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The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Motivation: Single cell RNA-Sequencing (scRNA-seq) has rapidly gained popularity over the last few years for profiling the transcriptomes of thousands to millions of single cells. This technology is now being used to analyse experiments with complex designs including biological replication. One question that can be asked from single cell experiments, which has been difficult to directly address with bulk RNA-seq data, is whether the cell type proportions are different between two or more experimental conditions. As well as gene expression changes, the relative depletion or enrichment of a particular cell type can be the functional consequence of disease or treatment. However, cell type proportion estimates from scRNA-seq data are variable and statistical methods that can correctly account for different sources of variability are needed to confidently identify statistically significant shifts in cell type composition between experimental conditions., Results: We have developed propeller, a robust and flexible method that leverages biological replication to find statistically significant differences in cell type proportions between groups. Using simulated cell type proportions data, we show that propeller performs well under a variety of scenarios. We applied propeller to test for significant changes in cell type proportions related to human heart development, ageing and COVID-19 disease severity., Availability and Implementation: The propeller method is publicly available in the open source speckle R package (https://github.com/phipsonlab/speckle). All the analysis code for the article is available at the associated analysis website: https://phipsonlab.github.io/propeller-paper-analysis/. The speckle package, analysis scripts and datasets have been deposited at https://doi.org/10.5281/zenodo.7009042., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Background: Despite in-depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals governing postnatal maturation of the human heart., Methods: Single-nucleus RNA sequencing of 54 140 nuclei from 9 human donors was used to profile transcriptional changes in diverse cardiac cell types during maturation from fetal stages to adulthood. Bulk RNA sequencing and the Assay for Transposase-Accessible Chromatin using sequencing were used to further validate transcriptional changes and to profile alterations in the chromatin accessibility landscape in purified cardiomyocyte nuclei from 21 human donors. Functional validation studies of sex steroids implicated in cardiac maturation were performed in human pluripotent stem cell-derived cardiac organoids and mice., Results: Our data identify the progesterone receptor as a key mediator of sex-dependent transcriptional programs during cardiomyocyte maturation. Functional validation studies in human cardiac organoids and mice demonstrate that the progesterone receptor drives sex-specific metabolic programs and maturation of cardiac contractile properties., Conclusions: These data provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.

Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined., Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF., Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance., Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity., Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling., Competing Interests: The authors have declared that no competing interests exist.

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

MicroRNAs (miRNAs) are translational regulatory molecules with recognised roles in heart development and disease. Therefore, it is important to define the human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine whether critical cardiac transcription factors such as NKX2-5 regulate miRNA expression. We used an NKX2-5 eGFP/w reporter line to isolate both cardiac committed mesoderm and cardiomyocytes. We identified 11 miRNAs that were differentially expressed in NKX2-5 -expressing cardiac mesoderm compared to non-cardiac mesoderm. Subsequent profiling revealed that the canonical myogenic miRNAs including MIR1-1, MIR133A1 and MIR208A were enriched in cardiomyocytes. Strikingly, deletion of NKX2-5 did not result in gross changes in the cardiac miRNA profile, either at committed mesoderm or cardiomyocyte stages. Thus, in early human cardiomyocyte commitment and differentiation, the cardiac myogenic miRNA program is predominantly regulated independently of the highly conserved NKX2-5 -dependant gene regulatory network.

The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation, and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches. We show that zebrafish lacking functional vegfc and vegfd signaling are devoid of a cardiac lymphatic network and display cardiac hypertrophy in the absence of injury, suggesting a role for these vessels in cardiac tissue homeostasis. Using two different cardiac injury models, we report a robust lymphangiogenic response following cryoinjury, but not following apical resection injury. Although the majority of mutants lacking functional vegfc and vegfd signaling were able to mount a full regenerative response even in the complete absence of a cardiac lymphatic vasculature, cardiac regeneration was severely impaired in a subset of mutants, which was associated with heightened pro-inflammatory cytokine signaling. These findings reveal a context-dependent requirement for the lymphatic vasculature during cardiac growth and regeneration., Competing Interests: Competing interestThe authors declare no competing interests.

Background: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time., Methods: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56)., Results: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation., Conclusions: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes., (© 2017 The Authors.)

