No evidence for association of the T102C polymorphism in the serotonin type 2A receptor with suicidal behavior in schizophrenia.
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Biomedical subjects
Publications and source records attributed to E C Tan.
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BACKGROUND: Genetic factors have been implicated in the pathophysiology of the movement disorder tardive dyskinesia, which may involve dopamine-serotonin interaction. Case-control association studies have identified the T102C polymorphism of the 5-HT2A receptor gene as being associated with schizophrenia and responsiveness to clozapine. In this study, we examine the association of this polymorphism in the 5-HT2A receptor gene as a risk factor for developing schizophrenia and tardive dyskinesia from prolonged treatment with neuroleptics. METHODS: Ninety-seven healthy control subjects with no history of mental illness and 221 schizophrenic patients (87 with tardive dyskinesia, 134 without) were genotyped by PCR-RFLP. RESULTS: Comparison between cases and control subjects revealed no significant association between the C allele and schizophrenia. There was significant difference in allele frequency (p = .044, OR = 1.54 95% CI = 1.02-2.33) between patients who developed tardive dyskinesia and those who did not. Significant difference remains even after adjusting for age and neuroleptic dosage (p = .041) with the odds ratio at 1.64 (95% CI = 1.02-2.62). CONCLUSIONS: A genetic variant of the 5-HT2A receptor may be associated with neuroleptic-induced tardive dyskinesia in schizophrenia. Further studies are needed to replicate the finding. The role of 5-HT2A receptor in the etiology of tardive dyskinesia or treatment-resistant schizophrenia should be further investigated.
Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia.
Neuroleptics are the mainstay of treatment for schizophrenia, but one of the complications is the development of tardive dyskinesia (TD). The pathophysiology of TD may involve dopamine-serotonin interaction. The serotonin transporter participates in the reuptake and termination of serotonin neurotransmission, and the gene that codes for this protein is thus a candidate gene for the development of TD. There is a functional polymorphism in the transcriptional control region of the serotonin transporter gene, and we investigated the association between this polymorphism and TD in Chinese schizophrenic patients. The patients who did not differ in age and sex distribution did not show variation on the rates of TD and Abnormal Involuntary Movements Scale (AIMS) scores with genotypes. Our findings suggest that 5-HTTLPR polymorphism is not a risk factor for TD in Chinese. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:712-715, 2000.
INTRODUCTION: Advances in genotyping, mapping and genome analysis methods over the last few years offer great promise towards the discovery of genes involved in the pathogenesis of schizophrenia, a mental disorder with a high degree of heritability. METHODS: This article draws on published reports in major international journals in the field of schizophrenia and human genetics. RESULTS: We summarise the major findings from family linkage studies, genome scan with microsatellite markers and association studies with polymorphisms in candidate genes. However, although recent developments in the technology for genotyping and gene identification have provided new leads to genetic abnormalities underlying schizophrenia, they have yet to result in the identification of any disease gene. There are both positive and negative data for reported linkages to specific chromosomal regions and candidate gene polymorphisms. CONCLUSIONS: Conflicting data and nonreplication of association and linkage studies are problems that need to be addressed. One solution might be clearer and narrower definition of subphenotypes and use of only a specific phenotypic marker in linkage and association studies. When successful, identification of susceptibility genes will lead to better understanding of cognitive functions and socio-emotional behaviour and also help in the formulation of preventive strategies for those found to be at high risk.
Laborious attempts at introducing a central venous catheter for parenteral nutrition in two women, aged 36 and 62 years, were followed by shortness of breath after 32 and 10 hours, respectively. This symptom was due to a (tension) pneumothorax not visible on earlier roentgenograms. Thoracic drainage led to recovery. In all patients with a central venous catheter an undetected delayed pneumothorax can be present. Urgent chest X-ray examination should be performed in all patients with acute respiratory symptoms. Patients undergoing elective intubation with positive pressure breathing should be examined carefully, since they are at risk of developing a late (tension) pneumothorax.
