Developmental and environmental origins of breast cancer: DDT as a case study

More than 20 studies of serum "DDT" and breast cancer have found little support for the hypothesis that exposure influences risk of breast cancer. However, studies share common limitations including the inability to account for exposure in early life when the breast may be most vulnerable and the inability to measure exposure to the primary components of commercial DDT. This paper (1) summarizes evidence regarding critical windows of exposure for breast cancer (2) summarizes lessons learned from initial efforts to study DDT and breast cancer (3) reviews evidence from the Child Health and Development Studies (CHDS) where exposure was measured in young women using blood samples obtained during active exposure, 1-3 days after delivery and (4) suggests approaches for human studies that might advance understanding of environmental stressors in the developmental origins of disease.     

Limitations of current medical treatments for depression: Disturbed circadian rhythms as a possible therapeutic target

The proportion of diagnosed depressives prescribed antidepressants has increased markedly over the last 20 years, mainly following the introduction of the selective serotonin reuptake inhibitors. However, currently available antidepressants have notable limitations, relating to their only moderate efficacy relative to placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms. There are links between pharmacological treatments and circadian rhythms in depression, which might represent another, new option for the development of a therapeutic approach to depression treatment. Many antidepressants affect sleep, some are sedative, and others have been used specifically in severely insomniac depressives. Disturbances in circadian rhythms may be an integral part of depressive mechanisms, and normalising them via an innovative mechanism of antidepressant action may be a fruitful avenue in the search for improved antidepressant agents.     

Reasons for alcohol use in young adulthood: validation of a three-dimensional measure

OBJECTIVE: To evaluate the reliability and validity of a measure of reasons for use, which is based on a cognitive mediational view of alcohol use as a means for affect regulation. METHOD: Data for this study were obtained from the Rutgers Health and Human Development Project. Self-reports of young men and women aged 25 to 31 years (N = 1,176; 598 women) were used to obtain measures of reasons for use, coping use, sex-enhancing use, use intensity and use problems. Regression analyses and structural equation modeling were used to assess a hypothesized model of relationships between these variables. RESULTS: Factor analysis of 33 reasons for use yielded three hypothesized dimensions: social reasons, disinhibition reasons and suppression reasons. Although moderately correlated with each other, they exhibited distinct relationships with other use variables. Increases in social reasons were related to decelerating increases in use intensity, but increases in disinhibition and suppression reasons were associated with accelerating increases in use intensity Social reasons did not relate to use problems, whereas suppression reasons were strongly related to use problems even when controlling for use intensity. CONCLUSIONS: Suppression reasons not only motivate reactive coping use in response to the appraisal of stressful situations, they are also likely to instigate "prophylactic" or proactive coping use in anticipation of the possible occurrence of stressors, thereby blunting the emotional impact of encounters that would otherwise have been appraised as stressful and aversive.     

Hypothermia associated with antipsychotic drug use: a clinical case series and review of current literature

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5-HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.     

Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.     

Development and validation of a scale for assessing reasons for substance use in schizophrenia: The ReSUS scale

This paper reports on the development of a questionnaire to assess self reported reasons for substance use in schizophrenia: the ‘reasons for substance use in schizophrenia’ (ReSUS) scale and explores the relationship between reasons for use, psychiatric symptoms and substance use in a sample of 230 people with psychosis. Principal components analysis revealed three subscales: “coping with distressing emotions and symptoms', “social enhancement and intoxication” and “individual enhancement”. Predicted associations were partially supported. ‘Coping’ reasons for use were related to positive symptoms, general symptoms, global functioning, depression and suicide behaviour as well as substance use (quantity of use and problems related to use). ‘Individual enhancement’ reasons were related to positive symptoms, to global functioning and to negative consequences of substance use. ‘Social enhancement and intoxication’ reasons were related to negative consequences of use but not to psychopathology. The findings suggest that the ReSUS is a reliable and valid instrument which can be used to explore self reported reasons for substance use and their relationship to psychotic symptoms in people with schizophrenia and other psychotic disorders.     

