Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees.

Several psychophysiological abnormalities associated with schizophrenia have been proposed as genetic trait markers of vulnerability to the disorder. Smooth pursuit eye tracking dysfunction and abnormal long latency event-related potentials are the most promising candidates. Both are independent of the effects of psychotropic medication or mental state at the time of testing, and twin studies demonstrate that each has a high level of heritability. Having recorded smooth pursuit eye tracking and event-related potentials in 20 high-density schizophrenic families, we find abnormalities in one or both measures in most of the families studied. The abnormalities, when present, occur in the family members with schizophrenia and other forms of functional psychosis, and they have a bimodal distribution with approximately half the nonschizophrenic relatives also showing eye tracking dysfunction and/or abnormal event-related potentials. Some of these relatives had psychiatric symptoms; others were normal. Our results suggest that psychophysiological examination can help to clarify the boundaries of schizophrenia spectrum disorder. By helping to decide the phenotypic status of nonschizophrenic family members, this should increase the power of DNA linkage studies.

Structure-based methods for the prediction of the dominant P450 enzyme in human drug biotransformation: consideration of CYP3A4, CYP2C9, CYP2D6.

Metabolic drug-drug interactions are receiving more and more attention from the in silico community. Early prediction of such interactions would not only improve drug safety but also contribute to make drug design more predictable and rational. The aim of this study was to build a simple and interpretable model for the determination of the P450 enzyme predominantly responsible for a drug's metabolism. The P450 enzymes taken into consideration were CYP3A4, CYP2D6 and CYP2C9. Physico-chemical descriptors and structural descriptors for 96 currently marketed drugs were submitted to statistical analysis using the formal inference-based recursive modelling (FIRM) method, a form of recursive partitioning. Generally accepted knowledge on metabolism by these enzymes was also used to construct a hierarchical decision tree. Robust methods of variable selection using recursive partitioning were utilised. The descriptive ability of the resulting hierarchical model is very satisfactory, with 94% of the compounds correctly classified.

Alcohol consumption and all-cause mortality.

BACKGROUND: Prospective studies of alcohol and mortality in middle-aged men almost universally find a U-shaped relationship between alcohol consumption and risk of mortality. This review demonstrates the extent to which different studies lead to different risk estimates, analyses the putative influence of abstention as a risk factor and uses available data to produce point and interval estimates of the consumption level apparently associated with minimum risk from two studies in the UK. METHOD: Data from a number of studies are analysed by means of logistic-linear modelling, taking account of the possible influence of abstention as a special risk factor. Separate analysis of British data is performed. RESULTS: Logistic-linear modelling demonstrates large and highly significant differences between the studies considered in the relationship between alcohol consumption and all-cause mortality. The results support the identification of abstention as a special risk factor for mortality, but do not indicate that this alone explains the apparent U-shaped relationship. Separate analysis of two British studies indicates minimum risk of mortality in this population at a consumption level of about 26 (8.5 g) units of alcohol per week. CONCLUSIONS: The analysis supports the view that abstention may be a specific risk factor for all-cause mortality, but is not an adequate explanation of the apparent protective effect of alcohol consumption against all-cause mortality. Future analyses might better be performed on a case-by-case basis, using a change-point model to estimate the parameters of the relationship. The current misinterpretation of the sensible drinking level of 21 units per week for men in the UK as a limit is not justified, and the data suggest that alcohol consumption is a net preventive factor against premature death in this population.

Binary and rate measures of life event experience: their association with illness onset in Edinburgh and London community surveys.

This report examines the extent to which a binary stress index (the experience of at least one severe event) and event rate measures were successful in predicting onset of psychiatric disorder amongst 1029 women. Analyses were based upon samples drawn from Edinburgh and London communities. Whilst the binary measures were successful in discriminating cases from non-cases within each sample, they were less powerful than measures based upon the rate at which events (usually severe) had been experienced. The results are discussed in terms of their relevance to issues of the health consequences of experiencing multiple events, and of the duration over which stressful events may have an influence on psychiatric health.

A QSAR study of anti-inflammatory N-arylanthranilic acids.

A detailed quantitative structure-activity relationship (QSAR) analysis of a series of 112 anti-inflammatory N-arylanthranilic acids has been performed to determine which physicochemical properties of these compounds are responsible for their anti-inflammatory activity. The results indicate that activity is modelled best by molecular shape parameters. The angle between the planes of the two benzene rings, dictated by the substitution pattern of the compounds, also appears relevant to activity. Dipole moments show some significance, but log P and other physiochemical parameters correlate poorly with activity. The best QSAR obtained was: [equation: see text] where B1 and B3 are Verloop substituent width parameters and mu(bond) is bond dipole (position in parentheses).

Design, synthesis and biological testing of a novel series of anti-inflammatory drugs.

