Fatal ulcerative and hemorrhagic typhlocolitis in a pregnant heifer associated with natural bovine enterovirus type-1 infection.

One 2-year-old, 7.5 months pregnant Aberdeen Angus out of a herd of 100 apparently healthy cows, died within 10 hours of hospitalization. At necropsy, multiple foci of mucosal hemorrhage and ulceration were observed in the spiral colon and cecum. Virus isolation from intestinal lesions yielded a cytopathic virus, which was revealed by electron microscopy to be an approximately 27 nm, nonenveloped virus. Further characterization by reverse transcription-polymerase chain reaction (RT-PCR), sequencing of the 5'UTR and partial VP1 coding region, and phylogenetic analysis classified the virus isolate as bovine enterovirus type 1 (BEV-1). No other significant pathogens were detected. This is the first report of BEV-1 isolated in the USA from an animal with fatal enteric disease in more than 20 years. Further investigation is required to determine the prevalence of BEV in North America and to establish the clinical relevance of this understudied virus.

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.

Bovine viral diarrhea virus type 2-induced meningoencephalitis in a heifer.

The brain from a 15-month-old, black female Angus, with a 48-hour history of central nervous system disease, was submitted to the Oklahoma Animal Disease Diagnostic Laboratory. Microscopic findings consisted of acute, multifocal meningoencephalitis, with neuronal degeneration and necrosis and gliosis. Viral isolation yielded noncytopathic bovine viral diarrhea virus (BVDV). Virus genotyping classified the virus as BVDV type 2. Immunohistochemical labeling for BVDV antigens with BVD MAb 3.12F1 clone was prominent in the cytoplasm of neurons, glial cells, ependymal epithelium, perivascular macrophages and spindle cells, smooth muscle cells, and intravascular monocytes of the cerebrum and brain stem. Laboratory results support that tissue alterations occurred as a result of BVDV type 2 infection. In the absence of other clinical signs related to BVDV infection and using the microscopic and laboratory evidence presented, we propose that the BVDV type 2 isolated from this case may represent a neurovirulent strain of the virus. To the best of our knowledge, this is the first report of brain lesions and neuronal viral antigen localization in BVDV genotype 2 viral infection, acquired either congenitally or postnatally.

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.

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.

Comparison of tissue stages of Hepatozoon americanum in the dog using immunohistochemical and routine histologic methods.

American canine hepatozoonosis is caused by Hepatozoon americanum, a recently described species of apicomplexan protozoan parasite. An immunohistochemical procedure using a polyclonal antibody to sporozoites of H. americanum clearly identified asexual stages of H. americanum in canine striated muscle. The method also detects hepatozoa present in naturally infected coyotes and raccoons and reacts with certain other apicomplexans. Use of this immunohistochemical procedure confirms the canine intermediate host-parasite relationships that were presumptively established using conventional histopathologic methods.

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).

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.

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.

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.

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.

A comparison of self-injury and self-poisoning from the Regional Poisoning Treatment Centre, Edinburgh.

Injury and poisoning episodes at the Regional Poisoning Treatment Centre, Edinburgh, were compared for the years 1980-1986. Injury was more likely to be associated with youth, male sex and single status. When these demographic differences were controlled for, injury was found to be associated with the following clinical variables: personality disorder, previous psychiatric inpatient status, use of alcohol at the time of parasuicide and alcohol problems, and the social variables-violence against others and received from relatives in the preceding 5 years, criminal record and unemployment. These have been consistently associated with repetition of parasuicide. A history of injury as a putative marker of repetition and the clinical implication of its association with alcohol problems are discussed.

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.

Suicide in England and Wales 1946-1985: an age-period-cohort analysis.

Four decades of suicide mortality data for England and Wales were analysed within an age-period-cohort framework. Marked differences in results were found by sex. The analysis of the male data showed that the risk of suicide increased with age until men were in their mid-fifties (after allowing for period and cohort effects), and that suicide risk declined for males born from 1876 to 1915, but had increased over 4-fold for certain later-born cohorts. Female suicide risk was found to decline with later nativity (after adjusting for age and period effects). The identification of period effects in terms of known changes in the carbon monoxide (CO) content of domestic gas successfully accounted for temporal variation in male suicide risk, but fitted less well to the data for females.

Medical admissions in men: the risk among drinkers.

Information on alcohol consumption was elicited by the same method from men in a general population survey and from male medical inpatients in a hospital serving that population. A measure of risk controlling for age, the logarithm of the odds ratio, showed that for liver disorders, upper gastrointestinal disorders, myocardial infarction, other cardiovascular disorders, and respiratory disorders, rising consumption of alcohol was related to increased risk of hospital admission relative to abstention. The risk of admission for the remaining heterogeneous category of disorders was lower than that for abstention, perhaps reflecting the effect of chronic illness on drinking habits, and also suggesting that the link between alcohol consumption and medical diagnoses is not simply due to greater frankness about drinking in hospital inpatients.