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Background: Though most people with COVID-19 disease show asymptomatic to mild illness, a substantial number of patients are at high risk of developing severe disease and adverse outcomes with long COVID-19 and death. Even though some studies showed that previously existing infections with parasites amend the host's body defenses to increase resistance to infection with SARS-CoV-2, there is limited data in Ethiopia., Objectives: This study is aimed at determining the COVID-19 disease severity and its association with intestinal parasite coinfection and urine biochemical parameters among COVID-19-confirmed patients admitted at Debre Markos University COVID-19 Center, 2021., Methods: A prospective cohort study was conducted on 136 RT-qPCR-confirmed COVID-19 patients admitted at Debre Markos University COVID-19 Center from January 1 to March 30, 2021. Sociodemographic and clinical data were collected by using standardized data collection forms. A urine biochemical test was performed using a dry urine dipstick kit and stool examination using direct wet mount microscopic examination and formalin-ether concentration method. The chi-square test, Fisher exact test, and ordinal logistic regression analysis were computed to assess association with outcome variables using Statistical Package for Social Science software (version 24)., Result: A total of 136 COVID-19-confirmed patients participated in this study. The median age of the participants was 48 years. The majority (86 (62.5%)) of them were male in sex. Of the 136 cases, 39 (28.7%) had died. Among the 136 patients, 22 (16.2%) were coinfected with intestinal parasites. COVID-19 patients who have intestinal parasite coinfection had lower odds of developing clinically severe COVID-19 compared to noninfected (AOR = 0.37; 95% CI = 0.147-0.944; P = 0.037). The majority (104 (76.5%)) of them have abnormal urine biochemical results. From the abnormal urine biochemical tests observed, the urine blood, glucose, and ketone tests were positive for 54 (39.7%), 36 (26.5%), and 30 (21.1%) patients, respectively. Among the 31 critical COVID-19 patients, 25 (80.6%) showed abnormal urine biochemical parameters. Age and comorbidity were significantly associated with COVID-19 severity ( P < 0.05)., Conclusion: Patients with old age and comorbidity had an increased risk of developing severe COVID-19 disease. Patients having SARS-CoV-2 and intestinal parasitic coinfections demonstrated mild COVID-19 disease severity. Abnormal urine biochemical results were common among critical COVID-19 patients. Thus, advanced study on the effect of the interaction among intestinal parasites on COVID-19 clinical severity and its mechanisms is essential., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Milkiyas Toru et al.)

Background: Hepatitis B vaccination is recommended for all children at birth within 24 hours or during childhood., Objective: This study was aimed to evaluate protective efficacy of hepatitis B vaccine and estimate the sero-prevalence of hepatitis B virus infection among vaccinated children., Materials and Methods: A community-based cross-sectional study was conducted from March, 2021 to October, 2021 in Debre Markos town. A simple random sampling technique was used to select 165 fully vaccinated children aged 5-12 years old. A serum sample was used to determine hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibody (anti-HBc), anti-hepatitis B surface antibody titer (anti-HBs) using ELISA., Results: The seroprevalence of HBsAg and anti-HBc anti-body was found to be 4.2% and 4.8% respectively. Of 165 fully vaccinated children, 129 (78.2%) had anti-HBs titer ≥ 10 mIU/ml. Among 129 sero-protected children, 76 (58.9%) were hypo-responders whereas the rest 53 (41.1%) were good responders. Those children within the age group of 5-7 years were 2.9 times (AOR: 2.873, 95% CI: 1.156, 7.141) (P<0.023) more likely to respond to HBV vaccine. Multivariate logistic regression revealed that children who were born from HBV positive mothers (AOR 3.917, 95% CI: 1.456, 5.365, P<0.027) and those who had history of injectable medications (AOR 9.232, 95% CI: 1.503, 11.697, P<0.016) were more likely to be HBsAg positive. Children who had history of hospital admission (AOR 6.973, 95% CI: 1.495, 8.530, P<0.013) were more likely to be anti-HBcAb positive., Conclusions: There was an intermediate prevalence of childhood HBV infection despite being vaccinated suggesting low protective efficacy of hepatitis B vaccine in the study area., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Adugna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Drug-resistant tuberculosis (TB) threatens global TB care and prevention, and it remains a major public health concern in many countries particularly in sub-Saharan countries. Pulmonary TB is the most common serious opportunistic infection on HIV-positive patients and it is the leading cause of death among HIV-positive patients in developing countries. Ethiopia is one of the high TB burden countries with high morbidity and mortality., Objective: To determine the prevalence, associated factors and rifampicin resistance of pulmonary TB among HIV-positive attending antiretroviral treatment clinic at East Gojjam., Methods: Hospital-based cross-sectional study was conducted at Debre Markos Referral Hospital, from February to June 2019. A total of 112 HIV-positive TB suspected patients were included using convenient sampling techniques and a bacteriological confirmation test for tuberculosis was performed using Gene-Xpert MTB/RIF assay from a spot sputum sample. Viral load was determined by using a quantitative real-time polymerase chain reaction (RT-PCR) from the blood sample. Socio-demographic and clinical data were collected by face-to-face interview using a semi-structured questionnaire. The data were analyzed by using Statistical Package for Social Sciences (SPSS) software (version 24)., Result: Out of the 112 study participants, the prevalence of Pulmonary TB was 11.6 %. Among TB positives 23.1 % were rifampicin resistant. Rifampicin resistance was 100 % among female patients. Having family members treated for pulmonary TB (P = 0.003, [AOR = 4.5; 95 % CI = 3.59-58.8]), cigarette smoking (P = 0.039, [AOR = 2.18; 95 %CI = 1.17-40.5]), being on WHO HIV disease clinical stage II (P = 0.024, [AOR = 1.81; 95 %CI = 1.50-30.99]), and having viral load (1000-9999) RNA copies/ml (P = 0.031, [AOR = 1.54; 95 %CI = 1.32-31.41]) were found to be significantly associated with pulmonary TB., Conclusion: The prevalence of pulmonary TB and rifampicin resistance was high among HIV patients. Having family members treated for Pulmonary TB, history of cigarette smoking, WHO HIV clinical stage, and high viral load were associated risk factors for TB. Therefore, strengthening awareness creation on TB transmission, drug resistance, and treatment adherence are essential. Moreover, early screening and treatment are vital for preventing the transmission and occurrence of drug-resistant TB among study populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is coronavirus isolated from SARS patients. As far as the researchers' knowledge, there was paucity of studies conducted in Ethiopia, particularly in the study area. As immune protection is arisen from our blood cells, assessing their level will provide a clue for controlling the disease and monitoring the prognosis. This study will also provide additional information for clinical intervention and patient management., Purpose: This study aimed to investigate the hematological profile and clinical outcome of coronavirus disease-19 (COVID-19) among patients admitted to the Debre Markos Isolation and Treatment Center (DMITC)., Material and Methods: A prospective cohort study was conducted among 136 COVID-19 adult patients at DMITC from January 1, 2020 to March 30, 2021. Data related to clinical, hematological profiles and socio-demographic factors were collected, entered into Epi data, and analyzed using STATA 14.2 software. Multivariable logistic regression was applied to determine the predictor variable and a p-value <0.05 was considered significant., Results: Of 136 COVID-19 patients, 28.68% had died. The mean age of patients was 47.21±1.29 years. The hematological profile of the patients revealed that 28% had abnormal leukocyte, 23% abnormal lymphocyte, 44.85% abnormal granulocyte, 22.06% abnormal monocyte, 30.15% abnormal RBC and 87% abnormal platelet counts. The prevalence of anemia was 13.24%., Conclusion: Leukocytosis (mainly granulocytosis and monocytosis) and lymphopenia, were the predominant abnormal findings of complete blood cell count (CBC) analysis of the patient's blood. Most of the patients had abnormally low platelet counts. RBC count and hematocrit determination were the only significant predictors of death. The clinician could manage cases according to the hematological findings of the patients. Further experimental studies should be conducted to determine hematological parameter changes and the clinical outcome of the disease., Competing Interests: The authors declared that there are no competing interests., (© 2022 Atnaf et al.)

