to be 83.9% and 68.6% respectively. The mean total score of staff's asthma related-attitudes became more favorable towards asthma education after intervention, it increased significantly from 53.5 to be 55.0. Total posttest knowledge score was the only predictor of both staff attitudes and management practices constituting 9.1% and 10.2% of their variance. The great majority cited lack of training (92%), unavailability school policy (86.8%), and shortage of educational resources (88.3%) as barriers against asthma education and management in their schools. Conclusions: Most of school staff had poor to fair level of asthma knowledge and management practices. Such simple educational intervention using pamphlets and demonstration of inhaler use and peaked flow meter was significantly successful in enhancing staff's asthma-related knowledge, attitudes and management practices among their pupils. It is very important that training is directed to all staff as pre-service and in-service programs.     

Dual neutralization of TNFR-2 and MMP-2 regulates the severity of <Emphasis Type="Italic">S. aureus</Emphasis> induced septic arthritis correlating alteration in the level of interferon gamma and interleukin-10 in terms of TNFR2 blocking

Severity of S. aureus septic arthritis is correlated to prolonged inflammation by inflammatory cytokines like TNF-α, IL-1β, and IL-6 even after successful elimination of bacteria. Role of TNF-α via TNFR2 is not well established in this aspect. IFN-γ induces TNF-α release from the macrophages augmenting the inflammatory arthritis. IL-10 modulates the levels of pro-inflammatory cytokines promoting resolution of inflammation. TNF-α-TNFR2 signaling upregulates both of these cytokines. Higher level of MMP-2 induction by inflammatory cytokines during arthritis promotes tissue destruction. Whether dual neutralization of TNFR-2 and MMP-2 regulates the severity of S. aureus arthritis by modulating local and systemic cytokine milieu mainly due to TNFR-2 blocking was an obvious question. Here, we attempted the effects of neutralization of MMP-2 and TNFR2 on S. aureus arthritis and its impact on pro-inflammatory cytokines and some other parameters related to tissue destruction. Reduction in arthritis index was noticed in infected mice treated with both MMP-2 inhibitor and TNFR2 antibody. Lowest levels of inflammatory cytokines, iNOS, RANKL, NF-κb, JNK kinase, ROS, and MPO, and lysozyme activity were observed in combined neutralization group at 9 and 15 dpi, but at 3 dpi, most of the above parameters remained elevated due to TNFR2 neutralization. Diminished IL-10 and IFN-γ levels as a result of TNFR2 neutralization at early and later phase of infection respectively might be responsible for these contrasting effects. Overall, it can be suggested that administration of MMP-2 inhibitor and TNFR2 antibody in combination is protective against the inflammation and tissue destruction associated with S. aureus infection during the arthritic episode.     

Learning by Doing and Learning by Observing: Training Parents in Saudi Arabia to Implement the Natural Language Paradigm

The present study trained six parents of children with Autism Spectrum Disorder to implement the Natural Language Paradigm in Saudi Arabia. Three of the parents participated in direct training using a Behavioral Skills Training (BST) model involving instructions, modeling, rehearsal, and feedback. As each of the three parents were being trained directly an additional parent observed the training (i.e., there were three trainee-observer dyads). While all of the parents learned from observing other parents being trained directly, only one observer met the predetermined performance criteria after observation alone, with the other two requiring direct training using BST. The parents demonstrated maintenance of their skills at follow-up, and social validity evaluations were strong. In addition, all parents implemented the NLP procedures at mastery criteria in another setting during generalization probes. Implications for further training research are provided.