G-protein-coupled receptor affinity prediction based on the use of a profiling dataset: QSAR design, synthesis, and experimental validation

A QSAR model accounting for "average" G-protein-coupled receptor (GPCR) binding was built from a large set of experimental standardized binding data (1939 compounds systematically tested over 40 different GPCRs) and applied to the design of a library of "GPCR-predicted" compounds. Three hundred and sixty of these compounds were randomly selected and tested in 21 GPCR binding assays. Positives were defined by their ability to inhibit by more than 70% the binding of reference compounds at 10 microM. A 5.5-fold enrichment in positives was observed when comparing the "GPCR-predicted" compounds with 600 randomly selected compounds predicted as "non-GPCR" from a general collection. The model was efficient in predicting strongest binders, since enrichment was greater for higher cutoffs. Significant enrichment was also observed for peptidic GPCRs and receptors not included to develop the QSAR model, suggesting the usefulness of the model to design ligands binding with newly identified GPCRs, including orphan ones.     

Multiple drug use: patterns and practices of heroin and crack use in a population of opiate addicts in treatment

One hundred and sixteen opiate addicts attending treatment services in south London were interviewed about their drug use patterns. In the month before interview, 90% reported heroin use, while 60% had used crack cocaine and 58% alcohol. In the same period, 70% of participants reported multiple drug use, particularly concurrent heroin and crack cocaine use. Of the patients who reported using other drugs with heroin, two-third used crack cocaine, 11% diazepam, 9% methadone and 8% cocaine powder. Twenty-six per cent of crack users sample had injected crack cocaine, which provides confirmation of the increasing prevalence of this recent trend in studies using similar samples. Male participants were significantly more likely to use benzodiazepines with heroin, while women were more likely to use crack alongside heroin (and used larger quantities). These findings have implications for the treatment and management of multiple drug users, for whom opiates may be only a part of their drug-using repertoire.     

Congenital hypothyroidism: a review of current diagnostic and treatment practices in relation to neuropsychologic outcome

Because thyroid hormone is essential for normal brain development, children born with congenital hypothyroidism who lack thyroid hormone during a circumscribed period of early development are at risk of brain damage and mental retardation. Since the advent of newborn screening programs in the 1980s, the diagnosis and treatment of this condition are now provided in the first 2-3 weeks of birth in most regions. While this is usually sufficient to prevent mental retardation, the children so identified attain mildly reduced IQs from expectation, and may still experience subtle and specific neurocognitive deficits. Their particular deficits are related to the brief period of thyroid hormone insufficiency they undergo, especially factors reflecting the severity of hypothyroidism at the time of diagnosis, the duration of hypothyroidism in infancy, and thyroid hormones at time of testing. In this article, we review the specific kinds of deficits demonstrated by children with congenital hypothyroidism who were diagnosed by screening and treated early, as well as the factors associated with their disease and its management that contribute to these deficits. The disease-related factors that will be reviewed will include the etiology of hypothyroidism and severity of disease at the time of diagnosis, while the treatment-related factors will include age at onset of therapy, starting and subsequent dose levels, compliance, and treatment-adequacy issues. Also examined will be the effects of hormone levels at the time of testing. In addition, the role of moderating variables such as social, genetic, and environmental influences, as well as the child's gender, will be discussed. Furthermore, several new issues including the quality of subsequent management, ultimate outcome, and pregnancy will be additionally reviewed. In conclusion, while outcome in congenital hypothyroidism is substantially improved by screening, affected children do still experience mild neuropsychologic deficits. To reduce the impact of persisting deficits, further research is needed to determine the optimal starting dose for the different etiologies, guidelines for subsequent management, and alternative therapies. Moreover, now that the original samples are reaching adulthood and, in females, childbearing age, further research is also needed regarding treatment during pregnancy in women with congenital hypothyroidism, as is research to determine how this population ultimately fares in adulthood.     

CHAT: development and validation of a computer-delivered, self-report, substance use assessment for adolescents

The current study was conducted to construct and validate a computer-delivered, multimedia, substance use self-assessment for adolescents. Reliability and validity of six problem dimensions were evaluated in two studies, conducted from 2003 to 2008. Study 1 included 192 adolescents from five treatment settings throughout the United States (N = 142) and two high schools from Greater Boston, Massachusetts (N = 50). Study 2 included 356 adolescents (treatment: N = 260; school: N = 94). The final version of Comprehensive Health Assessment for Teens (CHAT) demonstrated relatively strong psychometric properties. The limitations and implications of this study are noted. This study was supported by an SBIR grant.     