In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyocytes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigenetic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Relatively little is known about the epigenetic control mechanisms that guide postnatal organ maturation. The goal of this study was to determine whether DNA methylation plays an important role in guiding transcriptional changes during the first 2 wk of mouse heart development, which is an important period for cardiomyocyte maturation, loss of proliferative capacity and loss of regenerative potential. Gene expression profiling (RNA-seq) and genome-wide sequencing of methylated DNA (MBD-seq) identified dynamic changes in the cardiac methylome during postnatal development [2545 differentially methylated regions (DMRs) from P1 to P14 in the mouse]. The vast majority (~80%) of DMRs were hypermethylated between P1 and P14, and these hypermethylated regions were associated with transcriptional shut down of important developmental signaling pathways, including Hedgehog, bone morphogenetic protein, TGF-β, fibroblast growth factor, and Wnt/β-catenin signaling. Postnatal inhibition of DNA methylation with 5-aza-2'-deoxycytidine induced a marked increase (~3-fold) in cardiomyocyte proliferation and ~50% reduction in the percentage of binucleated cardiomyocytes compared with saline-treated controls. This study provides novel evidence for widespread alterations in DNA methylation during postnatal heart maturation and suggests that cardiomyocyte cell cycle arrest during the neonatal period is subject to regulation by DNA methylation., (© FASEB.)

Clozapine has superior effects in treating negative symptoms of schizophrenia and causes less extrapyramidal side effects than traditional antipsychotics. In this study, we investigated the effects of acute and long-term clozapine administration on [14C]2-deoxyglucose uptake (2-DG uptake) in rats, as measured using the [14C]2-deoxy-D-glucose method. The 2-DG uptake was reduced in fewer regions after chronic clozapine (46%) than after acute clozapine (97%). After chronic clozapine treatment, the 2-DG uptake was reduced in the shell, but not the core, of the nucleus accumbens. In addition, long-term clozapine treatment remained affecting 2-DG uptake in several regions of the extrapyramidal system and the thalamus. The pattern of 2-DG uptake changes after long-term clozapine administration may provide information for the regions related to the therapeutic effect of clozapine., (Copyright 2001 S. Karger AG, Basel.)

Repeated administration of high doses of methamphetamine (MAP) to rats can induce long-lasting neurotoxicity which may be related to permanent psychotic symptoms and negative symptoms in some MAP psychotic patients. In this study, we used the 2-[14C]deoxyglucose (2DG) method to analyze the effects of repeated MAP administration (12.5 mg/kg, i.p., 4 times every 2 hr within a day) 14 days and 60 days after drug administration. The results showed a widespread (26 of the 43 regions examined) decreases in the regional cerebral glucose utilization. The regions with decrease metabolism included all the extrapyramidal systems, the hippocampus formation and dorsal raphe nucleus. Rats tested 60 days after drug administration has similar finding to those with a 14-day abstinent period. The results of the functional change in this study provide support for the neurotoxic effects of repeated high dose MAP administration in rats. Furthermore, the neurotoxic effects are selective and long-lasting. We suggested the MAP neurotoxic model can be used to study the permanent psychosis and negative symptoms of MAP-induced psychosis in humans.

Risperidone (R 64 766, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyperidinyl]ethyl )-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one) has superior effects in treating negative symptoms of schizophrenia and causes less extrapyramidal side effects than traditional antipsychotics. In this study, we employed the [14C]2-deoxy-D-glucose method to map local cerebral metabolic activity of rats acutely administrated i.p. with 0.0, 0.1, 0.5, 1.0 and 2.0 mg kg(-1) risperidone. Risperidone in the highest dose produced a reduction of glucose utilization in 11 of the 38 regions examined. The results showed that the regions with metabolic change are somewhat different from those results studied with microdialysis and the Fos immunohistochemistry. Among the nuclei with metabolic changes, the hippocampus and the mediodorsal nucleus of the thalamus may be related to the therapeutic action of risperidone and require further study.

The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result.

A recent observation has shown that a common polymorphism in the alpha1-antichymotrypsin (ACT) confers a significant risk for Alzheimer's disease (AD). Furthermore, the apolipoprotein E epsilon4 allele (APOE*4) effect associated with AD risk is modified by the ACT polymorphisms. To evaluate the role of ACT polymorphism in AD, we conducted an association study of ACT polymorphisms in Chinese AD patients and normal controls. We found that the ACT polymorphism had no effect on the development of AD either alone or in combination with the APOE*4 allele.