Objective: This study is aimed to assess the prevalence and associated factors of intestinal parasitic infections among school children at Amber Primary School, Northwest Ethiopia., Methods: A school-based cross-sectional study was conducted at Amber Primary School from December 2019 to January 2020. Semi-structured questionnaire was used to collect socio-demographic data and clinical characteristics. Direct wet mount technique was applied for detection and identification of intestinal parasites., Result: A total of 384 participants were included in this study of which 50.3% were males and 65.4% were in the age group 9-12 years. The prevalence of at least one intestinal parasite was 26.8% (n = 103), of which 13.6% (n = 14) were mixed infections. Hymenolepis nana was the most prevalent intestinal parasite (5.2%) followed by Entamoeba histolytica/dispar (4.9%) and hookworm (4.7%). Male children (adjusted odds ratio = 0.624; 95% confidence interval: 0.392-0.993) and those whose mother completed elementary school (adjusted odds ratio = 2.171; 95% confidence interval: 1.012-4.658) were significantly associated with intestinal parasite infections (p < 0.05)., Conclusion: Intestinal parasitic infections remained an important health problem among school children in the study area. Appropriate intervention measures should be taken to reduce the burden and related morbidities., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Traditional medicine is still playing an important role in meeting the basic health care requirement of the peoples in different parts of Ethiopia. There is no published review that clearly indicates documented medicinal plants available in different parts of the country used for treating viral and fungal infections. Currently, viral epidemics with high mortality and morbidity like SARS COV-2 are emerging. Screening of promising drug from plant source is vital to control such viral and fungal infections. In addition, indicating the most commonly used parts of the plant and their route of administration will help for further drug formulation studies. This review aimed to present an indication of the ethnomedicinal plants used for the treatment of fungal and viral infections., Methods: The databases (Google Scholar, pub med, hinari, and research gate) were searched for published articles on the ethnobotany of medicinal plants used to treat viral and fungal infection in Ethiopia without restriction in the methodology and year of publication. Viral infections, fungal infections, anti-fungal and anti-viral activity, ethnobotany, Ethiopia, and medicinal plants were the key search terms. Studies that did not have complete ethnobotanical data and did not address viral and fungal infection as a disease treated traditionally by the practitioners were excluded., Results: A total of 249 articles were produced by database search. After amendment for exclusion criteria and duplicates, 15 articles were found appropriate for the review. The majority of the studies were qualitative and others were mixed type in nature. All of the medicinal plants traditionally used to treat viral and fungal infections in Ethiopia were not scientifically confirmed. Out of the 95 identified plants, 40.8% were herbs and from the plant parts used and 43.9% and 21.1% were leaves and roots, respectively. The majority, (48.8%), of the plant remedies were given orally. Rabies and Tinea capitis constitute the highest percentage of viral and fungal infections treated by traditional medicinal plants followed by hepatitis and Tinea corporis, respectively., Conclusion: Various plants have been used to treat viral and fungal infections. Information obtained from this review serves as a guide to discover novel antiviral and antifungal agents from plants. Therefore, it is advisable for field researchers to properly identify, document, conserve and conduct efficacy and safety studies on such medicinal plants in animal models., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Aschale et al.)

