10-year outcome study of an early intervention program for psychosis compared with standard care service.

BACKGROUND: Despite evidence on the short-term benefits of early intervention (EI) service for psychosis, long-term outcome studies are limited by inconsistent results. This study examined the 10-year outcomes of patients with first-episode psychosis who received 2-year territory-wide EI service compared to those who received standard care (SC) in Hong Kong using an historical control design. METHOD: Consecutive patients who received the EI service between 1 July 2001 and 30 June 2002, and with diagnosis of schizophrenia-spectrum disorders, were identified and matched with patients who received SC first presented to the public psychiatric service from 1 July 2000 to 30 June 2001. In total, 148 matched pairs of patients were identified. Cross-sectional information on symptomatology and functioning was obtained through semi-structured interview; longitudinal information on hospitalization, functioning, suicide attempts, mortality and relapse over 10 years was obtained from clinical database. There were 70.3% (N = 104) of SC and 74.3% (N = 110) of EI patients interviewed. RESULTS: Results suggested that EI patients had reduced suicide rate (χ2 (1) = 4.35, p = 0.037), fewer number [odds ratio (OR) 1.56, χ2 = 15.64, p < 0.0001] and shorter duration of hospitalization (OR 1.29, χ2 = 4.06, p = 0.04), longer employment periods (OR -0.28, χ2 = 14.64, p < 0.0001) and fewer suicide attempts (χ2 = 11.47, df = 1, p = 0.001) over 10 years. At 10 years, no difference was found in psychotic symptoms, symptomatic remission and functional recovery. CONCLUSIONS: The short-term benefits of the EI service on number of hospitalizations and employment was sustained after service termination, but the differences narrowed down. This suggests the need to evaluate the optimal duration of the EI service.

Genomics and integrated systems biology in Plasmodium falciparum: a path to malaria control and eradication.

The first draft of the human malaria parasite's genome was released in 2002. Since then, the malaria scientific community has witnessed a steady embrace of new and powerful functional genomic studies. Over the years, these approaches have slowly revolutionized malaria research and enabled the comprehensive, unbiased investigation of various aspects of the parasite's biology. These genome-wide analyses delivered a refined annotation of the parasite's genome, delivered a better knowledge of its RNA, proteins and metabolite derivatives, and fostered the discovery of new vaccine and drug targets. Despite the positive impacts of these genomic studies, most research and investment still focus on protein targets, drugs and vaccine candidates that were known before the publication of the parasite genome sequence. However, recent access to next-generation sequencing technologies, along with an increased number of genome-wide applications, is expanding the impact of the parasite genome on biomedical research, contributing to a paradigm shift in research activities that may possibly lead to new optimized diagnosis and treatments. This review provides an update of Plasmodium falciparum genome sequences and an overview of the rapid development of genomics and system biology applications that have an immense potential of creating powerful tools for a successful malaria eradication campaign.

A rapid enzyme-linked assay for ADAMTS-13.

BACKGROUND: A deficiency in the plasma metalloprotease ADAMTS-13 is associated with deposition of microvascular thrombi that cause thrombotic thrombocytopenic purpura. Current assays for ADAMTS-13 are technically complex and time-consuming. The objective of this study is to devise a rapid and sensitive assay for ADAMTS-13 activity in plasma and verify the site of cleavage. METHOD: A new enzyme-linked substrate, which contains a core ADAMTS-13-specific peptide conjugated to horseradish peroxidase (HRP) at the N-terminus, and labeled with biotin at the C-terminus, was constructed. After cleavage of this substrate by plasma ADAMTS-13 and removal of uncleaved substrate by adsorption with streptavidin-agarose, ADAMTS-13 activity was quantitated by determining the unadsorbed HRP activity remaining in solution. Levels of inhibitory antibodies in test plasma were also determined by measuring the residual ADAMTS-13 activity after varying amounts of test plasma were incubated with a known amount of ADAMTS-13. RESULTS: Plasma ADAMTS-13 activity was readily determined in approximately 60 min (coefficient of variation 5.8%) using 1 microL of test plasma. Amino acid sequencing of the cleavage product confirmed that cleavage occurred at the Tyr1605-Met1606 bond in the substrate. ADAMTS-13 activities in the plasma of five TTP patients were below 2%. Inhibitory antibody titers in these samples varied from undetectable to 81 BU mL(-1). CONCLUSION: The HRP-linked substrate provides a rapid, sensitive, and reproducible way of determining the levels of ADAMTS-13 activity and inhibitory antibodies in plasma.