Background: Disturbances in dopaminergic transmission have been implicated in the etiology of schizophrenia. Catalano et al reported an association between delusional disorder and the number of a 12-nucleotide (bp) repeat sequence in the first exon of dopamine D4 receptor gene (DRD4), which indicated a possible role of this polymorphism in the pathogenesis of psychotic disorders., Methods: DNA of 42 Chinese controls, 50 sporadic schizophrenic patients, and 30 familial schizophrenic probands were collected. Genotype of the 12-bp repeat polymorphism of DRD4 was determined with polymerase chain reaction and agarose gel electrophoresis. Genotypic and allelic frequencies were compared among the three groups using the chi-square test., Results: Forty-three (86%) sporadic schizophrenic patients, 25 (83.3%) familial schizophrenic probands, and 35 (83.3%) controls were A1 (two 12-bp repeat) homozygotes. One (2.0%) sporadic schizophrenic and 1 familial schizophrenic patient were A2 (one 12-bp repeat) homozygotes. There was no significant difference in allelic and genotypic distributions among the three groups., Conclusions: The present data do not support an association between schizophrenia and any specific allele of the 12-bp repeat polymorphism of DRD4. Significance of familial/sporadic division of schizophrenia cannot be supported regarding this repeat polymorphism.

Delirium, a transient organic psychiatric syndrome, is a common psychiatric diagnosis. It is associated with increased rates of morbidity and mortality in medical-surgical inpatients. There have been few reports describing the risk factors and prevalence of delirium among psychiatric inpatients. The purpose of the present study was to investigate the rate of delirium, the reasons for admission, the clinical features, the etiologies and the mortality during a 2 year follow-up in psychiatric inpatients admitted to a general hospital during a 3 year period. The results show that the rate of incidence of delirium in psychiatric and geriatric (age > or = 65 years) inpatients was 1.4 and 9.6% respectively. The most common cause of delirium was adverse effects of medication. The inpatient mortality (5.9%) was lower compared with reported mortality rates in medical-surgical inpatients. However, there was a high mortality rate during the 2 year follow-up period (39.4%), especially in older patients. The high mortality during follow-up stressed the importance of after-discharge care in these patients.

It has been reported that panic attacks might cause mitral valve prolapse (MVP) via haemodynamic or indirect effects. Such prolapse can be classified as being physiological (benign course) or pathological (poor course). It is therefore important to consider whether panic attacks, as a risk factor for MVP, are associated with its physiological or pathological type. Our study sample consisted of two groups of patients with panic disorder (PD), one having onset within 1 year (n=24) and the other with a history of more than 10 years (n=21). Demographic data, symptom presentations, auscultatory and echocardiographic findings of both groups were compared, but no significant difference was found except with regard to anticipatory anxiety. It is concluded that panic attack exerts no significant effect on mitral valve prolapse.

Repeated amphetamine administration can cause an augmentation of regional cerebral metabolic activity. This study analyzed the regional cerebral metabolic changes which occurred in rats after pretreatment with the selective dopamine D1 and D2 receptor agonists, (+/-)SKF 38393 ((+/-)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl) and quinpirole (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3, 4-g)quinoline), as measured by the 2-[14C]deoxyglucose method. The results showed selective metabolic augmentation in rats pretreated with SKF 38393 but not in those pretreated with quinpirole alone or with quinpirole in combination with SKF 38393. These findings demonstrated that dopamine D1 receptors may play a critical role in the development of metabolic augmentation after repeated stimulant administration.

Variation in the number of tandem repeats of a 48 base pair (bp) unit was found in the gene of the dopamine D4 receptor (DRD4). The number of repetitions of the 48bp unit was shown to influence the binding of clozapine, which suggests that different alleles may function differently in vivo and affect the pathogenesis of schizophrenia. Genotypes of DRD4 polymorphism were analyzed for 47 schizophrenic probands who had at least one living sibling with a diagnosis of schizophrenia, 35 unaffected siblings of the schizophrenic proband, 42 sporadic schizophrenic patients, and 43 healthy controls without a family history of psychosis. There was no significant difference in genotypic or allelic distributions among the four groups. Significant differences in the frequencies of two- and seven-repeats alleles between the Chinese and Caucasians controls were noted. The present study did not support that a particular allele or genotype of the 48bp-repeat of DRD4 was associated with schizophrenia.