Background: Hepatitis B virus is a public health problem in the world. It is a major cause of chronic hepatitis, cirrhosis, and hepatic cellular carcinoma. The presence of a confirmed HBsAg result is indicative of ongoing HBV infection. This study aims to assess the sero-prevalence and associated factors of the hepatitis B virus among pregnant women in North West Ethiopia., Methods and Materials: An institution-based cross-sectional study was conducted at Debre Markos Referral Hospital from January to July 2017. A consecutive 338 pregnant women attending the antenatal clinic were included. A structured questionnaire was used to assess hepatitis B virus infection associated factors and some socio-demographic characteristics. A 5 mL of venous blood was collected from each study participant and plasma was separated and analyzed using a rapid HBsAg kit and further confirmed by double sandwich ELISA. The data were analyzed using SPSS software version 24., Results: The mean age of the study participants was 27 (SD ± 4.75) years. The sero-prevalence of hepatitis B virus in pregnant women was 28 (8.3%). Body tattooing practice (AOR = 4.94 95% CI, 1.87-13.0), multi-partner sexual intercourse (AOR = 4.48 95% CI, 1.89-10.5) and family hepatitis B history (AOR = 7.40 95% CI, 2.23-24.5) were statistically significantly associated with HBV infection (p = 0.001)., Conclusion: The prevalence of hepatitis B infection is very high among pregnant women in the study area. Awareness creation on modes of transmission and early screening of all pregnant women attending antenatal care must be strengthened to minimize and control infection., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Demeke et al.)

Background: Intestinal parasitosis is a common disease that causes misery and disability in poor populations. The number of individuals affected is staggering. From two billion peoples who harbor parasites worldwide, 300 million suffer severe morbidity and more than 25% of pregnant women are infected with hookworm, which causes intestinal bleeding and blood loss, and has been most commonly associated with anemia. Intestinal parasite infection during pregnancy has been associated with iron deficiency, maternal anemia, and impaired nutritional status, as well as decreased infant birth weight., Objective: This study aimed to assess the effects of intestinal parasite infection on hematological profiles of pregnant women attending antenatal care in Debre Markos Referral Hospital from December 2017 to February 2019., Method: A prospective cohort study design was conducted among 94 intestinal parasite-infected pregnant women as an exposed group and 187 pregnant women free from intestinal parasite were used as a control group. The effect of intestinal parasites on hematological profiles of pregnant women was assessed at Debre Markos Referral Hospital antenatal care ward. Socio-demographic data and nutrition status were assessed by using structured questionnaires and mid-upper arm circumference (MUAC), respectively. Two ml of venous blood and 2 gm of stool samples were collected to analyze the hematological profiles and detect intestinal parasites, respectively. Wet mount and formol-ether concentration (FEC) techniques were used to detect intestinal parasites. Hematological profile was analyzed using Mind ray BC-3000 plus instrument. Data were double entered into EpiData version 3.1 software and exported to SPSS version 24 software for analysis. Results were presented using tables and graphs. Associations of hemoglobin levels with intestinal parasitic infections were determined using binary logistic regression models. P≤0.05 was considered statistically significant. The mean hematological profile difference between parasite-infected and parasite-free pregnant women was computed using independent t-test., Results: In the present study, the predominant parasites identified were Entamoeba histolytica, hookworm, Giardia lamblia, Schistosoma mansoni, and Ascaris lumbricoides. About 8.2% of intestinal parasite-infected pregnant women had mild anemia while 4% had moderate anemia. Only 1.2% of intestinal parasite-free pregnant women developed moderate anemia. The mean HGB, HCT, MCV, MCH, and MCHC values of intestinal parasite-infected pregnant women were 12.8g/dl, 38.2%, 94.7fl, 33.1pg and 34.7g/dl, respectively. But the mean HGB, HCT, MCV, MCH and MCHC values of pregnant women who were free from intestinal parasites were 14.4 g/dl, 39.8%, 94.9fl, 33.9pg and 35.5g/dl, respectively. Anemia was strongly associated with hookworm (AOR = 21.29, 95%CI: 8.28-54.75, P<0.001), S.mansoni (AOR = 63.73, 95% CI: 19.15-212, P<0.001) and A.lumbricoide (AOR = 14.12, 95% CI 3.28-60.65, P<0.001)., Conclusion: Intestinal parasitic infection in pregnant women caused adverse impact on hematological profiles and was an independent predictor of anemia. Intestinal parasitic infection significantly decreased pregnant the level of HGB, HCT, MCV, MCH, and MCHC values. To minimize maternal anemia deworming could be good before pregnancy., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: The HUC-HEART Trial (ClinicalTrials.gov Identifier: NCT02323477) was a controlled, prospective, phase I/II, multicenter, single-blind, three-arm randomized study of intramyocardial delivery of human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) combined with coronary artery bypass-grafting (CABG) in patients with chronic ischemic cardiomyopathy (CIC). The trial aimed to assess (i) the safety and the efficacy of cell transplantation during one-year follow-up, (ii) to compare the efficacy of HUC-MSCs with autologous bone-marrow- derived mononuclear cells (BM-MNCs) in the same clinical settings., Methods and Results: Fifty-four patients who were randomized to receive HUC-MSCs (23×10 6 ) (n=26) or BM-MNCs (70×10 7 ) (n=12) in combination with CABG surgery. The control patients (n=16) received no cells/vehicles but CABG intervention. All patients were screened at baseline and 1, 3, 6, 12 months after transplantation. Forty-six (85%) patients completed 12 months follow-up. No short/mid-term adverse events were encountered. Decline in NT-proBNP (baseline∼ 6 months) in both cell-treated groups; an increase in left ventricular ejection fraction (LVEF) (5.4%) and stroke volume (19.7%) were noted (baseline∼6 or 12 months) only in the HUC-MSC group. Decreases were also detected in necrotic myocardium as 2.3% in the control, 4.5% in BM-MNC, and 7.7% in the HUC-MSC groups. The 6-min walking test revealed an increase in the control (14.4%) and HUC-MSC (23.1%) groups., Conclusions: Significant findings directly related to the intramyocardial delivery of HUC-MSCs justified their efficacy in CIC. Stricter patient selection criteria with precisely aligned cell dose and delivery intervals, rigorous follow-up by detailed diagnostic approaches would further help to clarify the responsiveness to the therapy.