Crystal structure of a 30 kDa C-terminal fragment from the gamma chain of human fibrinogen.

BACKGROUND: Blood coagulation occurs by a cascade of zymogen activation resulting from minor proteolysis. The final stage of coagulation involves thrombin generation and limited proteolysis of fibrinogen to give spontaneously polymerizing fibrin. The resulting fibrin network is covalently crosslinked by factor XIIIa to yield a stable blood clot. Fibrinogen is a 340 kDa glycoprotein composed of six polypeptide chains, (alphabetagamma)2, held together by 29 disulfide bonds. The globular C terminus of the gamma chain contains a fibrin-polymerization surface, the principal factor XIIIa crosslinking site, the platelet receptor recognition site, and a calcium-binding site. Structural information on this domain should thus prove helpful in understanding clot formation. RESULTS: The X-ray crystallographic structure of the 30 kDa globular C terminus of the gamma chain of human fibrinogen has been determined in one crystal form using multiple isomorphous replacement methods. The refined coordinates were used to solve the structure in two more crystal forms by molecular replacement; the crystal structures have been refined against diffraction data to either 2.5 A or 2.1 A resolution. Three domains were identified in the structure, including a C-terminal fibrin-polymerization domain (P), which contains a single calcium-binding site and a deep binding pocket that provides the polymerization surface. The overall structure has a pronounced dipole moment, and the C-terminal residues appear highly flexible. CONCLUSIONS: The polymerization domain in the gamma chain is the most variable among a family of fibrinogen-related proteins and contains many acidic residues. These residues contribute to the molecular dipole moment in the structure, which may allow electrostatic steering to guide the alignment of fibrin monomers during the polymerization process. The flexibility of the C-terminal residues, which contain one of the factor XIIIa crosslinking sites and the platelet receptor recognition site, may be important in the function of this domain.

Microangiopathic hemolytic anemia due to ADAMTS-13 loss in idiopathic systemic capillary leak syndrome.

Essentials Idiopathic systemic capillary leak syndrome (SCLS) is characterized by episodes of vascular leakage. We present the case of a patient with SCLS who developed microangiopathic hemolytic anemia (MAHA). We propose that this anemia is the result of ADAMTS-13 loss in the third-space fluid. This suggests that MAHA can occur in patients with significant extravasation of proteins. SUMMARY: Idiopathic systemic capillary leak syndrome (SCLS) is a rare process characterized by acute and recurrent episodes of vascular leakage with severe hypotension, hypoalbuminemia, hemoconcentration and edema. Anemia and thrombocytopenia are not part of this syndrome, but here we present the case of a pediatric patient with a clinical presentation consistent with SCLS who subsequently developed microangiopathic hemolytic anemia at a time when she had significant fluid loss and anasarca. Based on serial ADAMTS-13 levels, we propose that the anemia in this patient developed as a result of ADAMTS-13 loss in the third-space fluid, a novel mechanism for acquired microangiopathic hemolytic anemia.

The mechanism of ADP-ribosylation of elongation factor 2 catalyzed by fragment A from diphtheria toxin.

Measurements of the initial rate of ADP-ribosylation of elongation factor 2 (EF-2) catalyzed by Fragment A from diphtheria toxin support a sequential mechanism and suggest that the reaction proceeds through a central ternary complex involving Fragment A and the substrates, EF-2 and NAD. The Michaelis constants for EF-2 and NAD are 0.15 and 1.4 muM, respectively. As determined by equilibrium gel permeation, EF-2 does not bind Fragment A significantly, alone or in the presence of adenine, ADPribose, nicotinamide or NADH. Based on these and earlier results, we propose an ordered sequential mechanism for the reaction; the sequence of binding of substrates is NAD, followed by EF-2.

Prevalence of dementia in Chinese elderly in Hong Kong.

