An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

1,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate.

Inhibitors of squalene synthase have the potential to be superior cholesterol-lowering agents. We previously disclosed that lipophilic 1,1-bisphosphonates I are potent squalene synthase inhibitors and orally active cholesterol-lowering agents in animal models (Ciosek, C. P., Jr.; et al. J. Biol. Chem. 1993, 268, 24832-24837). In this paper, we describe modifications to the bisphosphonate moiety, in an attempt to reduce the number of acidic functions contained in these inhibitors. Replacing one of the acidic groups with a methyl (II, R2 = CH3) results in potent inhibitors when paired with a close mimic of the naturally occurring farnesyl moiety (R1 = farnesylethyl) but not when paired with the shorter isoprene surrogates (R1 = geranylethyl or 4-biphenylpropyl). In contrast, all three corresponding bisphosphonates I are potent squalene synthase inhibitors. Inhibitory potency is recovered with the shorter isoprene surrogates when R2 is CH2OH or CH2OCH3. It is proposed that these R2 groups serve as hydrogen bond acceptors with the active site of the enzyme. The properties of these compounds as cholesterol biosynthesis inhibitors in rats are described, and synthetic routes to these and related compounds are detailed.

Rapid oral desensitization to trimethoprim-sulfamethoxazole in infants and children.

BACKGROUND: Although trimethoprim-sulfamethoxazole is the preferred chemoprophylaxis against Pneumocystis carinii pneumonia, there are frequent IgE-mediated reactions among children infected with the human immunodeficiency virus (HIV). Oral desensitization allows more patients to receive chemoprophylaxis, but it has been studied in only a limited number of children. METHODS: We desensitized five children infected with the HIV using a rapid, 4-h oral protocol. RESULTS: Three children (including two infants) successfully completed desensitization and started maintenance therapy, but the other two experienced reactions that precluded further administration of trimethoprim-sulfamethoxazole. CONCLUSIONS: We conclude that a rapid, oral trimethoprim-sulfamethoxazole desensitization protocol is safe and, in some instances, effective among HIV-infected children and infants with a history of non-life-threatening, IgE-mediated reactions to trimethoprim-sulfamethoxazole.

Treatment of fungal infections with semisynthetic derivatives of amphotericin B alpha.

AME appeared to be as effective as AmB in the treatment of mycoses in humans. AME was much less nephrotoxic than AmB, and was better tolerated in terms of rapid onset and reversible adverse reactions. AME may be more ototoxic than AmB. AME, even as AmB and OAME, may cause neurotoxicity and leukoencephalopathy, particularly when high doses are given for long periods.

Total ionized serum calcium and parathyroid hormone levels in patients with disseminated coccidioidomycosis.

Twenty-one patients with severe coccidioidomycosis, including eight with osseous lesions, were admitted to the University of California, Davis, Medical Center, during a recent epidemic. Transient mild ionized hypercalcemia occurred in only two patients, and a tendency toward low normal ionized calciums was noted. Parathyroid hormone levels appeared to be appropriate for the ionized calcium in these patients. There were no significant differences in ionized calcium levels of parathyroid hormone levels among patients with and without osseous coccidioidomycosis. We conclude that hypercalcemia is rare in coccidioidomycosis, even with extensive bony involvement.

Given the benefits of breastfeeding, what contraindications exist?

Breastfeeding is not contraindicated in association with environmental hazards in the United States under ordinary circumstances. Unusual massive exposure should be assessed on an individual basis. In the face of any possible contraindication to breastfeeding, the tremendous benefits of being breastfed should be compared with the theoretic risk for the hazard involved and a decision made on an individual basis.

Phantom pain: a new hypothesis.

This paper deals with a new concept as to the possible nerve circuitry involved in phantom limb paid as well as in other similar disorders associated with an autonomic nervous system dysfunction. The paper deals with a new therapy promulgated by Melzack and Loeser originally presented in the journal "Pain". A discussion of the paper was also given in the Journal of the American Medical Association (editorial section) by R. De Jong. It is our contention that there may be a direct connection between the sympathetic nervous system fibers, carried on the blood vessels, and the central nervous system particularly through the hypothalamic-thalamic axis. This may explain why despite a complete transection of the spinal cord at higher levels (such as in the upper dorsal area) and even with an interruption of the sympathetic chain, pain impulses still reach the higher central nervous system.

Psychiatric symptomatology in early-onset Binswanger's disease: two case reports.

We describe two cases of Binswanger's disease of pre-senile onset which presented with affective and psychotic symptoms well before the appearance of cognitive deterioration and neurological signs, initially evading an accurate diagnosis. Psychiatrists should be aware of white matter disease and its role in the pathogenesis of psychiatric illness. Particular attention should be given to a history of hypertension as a risk factor in the early identification of these cases.

