The evolution of drug development in schizophrenia: past issues and future opportunities.

Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored.     

Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake

A 2-year-old boy had signs and symptoms of chronic hypervitaminosis A. A course of increasing severity led to eventual death. A younger brother later had similar clinical features. Chicken liver spread containing up to 420 IU/g vitamin A was the likely source of intoxication. Markedly elevated circulating retinyl ester levels have persisted in the surviving sibling for 3 subsequent years despite severe restriction of vitamin A intake. A therapeutic trial of the carbohydrate-derived complexing agent 2-hydroxypropyl-beta-cyclodextrin was initiated. Circulating retinyl esters transiently increased during the infusion (from 407 to 4791 micrograms/dL), and urinary total vitamin A excretion, undetectable before infusion, increased to 23 micrograms/dL after infusion. The frequency of hypervitaminotic episodes has decreased somewhat in the 2 years since the infusion, probably related to dietary vitamin A restriction. The occurrence of this syndrome in two brothers, while a sister ingesting the same diet remains completely healthy, suggests an inherited variance in tolerance to vitamin A intake.     

Determination of malondialdehyde-induced DNA damage in human tissues using an immunoslot blot assay

Malondialdehyde (MDA) is a product of lipid peroxidation and prostaglandin biosynthesis. It is mutagenic and carcinogenic and the major adduct formed by reaction with DNA, a highly fluorescent pyrimidopurinone (M1-dG), has been detected in healthy human liver and leukocyte DNA. Analytical methods used so far for the detection of M1- dG have not been applied to a large number of individuals or variety of samples. Often, only a few microg of DNA from human tissues are available for analysis and a very sensitive assay is needed in order to detect background levels of M1-dG in very small amounts of DNA. In this paper, the development of an immunoslot blot (ISB) assay for the measurement of MI-dG in 1 microg of DNA is described. The limit of detection of the assay is 2.5 adducts per 10(8) bases. A series of human samples were analysed and levels of 5.6-9.5 (n = 8) and 3.1-64.3 (n = 42) of M1-dG per 10(8) normal bases were detected in white blood cell and gastric biopsy DNA, respectively. Results on four human samples were compared with those obtained using an HPLC/32P-post- labelling (HPLC/PPL) method previously developed and indicated a high correlation between M1-dG levels measured by the two assays. The advantages of ISB over other assays including HPLC/PPL, such as the possibility of analysing 1 microg DNA/sample and the fact that it is less time-consuming and laborious, means that it can be more easily used for routine analysis of a large number of samples in biomonitoring studies.      

New strategies for glucose control in patients with type 1 and type 2 diabetes mellitus in pregnancy

Over the past 5 decades, perinatal outcome in pregnancies complicated by diabetes mellitus has improved dramatically due in large part to better maternal glycemic control. Self-blood glucose monitoring in combination with flexible or intensive insulin treatment including the use of newer insulin analogs and insulin pump therapy has dramatically improved glucose control in most pregnancies complicated by diabetes. In developing an insulin regimen, careful attention must be paid to both basal and prandial insulin needs. Every effort must be made to avoid hypoglycemia and prevent ketoacidosis. A team approach including the patient, diabetes nurse educator, nutritionist, and social worker is ideal.     

Screening and diagnosis of gestational diabetes mellitus

Screening, diagnosis, and treatment of gestational diabetes mellitus (GDM) are common practice, despite controversy regarding benefits. A review of the literature from 1950 to 2006 revealed 3 randomized controlled trials evaluated the treatment of GDM but 2 of these studies lacked power to detect a difference in outcomes. The single trial with sufficient power showed a 67% lower rate of serious perinatal complication (a composite of shoulder dystocia, nerve injury, fracture, and death) and a 53% lower rate of macrosomia with treatment of GDM. There are no well-designed studies evaluating screening or diagnostic strategies. Treatment of GDM may improve some neonatal and obstetric outcomes, but there is limited evidence useful for determining the best screening method or diagnostic test, strategy, and criteria. Ongoing studies may provide some evidence to guide future research and clinical practice.     

Inflammatory mediators in gestational diabetes mellitus

The connection between inflammation and insulin resistance has garnered much interest in the past decade. Epidemiologic as well as experimental data have supported the association. The purpose of this article is to review the current evidence linking inflammatory mediators and gestational diabetes mellitus.     

肿瘤治疗存在的问题及中西医结合的研究重点

目前的肿瘤治疗主要存在以下几个问题：(1)肿瘤的过度治疗普遍存在；(2)急功近利而缺乏长远规划；(3)综合治疗缺乏合理的内涵；(4)缺少有效的个体化治疗方案；(5)对中医药的优势认识不足、发挥不够。中西医结合在肿瘤防治中大有可为，应重点围绕以下几个方面开展研究工作：(1)加强中医对恶性肿瘤基础知识的认识和研究；(2)加强中西医结合治疗肿瘤合理化、规范化方案的研究；(3)加强中西医结合治疗恶性肿瘤疗效标准的研究；(4)加强中西医结合防治肿瘤术后复发、转移的研究。     

Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity

Monocrotaline (MCT) produces vascular injury to the lung, pulmonary hypertension, and right ventricular hypertrophy when injected into rats. It is well established that the pneumotoxicity of MCT depends on its hepatic bioactivation to monocrotaline pyrrole (MCTP) and perhaps other toxic metabolites. To test whether MCTP requires further bioactivation, we synthesized this metabolite chemically, confirmed its structure using fast-atom bombardment-mass spectrometry and nuclear magnetic resonance, and injected it into rats previously treated with an inducer or inhibitor of MFOs. Pretreatment with either phenobarbital or SKF-525A did not alter the pneumotoxic effects of an intravenous injection of MCTP. Rats given the same intravenous dose of either MCT, MCT N-oxide, or MCTP responded with toxicity only to MCTP. MCTP added to rat serum in vitro resulted in a color change (Amax = 477 nm) that developed over several seconds, an observation consistent with degradation of MCTP in serum. To explore the possibility that aqueous degradation products might contribute to its toxicity, the same intravenous dose of MCTP was administered to rats in N,N-dimethylformamide (DMF), serum, or saline. Only MCTP administered in in DMF resulted in toxicity. These results support the contention that MCT requires metabolism to MCTP to produce pneumotoxicity and that exposure to aqueous media renders MCTP incapable of causing lung injury.