A bioinformatics approach to the identification of novel deleterious mutations of human TPMT through validated screening and molecular dynamics.

Polymorphisms of Thiopurine S-methyltransferase (TPMT) are known to be associated with leukemia, inflammatory bowel diseases, and more. The objective of the present study was to identify novel deleterious missense SNPs of TPMT through a comprehensive in silico protocol. The initial SNP screening protocol used to identify deleterious SNPs from the pool of all TPMT SNPs in the dbSNP database yielded an accuracy of 83.33% in identifying extremely dangerous variants. Five novel deleterious missense SNPs (W33G, W78R, V89E, W150G, and L182P) of TPMT were identified through the aforementioned screening protocol. These 5 SNPs were then subjected to conservation analysis, interaction analysis, oncogenic and phenotypic analysis, structural analysis, PTM analysis, and molecular dynamics simulations (MDS) analysis to further assess and analyze their deleterious nature. Oncogenic analysis revealed that all five SNPs are oncogenic. MDS analysis revealed that all SNPs are deleterious due to the alterations they cause in the binding energy of the wild-type protein. Plasticity-induced instability caused by most of the mutations as indicated by the MDS results has been hypothesized to be the reason for this alteration. While in vivo or in vitro protocols are more conclusive, they are often more challenging and expensive. Hence, future research endeavors targeted at TPMT polymorphisms and/or their consequences in relevant disease progressions or treatments, through in vitro or in vivo means can give a higher priority to these SNPs rather than considering the massive pool of all SNPs of TPMT.

Prevalence and clinical correlates of obsessive-compulsive disorder in schizophrenia.

Obsessive compulsive symptoms frequently occur in a substantial proportion of patients with schizophrenia. The term schizoobsessive has been proposed to delineate this subgroup of schizophrenia patients who present with obsessive-compulsive symptoms/disorder. However, whether this co-occurrence is more than just co-morbidity and represents a distinct subgroup remains controversial. A striking variation is noted across studies examining prevalence of obsessive-compulsive symptoms/disorder in schizophrenia patients and their impact on clinical profile of schizophrenia. Hence, in this study, we examined the prevalence of obsessive-compulsive symptoms/disorder in a large sample of consecutively hospitalized schizophrenia patients and compared the clinical and functional characteristics of schizophrenia patients with and without obsessive-compulsive symptoms/disorder. We evaluated 200 consecutive subjects with the DSM-IV diagnosis of schizophrenia using the Structured Clinical Interview for DSM-IV Axis I disorders, Positive and Negative Syndrome Scale, Yale-Brown Obsessive-Compulsive Scale, Brown Assessment of Beliefs Scale, Clinical Global Impression-Severity scale, Global Assessment of Functioning Scale, Family Interview for Genetic Studies and World Health Organization Quality of Life scale. The prevalence of obsessive-compulsive symptoms in patients with schizophrenia was 24% (n=48); 37 of them had obsessive-compulsive disorder (OCD) and 11 had obsessive-compulsive symptoms not amounting to a clinical diagnosis of OCD (OCS). Schizophrenia patients with OCS/OCD had an earlier age at onset of schizophrenia symptoms, lower positive symptoms score, higher co-morbidity with Axis II disorders, higher occurrence of OCD in family and better quality of life. Findings of the study indicate a higher prevalence of OCS/OCD in schizophrenia. Schizophrenia patients with and without OCS/OCD have comparable clinical profile with few exceptions. High rates of OCD in first degree relatives suggest possible genetic contributions and differences in neurobiology. Finally, evidence to consider schizoobsessive as a distinct diagnostic entity is inconclusive and warrants further studies.

Comorbidity of anxiety disorders in patients with remitted bipolar disorder.

Comorbidity between bipolar disorder and anxiety disorders has attracted considerable attention in recent years. However, a majority of the earlier studies examined anxiety disorders in acutely ill patients resulting in a possible confounding effect of the affective episodes. This study examines the prevalence of anxiety disorders in remitted bipolar subjects recruited from a psychiatric hospital in India and their effect on the severity of bipolar illness. A total of eighty remitted DSM-IV adult bipolar subjects and 50 non-psychiatric controls were recruited over a 10-month period. They were evaluated using a structured interview and various scales. The effect of anxiety disorders on bipolar severity was analyzed using multiple regression analyses. Anxiety disorders were highly prevalent in bipolar subjects compared to controls (49 [61%] vs. 7 [14%], chi(2) = 28.01, P < 0.001). Commonest lifetime anxiety disorder was obsessive-compulsive disorder (35%). Lifetime anxiety disorder had significant effect on all four indices of severity of illness, that included (1) percentage of time spent in episodes (Beta = 18.67, SE = 5.11, P < 0.001), (2) maximum period of continuous euthymia in the preceding 2 years (Beta = -5.26, SE = 1.71, P = 0.003), (3) presence of psychosis (Beta = 3.22, SE = 1.02, P = 0.002), and 4) response to mood stabilizers (Beta = -2.11, SE = 0.76, P = 0.006). The findings of this study confirm previous observations of the high prevalence and negative impact of comorbid anxiety disorders in bipolar disorder and also demonstrate that the findings are similar in culturally diverse settings. Future studies should systematically examine the various treatment options for anxiety disorders in bipolar patients. It is also necessary to examine the neurobiological and family/genetic correlates of anxious bipolar subjects to validate if they are a subgroup of bipolar disorders.

Life events and somatoform disorders.

Presumptive Stressful Life Events Scale (PSLES) was administered to 69 physically ill, 23 patients with somatoform disorders and 45 patients with psychiatric disorders other than somatoform disorders who sought medical help in primary health care settings. The 137 patients were cluster analysed in orderto obtain the patterns of distribution of 39 life events. Five clusters emerged. All the patients in cluster Vhad somatoform disorders and life events had a significant occurrence and discrimination.

Social dysfunctioning as a measure of severity of psychiatric illness.

A study was carried out to examine the validity of social dysfunctioning as a measure of severity of illness. Modified version of KAS, R2 inventory was used to measure social functioning. Since there can be no absolute measure of severity of psychiatric illness, the validity was tested through indirect means. It was decided that if the scores on social dysfunctioning were higher amongst the mentally ill compared to normals, higher in Psychotics compared to Neurotics and higher in those assessed by a relative as well as the Consultant Pyshciatrist to be more severely ill than those judged as less severely ill, the validity of social dysfunctioning as a measure of severity of Psychiatric illness would stand established. This was indeed found to be the case in the study which was carried out with 200 consecutive patients from a psychiatric out-patient department and their matched normal controls.