BACKGROUND: Intraarterial infusion of the free radical donor tert. -butyl-hydroperoxide (tert.-BuOOH) into one extremity of the rat induces vascular permeability and considerable skeletal muscle damage. However, it remains unclear what the role of polymorphonuclear neutrophils (PMNs) is in oxidative stress-related processes. Therefore, we investigated possible differences between neutropenic and normal animals in this model. METHODS: Neutropenia was induced in male rats by intraperitoneal administration of cyclophosphamide. tert.-BuOOH was continuously infused intraarterially into one hindlimb of normal or neutropenic nonanesthetized rats for 24 h. The control neutropenic rats were infused with the same volume of saline. After the infusion, 99mTc-IgG was administered intravenously followed by scintigraphic imaging analysis of the left/right uptake ratio of the hindlimbs and by gamma counting of the tissue samples of the gastrocnemius and gluteus maximus muscles. Samples of these muscles were analyzed by light microscopy. RESULTS: The uptake ratios were significantly increased in the normal and neutropenic tert.-BuOOH-infused animals as compared with the saline-infused neutropenic rats (P < 0.05). The uptake ratios were significantly higher in normal than in neutropenic tert.-BuOOH-infused rats (P < 0.05). Histological analysis of the saline infused skeletal muscles showed unaffected skeletal muscles with intact arterioles and arteries. In the gastrocnemius and gluteus maximus muscles of the normal tert. -BuOOH-infused and neutropenic rats, similar morphological damage was observed. CONCLUSIONS: PMNs can increase, to some extent, the vascular permeability of the free radical damaged small arteries and arterioles of a tert.-BuOOH-infused hindlimb. However, in the present animal model, tert.-BuOOH alone can induce oxidative stress-related abnormalities with skeletal muscle tissue damage that is mainly independent of the presence of PMNs.
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The genetics of asthma and atopy is complex, but can be approached by studies of both candidate genes and mapping of susceptibility loci. Genetic factors conferring susceptibility to disease may vary among ethnic groups. We present our experience with some candidate gene studies for asthma and atopy and susceptibility locus mapping for linkage to chromosome 5q.
Oxygen-derived free radicals are suspected to play an important role in the pathogenesis of inflammation and ischemia/reperfusion of an extremity. In this study we investigated the repair capacity of a free radical-damaged hindlimb of the rat and the effect of the anti-oxidant N-acetyl-L-cysteine (NAC). In nonanesthetized rats (n = 39), the left hindlimb was continuously infused intra-arterially (1 ml/hr) for 24 hr with the free radical donor tert-butylhydroperoxide (tert-BuOOH, 25 mM). Subsequently the infusion system was disconnected and the repair of soft tissue damage was observed with special attention to various pain tests, vascular permeability ((99m)Tc-IgG scintigraphy), and histology for a maximum period of 6 weeks. In 12 of these tert-BuOOH-infused rats the antioxidant NAC was injected intraperitoneally. Six of the NAC-treated rats were killed after 24 hr of infusion, while the remaining 6 rats were disconnected, reinjected with NAC, and observed for 1 week. Tert-BuOOH infusion for 24 hr led to significantly increased pain sensations, vascular permeability, and histological damage. Treatment with NAC significantly reduced pain sensations and vascular permeability, though not to control levels. One week after disconnection, tissue damage was almost completely repaired in the NAC-treated rats. In the untreated rats, repair took longer but histology and vascular permeability were completely normalized within the observation period. Soft tissue damage, induced by 24-hr infusion of the free radical donor tert-BuOOH, showed spontaneous repair within 6 weeks. The antioxidant NAC significantly reduced the soft tissue damage and shortened the repair period.
While the pathogenic mechanisms responsible for calcium nephrolithiasis remain unknown, the influence of heparan sulphate proteoglycan (HSPG) on disease progression of other diseases, such as polycystic kidneys and diabetic glomerulosclerosis, makes it an important candidate for the study of stone formation. Using the indirect immunofluorescence assay and image analysis, we were able to quantify and visualize the loss of HSPG localized in the basement membrane of the glomerulus and the mucosa of ureter or renal pelvis in patients with recurrent calcium nephrolithiasis as compared to normal subjects. However, no significant change in HSPG was observed in the basement membrane of the tubular epithelium. The decreased HSPG in the glomerulus may reflect the potentially disrupted anion/neutral barrier for glomerular filtration, which would encourage the accumulation of stone solutes. The drop in HSPG staining intensity in the basement membrane of the mucosa of ureter/renal pelvis may suggest the tendency of adhesion of crystal to urothelial surfaces. Based on these immunological data, it appears that HSPG plays a modulatory role in the pathogenesis of this disease.