Many of the non-steroidal anti-inflammatory drugs (NSAIDs) currently marketed produce severe gastro-toxic side effects. The benefits of producing NSAIDs without these side effects are obvious, particularly for patients requiring long-term therapy. The aim of this investigation was to produce novel NSAIDs, based on paracetamol, that exhibit little or no gastro-toxicity. The work covers design, synthesis and testing of 13 drug candidates. The analgesic and anti-inflammatory potencies of the drug candidates were measured using the mouse abdominal constriction assay and the carrageenan-induced rat paw oedema assay, respectively. The stomachs of the rats were examined post-mortem, to assess the gastro-toxicity of the drugs. Of the 13 compounds described herein, 11 were shown to possess analgesic activity at 2-10 times the potency of aspirin, while 8 demonstrated anti-inflammatory activity at 3-10 times the potency of aspirin. Significantly, all of the compounds showed very low gastro-toxicity when compared with aspirin. The results of this study indicate that it is possible to develop novel, potent NSAIDs based on the structure of paracetamol. These compounds have the advantage of demonstrating much lower gastro-toxicity than NSAIDs currently available. Drugs of this type may, in future, provide effective treatments for inflammatory disorders.

The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints.

Quantitative structure-activity relationship (QSAR) analysis of four toxicological data sets is described. The toxicological data include three data sets retrieved from the literature (the toxic and metabolic effects of 23 aliphatic alcohols on the perfused rat liver; the toxicity of 21 pyridines to mice; the lethality of 55 halogenated hydrocarbons to the mould Aspergillus nidulans). In addition, the toxicity of 13 mono- and di-substituted nitrobenzenes in a 15 min assay using the alga Chlorella vulgaris was analysed. QSARs were developed successfully using descriptors to describe uptake in the organism (i.e. hydrophobicity as quantified by the logarithm of the octanol-water partition coefficient, log P) and reactivity at the site of action (i.e. electrophilicity as quantified by the energy of the lowest unoccupied molecular orbital, E(LUMO)). A further parameter describing molecular branching as also required to model the data for the aliphatic alcohols. The results demonstrate that mechanistically based QSARs can be developed for these diverse endpoints which are, in terms of statistical quality as good as, if not better, than QSARs based on less mechanistically interpretable descriptors.

Ego strength and confidence thresholds in two methods of paired-associate learning.

Two experiments contrasted the effects of high and low wgo strength (as measured by Cattell's Sixteen Personality Factor Questionaire) on confidence thresholds (FG scores) under the anticipation and recall methods. High ego strength resulted in larger FG scores under the anticipation method- weakly so in Experiment I but significantly so in Experiment II, where subjects were selected from greater extremes of ego strength. This inferiority extended to trails to criterion and a measure of the associative-learning stage as well. Tasks for extending the generality of the obtained relationship of ego strength and confidence thresholds in paired-associate learning are suggested.

Emergency mental health services during and after a major aircraft accident.

A major commercial aircraft accident mobilizes a sophisticated disaster response by the federal government and local disaster teams. However, there is no effort to deal with the significant mental health needs of survivors, airline crew, ground personnel, and rescuers. The time has come to deal with the human tragedy and its emotional consequences. The development of an emergency protocol for response to mental health crises at the time of an accident must be confronted. An appropriate response on the part of the mental health community must address all persons involved in the accident. Management would involve a relatively brief length of time. Team members can include psychiatrists, physicians, nurses, psychiatric aides, airline representatives, clergy, and other trained personnel. The establishment of such a mental health preparedness program in crisis intervention must be the responsibility of the airlines, federal agencies, and others if the program is to be a success.

Management of the insensitive foot in diabetes: lessons learned from Hansen's disease.

Diabetes mellitus is the number one cause of lower extremity amputation (LEA) in the United States, accounting for about 60,000 cases per year. While the combination of reduced blood supply and the loss of sensation to the foot in a diabetic are responsible for the high incidence of LEAs, in most cases it is the loss of sensation that is primarily responsible for the initial foot wound and its failure to heal. The authors review the four mechanical causes for foot ulceration and eventual amputation. Based on an understanding of how feet ulcerate, the National Foot Treatment Center in Carville, LA has developed an insensitive foot screening and treatment program for "diabetic" foot ulcers that is more than 90% effective in healing plantar ulcers.

Consultation in the aftermath of an air tragedy.

In the early morning hours of December 12, 1985, a chartered jet airliner carrying 248 soldiers crashed shortly after takeoff, killing all aboard. The day after, the authors were designated as a consultation team to the mental health staff at Fort Campbell who were providing services in the aftermath of the crash. This report describes and analyzes the experiences of this consultation on disaster management. Our consulting experience has been one of the most profound and demanding events of our professional lives. Salient lessons of the consultation include: (a) the need to clarify leadership roles among the local mental health care team; (b) the need to help the local team establish clear roles among team members; (c) the value of enabling the local team to mourn the loss of their fellow soldiers and community members; and (d) the value of establishing a clear plan of mental health services for both short-term and long-term management.