Psychiatric symptoms in patients with focal cortical degeneration.

The psychiatric phenomenology exhibited by a mixed group of patients with focal cortical degeneration (FCD) is described. The diagnosis of FCD was made in the presence of a slowly progressive focal neuropsychological deficit without evidence of infarct or neoplasm. Localized or asymmetric atrophy was present on neuroimaging (CT or MRI) and positron emission tomography demonstrated focal hypometabolism or in those assessed later in the disease an area of maximal hypometabolism which correlated with the neuropsychological deficit. FCD patients exhibited prominent obsessive-compulsive behaviour. Obsessive-compulsive features were often repetitive, stereotyped and bizarre and occurred in association with frontal and left temporal atrophy and hypometabolism and were absent in those with predominant posterior cortical pathology.

The role of flexible bronchoscopy in children with AIDS: an update of the New York University experience.

The clinical courses of children with acquired immunodeficiency syndrome (AIDS) who underwent diagnostic flexible bronchoscopy at Bellevue Hospital from 1987-1992 were reviewed to determine the value of the procedure in patient management. Twenty-eight children (age 13 days to 12 years) underwent 31 bronchoscopies for indications including respiratory distress, fever and abnormal chest radiograph. Procedures were well tolerated. Complications were limited to transient hypoxia and epistaxis. Although 58% of bronchoscopies yielded a diagnosis (Pneumocystis carinii, Streptococcus viridans, Pseudomonas aeruginosa, Cytomegalovirus, atypical mycobacterium, giant cell pneumonia, and mechanical obstruction), empiric medical therapy was altered in only 16% of cases. Bronchoscopic diagnoses are correlated with Centers for Disease Control (CDC) classification, immune status, treatment and outcome.

Diagnostic flexible bronchoscopy in human immunodeficiency virus (HIV)-positive children.

Twelve children with laboratory evidence of human immunodeficiency virus (HIV) infection underwent diagnostic flexible bronchoscopy with washings or bronchoalveolar lavage at Bellevue Hospital Center from October 1987 to April 1989. The patients included 7 boys and 5 girls ranging from age 3.5 months to 10 years 5 months. Indications for bronchoscopy included respiratory distress with or without focal changes on chest radiograph in 11 patients, and persistent but asymptomatic right middle lobe collapse in one child. The etiology of pneumonia was diagnosed in 7 children and included Pneumocystis carinii, (PCP) (17%), Streptococcus viridans (17%), mechanical obstruction (17%) and cytomegalovirus (CMV) (8%). Bronchoscopy was non-diagnostic in 5 cases. Techniques for maximal yield of information using flexible bronchoscopy in HIV-positive children are discussed.

Knowledge and attitudes about acquired immunodeficiency syndrome in nursing and nonnursing groups.

A study was undertaken to determine the difference in knowledge and attitudes about acquired immunodeficiency syndrome (AIDS) in nursing and nonnursing groups, and to determine the effect that knowledge acquisition would have on attitudes about AIDS. The total study population consisted of 60 registered nurses, 50 baccalaureate nursing students, 42 liberal arts college students, and 30 nonnurse adults. An AIDS knowledge and attitude assess test was developed and used in the study. Univariate descriptive methodology, descriptive correlational analysis, and a pretest-posttest design were used. Phase I showed that professional nurses with graduate degrees have the highest knowledge base and the most positive attitudes about AIDS; and that nursing students' attitudes are more similar to the attitudes of nonnursing students than of professional nurses. Phase II showed that people's attitudes about AIDS could be changed by increasing their knowledge levels, and nursing students showed more increase in knowledge and more significant changes in attitudes following education than liberal arts college students.

The nurse and job related stress: responses, Rx, and self-dependency.

There is no simple answer to the complex problem of job related stress, which is inherent in the practice of nursing. However, some solution to the problem has to be found otherwise young people will not enter the profession and older, experienced nurses will continue to leave the profession, resulting in a continuation of the current shortage and generating more critical future shortages. Teaching nurses to become self-dependent and to assume the role of avatar offers one possible solution to cope with the problem, a solution which requires active participation by the persons involved.

Helping patients cope with the stress of myocardial infarction.

The victims of myocardial infarction pose a real challenge to nursing. Effective nursing intervention is based on an understanding of human responses to the stress of heart disease and the series of behavioral changes individuals undergo in an attempt to cope with the stress. Cardiac teaching is an essential aspect of this intervention. After a myocardial infarction, patients first go through two stages on the way to recovery--independency and dependency--before they are receptive to teaching. It is during the next two stages--interdependency and self-dependency--that nurses can use specific behavioral changes of the patients to plan health teaching and to negotiate contracts with them to effect learning and permanent behavioral change.