Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease

Alzheimer's disease (AD) is one of the most important neurodegenerative disorders, bringing about huge medical and social burden in the elderly worldwide. Many aspects of its pathogenesis have remained unclear and no effective treatment exists for it. Within the past 20 years, various mice models harboring AD-related human mutations have been produced. These models imitate diverse AD-related pathologies and have been used for basic and therapeutic investigations in AD. In this regard, there are a wide variety of preclinical trials of potential therapeutic modalities using AD mice models which are of paramount importance for future clinical trials and applications. This review summarizes more than 140 substances and treatment modalities being used in transgenic AD mice models from 2001 to 2011. We also discuss advantages and disadvantages of each model to be used in therapeutic development for AD.     

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): translation and validation study of the Iranian version

The objective of this study was to test the reliability and validity of the Iranian version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The English-language version of the questionnaire was translated into Persian (Iranian language), and its final form was approved by the EORTC Study Group on Quality of Life before it was used in this study. The questionnaire was administered at two time points to a consecutive sample of 168 newly diagnosed breast cancer patients, and almost all of them (99%) found the questions easy to understand and acceptable. Crohnbach's alpha coefficient for multi-item scales (to test reliability) ranged from 0.48 to 0.95 at baseline and from 0.52 to 0.98 at follow-up administration of the questionnaire. Validity was checked using two methods: inter-scale correlation and known-groups comparison. Almost all inter-scale correlations were statistically significant in the expected direction. Known-groups comparison analysis showed that all functioning and symptom scales discriminated between subgroups of patients differing in clinical status as defined by their performance status and disease stage. In general, the findings of this study indicate that the Iranian version of the EORTC QLQ-C30 is a reliable and valid measure of quality of life in cancer patients and can be used in clinical trials and studies of outcome research in oncology.     

Oral lichen planus and the p53 family: what do we know?

J Oral Pathol Med (2011) 40 : 281–285 Oral lichen planus (OLP) is a relatively common chronic disease of the oral mucosa for which the aetiopathogenesis is not fully understood. It mainly affects middle aged and elderly. The finding of autoantibodies against p63, a member of the p53 family, is a strong indication of autoimmunity as a causative or contributing factor. The WHO classified OLP as a potentially malignant disorder, but still there is an ongoing debate in the literature on this subject. The TP53 gene encodes a tumour suppressor protein that is involved in induction of cell‐cycle arrest or apoptosis of DNA‐damaged cells. The p63 gene encodes six different proteins that are crucial for formation of the oral mucosa and skin. The coordinated stabilization of p53 and decreased expression of p63 seen in OLP cause induction of apoptosis enabling removal of DNA‐damaged cells. In view of the complexity of cancerogenesis, no firm statement can at present be made about the relevance of the observed relationship between p53 and p63 and the possible malignant transformation of OLP.     

Assessing college students’ ego-identity status and their use of motivational regulation strategies

Using correlational analyses and structural equation modeling, this study tests three hypotheses: students’ reported use of motivational strategies is 1) correlated with their ego-identity status; 2) positively correlated with their reported use of learning strategies and negatively associated with their level of procrastination; and 3) related to their existing motivational beliefs and attitudes. Participants were American college students (N?=?113). The findings support all three hypotheses.

The study computed Pearson product moment correlations (listwise) among the ego identity and motivation measures; significant correlations ranged from 0.19 to 0.29. To test the hypothesized conceptual model, the study subjected the correlations to a confirmatory factor analysis. The five model varimax solution had excellent loadings on 16 variables; their standardized path coefficients were highly significant (p?df?=?161, p?=?0.0003; goodness of fit (GFI)?=?0.913; RMSEA?=?0.056).

The findings support the existence of a positive relationship between college students’ identity status and their use of motivational regulation strategies. They also suggest students’ use of motivational strategies is closely related to their use of cognitive and metacognitive strategies, but not to their level of academic procrastination. This article discusses practical applications for mental health providers and educators.     

Changes in miRNA expression in sera and correlation to duration of disease in patients with multifocal mucosal lichen planus

J Oral Pathol Med (2012) 41 : 86–89 Background: Mucosal lichen planus is a severe variant of lichen planus, Lichen planus (LP), which in many ways affect patients’ lives. The aetiology is not fully understood, and there is no treatment clearing the disease once and for all. Oral LP has by the WHO been classified as a precancerous lesion. Micro‐RNAs, miRNAs, are non‐coding, small single‐stranded RNAs involved in biological processes like apoptosis, proliferation, differentiation, metastasis, angiogenesis and immune response. Methods and Results: In sera from 30 patients with multifocal mucosal LP, 15 miRNAs were identified as significantly differentially expressed compared with controls. The three most up‐regulated miRNAs are all connected to oral squamous cell carcinoma or epithelial carcinoma in general. Discussion: Even if no specific LP‐associated miRNA profile was found, data clearly indicate that miRNAs could play a role in the earlier phases of lichen planus.     