Background: Pre-eclampsia is a pregnancy-induced hypertension that occurs after 20 weeks of gestation. It is the leading cause of maternal and perinatal morbidity and mortality globally, but it is higher in developing countries. In Ethiopia, conducting research on the incidence and predictors of pre-eclampsia is crucial due to the paucity of information., Methods: A prospective cohort study was undertaken using 242 pregnant women between November 1, 2018 and March 30, 2019 at Debre Markos Referral Hospital. All eligible women who fulfilled the inclusion criteria were included in this study. Data were entered into the epic-data Version 4.2 and analyzed using the STATA Version 14.0 software. The Cox-proportional hazard regression model was fitted and Cox-Snell residual test was used to assess the goodness of fit. Pre-eclampsia free survival time was estimated using the Kaplan-Meier survival curve. Both bivariable and multivariable Cox-proportional hazard regression models were fitted to identify predictors of pre-eclampsia., Results: The overall incidence rate of pre-eclampsia was 3.35 per 100 person-years. Having a pre-existing history of diabetes mellitus [AHR=2.7 (95% CI=1.43-8.81)], having a history of multiple pregnancy [AHR=3.4 (95% CI=2.8-6.9)] and being ≥35 years old age [AHR=2.5 (95% CI=1.42-3.54)] were the significant predictors of pre-eclampsia., Conclusion: The incidence of pre-eclampsia was high in this study. Having (pre-existing diabetes and multiple pregnancy) and being ≥35 years old age were the significant predictors of pre-eclampsia. Inspiring pregnant women's health-seeking behavior should provide a chance to diagnose pre-eclampsia early to prevent the medical complication of pre-eclampsia., Competing Interests: The authors have declared that they have no competing interests., (© 2020 Birhanu et al.)

Ideberg type III glenoid fractures are relatively rare, and the mechanisms of injury and treatment strategies remain controversial. We reviewed the fracture patterns and final radiological findings in four cases. All fractures were wider on the medial side than on the side of the articular surface. All patients had multiple ipsilateral rib fractures; three out of four patients had a concomitant acromion fracture. Therefore, the mechanism of injury for the fracture is assumed to be external force applied in the caudal direction to the medial side of the body of the scapula. The superior shoulder suspensory complex was disrupted in most cases. A good clinical outcome was obtained in two patients with percutaneous screw fixation for the glenoid fracture and rigid plate fixation for the acromion fracture and in one patient who did not have an acromion fracture. However, one patient who did not undergo fixation of the acromion fracture developed osteoarthrosis of the shoulder joint. In this type of fracture, it is important to stabilize the acromion fracture at the same time as fixation of the glenoid fracture., Competing Interests: The authors declare that they have no conflicts of interest in connection with this paper. All authors confirm that they have no financial or personal relationships with other people or organizations that could inappropriately influence this work., (© 2020 Published by Elsevier Ltd.)

Following publication of the original article [1], the authors reported that one of the authors' names was spelled incorrectly. In this Correction the incorrect and correct author name are shown.

Objective: This study was done to determine the prevalence and phenotypic characterization of Enterococcus species isolated from clinical samples of pediatric patients in Jimma University Specialized Hospital, Southwest Ethiopia., Results: The overall prevalence of Enterococci species was 5.5% (22/403). Five (22.7%) of Enterococci species were vancomycin resistant. Haemolysin, gelatinase and biofilm production was seen among 45.5, 68.2 and 77.3% of isolates respectively. The overall rate of antibiotic resistance was 95.5% (21/22). High resistance was observed against norfloxacin (87.5%), and tetracycline (77.3%). Whereas, low resistance (36.5%) was observed against ciprofloxacin and eighteen (80.8%) of the isolates were multi-drug resistant.

Robust brain magnetic resonance (MR) segmentation algorithms are critical to analyze tissues and diagnose tumor and edema in a quantitative way. In this study, we present a new tissue segmentation algorithm that segments brain MR images into tumor, edema, white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). The detection of the healthy tissues is performed simultaneously with the diseased tissues because examining the change caused by the spread of tumor and edema on healthy tissues is very important for treatment planning. We used T1, T2, and FLAIR MR images of 20 subjects suffering from glial tumor. We developed an algorithm for stripping the skull before the segmentation process. The segmentation is performed using self-organizing map (SOM) that is trained with unsupervised learning algorithm and fine-tuned with learning vector quantization (LVQ). Unlike other studies, we developed an algorithm for clustering the SOM instead of using an additional network. Input feature vector is constructed with the features obtained from stationary wavelet transform (SWT) coefficients. The results showed that average dice similarity indexes are 91% for WM, 87% for GM, 96% for CSF, 61% for tumor, and 77% for edema.

Aim: Piriformis syndrome is a rare neuromuscular disorder that occurs when the piriformis muscle compresses or irritates the sciatic nerve. The treatment of piriformis syndrome includes injections into the piriformis muscle around the sciatic nerve. These invasive approaches have been used with various techniques to increase the safety of the procedure. Computed tomography (CT)-guided injection of the piriformis muscle and the clinical outcome of the patients are discussed., Material and Methods: The authors presented 10 consecutive patients that underwent CT-guided piriformis injection between March and December 2007. Three patients had a history of a severe fall on the buttocks, one had gluteal abscess formation following deep intramuscular injection, and another one had a habit of prolonged sitting on the carpet. Etiology was not identified in the other patients. Main complaints of the patients were pain and numbness in the legs. Hypesthesia was the major neurological finding. Magnetic resonance imaging (MRI) and electromyography (EMG) were performed in all patients., Results: Nine patients had full and sustained recovery of their symptoms after piriformis injection. Only the patient who had gluteal abscess formation following deep intramuscular injection showed moderate improvement. Another patient was operated on in the 6th month after piriformis injection due to an extruded disc herniation., Conclusion: CT-guided piriformis injection is a safe and effective method in the treatment of piriformis syndrome.

Schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide. The etiology remains unclear, despite massive research efforts. Hyperactive dopaminergic signal transduction in the central nervous system is suggested to be involved in the pathophysiology of schizophrenia (the dopamine hypothesis). The dopamine D(2)-receptor (DRD2) gene is thus a promising candidate for associations with risk of schizophrenia. We investigated DRD2 and found a novel missense nucleotide change causing an amino acid substitution of serine with cysteine at codon 311 (Ser311Cys). We performed an association study using 156 schizophrenia patients and 300 controls. Cys311 in DRD2 was significantly associated with schizophrenia. Patients with the Cys311 allele displayed shorter duration of hospitalization and less severe negative symptoms and were more frequently married compared to patients without this allele, suggesting good response to treatment. We expanded samples to 291 patients with schizophrenia (including 11 postmortem brain samples), 579 controls, and 78 patients with affective disorders in a further case-control study. Cys311 was associated with schizophrenia, particularly in patients without negative symptoms, and bipolar disorder with mood-incongruent psychotic symptoms. Three meta-analyses using over 20 published studies confirmed the association. In vitro studies showed that Cys311-type D(2) receptor impairs dopamine-induced sequestration, which appears to be consistent with the dopamine hypothesis.

Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene. A case-control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P = 0.05, Mann-Whitney test), with longer alleles overly represented in patients. An in-vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)(n) repeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P = 0.01, Spearman's Rank test). These results illustrate a genotype-phenotype correlation in schizophrenia and suggest that the longer (GT)(n) stretch may act as a risk-conferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.

Dysregulation in dopaminergic neurotransmission might play a role in the pathogenesis of schizophrenia, and therefore genetic components of the dopamine (DA) pathway may confer risk. The NR4A2 (Nurr1) gene is essential for the development and maintenance of mesencephalic DA-synthesizing neurons. Moreover, Nurr1 forms a heterodimer with the retinoid X receptor and disturbances in the retinoid-signaling cascade may be involved in susceptibility to schizophrenia. To investigate the potential genetic contribution of NR4A2, we performed a case-control association study using three common variants in the gene [-2922(C)2-3, IVS6 + 17 approximately +18insG, EX8 + 657(CA)9-10] that were in strong linkage disequilibrium with each other. We did not detect a significant allelic or genotypic association. Haplotypes derived from all three polymorphisms generated similar results. These data do not support the notion that the NR4A2 gene plays a major role in risk for schizophrenia among Japanese individuals., (Copyright 2003 Wiley-Liss, Inc.)

Platelet-activating factor (PAF) is a potent phospholipid mediator that plays various roles in neuronal function and brain development. It is involved in NMDA receptor function. Release and degradation of PAF is controlled by intracellular and plasma PAF-acetylhydrolase (PAFAH). The plasma PAFAH gene (PLA2G7) is located on chromosome 6p. A previous study showed weak associations of the Ile198Thr and Val379Ala polymorphisms of this gene with schizophrenia that did not reach statistical significance after correction for multiple comparisons. Another study showed that a functional alteration of the enzyme with these two polymorphisms is likely, but the magnitude may be modest. Approximately 4% of the Japanese population lack plasma PAFAH because of a loss-of-function mutation (Val279Phe) in the PAFAH gene. Thus, the Val279Phe mutation is useful for examining whether a causal relation exists between PAFAH function and schizophrenia. We looked for an association between the Val279Phe mutation and schizophrenia in 191 Japanese patients with schizophrenia and in 188 Japanese controls. Similar genotypic and allelic distributions were observed in the two groups. These observations indicate that functional differences in the plasma form of PAFAH do not play a substantial role in the etiology of schizophrenia. However, the present study leaves open the possibility that other isoforms are involved.

Morphological alterations in the brains of schizophrenia patients suggest that neurodevelopmental dysfunction is involved in the etiology of the disease.(1) Such dysfunction may be due to functional alterations of cell adhesion molecules, which play important roles in cell migration, axonal growth, fasciculation, synaptogenesis, and synaptic remodeling. We screened for mutations in the coding region of the close homologue to L1 gene (CHL1), which is located on human chromosome 3p26, in 24 Japanese patients with schizophrenia. A missense polymorphism (Leu17Phe) in the signal peptide region was identified. A case-control comparison revealed significantly higher frequencies of the Leu/Leu genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 Japanese schizophrenic patients than in 229 Japanese control subjects. The estimated odds ratio for schizophrenia was 1.83 (95% CI, 1.28-2.26) for the Leu/Leu genotype compared with the other genotypes. An association between this CHL1 gene polymorphism and schizophrenia supports the notion that cell adhesion molecules are involved in the etiology of schizophrenia.

The tetrapeptide of cholecystokinin (CCK), CCK-4, is known to induce panic attacks in human subjects, while CCK-8 is reported to have a therapeutic effect on schizophrenia symptoms. Recently, we have identified a novel microsatellite polymorphism in the 5' upstream region of the CCK gene and shown a significant association between this polymorphism and panic disorder. In this study, we have investigated the CCK-B receptor (CCKBR) gene, which is the main constituent of the CCK receptor in the CNS. Recently, a dinucleotide repeat, (CT)(n), in the 5' regulatory region of the CCKBR gene was reported to be associated with panic disorder in Canadian samples. To evaluate an association of the CT repeat with panic disorder and schizophrenia, we genotyped 71 subjects with panic disorder, 154 schizophrenics and 199 controls. However, no evidence of allelic association was found between the polymorphic repeat of the CCKBR gene and either panic disorder or schizophrenia (P = 0.186 and 0.987, respectively). Together with the negative reports on association analyses using other polymorphisms of the CCKBR gene and Japanese samples, the present results exclude a major genetic contribution of the CCKBR gene to susceptibilities to panic disorder and schizophrenia in Japanese cohorts., (Copyright 2001 Wiley-Liss, Inc.)

Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia.

Thought disorder is one of the main symptoms observed in schizophrenia and has been investigated in terms of language dysfunction. The purpose of the present study was to find whether there were any differences in identifying and processing between content (semantic) and function (syntax) words, and to elucidate whether semantic or syntax is more impaired for the schizophrenics. Event-related potentials were recorded in 13 patients with schizophrenia and 14 healthy controls, while they silently read three sets of passages. Event-related potentials were recorded for content words (noun, verb) and function words (auxiliary verb, particle) separately. For the healthy control group, the mean amplitude of P200 for the content word class was greater than for the function word class with fronto-central dominance. In contrast, no such difference was found for the schizophrenics mainly due to the reduction of P200 amplitude of the content words. Larger P200 for the content than the function word class suggests that greater resources were used to identify the content words. Lack of this difference found in patients with schizophrenia suggested that the disturbances in the semantics may be more attributable to the linguistic impairment than those in the syntax.

The exploratory eye movements of patients with schizophrenia reportedly differ from those of patients without schizophrenia and healthy controls. In an attempt to determine whether exploratory eye movements provide valid markers for schizophrenia, the present collaborative study was conducted in six countries to analyze the stability of and variation in the following parameters of exploratory eye movements: the number of eye fixations (NEFs) and mean eye scanning length (MESL) in a retention task; the cognitive search score (CSS) that indicates how frequently the eye focused on each important area of a figure in order to recognize it in a comparison task; and the responsive search score (RSS), which reflects the frequency of eye fixations on each section of a figure in response to questioning in a comparison task. In addition, we investigated the validity of the currently employed discriminant function to extract a common feature of schizophrenia by applying it to the findings of the present study. The exploratory eye movements of 145 patients with schizophrenia, 116 depressed patients and 124 healthy controls at seven WHO collaborative centers in six countries were measured using eye mark recorders during viewing of stationary S-shaped figures in two sequential tasks. The RSSs of patients with schizophrenia were found to be significantly lower than those of depressed patients or healthy controls irrespective of geographical location, with no significant difference existing between the RSSs for depressed patients and those for healthy controls. By inserting the RSS and NEF data for each subject into the formula used to calculate discriminant function, patients with schizophrenia could be discriminated from depressed patients and healthy controls with a sensitivity of 89.0% and a specificity of 86.7%. The RSS is an exploratory eye movement parameter that detected schizophrenia irrespective of culture, race and various other subject variables. Furthermore, it is indicative of the stable, significant difference that exists between subjects with and without schizophrenia. The results of discriminant analysis confirm the previously reported validity of discriminant function.

Since the recognition that adults with velocardiofacial syndrome (VCFS), which is associated with hemizygous interstitial deletions of chromosome 22q11, frequently show psychotic symptoms, deletion of the 22q11.2 region has been proposed as a common genetic abnormality associated with schizophrenia. In studies of schizophrenia patients, such deletions have been detected in more than 1% of schizophrenics, indicating the likely presence of this deletion in a significant number of patients. In this study, we screened for 22q11.2 deletions by genotyping microsatellite markers in 300 schizophrenics and 300 normal controls. The 22q11.2 deletion was confirmed by fluorescent in situ hybridization (FISH). One patient with schizophrenia was found to have a 22q11.2 deletion. The patient was mildly retarded but did not have craniofacial, palatal, or cardiac malformations characteristic of VCFS. Our results indicate that 22q11.2 deletion does not contribute substantially to the development of schizophrenia in general. However, our findings establish the existence of physically near-normal individuals with 22q11.2 deletion among learning disabled or mildly retarded persons with schizophrenia.

The two famous hypotheses for the pathophysiology of affective disorders examined the role of deficiencies in catecholamine(Schildkraut, 1965) and indoleamine(Coppen, 1967). In the catecholamine hypothesis, Schildkraut proposed that some depressions were associated with an absolute or relative decrease in available norepinephrine at central adrenergic receptor sites. In the indoleamine hypothesis, there was evidence that the biochemical disturbances in three main areas; in amine metabolism, electrolyte distribution and hormonal function, played a role in affective disorders. This review attempts to find newer studies of affective disorders influenced by the two hypotheses. With the development of neurobiology and the availability of new tools over the last three decades, authors have generated newer theories for current studies. The functional roles of GABA, glutamate and dopamine have lead to the generation of newer hypotheses. The neurogenesis hypothesis provides evidence of a novel concept for the pathophysiology of affective disorders.

Disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia. We searched for mutations in the exons of the metabotropic glutamate receptor mGluR4 (GRM4) gene on human chromosome 6p21.3 and evaluated associations between these polymorphisms with schizophrenia in Japanese patients. Nine nuclear variants of 450G > T, 1455T > C, 2202A > G, 2389G > A (Val797 > Ile797), 2890A > G, 3601C > T, 3639C > T, IVS4-36G > A, and IVS5 + 29(CCGGG)1-2, were found. The Val797Ile variant, although found in both the patient and control groups, was rare and the only variant that causes a non-synonymous amino acid change. There was no statistically significant association between any mGluR4 gene polymorphism and schizophrenia. Thus, this study did not provide evidence for the contribution of the mGluR4 gene to schizophrenia in the Japanese.