This study examines the prevalence of dementia in elderly Chinese aged 70 years and older in Hong Kong using a two-phase design. In phase 1, 1,034 elderly were interviewed with the Cantonese version of the Mini-Mental State Examination. Those who scored below the cutoff points and a subsample of those with scores in the normal range were interviewed in phase 2 to identify those with dementia. The overall weighted prevalence of dementia in our subjects was 6.1 +/- 0.7%, which is at the lower end of the range of rates reported in whites. Alzheimer's disease (AD) accounted for 64.6% and vascular dementia, 29.3%. Our results, together with previous studies in Chinese populations, suggest that the rates of AD in Chinese are low compared with those in whites. Substantial differences are possible in the epidemiology of dementia across cultures related to interactions of genetic and environmental factors.

Sleep problems in Chinese elderly in Hong Kong.

BACKGROUND: To examine the sleep habits and one-year prevalence of sleep disturbance (difficulty in falling asleep, broken sleep and early morning wakening) as well as insomnia (subjectively inadequate or poor sleep) in an elderly Chinese population in Hong Kong. METHOD: In Phase 1, a representative sample of elderly aged 70 years or above were interviewed with a sleep questionnaire, and Cantonese versions of the Mini-Mental State Examination (CMMSE) and Geriatric Depression Scale(CGDS). In Phase 2, those with scores suggestive of cognitive impairment on CMMSE or depression on CGDS were interviewed by psychiatrists for making clinical diagnoses according to DSM IV. RESULTS: 1,034 elderly were interviewed in Phase 1. Occasional or persistent sleep disturbance were reported by 75% and insomnia in 38.2% of elderly. Slightly less than half of elderly with sleep disturbance complained of insomnia. Advancing age was associated with a higher rate of sleep disturbance while females had a higher rate of insomnia. Factors associated with sleep disturbance and insomnia included poor perceived health, past history of smoking, current depressive disorders, more chronic physical illness, more life events and more somatic complaints. Only 2.8% of the sample had taken sleeping pills within a one-year period. CONCLUSIONS: Sleep disturbance and insomnia are two separate but overlapping constructs and should be differentiated. Sleep disturbance is very common in the elderly and may be due to physiological changes with ageing. In contrast, those with a concommitant complaint of insomnia have impaired physical and mental health and may merit more medical attention.

The biosynthesis of bovine fibrinogen, prothrombin, and albumin in a cell-free system.

Preparative amounts of poly A-containing mRNA were isolated from bovine liver. In the presence of a cell-free system from rabbit reticulocytes, this mRNA stimulated the synthesis of a number of plasma proteins including albumin, fibrinogen, prothrombin, and antithrombin III. Automatic Edman degradation of immunoprecipitated albumin showed that this protein was synthesized as preproalbumin containing an NH2-terminal extension of 18 amino acid residues. Prothrombin is also synthesized as a precursor (preprothrombin), and the signal sequence for this protein is also rich in hydrophobic amino acids. The three chains of fibrinogen are synthesized from individual mRNAs, which are then linked by disulfide bonds to form the mature protein.

Cloning of fibrinogen genes and their cDNA.

Cross-species hybridizations have enabled us to isolate and clone the gene for the beta chain of human fibrinogen. Highlights of the gene for the beta chain revealed by nucleotide sequence analyses, particularly in areas that have a direct bearing on defining the overall organization of the gene, have been presented. Nucleotide sequence determination has confirmed the presence of seven intervening sequences. The positions where several of these intervening sequences interrupt the coding region appear to be related to the functional domains of the polypeptide. A putative signal peptide has been identified. Studies on the cDNA for the human alpha chain indicate that the alpha chain polypeptide may be synthesized in a precursor form with a COOH-terminal extension of 15 amino acids as compared to the alpha chain present in the mature molecule found in plasma. We are in the process of isolating the genes for the alpha and gamma chains by a similar approach. We are hopeful that these studies will provide information as to how they are regulated and how they have undergone changes in the course of evolution.

The Zung Self-rating Depression Scale: screening for depression among the Hong Kong Chinese elderly.

