Bypass of heterology during strand transfer by Saccharomyces cerevisiae Rad51 protein.

During recombination-mediated repair of DNA double-strand breaks, strand transfer proteins must distinguish a homologous repair template from closely related genomic sequences. However, some tolerance by strand transfer proteins for sequence differences is also critical: too much stringency will prevent recombination between different alleles of the same gene, but too much tolerance will lead to illegitimate recombination. We characterized the heterology tolerance of Saccharomyces cerevisiae Rad51 by testing bypass of small heterologous inserts in either the single- or double-stranded substrate of an in vitro strand transfer reaction that models the early steps of homologous recombination. We found that the yeast protein is rather stringent, only tolerating heterologies up to 9 bases long. The efficiency of heterology bypass depends on whether the insert is in the single- or double-stranded substrate, as well as on the location of the insert relative to the end of the double-stranded linear substrate. Rad51 is distinct in that it can catalyze strand transfer in either the 3'-->5' or 5'-->3' direction. We found that bypass of heterology was independent of the polarity of strand transfer, suggesting that the mechanism of 5'-->3' transfer is the same as that of 3'-->5' transfer.

Mechanisms of separation of the complementary strands of DNA during replication.

This article is a perspective on the separation of the complementary strands of DNA during replication. Given the challenges of DNA strand separation and its vital importance, it is not surprising that cells have developed many strategies for promoting unlinking. We summarize seven different factors that contribute to strand separation and chromosome segregation. These are: (1) supercoiling promotes unlinking by condensation of DNA; (2) unlinking takes place throughout a replicating domain by the complementary action of topoisomerases on precatenanes and supercoils; (3) topological domains isolate the events near the replication fork and permit the supercoiling-dependent condensation of partially replicated DNA; (4) type-II topoisomerases use ATP to actively unlink DNA past the equilibrium position; (5) the effective DNA concentration in vivo is less than the global DNA concentration; (6) mechanical forces help unlink chromosomes; and (7) site-specific recombination promotes unlinking at the termination of replication by resolving circular dimeric chromosomes.

HIV public policy and psychiatry. An examination of ethical issues and professional guidelines.

The authors examine the interfaces among public policy, legal issues, ethical issues, and physician responsibility for the human immunodeficiency virus (HIV)-infected psychiatric patient within the realms of civil liberties and public health. Current professional guidelines on caring for HIV-infected psychiatric patients are discussed, including discussion of psychotherapy and the potential for behavioral change. The impact of the Tarasoff decision on confidentiality is reviewed, including discussion of whether a precedent was set mandating that a psychiatrist warn identifiable third persons at risk of becoming infected by his or her patient. The management of HIV-infected psychiatric inpatients who continue to put other patients at risk and the impact of HIV carriers on ward milieu are also addressed, as are difficulties encountered with the chronically mentally ill.

Consultation-liaison psychiatry and HIV-related disorders.

Acquired immune deficiency syndrome (AIDS) and related disorders are increasingly and unsettlingly prevalent. The authors describe neuropsychiatric, psychosocial, and ethical-legal problems associated with HIV infections that are commonly encountered in a consultation-liaison psychiatry setting. Because of HIV's potential for undermining cognitive function, they recommend a systematic neurobehavioral assessment for the differential diagnosis of emotional disturbance, including a test battery that also identifies neurotoxic effects of pharmacological agents. Among significant psychosocial and ethical-legal problems are patient's reactions to AIDS, their fears of social abandonment, staff burn-out, antibody testing, confidentiality, and the use of life-support measures. The consultation-liaison psychiatrist's awareness of the complexities of HIV-related neuropsychiatric symptoms and psychosocial issues can be of enormous benefit to medical caregivers and to the patients themselves.

Psychostimulant response in AIDS-related complex patients.

Methylphenidate or dextroamphetamine was used to treat 17 of 32 patients with AIDS-related complex who were referred for neuropsychiatric evaluation of symptoms representative of cognitive and/or affective dysfunction. All 17 patients were found to have some degree of cognitive impairment. Psychiatric diagnoses included organic mental disorder (8), adjustment disorder (5), and major depression (4). The 17 patients were receiving no other psychoactive or neurotoxic medications nor were they receiving concomitant investigational antiviral or chemotherapeutic agents. Clinical response to psychostimulant therapy was rated using the Efficacy Index of the Clinical Global Impressions. Pharmacotherapy with either psychostimulant was clinically effective in improving affective parameters in 89.5% (15) of the 17 patients, with 79% (13) of the 17 achieving a moderate to marked response. No adverse side effects were encountered.

Treatment of severe, refractory agitation with a haloperidol drip.

A case of agitated delirium secondary to bilateral occipital cerebral infarctions in a cancer patient was refractory to trials of large doses of intravenous psychotropic agents, but continuous intravenous infusion of haloperidol controlled agitation rapidly and safely. A total haloperidol dose of 600 mg/day was used without complications. Haloperidol by continuous infusion should be considered in the management of severe, refractory agitation in patients who are medically ill.

Controlled study of extrapyramidal reactions in the management of delirious, medically ill patients: intravenous haloperidol versus intravenous haloperidol plus benzodiazepines.

In a prospective study, the intensity of extrapyramidal symptoms (EPS) was rated in two groups of delirious, medically ill patients. Fourteen patients received intravenous (IV) haloperidol and benzodiazepines for control of severe agitation and four received IV haloperidol alone. Patients were rated daily by a standardized scale for EPS by raters blind to the dose of haloperidol and benzodiazepines. Patients receiving haloperidol and benzodiazepines had significantly (p less than 0.001) less EPS than patients receiving IV haloperidol alone. In the haloperidol and benzodiazepine group there were only one case of very mild parkinsonian-like EPS and no cases of akathisia or dystonia. No adverse respiratory or cardiac reactions were seen in any patients. The literature on the use of IV haloperidol alone and in combination with benzodiazepines is briefly reviewed and possible explanations of the lower intensity of EPS with IV haloperidol in combination with benzodiazepines are discussed.

Decreased extrapyramidal symptoms with intravenous haloperidol.

In a preliminary, prospective study, the intensity of extrapyramidal symptoms was rated in four patients receiving intravenous haloperidol and six patients receiving oral haloperidol. The raters were blind to the route of administration. In this pilot study, the first systematic evaluation of intravenous haloperidol and extrapyramidal symptoms, the patients receiving intravenous haloperidol experienced significantly (p less than .01) less intense extrapyramidal symptoms than did the patients receiving oral haloperidol. The literature on intravenous haloperidol is briefly reviewed, and possible explanations of the lower intensity of extrapyramidal symptoms with intravenous haloperidol in the patients studied are discussed.

Analgesic effect of alprazolam in patients with chronic, organic pain of malignant origin.

Effective analgesia is a crucial factor in promoting quality of life for cancer patients. While undergoing treatment with the minor tranquilizer alprazolam for a coincidental psychiatric disturbance, 39 patients with malignancies and an associated causalgic pain syndrome had a marked analgesic response. Diagnostic and treatment guidelines for organic pain syndromes are reviewed, as are indications for the use of anticonvulsants and benzodiazepines as analgesic adjuvants. The results of this study suggest that the use of benzodiazepines for patients with this refractory pain syndrome should be evaluated further.