OBJECTIVE: To define a subgroup of staghorn stones that is amenable to extracorporeal shockwave lithotripsy (ESWL) monotherapy and review the need for prophylactic ureteric stents. METHODS: Fifty-eight renal units with staghorn calculi in 56 patients (30 males and 26 females) were treated by ESWL monotherapy on the EDAP LT-01 lithotripter. The stones were grouped as complete staghorn (11, 19%), partial staghorn (34, 59%) and borderline staghorn (13, 22%). Results of treatment were analysed in relation to subgroup and calyceal dilatation. Post-treatment complications were studied and the influence of prophylactic ureteric stents examined. RESULTS: The average number of ESWL sessions was 3.1 (range: 1 to 8). The mean follow-up period was 13 months. Stone-free rate at 10 months was 52%. When clinically insignificant residual fragments less than 4mm were included, the overall clearance rate was 75%. Favourable factors influencing treatment outcome included smaller stone burden, peripheral distribution of stone mass and absence of pelvicalyceal dilatation. The overall complication rate was 39% with urosepsis being the commonest. Complications were related to stone burden. More than half of the renal units with complete staghorn stones developed one or more complications. Auxiliary procedures were required in 18% of the renal units. Twenty of 39 renal units with a stone burden (sum of length and width) greater than 50mm had pretreatment ureteric stenting using the double-J (DJ) siliastic stent. A urosepsis rate of 50% was noted in those with ureteric stents compared to 26% in those not stented. The stents did not offer any advantage in preventing post-treatment obstruction by fragments. Six of 7 renal units with post-treatment obstruction had in-situ stents. CONCLUSIONS: ESWL monotherapy is suitable for selected staghorn stones. Prophylactic ureteric stents do not offer any advantage and may predispose to urosepsis.
We evaluated the efficacy of immune and scarification Bacillus Calmette-Guerin (BCG) in the treatment of carcinoma in situ and prophylaxis against recurrence in patients with superficial transitional carcinoma of the bladder. A single-blind, randomised, comparative trial involving 43 patients with a median follow-up of 39 months was analysed. The end points were progression to muscle invasive disease or recurrence. The overall response rate was 93% after one to two courses. There was no difference between the two preparations and no statistically significant difference between the response or progression rates of the carcinoma in-situ or prophylactic groups. However, the response to BCG was found to be a significant prognostic indicator in a multivariate analysis.
Symptomatic bladder outlet obstruction due to benign prostatic hyperplasia (BPH) has been conventionally treated by transurethral resection. In recent years, a better understanding of the natural history and pathophysiology of BPH coupled with significant morbidity of prostate surgery has led to renewed interest in the medical therapy of BPH. Both alpha 1 blockers and 5 alpha-reductase inhibitors have been shown to be effective in recent clinical trials in the treatment of BPH. Both these drugs are safe and their side effects reversible. Medical therapy has a bigger role to play now especially for those high risk patients with moderate to severe symptoms of BPH. Further development of more effective alpha blockers and anti-androgens with less side effects would make pharmacotherapy an even more attractive alternative than the more invasive procedures.
GTPase-activating proteins (GAPs) modulate the activity of the ras superfamily of proteins by converting active GTP-bound to inactive GDP-bound p21s. Employing a novel GAP overlay assay (Manser, E., Leung, T., Monfries, C., Teo, M., Hall, C., and Lim, L. (1992) J. Biol. Chem. 267, 16025-16028), we demonstrated a diversity of proteins with GAP activities in different tissues. Using a polymerase chain reaction strategy exploiting conserved residues in the GAP domains of n-chimaerin and the product of the breakpoint cluster region gene (BCR), we isolated a human brain 5.3-kilobase cDNA containing a 486-base pair region with complete identity to a previously reported active BCR-related (ABR) gene sequence on human chromosome 17. The brain cDNA encoded a 98-kDa protein (ABR) resembling BCR (68% identity), containing both the oncogene dbl-related domain at the N terminus and the GAP domain at the C terminus; however, it lacks the N-terminal BCR protein kinase domain. The ABR GAP domain expressed as an Escherichia coli fusion protein was active against Rac1 and Cdc42 of the rho subfamily. The ABR mRNA is highly enriched in the brain. ABR probably corresponds to the brain-enriched 100-kDa GAP for Rac and Cdc42Hs previously detected. The relationship of ABR to Miller-Dieker syndrome, a neurological disorder co-mapping to 17p13.3, is discussed.