The benzodiazepine receptor (peripheral) (BZRP) plays an important role in the steroid syntheses of the adrenal glands and brain, which is possibly involved in the pathophysiology of mood disorders. We evaluated an association study between two missense variations of the BZRP gene and mood disorders in a Japanese sample. However, no statistically significant associations with either bipolar disorders or depressive disorders were observed in the allele frequencies, genotype counts, or haplotype distributions for the two variations, although the present sample size had a moderate power (0.46-0.86). These results do not suggest that the BZRP gene plays a role in the genetic predisposition of affective disorders., (Copyright 2001 Wiley-Liss, Inc.)

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.

NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted.

L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

Abnormalities in neural transmission of dopamine play an important role in development of schizophrenia. Dopamine 1 (D1)-like receptors in 16 areas of the cerebral cortex were measured in the postmortem brains of 13 schizophrenics and 10 controls, using [3H]SCH23390 as a ligand for receptor binding. The specific [3H]SCH23390 bindings were statistically significantly increased in the medial and inferior cortex (Brodmann Area (BA) 20 & 21) and superior parietal cortex (BA 7) of schizophrenic patients, compared to those of the controls. The increases were also marked in the cerebral cortices of off-drug cases of patients with schizophrenia, who had not received antipsychotic drugs for more than 40 days before death. These results suggest that there are changes in dopaminergic transmission through the D1 receptors in the parieto-temporal cortex of schizophrenia, and that the altered functions are involved in the pathophysiology of the disease.

Tyrosine hydroxylase (TH) is the rate limiting enzyme in the synthesis of dopamine and norepinephrine. A polymorphic repeat of the tetranucleotide (TCAT) in the first intron of the TH gene may behave as a regulatory element for the gene expression. Allelic fragments of the tandem repeat were typed by a PCR-based process with a pair of primers specific for the polymorphic sequence. The association between the polymorphism and schizophrenia was examined in a Japanese sample. There was a statistically significant association between the polymorphism and schizophrenia in females (chi2 = 26.018, p = 0.010), but not in males (chi2 = 15.995, p = 0.305). The genotype heterozygous for the TH9 and TH6 was significantly decreased in female schizophrenics (chi2 = 5.125, p = 0.0236). These results suggest that TH could be considered as a minor gene contributing to the susceptibility of Japanese female schizophrenia.

Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.

Lack of Fyn tyrosine kinase increases alcohol sensitivity. Fyn phosphorylates a component of the NMDA receptor, which may be involved in schizophrenia. The Fyn gene is located on human chromosome 6q21, to which linkage of schizophrenia has been suggested. We hypothesized that the Fyn gene is a candidate for predisposition to alcoholism and schizophrenia, and we performed a mutation study of the 5'-flanking region, all coding exons, and exon-intron junctions of the Fyn gene. The SSCP mutation analysis was performed in 48 unrelated alcoholics and 16 unrelated schizophrenics. Three polymorphisms, -93A/G in the 5'-flanking region, IVS10+37T/C in intron 10, and Ex12+894T/G in the 3'-untranslated region, were identified. A rare variant of Ex12+1162TG in the 3'-untranslated region was also detected. Neither missense nor nonsense mutations were found. Case-control studies using a larger sample of unrelated patients and controls did not reveal significant associations between these polymorphisms and alcoholism or schizophrenia. In addition, genotyping a microsatellite marker, D6S302, located in intron 10 of the Fyn gene, did not show a significant association between the marker and alcoholism or schizophrenia. Results of the present study did not provide evidence for the involvement of the genomic Fyn gene mutations in alcoholism or schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:716-720, 2000., (Copyright 2000 Wiley-Liss, Inc.)

We examined the effects of neonatal treatment with MK-801 on 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shaking as well as [(3)H]ketanserin binding in adult rats. Neonatal rats were injected with MK-801 (0.25 mg/kg, s.c., twice daily) or with saline from postnatal days (PND) 7-18. At PND 60, a statistically significant increase in the frequency of head shaking induced by DOI (1.0 mg/kg, s.c.) was observed in the rats neonatally treated with MK-801, compared to saline-treated rats, without any change in the specific [(3)H]ketanserin binding in the frontal cortex. These results suggest that repeated NMDA receptor blockades during the critical period of brain development produce a long lasting hyper-responsiveness in the 5-HT(2A) receptor-mediated behavior, interfering with the development of neural circuits related to the behavior.

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.

We present a child with Wegener's granulomatosis who showed lung lesions progressing from nodules to cavities within a 1-month period on CT.

Synapsins are a family of neuron-specific, synaptic vesicle-associated phosphoproteins that have been implicated in the modulation of neurotransmitter release. Synapsins are coded by three distinct genes for synapsin I. II, and III. The synapsin III gene is located on human chromosome 22q12-q13, where a possible schizophrenia susceptibility locus is located. Using the single strand conformation polymorphism method, we searched for variants in 13 exons and the 5'-flanking region of the synapsin III gene in schizophrenia. Three polymorphisms, -631C/G, -271T/C, and E525Q, and one rare variant, -669C >A, were identified. Case-control comparisons of these polymorphisms revealed no significant differences in the allelic and genotypic distributions between schizophrenic and control subjects. The present study did not provide evidence for an association between the synapsin III gene and schizophrenia.

Using positron emission tomography (PET) and [11C]N-methylspiperone (NMSP), we examined 5-HT2 receptors in the cortex of schizophrenic patients in whom we previously observed decreased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [11C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

Although amantadine is relatively free of side effects compared with levodopa, the incidence and severity of unwanted effects, such as hallucinations, insomnia and dizziness, markedly increase when the daily dose exceeds 200 mg. A 63-year-old schizophrenic female developed the Pisa syndrome following neuroleptic medication. She was started on a regimen of amantadine, 200 mg per day, on September 4, and the electroencephalogram (EEG) on September 11 was within normal limits. The dosage was increased to 300 mg on September 18 because there was no improvement and no side effects. Two days later a generalised convulsion occurred and an EEG revealed frequent multiple spikes or sharp waves with slow waves. No epileptic seizure has been observed since the amantadine was discontinued. The EEG on September 27 was again within normal limits. To our knowledge, the EEG of a patient with convulsion induced by amantadine has not been described previously. The epileptic mechanisms of amantadine have not been elucidated; however, it may be related to a modulating role of dopamine in the central nervous system.