Two studies were conducted respectively to examine the reliability and validity of the standard Zung Self-rating Depression Scale (SDS), and a 10-item shorter version of the same test. In particular, the scale's usefulness as a screening instrument for depression among the Hong Kong Chinese elderly was investigated. In addition to the SDS, the Geriatric Depression Scale and the Chinese Hamilton Depression Scale were used to assess the convergent validity of the SDS. Data were collected from 113 nondepressed community-dwelling and 80 depressed elderly subjects. The findings showed that both the original and the shorter version of the SDS were highly reliable and valid. Both versions were appropriate for use as screening instruments for geriatric depression in Hong Kong. When compared with the original scale, the shorter version appeared to be slightly superior in its sensitivity and specificity in discriminating between the depressed and nondepressed subjects.

Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rats.

The purpose of this study was to investigate the potential subchronic toxicity of plant sterol esters by a 13-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 1000, 3000 and 9000 mg/kg/day for 13 weeks. At the end of treatment period, 10 rats/sex/group were sacrificed, while six rats/sex in the negative control and highest dose groups were sacrificed after a 4-week recovery period. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. Slight decreases in body weight gain were noted at lower doses but were only statistically different from the control animals in the highest dose group. In histopathological examinations, an increase in the incidence of cardiomyopathy with mononuclear cell infiltration was observed in males of the 9000 mg/kg group. Decreased body weight gain and increased incidence of cardiomyopathy observed in the highest dose group were not recovered until the end of the recovery period. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights in any treatment group. Based on these results, it was concluded that the 13-week repeated oral dose of plant sterol esters resulted in the suppression of body weight gains in both sexes and cardiomyopathy in males at a dose level of 9000 mg/kg/day. The target organ was determined to be heart in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 3000 mg/kg/day for both sexes.

Reliability, validity and structure of the Chinese Geriatric Depression Scale in a Hong Kong context: a preliminary report.

Depression is one of the commonest psychiatric illness in the elderly. Screening instruments of depression can greatly facilitate its identification in the community, leading to early recognition and diagnosis. The Geriatric Depression Scale was translated into Chinese and its reliability, validity and factor structure examined in a population of Chinese elderly in Hong Kong. One hundred and thirteen normal and 80 depressed elderly subjects were studied and a cut-off score of 15 on the scale was found to be optimal. The scale's reliability and validity was satisfactory and thus it is a promising instrument for screening geriatric depression in Hong Kong.

Developments in early intervention for psychosis in Hong Kong.

The year 2011 marked the 10-year milestone of early intervention for psychosis in Hong Kong. Since 2001, the landscape of early psychosis services has changed markedly in Hong Kong. Substantial progress has been made in the areas of early intervention service implementation, knowledge generation, and public awareness promotion. Favourable outcomes attributable to the early intervention service are supported by solid evidence from local clinical research studies; early intervention service users showed improved functioning, ameliorated symptoms, and decreased hospitalisation and suicide rates. Continued development of early intervention in Hong Kong over the decade includes the introduction and maturation of several key platforms, such as the Hospital Authority Early Assessment Service for Young People with Psychosis programme, the Psychosis Studies and Intervention Unit by the University of Hong Kong, the Hong Kong Early Psychosis Intervention Society, the Jockey Club Early Psychosis Project, and the postgraduate Psychological Medicine (Psychosis Studies) programme. In this paper, we reviewed some of the major milestones in local service development with reference to features of the Hong Kong mental health system. We describe chronologically the implementation and consolidation of public early intervention services as well as recent progresses in public awareness work that are tied in with knowledge generation and transfer, and outline the prospects for early intervention in the next decade and those that follow.

Nanoscale mapping of ion diffusion in a lithium-ion battery cathode.

The movement of lithium ions into and out of electrodes is central to the operation of lithium-ion batteries. Although this process has been extensively studied at the device level, it remains insufficiently characterized at the nanoscale level of grain clusters, single grains and defects. Here, we probe the spatial variation of lithium-ion diffusion times in the battery-cathode material LiCoO(2) at a resolution of ∼100 nm by using an atomic force microscope to both redistribute lithium ions and measure the resulting cathode deformation. The relationship between diffusion and single grains and grain boundaries is observed, revealing that the diffusion coefficient increases for certain grain orientations and single-grain boundaries. This knowledge provides feedback to improve understanding of the nanoscale mechanisms underpinning lithium-ion battery operation.