Characterization of Influenza B Virus Variants with Reduced Neuraminidase Inhibitor Susceptibility.

Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs), which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B virus infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to those of NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyze within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had NA enzyme function similar to that of its wild type but had slightly reduced replication and transmission efficiency in vivo The D197N variant had impaired NA enzyme function, but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B virus variant with the H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.

Bidirectional amyloid fiber growth for a yeast prion determinant.

The polymerization of many amyloids is a two-stage process initiated by the formation of a seeding nucleus or protofibril. Soluble protein then assembles with these nuclei to form amyloid fibers. Whether fiber growth is bidirectional or unidirectional has been determined for two amyloids. In these cases, bidirectional growth was established by time lapse atomic-force microscopy. Here, we investigated the growth of amyloid fibers formed by NM, the prion-determining region of the yeast protein Sup35p. The conformational changes in NM that lead to amyloid formation in vitro serve as a model for the self-perpetuating conformational changes in Sup35p that allow this protein to serve as an epigenetic element of inheritance in vivo. To assess the directionality of fiber growth, we genetically engineered a mutant of NM so that it contained an accessible cysteine residue that was easily labeled after fiber formation. The mutant protein assembled in vitro with kinetics indistinguishable from those of the wild-type protein and propagated the heritable genetic trait [PSI(+)] with the same fidelity. In reactions nucleated with prelabeled fibers, unlabeled protein assembled at both ends. Thus, NM fiber growth is bidirectional.

Competency determinations in civil commitment.

The authors present a brief overview of competency determinations in criminal justice and civil commitment proceedings and review the American Psychiatric Association's Model Commitment Statute, which gives competency a central role. They present an alternative proposal that involves determining a person's competency to undergo civil commitment before a formal commitment hearing and delineates the responsibilities of legal and medical decision makers in the commitment process.

The legal basis of forensic psychiatry: statutorily mandated psychiatric diagnoses.

Using the Oregon statutory scheme as an example, the authors review certain areas of the law where psychiatric expertise is mandated by statute. This review points out the diversity of determinations where forensic psychiatric expertise is required by law. The authors' thesis is that forensic psychiatry draws its vitality from the law. Legal requirements, however, should not dictate psychiatric response, which should be guided by psychiatric knowledge and ethical concerns.

Psychiatric participation in the Hootch case: effects on Alaska native education.

The Hootch case was a class action suit that established the right of Alaska Native students to attend secondary school in their home communities. The authors review the history of Native education, give the background of the suit, and present behavioral science data on school adjustment of Alaska Natives and American Indian students. These data, included in an amicus curiae brief, were incorporated into the court decision. The authors consider this case a positive example of psychiatric involvement in social policy matters.

The use of DSM-III axis III in recording physical illness in psychiatric patients.

The randomly selected charts of 50 discharged psychiatric inpatients were reviewed for documentation of medical illness and DSM-III axis III diagnoses. Twenty-eight percent of the patients had had medical symptoms, 56% had had medical findings, 36% had had laboratory findings, and 60% had been given axis III diagnoses. In at least seven cases, the medical findings were poorly reflected in the final axis III diagnosis. In no case did the record indicate that medical factors were viewed as the cause of a patient's immediate psychiatric syndrome.

Monitored conditional release of persons found not guilty by reason of insanity.

This article reviews the recent literature documenting changes that have taken place in the management and treatment of insanity defense acquittees with the development of conditional release and monitored community treatment. The review demonstrates that conditional release is particularly important as a means of balancing the protection of society with the treatment of insanity defense acquittees in the least restrictive environment. The review also highlights the development of community programs based on treatment models for the chronically mentally ill. In addition, monitored community treatment programs appear cost-effective when compared with hospital-based programs. These factors point to the development in the 1990s of program standards for the release of insanity defense acquittees.

Training psychiatrists to work with community support systems for chronically mentally ill persons.

Community support programs are becoming a major priority in community mental health centers throughout the country. The authors present a training design that integrates principles and skills associated with this model into a 4-year residency training program. The aim of such programs is to keep young psychiatrists involved and in the forefront of the newer approaches to the treatment of chronically mentally ill persons.