The benzodiazepine receptor (peripheral) (BZRP) mainly localized on glial cells plays a role in neurosteroid synthesis, and increases with glial proliferation. We have recently reported a significant decrease in the density of BZRP labeled by [3H] PK 11195 in the postmortem brain of chronic schizophrenics, suggesting that dysfunctions of the BZRP are involved in the pathophysiology of schizophrenia. We screened 11 patients with schizophrenia and 10 controls, which were used in a previous postmortem study, for their genomic sequences of the BZRP gene in order to find DNA sequence variations. One novel missense polymorphism (His162Arg) and another previously reported missense mutation (Ala147Thr) were detected. An association study of the identified variations was then performed in an extended Japanese sample of 304 schizophrenic patients and 369 controls. While there was an increased tendency in the frequency of the 162Arg allele of schizophrenics compared to that of the controls (p = 0.0603), no statistically significant association with schizophrenia was observed in the Ala147Thr allele (p = 0.1016). These results do not suggest that the two missense polymorphisms play a major role in the genetic predisposition of schizophrenia in the Japanese sample.

To examine the neurophysiological and cognitive characteristics of language disorder in schizophrenia, the N400 component and late positive component (LPC) of event-related potentials (ERPs) were investigated in medicated schizophrenic patients and health comparison subjects. The subjects were required to indicate whether Japanese sentence completions were semantically congruous or incongruous. The ERPs for the range of 300-500 ms to the incongruous completions contained a more negative component (N400), followed by LPC, which was inversely more positive for the incongruous than congruous condition. The N400 effect and the mean amplitude of the LPC were reduced in the patients. The attenuated N400 effect in schizophrenics mainly originated from an enhanced negativity for the congruous completions, suggesting that the use of context is poor in schizophrenia.

Catechol-O-methyltransferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. There is a functional polymorphism of the COMT gene, Val108Met in the soluble form of the enzyme (Val158Met in the membrane-bound form). Involvement of the dopaminergic systems in alcoholism has been suggested in mice and humans. We examined associations between this polymorphism and alcoholism in 175 Japanese alcoholics and 354 age- and gender-matched Japanese controls. No significant difference in the allelic distributions in alcoholics and controls and no significant associations between antisocial behaviors in alcoholics and this polymorphism were observed. Therefore, the COMT gene is not likely to play a significant role in alcoholism.

Background: Involvement of the serotoninergic system (S/S) in alcoholism has been suggested in both mice and humans. Previous studies have suggested the S/S genotype of the serotonin transporter gene promoter polymorphism to be associated with severe alcohol dependence marked by severe withdrawal symptoms. It has also been associated with alcoholics who exhibit a dissocial personality disorder., Methods: We examined the polymorphism in 166 Japanese alcoholics who experienced withdrawal seizure or delirium and 290 Japanese controls., Results: The S/S genotype was not increased in the patients. Exploratory analyses showed significantly less frequent S allele and S/S genotype frequencies in the alcoholics with a history of drinking-related arrests than in the controls (p = 0.009 and p = 0.03, respectively), perhaps reflecting previously reported harm avoidance personality traits associated with S/S. Alcoholics with the L allele had a significantly earlier onset of alcohol dependence than those with the S/S genotype (p = 0.01)., Conclusions: The present study failed to provide supportive evidence for an association of the S/S genotype with severe alcoholism marked by physical withdrawal symptoms or with antisocial behaviors among the Japanese. Although our data support involvement of the central serotoninergic system in some types of alcoholism, the potential association findings of this study emerged as only exploratory and, therefore, should be understood as tentative until replicated in other studies.

The human dopamine D4 receptor gene (DRD4) is an important candidate gene for schizophrenia. We identified a novel -521C>T polymorphism in the 5'-promoter region of DRD4. A transient expression method revealed that the T allele of this polymorphism reduces the transcriptional efficiency by 40% compared with the C allele. This polymorphism is of interest because of reported elevation of D4-like sites and DRD4 mRNA in the postmortem schizophrenic brain. The C allele frequency was significantly higher in 252 Japanese schizophrenics (0.48) than in 269 Japanese controls (0.41) (p = 0. 02) [odds ratio = 1.35 (95% confidence interval 1.05 - 1.72)]. Although the association is weak and should be considered tentative until other studies replicate it, this polymorphism provides a tool with the potential to examine whether DRD4 is related to susceptibility to and neuroleptic response in schizophrenia., (Copyright 1999 Academic Press.)

The activity of dopamine-containing neurons in the ventral tegmental area and nucleus accumbens may play a role in alcoholism. Cholecystokinin (CCK) co-exists in a large proportion of A10 dopamine neurons to exert some effect on dopamine-induced behavior. Recently, a C-45T polymorphism was discovered in the Sp1 binding site in the CCK gene promoter region. We investigated an association between the polymorphism and alcoholism in 209 Japanese DSM-III-R alcoholics and 113 Japanese control subjects. The patients and the control subjects had similar allele and genotype frequencies: the T allele frequencies were 0.27 in the patients and 0.28 in the control subjects and the CC, CT, and the TT genotype frequencies 0.53, 0.39, and 0.08 in the alcoholics and 0.53, 0.37, and 0.10 in the control subjects. Frequencies of clinical characteristics of Feighner's criteria for the lifetime diagnosis of alcoholism were not significantly different among the patient groups divided by the genotype. These findings indicate that the polymorphism has no major effect on the etiology of alcoholism.