Cholestasis induces apoptosis in mice cardiac cells: the possible role of nitric oxide and oxidative stress

Background/Aims: Acute cholestasis is associated with cardiovascular complications. The purpose of the present study was to investigate the effect of cholestasis on heart apoptosis and the involvement of nitric oxide (NO) and oxidative stress in the possible altered apoptosis of cholestatic hearts. Methods: Cholestasis was induced by bile duct–ligation, and sham‐operated mice served as controls. Three days after the surgery, heart tissues were evaluated for apoptosis and the level of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been studied in cardiac tissues. The role of treatment with l ‐NAME, a non‐selective inhibitor of NO synthase, or with d ‐NAME, an inactive isomer of l ‐NAME, on cholestatic and sham cardiac apoptosis, level of MDA and CAT, SOD and GSHPx activities was also investigated. The content of NO in cardiac tissue was also determined. Results: Cholestatic hearts showed structural abnormalities and increased apoptosis compared with sham hearts. Treatment with l ‐NAME, but not d ‐NAME, improved both structural abnormalities and enhanced apoptosis of cholestatic hearts. Cholestatic hearts also had an increased level of MDA and decreased activities of CAT and GSHPx, which were not modified by d ‐NAME treatment. By l ‐NAME treatment, the level of MDA decreased and activities of CAT, GSHPx and SOD increased in BDL mice. The content of NO was higher in cholestatic cardiac tissue, which was decreased by l ‐NAME treatment. Conclusion: In conclusion, apoptosis in cholestatic heart might have occurred because of NO overproduction, which could induce oxidative stress in the heart of cholestatic mice.     

Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography

It was previously reported that event-free survival rates of symptomatic patients with coronary artery disease (CAD) diagnosed by computed tomographic angiography decreased incrementally from normal coronary arteries to obstructive CAD. The aim of this study was to investigate the clinical outcomes of symptomatic patients with nonobstructive CAD with luminal stenoses of 1% to 49% on the basis of coronary plaque morphology in an outpatient setting. Among 3,499 consecutive symptomatic subjects who underwent computed tomographic angiography, 1,102 subjects with nonobstructive CAD (mean age 59 ± 14 years, 69.9% men) were prospectively followed for a mean of 78 ± 12 months. Coronary plaques were defined as noncalcified, mixed, and calcified per patient. Multivariate Cox proportional-hazards models were developed to predict all-cause mortality. The death rate of patients with nonobstructive CAD was 3.1% (34 deaths). The death rate increased incrementally from calcified plaque (1.4%) to mixed plaque (3.3%) to noncalcified plaque (9.6%), as well as from single- to triple-vessel disease (p <0.001). In subjects with mixed or calcified plaques, the death rate increased with the severity of coronary artery calcium from 1 to 9 to ≥ 400. The risk-adjusted hazard ratios of all-cause mortality in patients with nonobstructive CAD were 3.2 (95% confidence interval 1.3 to 8.0, p = 0.001) for mixed plaques and 7.4 (95% confidence interval 2.7 to 20.1, p = 0.0001) for noncalcified plaques compared with calcified plaques. The areas under the receiver-operating characteristic curve to predict all-cause mortality were 0.75 for mixed and 0.86 for noncalcified coronary lesions. In conclusion, this study demonstrates that the presence of noncalcified and mixed coronary plaques provided incremental value in predicting all-cause mortality in symptomatic subjects with nonobstructive CAD independent of age, gender, and conventional risk factors.     

A large population-based study on the prevalence of electrocardiographic abnormalities: A result of Mashhad stroke and heart atherosclerotic disorder cohort study

Background

Twelve-lead electrocardiogram (ECG) is a common and inexpensive tool for the diagnostic workup of patients with suspected cardiovascular disease, both in clinical and epidemiological settings. The present study was designed to evaluate ECG abnormalities in Mashhad population.

Methods

ECGs were taken as part of MASHAD cohort study (phase1) and were coded according to the Minnesota coding criteria. Data were analyzed using SPSS.

Results

Total 9035 ECGs were available for final analysis including 3615 (40.0%) male and 5420 (60.0%) female. Among ECG abnormalities precordial Q wave, major T-wave abnormalities, inferior Q wave, sinus bradycardia, and left axis deviation were the most prevalent abnormalities. The frequency of precordial and inferior Q wave, inferior QS pattern, major and minor ST abnormalities, major and minor T abnormalities, Wolff-Parkinson-White and Brugada pattern, sinus bradycardia, sinus tachycardia, left axis deviation, ST elevation, and tall T wave were significantly different between two genders. Moreover, the frequency of Q wave in precordial and aVL leads, QS pattern in precordial and inferior leads, major and minor T-wave abnormalities, Wolff-Parkinson-White, atrial fibrillation, sinus bradycardia, left axis deviation, and ST elevation were significantly different in different age groups. A comparison of the heart rate, P-wave duration, and QRS duration between men and women indicated that there was a significant difference.

Conclusions

Our finding indicated that the prevalence ECG abnormalities are different between men and women and also it varied in different age groups.     

TNF-α gene polymorphisms in Iranian Azeri Turkish patients with Behcet’s Disease

Genetic factors that predispose individuals to Behcet’s disease (BD) are considered to play an important role in the development of the disease. The serum level of tumor necrosis factor (TNF) is elevated in patients with BD, and a dramatic response to anti-TNF-α antibody treatment further supports the role of TNF in BD. We investigated the distribution of TNF-α promoter −1031T/C and −308G/A polymorphisms in 53 BD patients of Iranian Azeri Turks and 79 matched healthy controls, via the PCR–RFLP technique. The frequency of the TNF-α −1031C allele was significantly higher in Behcet’s patients than in healthy controls (p < 0.0001, OR = 3.08; 95% CI = 1.73–5.47), whereas the frequency of the TNF-α −308A allele was similar in the two compared groups. The frequency of CG haplotype was significantly higher (p < 0.0001, OR = 3.42; 95% CI = 1.89–6.18), and that of the TA haplotype was significantly lower in BD patients than in healthy controls. These results suggest that TNF-α is a susceptibility gene for BD in patients from Iranian Azeri Turk ethnic group.