Residency curriculum in forensic psychiatry.

The authors describe the development of a curriculum in forensic psychiatry in a general psychiatric residency training program. Educational objectives for both knowledge and skills are presented. The authors detail training experiences at each level of psychiatric residency, including electives available for fourth-year residents. They encourage other training programs to share similar reports with a view toward the development of standards in the training of residents in forensic psychiatry.

An Indochinese refugee psychiatric clinic: culturally accepted treatment approaches.

In 1978 the authors established a weekly psychiatric clinic for Indochinese refugees. During the first 20 months, 50 patients were evaluated and treated at the clinic; a Vietnamese psychiatric resident and several native Indochinese mental health counselors bridged the language and cultural barriers between patients and clinic personnel. Most of the patients seen at the beginning of the program were psychotic and severely impaired. However, patients seen later suffered from a wider variety of problems. A flexible approach to treatment was adopted that would be compatible with the cultural expectations of the refugees. This resulted in the use of different forms of therapy and special emphasis on the medical approach of the physician, a role familiar to Indochinese patients. Gradually the clinic gained acceptance by members of the local refugee community.

Required educational objectives in community psychiatry.

Community psychiatry is an essential requirement of approved residency training. The authors present a format of required educational objectives for this experience. They feel that recent attempts to limit psychiatric consultation to the consultation-liaison model are restrictive and incomplete. In their view of the psychiatrist's role, community consultation techniques are essential skills for the psychiatric practitioner.

Insanity defenses: contested or conceded?

The authors examined 316 Oregon criminal cases in which the accused successfully pleaded the insanity defense. Prosecutors agreed to the insanity verdict in more than four out of five cases. In most cases all examining experts diagnosed the defendant as psychotic. The smaller number of defendants who were diagnosed by the state hospital staff as displaying only personality disorders accounted for a disproportionately large percentage of the contested trials. Observing that Oregon's insanity defense system is run by consensus, the authors suggest a reorientation of the insanity defense debate.

An empirical study of emergency commitment.

The authors examine the emergency commitment process in one Oregon county and present data that document the impact of a local detention facility. The study reconfirms the dependence of commitment processes on the mental health system in which they occur, illustrates the relative inability of specific laws to determine the actual nature of commitment processes, provides support for the concept of community care for the people involved, and points to the need for additional research to clarify the effects of commitment procedures.

Psychiatric consultation to a state board of medical examiners.

This article describes the evolution of psychiatric consultation to the Oregon Board of Medical Examiners. The board is charged with the licensing and regulation of physicians in the state of Oregon in order to protect the public and uphold the standards of the medical profession. Psychiatric consultation has focused on the board's investigations of physicians with mental illness and/or substance abuse and physicians who inappropriately prescribe psychoactive drugs or sexually abuse patients. Each of these physician groups is described, and remedial programs for each group are discussed. The authors conclude that psychiatric consultation to medical boards is a feasible and productive activity that can make a positive contribution to the lives of a large number of physicians and patients.

A method for quantifying and comparing civil commitment processes.

The authors present a three-step civil commitment model and formulas for calculating 1) the probability of release from the commitment process and 2) the relative importance of the three steps in determining outcome. Using data from Oregon's civil commitment process, they present five examples that demonstrate how their method might be used to study and monitor civil commitment processes within and between jurisdictions. The major public policy and research implications are discussed.

Attitudes of Oregon psychiatrists toward physician-assisted suicide.

