Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU

Adhesion-preventing properties of 4% icodextrin and canola oil: a comparative experimental study

OBJECTIVE: Postsurgical abdominal adhesions are common, serious postoperative complications. The present study compared the usefulness of 4% icodextrin and canola oil in preventing postoperative peritoneal adhesions. METHODS: Twenty-four Wistar albino rats were divided into three groups. Following a laparotomy, a serosal abrasion was made by brushing the cecum, and 3 mL of 0.9% NaCl, 4% icodextrin, or 3 mL of canola oil were intraperitoneally administered for the control, icodextrin, and canola oil groups, respectively. The abdomen was then closed. All of the rats were sacrificed at day 10. Macroscopic, histopathological, and biochemical evaluations were performed. The results were statistically analyzed using Kruskal-Wallis and ANOVA tests. RESULTS: Macroscopic analyses revealed that both canola oil and 4% icodextrin reduced adhesion formation, but the difference was not statistically significant (p = 0.17). The histopathological examinations revealed no significant differences in terms of giant cell, lymphocyte/plasmocyte, neutrophil, ICAM1, or PECAM1 scores. However, both canola oil and 4% icodextrin significantly reduced fibrosis (p = 0.025). In the canola oil group, the histiocytic reactions were significantly increased (p = 0.001), and the hydroxyproline levels were significantly lower than those in the other groups (p = 0.034). CONCLUSIONS: In the present study, canola oil was determined to be superior to 4% icodextrin in lowering hydroxyproline levels and increasing histiocytic reactions. Considering these results, we believe that canola oil is a promising agent for preventing adhesion formation

Psychiatric co-morbidity and attachment styles in obese adults: A comparative study with healthy volunteers

INTRODUCTION: Psychiatric co-morbidity and attachment issues are prevalent in obese patients. A possible relationship between insecure attachment styles and eating disorder risk has been proposed. The aim of this study is to determine the psychiatric co-morbidity, attachment styles and related risk factors in obese patients. METHODS: Obese patients with body mass index of 30 kg/m2 or higher and non-obese controls matched for age, sex and education were included with a total sample of 173 participants. Diagnostic assessment using Structured Clinical Interview for DSM-IV Axis I Disorders and the Adult Attachment Scale, Hamilton Depression, and Hamilton Anxiety scales were carried out. Attachment styles were classified as anxious/ambivalent, avoidant and secure. The anxious/ambivalant and avoidant groups were combined and compared with the secure group. RESULTS: Fifty three (40.8%) obese patients had psychiatric disorders including major depression (n=44; 33.8%). Anxiety was found to be a risk factor with obesity and BMI in both patients with or without any psychiatric co-morbidity. Psychiatric co-morbidity was significantly higher in obese patients (40.8%) than controls (18.6%). 55.4% of the participants had insecure attachment styles, it was significantly higher in obese patients. Insecure attachment styles were higher with psychiatric co-morbidity. DISCUSSION AND CONCLUSION: Psychiatric co-morbidity and insecure attachment styles were prevalent in obese patients, and the symptom of anxiety was found to be a predictor of obesity and body mass index. Psychiatric examinations including attachment styles and anxiety will help to advance better treatment strategies for obese patients

The evaluation of doxorubicin-induced cardiotoxicity: Comparison of Doppler and tissue Doppler-derived myocardial performance index

Background: Doxorubicin is a chemotherapeutic agent used in a wide spectrum of cancers. However, cardiotoxic effects have limited its clinical use. The early detection of doxorubicin-induced cardiotoxicity is crucial. The purpose of our study was to assess values of Doppler and tissue Doppler imaging (TDI)-derived myocardial performance index (MPI) in adult cancer patients receiving doxorubicin treatment. Methods: A total of 45 patients underwent echocardiographic examinations before any doxorubicin had been administered and then after doxorubicin. Doppler and TDI-derived MPI of left ventricular (LV) were determined in the evaluation of cardiotoxicity. Additionally, TDI-derived MPI of right ventricular (RV) was determined. Results: All patients underwent control echocardiographic examination after mean 5 ± 1.7 months. The LV MPI obtained by both Doppler and TDI were increased after doxorubicin treatment (0.56 ± 0.11, 0.61 ± 0.10, p = 0,005 vs 0.51 ± 0.09, 0.59 ± 0.09, p = 0.001, respectively). There was no correlation between Doppler-derived MPI and cumulative doxorubicin dose (coefficient of correlation 0.11, p = 0.6). TDI-derived MPI was correlated with cumulative doxorubicin dose (coefficient of correlation 0.35, p = 0.015), but this correlation is weak (r = 0.38). The study population was divided into two groups according to doxorubicin dose (below and above 300 mg level). There was a moderate correlation between TDI-derived MPI and less than 300 mg of doxorubicin dose (coefficient of correlation 0.51, p = 0.028). However, Doppler-derived MPI was not correlated with less than 300 mg of doxorubicin dose (coefficient of correlation 0.38, p = 0.123). Also, there was no significant change in the TDI-derived RV-MPI (0.49 ± 0.14, 0.50 ± 0.12, p = 0.56). Conclusions: TDI-derived MPI is a useful parameter and an early indicator compared with Doppler-derived MPI in the detection of cardiotoxicity during the early stages. Also, doxorubicin administration does not affect RV function

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population

Psychometrics in Psychiatry: Basic Concepts

Understanding human mental process as a natural event is the mainstay for positive science. Measurement or scaling these processes is the basic component of positive science. If we call the science of psychometrics as “mind measuring”, then the scales should be remarked as the tools of “mind meter”. Besides, if science is considered as a play in which your assertions are only within the limit of your measurements, and then the book of rules ought to be written precisely and updated regularly. In the history of science, there are many incidents in which different tools which had been marked to measure several variables or things were later found to be unable to implement the measurement it had been assigned. Thus the book of rules should set the boundaries of measurements, where to start and to finish, by preventing any confounding factors. Validity and especially construct validity of the scales set the basic conceptual framework. But, positive science should present the proof of reliability before providing the validity. Reliability –how you measure- is considered to put an upper limit on validity because any problem in reliability makes it harder to detect a valid “signal”. Another important step in measurement is to apply same directives to all participants to assure standardization. Thereby, we could ensure that the entire world keep same standard in the evaluation and application of the scale. Other process is to obtain normative value according to related variables in order to prevent confounding possible cultural factors. All of these steps has been comprised under the title of standardization. With this article, we would like to make sense to the reader concerning what is meant by psychometric properties of scales and focus on the process of standardization and its components