Clozapine has been shown to have superior effectiveness compared with classic neuroleptics in treating refractory schizophrenia in Caucasians, but its efficacy and safety in Chinese have not been adequately studied. Forty Chinese schizophrenic patients were recruited in a 12-week, double-blind, comparative trial. Twenty-one patients were randomly assigned to clozapine treatment and 19 to chlorpromazine treatment. The average dose was 543 +/- 157 and 1163 +/- 228 mg/day for clozapine and chlorpromazine, respectively. The results showed that six clozapine-treated patients (28.6%) had more than 20% improvement in Brief Psychiatric Rating Scale score and were classified as responders, whereas none of the chlorpromazine-treated patients was classified as a responder. The degree of improvement in positive symptoms, negative symptoms and Brief Psychiatric Rating Scale scores in the clozapine group was inversely correlated with the severity of negative symptoms at entry into the trial. Two clozapine-treated patients were withdrawn from the study, one because of leukopenia and nausea, and the other because of vomiting and hypotension. Chlorpromazine treatment was prematurely discontinued in two patients, because of jaundice and over sedation in one, and because of severe weight loss in the other (9 kg). The rate of moderate-to-severe sialorrhea was high in clozapine-treated patients (28.6%). Two clozapine-treated patients and two chlorpromazine-treated patients showed significant improvement in previously existing tardive dyskinesia and one chlorpromazine-treated patient exhibited aggravation of tardive dyskinesia. The results of this study indicate that clozapine treatment might have advantages over chlorpromazine for Chinese schizophrenic patients who are refractory to typical neuroleptic treatment.

Organic delusional disorder (ODD) is rarely diagnosed in psychiatric in-patients, and may be misdiagnosed as delusional disorder (DD) from a similar clinical presentation. The aim of the present study was to investigate the characteristics of ODD and to make a comparison with those of DD patients. Patients who conformed to DSM-III-R criteria for ODD were recruited from an 8-year psychiatric in-patient database. Matching controls were DD patients admitted over the same time period. The prevalence of ODD according to DSM-III-R criteria was 0.4% of total admissions and 2.9% of organic mental disorders. Compared to DD patients, ODD patients less often had a family psychiatric history, and had an older age of onset of psychiatric disorder, longer hospital stays and lower treatment dosage of antipsychotic drugs. It is suggested that a detailed medical history and examination are needed in patients with delusion, especially in patients with a late onset of psychiatric symptoms and no family psychiatric history.

Behavioral sensitization elicited by repeated administration of amphetamine does not fully develop until a period after discontinuation of amphetamine, but then persists undiminished for a long time. This experiment investigated the regional metabolic changes in rats pretreated with amphetamine and challenged after different abstinence periods (2, 7 and 28 days), using the 2-[14C]deoxyglucose method. The results demonstrated that chronic amphetamine administration enhanced rates of local cerebral glucose utilization in specific cerebral regions. The magnitude and distribution of effects varied with the abstinence period. A challenge dose of d-amphetamine 2 days after pretreatment was found to have no more, or only mildly elevated, local cerebral glucose utilization compared with that following a single acute dose. In rats challenged at the 7th and 28th day, a supersensitive metabolic response was found in dopaminergic and non-dopaminergic areas. This finding suggested regional differences in the development of sensitization and underscored the importance of an abstinence period in the study of sensitization and amphetamine psychosis.

Inpatients in general hospital often presented with psychological problems and some of them need emergent psychiatric interventions. However, there have been little attention on the psychiatric emergency consultation. The purpose of this paper is to review the psychiatric emergency service in a general hospital over 3-year period. During this period, there were 88 psychiatric emergency consultations that represented 2.3% of all psychiatric consultations. The emergency group showed no difference in sex and age, but received more diagnoses of delirium (58.0%) than the other referrals. About one fourth of these patients had psychiatric history. Stated requests for "agitation and irritability", "psychiatric symptoms" and "uncooperation with treatment" were the most frequent reasons. Sixty-five percent of the patients receive recommendations of medication treatment. Among them, neuroleptics and anxiolytics were most common used. About one half of the patients needed further medical tests. After psychiatric interventions, most of the patients got improved within 2 days but 15 patients died during hospitalization. These findings indicated that psychiatric emergency consultation though the request rate is low. When making diagnoses in emergency consultation, past psychiatric history is important and organic mental disorders should be ruled out first. After psychiatric interventions, most of the psychiatric emergency could be improved. It suggested that the setting of psychiatric emergency consultation could improve the quality of patient care in a ageneral hospital.