OBJECTIVE: After passage, in November 1994, of Oregon's ballot measure legalizing physician-assisted suicide for terminally ill persons, the authors surveyed psychiatrists in Oregon to determine their attitudes toward assisted suicide, the factors influencing these attitudes, and how they might both respond to and follow up a request by a primary care physician to evaluate a terminally ill patient desiring assisted suicide. METHOD: An anonymous questionnaire was sent to all 418 Oregon psychiatrists. RESULTS: Seventy-seven percent of psychiatrists (N = 321) returned the questionnaire. Two-thirds endorsed the view that a physician should be permitted, under some circumstances, to write a prescription for a medication whose sole purpose would be to allow a patient to end his or her life. One-third endorsed the view that this practice should never be permitted. Over half favored Oregon's assisted suicide initiative becoming law. Psychiatrists' position on legalization of assisted suicide influenced the likelihood that they would agree to evaluate patients requesting assisted suicide and how they would follow up an evaluation of a competent patient desiring assisted suicide. Only 6% of psychiatrists were very confident that in a single evaluation they could adequately assess whether a psychiatric disorder was impairing the judgment of a patient requesting assisted suicide. CONCLUSIONS: Psychiatrists in Oregon are divided in their belief about the ethical permissibility of assisted suicide, and their moral beliefs influence how they might evaluate a patient requesting assisted suicide, should this practice be legalized. Psychiatrists' confidence in their ability to determine whether a psychiatric disorder such as depression was impairing the judgment of a patient requesting assisted suicide was low.

The effect of depression treatment on elderly patients' preferences for life-sustaining medical therapy.

OBJECTIVE: This study was undertaken 1) to test the hypothesis that remission of depression results in an increase in desire for life-sustaining medical therapy and 2) to characterize patients whose desire for life-sustaining treatment increases substantially following depression therapy. METHOD: Elderly patients, suffering from major depression, were interviewed on admission to a psychiatric inpatient unit and at discharge about their desire for specific medical therapies in their current state of health and in two hypothetical scenarios of medical illness. A psychiatrist rated the impact of depressive thinking on the subject's response to these questions. Forty-three subjects completed the study, and 24 were in remission from depression at the time of discharge. RESULTS: In the majority of patients, remission of depression did not result in an increase in desire for life-sustaining medical therapy. However, a clinically evident increase in desire for life-sustaining medical therapies followed treatment of depression in subjects (N = 11 [26%]) who had been initially rated as more severely depressed, more hopeless, and more likely to overestimate the risks and to underestimate the benefits of treatment. CONCLUSIONS: In major depression of mild to moderate severity, a patient's desire to forgo life-sustaining medical treatment is unlikely to be altered by depression treatment. On the other hand, severely depressed patients, particularly those who are hopeless, overestimate the risks of treatment, or underestimate the benefits of treatment, should be encouraged to defer advance treatment directives. In these patients decisions about life-sustaining therapy should be discouraged until after treatment of the depression.

Potential antiatherosclerotic agents. 6. Hypocholesterolemic trisubstituted urea analogues.

The discovery that a series of N,N-dialkyl-N'-arylureas were inhibitors of the ACAT enzyme has led to a structure-activity study involving the systematic modification of three sites of the urea backbone. This study culminated in the selection of N'-(2,4-dimethylphenyl)-N-benzyl-N-n-butylurea (115) for more extensive biological evaluation. ACAT inhibitors are seen as potentially beneficial agents against hypercholesterolemia and atherosclerosis.

Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines.

This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracycline-susceptible and -resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.

The No Harm Contract in the emergency assessment of suicidal risk.

BACKGROUND: The No Harm Contract has been widely accepted in clinical practice, yet there is no broad consensus as to its value. This paper examines the contract and offers recommendations for its use as well as cautions about its misuse. METHOD: After a literature review, the No Harm Contract is examined from diagnostic, therapeutic, and medicolegal perspectives. RESULTS: Diagnostically, the No Harm Contract can be used to assess the nature and severity of a patient's suicidality, uncover specific troubling issues precipitating suicidal thoughts, and evaluate the patient's competency to contract. Therapeutically, the contract affords an opportunity to initiate a therapeutic alliance, establish the limits of the psychotherapeutic framework, and reduce both patient and clinician anxiety. Medicolegally, the contract is not legally binding and grants no suicide malpractice suit protection. CONCLUSION: Although the No Harm Contract is a frequently used clinical tool that can provide diagnostic information and therapeutic advantage, it can also short-circuit comprehensive suicidal assessment and disposition decisions.