基于医嘱审核循环体系的建立某院PPIs的使用情况分析

目的:通过全医嘱点评、临床宣教、医嘱审核、数据分析相结合的医嘱审核体系的建立,进行苏州大学附属第一医院质子泵抑制剂(proton pump inhibitors,PPIs)的医嘱专项审核后,分析该院PPIs审核前后使用情况,评价医嘱审核的效果.方法:基于医嘱审核循环体系统计2020年1月至2021年3月5个季度使用PP...     

安徽省各级医疗机构药品使用现状及目录共同性研究

目的：分析安徽省各级医疗机构药品使用现状及药品目录的共同性。方法：从安徽省医药集中采购平台上随机抽取9家三级医疗机构、10家二级医疗机构、20家一级医疗机构2018年的药品采购数据,采用R软件和Excel软件进行分析。结果：从药理学分类来看,安徽省一级医疗机构药品结构与二、三级医疗机构差异较大,而二、三级医疗机构药品结构相似;国家基本药物品种数和金额占比均随医疗机构级别的升高而降低,国家医保药物与之趋势相同;进口药品的品种和金额占比均随医疗机构级别的升高而增加。2018年采购数据显示,各级医疗机构院均药品数分别为241,405,802种,而同级医疗机构相同药品数仅分别为20,19,186种;39家样本医疗机构共有药品数仅8种。结论：各级医疗机构药品共同性小,不利于分级诊疗中患者转诊用药的上下衔接。     

Pharmacokinetics of morphine and its surrogates V: Naltrexone and naltrexone conjugate pharmacokinetics in the dog as a function of dose

Sensitive reversed-phase HPLC assays with electrochemical detection, developed to quantify naltrexone, 6 beta-naltrexol, and their conjugates in biological fluids, provided assay sensitivities of 2-14 ng/mL in plasma, urine, and bile. Plasma, urine, and bile were monitored in dogs after bolus administrations of 0.5 and 5.0 mg/kg iv naltrexone hydrochloride. Plasma-time data showed two sequential half-lives of 5 +/- 1 (SEM) and 47 +/- 5 min. Pharmacokinetics were dose-independent; total and renal clearances were 1043 +/- 98 mL/min and 72 +/- 11 mL/min, respectively, with a similar renal clearance (85 +/- 12) for the conjugate. The percentages of the dose excreted in the urine as naltrexone and its conjugate were 7 +/- 1% and 58 +/- 3%, respectively, with the remainder being excreted in the bile as conjugates. As much as 36% was collected as conjugate in the total bile of the bile-cannulated dog. There was no biliary secretion of unchanged naltrexone. The conjugate was apparently enterohepatically recirculated. 6 beta-Naltrexol is not a metabolite of naltrexone in dogs. Within the limits of analytical detection (2 ng/mL) neither 6 beta-naltrexol nor its conjugates appeared in any monitored biological fluids when such fluids were assayed quickly after sampling.     

Drugs effects on ventricular repolarization: a critical evaluation of the strengths and weaknesses of current methodologies and regulatory practices

A growing number of drugs and drug combinations inhibit cardiac potassium ion conductance and ventricular repolarization, and increase cardiac APD, QT interval, and risk of potentially fatal TdP. The past decade has seen an explosion of research advances into the mechanism of action underpinning these observations, and an unprecedented level of collaboration between academia, industry, and regulatory authorities to define effective strategies for accurate prediction of increased TdP risk (if any) in humans, based upon nonclinical and/or clinical endpoints. Because the incidence of TdP is so very low, even for drugs for which the association is known, the risk can only be assessed based upon surrogate markers (signals) in in vitro and in vivo non-clinical studies as well as in clinical trials. In this article, we review both the strengths and weaknesses of current methodologies and regulatory practices for assessment of TdP risk for pharmaceuticals.