Objective: The purpose of this study was to investigate the psychiatric consultation condition in the obstetric ward with particular attention paid to the reasons for referral, psychiatric diagnoses and recommendations., Methods: This study was conducted in a medical center with 73 obstetric beds. All psychiatric consultations of obstetric inpatients during a 3-year period were included in this study. Data were derived from clinical charts and consultation records that included demographic data, reasons for referral, psychiatric diagnoses and treatment recommendations., Results: Within the 3-year period, 28 patients were referred for psychiatric consultation, or 0.3% of the 9,972 obstetric admissions. The obstetric group represented 0.7% of all the psychiatric consultations. The most common reason for the referral was anxiety. Many obstetric problems, medical histories and psychiatric histories were found in these 28 patients. The most common diagnoses were depression or dysthymia, and schizophrenia. The diagnosis of organic mental disorders was rarely found. The vast majority of the psychiatric consultants were likely to recommend medication and psychological intervention., Conclusion: Even though there is a low psychiatric consultation rate among the obstetric inpatients, it does not mean that the prevalence rate of mental disorders is low in the obstetric patients. Psychiatric problems may be neglected or happen after patients are discharged. Organic mental disorders were rarely found in the obstetric patients which suggested a different pattern of mental disorders in the obstetric patients compared to other patients. The stress during child delivery needs further study for it may exacerbate or predispose a mental disorder. It is suggested that collaboration between obstetric staff and the consultation-liaison psychiatrists may provide better care for pregnant women patients.

We examined the apolipoprotein E genotype in 56 Chinese patients with late-onset sporadic Alzheimer's disease (AD) and 57 Chinese control subjects of similar age. The frequency of epsilon 4 in the AD group was significantly higher than that in the control group (23.2% versus 7.9%, p = 0.003). The odds ratio for AD in individuals with either one or two epsilon 4 was 2.96 (95% CI 1.11 to 8.03). The linear trend for AD in proportion to alleles of epsilon 4 was also significant (chi 2 = 8.2, p = 0.004). Our results support the association between epsilon 4 and AD in the Chinese.

Background: Hyperthyroidism has numerous physical and mental concomitants. This study attempted to explore the clinical features, treatment and outcome of a psychiatric disturbance which developed during hyperthyroid disease., Methods: A retrospective study was made of 30 patients, hospitalized with psychiatric disturbances and concurrent diagnoses of hyperthyroidism between January 1990 and May 1994. Data included age, sex, date of admission or consultation, age of onset of thyroid and psychiatric disorders, duration of thyroid and psychiatric disorders, psychiatric discharge diagnoses, psychiatric symptoms/signs, treatment and outcome. Follow-up investigations were done after one year., Results: Among the 30 patients, 27 (90.0%) were female and 3 (10.0%) were male. The psychiatric disturbances had persisted from a few days to a decade following the presenting hyperthyroidism, with an average of seventeen months. There were 6 (20.0%) patients who were diagnosed with neurotic disorders, 11 (36.7%) with mood disorders, 8 (26.7%) with schizophrenia-like syndromes and 5 (16.7%) with delirium. The psychiatric features were variable; insomnia, irritability and anxiety most commonly occurred. Most (96.7%) of these patients accepted both antithyroid and psychotropic medication therapy. Follow-up investigations were made after one year. Twenty-six patients were analyzed, including 13 (50%) who had recovered completely, 9 (34.6%) who recovered partially, and 4 (15.4%) who showed no change in mental status., Conclusions: A variety of psychiatric features were found in the hyperthyroid patients, concomitantly with their psychiatric disturbances. Half of the patients showed a chronic or unremitting psychiatric condition after normalization of thyroid function tests. It is possible that the present psychiatric disturbances could be caused or precipitated by hyperthyroidism, or simply occur independently by chance. It is suggested a foremost benefit would be incorporation of internist and psychiatrist into the care of hyperthyroid patients with psychiatric disturbances which may improve the clinical condition.

Background: The problems of drug abuse has been growing rapidly in Taiwan area recently. Adolescents hospitalized due to drugs related problems were a special population and research of this population may contribute to the whole view of the drug abuse problems in our society., Methods: Psychiatric inpatient records of Veterans General Hospital-Taipei from January, 1991 to June, 1993 were reviewed. Among totally 296 admissions of 260 adolescents, 38 admissions of 27 adolescents were related to drug abuse. The discharge diagnosis, urine drug screen test during admission, hospitalization course, follow-up condition of the 38 admissions as well as the demographic data, pattern of drug abuse, family and personal problems of the 27 adolescents were collected and analyzed., Results: Among the 27 patients, 21 (78%) abused amphetamine only or mainly, and 14 (52%) of them also drank alcohol daily. As a whole, they began to drink at age 15.6 +/- 1.5 years, to abuse amphetamine at 16.8 +/- 1.2 years. Those who sniff glue started at the age of 15.4 +/- 1.8 years and those who abuse heroin started at the age of 18 years. 14 patients (51%) had previous abstinence history, and the most common reason of failure were craving, peer pressure and boredom. Personal and family factors were the major difficulties encountered in the process of abstinence, according to the evaluation of their incharge doctors. 16 (59%) of them had definite family problems, including loss of parent(s), marital discord or inconsistent attitude of parents, and psychotic history of mother. Interestingly, 15 (56%) of the patients were the youngest, 5 (18%) were the only sons and only 3 (11%) were the eldest in their family. Among the 38 admissions, 34 (89%) were diagnosed as "organic delusional disorder", or "organic hallucinosis" by DSM-III-R criteria., Conclusions: Amphetamine has become one of the most popular drugs of abuse in Taiwan area in recent years. Many drugs of abuse in Taiwan area 10 years ago were not found in this study. Because of the psychidelic effect of amphetamine, many amphetamine abusers were hospitalized and the drug abusers among adolescent psychiatric inpatients have increased almost 5 times in the past 10 years. Family problems played a significant role. Family approach would thus be very important in prevention, treatment and rehabilitation of the adolescent drug abusers.

Emotional problems are not uncommon in hospitalized children. The authors reviewed psychiatric consultations on a pediatric ward in a medical center and compared the findings with a non-pediatric group and the Western reports. Forty consultations were requested in a three-year period which represented 0.35% of all admissions to pediatric ward and 1.0% of all psychiatric consultations in that period. The consultation rate of the pediatric ward is significantly lower than that of the non-pediatric wards. The most common reason for the referrals was for the evaluation of possible psychopathogeneses from unexplained physical symptoms. A wide range of psychiatric diagnoses were found. Among them, adjustment disorders, anxiety or somatoform disorders, diagnosis deferred and no psychiatric diagnosis were the most commonly made. Pediatric patients had a similar percentage diagnosis of adjustment disorders compared with the non-pediatric group but far less organic mental disorders. Besides medication, psychological and family intervention were frequently recommended by the psychiatrists. These findings suggest that there were unique psychological characteristics in the hospitalized children which required specialists and further studies. It is hoped that increasing the collaboration between pediatricians and psychiatrists can improve the medical care of these sick children.

The rapid growth of the over 65 population in Taiwan during recent decades has brought into focus the planning to provide health care for aged citizens. It is generally agreed that the incidence of mental disorders rises with age. With the stress on rapid treatment and early return to community, the concept of short-term hospitalization for the geropsychiatric patients has become more accepted. In this study we examined characteristics, diagnostic classification and treatment outcomes of 524 consecutive patients (age > or = 65) admitted to the geropsychiatric unit of a general hospital over a 5-year period. Results demonstrated that 45.9% of the patients had organic mental disorders. Among them, almost half of the patients were diagnosed as having dementia; delirium was the second most common diagnosis. The average length of stay was 26.7 days for all patients and it was not affected by diagnostic subtype. No significance was found in the length of stay between the geropsychiatric inpatients and the other psychiatric inpatients. Outcomes measure showed favorable response to hospitalization in most of these patients. These data suggested that there is a specific diagnostic distribution in the geropsychiatric inpatients. Rigorous organic work-up in these patients is necessary to rule out organic problems. The favorable response after short-term hospitalization indicated the restorative and rehabilitative functions of the general hospital geropsychiatric care. The hospital's fears of being burdened with a chronic population could be lessened with a suitable referral system. Further study is needed to explore whether early geropsychiatric intervention may obviate the need for admission or reduce the length of stay.

The 2-deoxyglucose (2-DG) method was used to study regional metabolic changes in rats following chronic d-amphetamine treatment without subsequent challenges. Four groups of rats were pretreated (intraperitoneal administration) with d-amphetamine (0, 1, 5, or 10 mg/kg) once per day for 14 days. After a 7-day abstinence period without further challenge, the 2-DG method was used to measure the rates of local cerebral glucose utilization (LCGU). Significant metabolic changes among the four groups were found in five brain regions, including the nucleus accumbens and the lateral habenular nucleus. Another four groups of rats with the same pretreatment regimens, challenged with 5 mg/kg d-amphetamine, were used for behavioral testing. The results showed intense stereotyped behaviors in the 5 mg/kg and the 10 mg/kg groups. In the steady state, however, there were no significant glucose utilization changes in the nigrostriatal system, which is thought to be related to stereotyped behaviors. During steady state, metabolic changes were found in a limited number of brain regions. No difference in LCGU was found in the sensitization-related regions. Further challenges with stimulants may be necessary to investigate the metabolic responses after sensitization.

Chronic amphetamine (AMPH) treatment may cause behavioral sensitization in animals and can be used as an animal model of psychosis. The aim of the study was to check the behavioral and metabolic response in this animal model. In rats pretreated with normal saline (NS) or AMPH, with or without AMPH challenge, the [14C]deoxyglucose method was employed to check the metabolic changes in 42 regions. Behavioral testing was performed in rats with the same treatment. The results showed that after challenge with AMPH, glucose utilization was enhanced in most of the regions investigated. However, metabolic enhancement of the AMPH-pretreated group was lower in the caudate nucleus when compared with that of the NS-pretreated group though the stereotypy rating was higher in the former. Dissociation between the metabolic enhancement and behavioral response was noted. Furthermore, more significant differences between the two pretreated conditions of glucose utilization were found with challenge than without challenge. Further evaluation using procedures which include advanced techniques can be applied in further investigation.

The daily dose of amphetamine pretreatment may affect the development of behavioral-sensitized patterns in rodents and amphetamine psychosis in humans. This experiment investigated the regional cerebral metabolic changes in rats after pretreatment with different doses of amphetamine by the 2-[14C]deoxyglucose method. Rates of local cerebral glucose utilization were examined in 37 regions of the rat brain. The result showed generally maximal metabolic augmentation in the 5.0 mg/kg group instead of in the 1.0 or the 10.0 mg/kg groups. Behavioral testing using motor activity cages in rats with the same regimen found no difference among groups. The findings demonstrate that there might be a window effect by daily amphetamine dose on the development of drug dependence and amphetamine psychosis. It was suggested that the 2(-)[14C]deoxyglucose method could be used for further study of animal models of amphetamine psychosis.

Acupuncture treatment is currently generating increased interest in various parts of the world. The effectiveness of this quasi-medical procedure, which has survived for almost 5 000 years, is considered on the strength of statistical data obtained at an institution where such treatment is applied under acceptable scientific circumstances. Explanations are sought for the encompassing extent of treatment claims and the continued support for this technique which is often subjected to severe criticism in modern contexts. The roles of literacy, tradition and convention, a placebo effect and psychological factors as explanatory agents are discussed. The procedure also has possible psychophysical and physiological foundations which sufficiently warrant further scientific effort to find an explanation for this phenomenon.

Serum cortisol levels were determined in 40 normal Chinese and dopamine beta-hydroxylase activities were measured in 22 normal subjects before and after acupuncture treatment. All subjects were studied twice with an interval of one week or more. In the self-control study, the subjects were needled at 5 non-acupuncture loci. In the experimental study, they were needled at the following 5 traditional acupuncture loci--right side GB-20, both sides EH-6, and both sides St-36. Blood samples were withdrawn before acupuncture and 15 and 45 min. after acupuncture. No change of serum dopamine beta-hydroxylase activity was observed. Serum cortisol levels increased significantly after needling on the traditional acupuncture loci. After acupuncture for 15 and 45 min., the cortisol increase was 28 and 50%, respectively, as compared to the self-control studies. The beneficial effect of acupuncture in the treatment of functional disorders, therefore, may be mediated by cortisol or other hormones and neurohormones.