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.

Biofilm accumulation on endotracheal tubes following prolonged intubation.

OBJECTIVE: To demonstrate that patients who have been intubated for prolonged periods of time will have an increased likelihood of developing bacterial biofilm on their endotracheal tubes. METHODS: We collected endotracheal tubes from patients at the time of extubation, and analysed representative sections with scanning electron microscopy for morphologic evidence of biofilms. RESULTS: From September 2007 to September 2008, 32 endotracheal tubes were analysed with electron microscopy. Patients who had been intubated for 6 days or longer had a significantly higher percentage of endotracheal tubes that exhibited bacterial biofilms, compared with patients intubated for less than 6 days (88.9 versus 57.1 per cent, p = 0.0439). CONCLUSIONS: Longer duration of intubation is associated with a higher incidence of bacterial biofilm. Further research is needed to link the presence of bacterial biofilms to acquired laryngotracheal damage.

Ethnic segregation in Kosovo's post-war health care system.

BACKGROUND: Seven years after the end of war in Kosovo, Final Status Negotiations have begun to determine the long-term political future of the province. This article provides an overview of the present situation regarding ethnic groups and their relations in Kosovo's health care system that might be helpful in preparing for the array of potential ramifications and repercussions that could arise at the conclusion of the negotiations. METHODS: A review of the literature (including grey) was performed, and 16 interviews and two focus groups with key informants were conducted in Kosovo during October and November 2004. In addition, six informal discussions were held in-person or by telephone in London. Information collected in 2004 was re-confirmed and partially updated in October and November 2005, when three additional interviews were conducted in Kosovo. RESULTS: Ongoing ethnic tensions in Kosovo, mainly between the Albanian and Serb populations, perpetuate a rigidly segregated health care system. Some other minority communities, such as the Roma, Ashkali and Egyptians, are afflicted by the double burden of getting caught up in the middle of these ethnic disputes and at the same time suffering from poverty and discrimination. CONCLUSION: While efforts have been put forward to promote peace-building within Kosovo's post-war health sector, very little progress has been achieved in fostering ethnic integration, reconciliation, cooperation or even co-existence. This failure reflects Kosovo's broader unresolved inter-ethnic problems. Final Status Negotiations are one of the last opportunities for the international community to address the problems of ethnic segregation in the province.

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.

Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation: resistance maps to the UL6 gene.

In our search for novel inhibitors of herpes simplex virus type 1 (HSV-1), a new class of thiourea inhibitors was discovered. N-(4-[3-(5-Chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl)-acetamide and its 2-fluoro-benzamide derivative inhibited HSV-1 replication. HSV-2, human cytomegalovirus, and varicella-zoster virus were inhibited to a lesser extent. The compounds acted late in the replication cycle by impairing both the cleavage of concatameric viral DNA into progeny genome length and the packaging of the DNA into capsids, indicative of a defect in the encapsidation process. To uncover the molecular target of the inhibition, resistant HSV-1 isolates were generated, and the mutation responsible for the resistance was mapped using marker transfer techniques. Each of three independent isolates had point mutations in the UL6 gene which resulted in independent single-amino-acid changes. One mutation was located in the N terminus of the protein (E121D), while two were located close together in the C terminus (A618V and Q621R). Each of these point mutations was sufficient to confer drug resistance when introduced into wild-type virus. The UL6 gene is one of the seven HSV-1 genes known to play a role in DNA packaging. This novel class of inhibitors has provided a new tool for dissection of HSV-1 encapsidation mechanisms and has uncovered a new viable target for the treatment of herpesviral diseases.

A 36-year history of fatal road rage in Marion County, Oregon: 1963-1998.

This paper documents the 36-year history, with five examples, of fatal road rage in Marion County, Oregon. Relevant details (all that were available) from each case are presented. Alcohol intoxication was present in four of our five cases. We include two deaths by gunshot at close range, two deaths as a result of a motor vehicle traffic accident, and one natural death. All subjects were males. Three were Caucasian and two were Hispanic. The three subjects in Cases 1, 2 and 3 were complete strangers to the occupants of the other involved vehicles. The subjects in Cases 4 and 5 (along with the occupants of their own vehicles) were acquaintances of the occupants of the involved vehicle. There appears to be no previous forensic, medical or psychiatric literature on road rage as such. We present an initial psychiatric evaluation of the perpetrators of this type of fatal assault. There are no specific statutes in Oregon, at the state or county levels, regarding road rage. However, the city of Gresham, Oregon, recently enacted an ordinance regarding road rage. We stress the need for further study of this phenomenon, especially through the use of the psychological-psychiatric autopsy.

An administrative model for close monitoring and managing high risk individuals.

The public expects central government to have immediate knowledge of the condition and circumstances of certain vulnerable or dangerous individuals such as insanity acquittees, and to take action in individual cases to protect the individual and the public. Therefore, such persons conditionally released to community settings require an unusual degree of close monitoring and management. Being immediately aware of the condition and circumstances of its assignees, together with other duties of a board or commission responsible for that monitoring and management, is largely an information management function. The Psychiatric Security Review Board in Oregon is used to illustrate this unique mission, operations, and information management. In this paper, the Psychiatric Security Review Board is described in terms of its core and secondary businesses, together with a model information system that is based on information and information management processes actually employed by the Board.

Inhibition of influenza A virus replication by compounds interfering with the fusogenic function of the viral hemagglutinin.

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.

Ensuring the survival of academic psychiatry in the new health care era.

The authors contend that academic psychiatry will only survive in the future if it helps to fulfill the crucial requirement of academic medicine in the new health care era. They present six basic requirements of academic medicine: 1) effective, efficient, and responsible organizations; 2) quality educational programs of appropriate type and size; 3) linkage to health care networks; 4) primary care capacity and services; 5) restructured systems for research; and 6) effective leadership. Specific strategies for departments of psychiatry to help meet the requirements of academic medicine are outlined. The authors present major implications of these proposed strategies for psychiatric chairs, faculty, and the professional organizations that serve them.

Changes in questions about psychiatric illness asked on medical licensure applications between 1993 and 1996.

OBJECTIVE: This study examined the nature of questions about previous mental illness, physical illness, and substance abuse asked on applications for state medical licensure, partly to determine if questions focused more appropriately on any current, rather than past, disability. METHODS: In 1993 and 1996 the 66 members of the Federation of State Medical Boards of the United States, Inc., were asked to provide copies of the forms they used for medical licensure applications and renewal. The forms were reviewed to determine the presence of questions about previous mental illness, physical illness, and substance abuse and whether the questions specifically addressed the effects of the condition on the ability to practice medicine. RESULTS: On initial licensure applications, medical boards commonly asked questions about mental illness. Seventy-five percent of responding boards did so in 1993, and 80 percent did so in 1996. The proportion of boards that inquired about whether the mental illness might affect the applicant's ability to practice medicine increased from 42 percent in 1993 to 75 percent in 1996. Applicants were asked about substance abuse by 83 percent of the boards in 1993 and by 94 percent in 1996. Boards asked about physical conditions less often than mental conditions but were more likely to ask about physical conditions in 1996 (65 percent) than in 1993 (49 percent). Questions about physical illness almost always addressed the effect of the condition on medical practice. On license renewal requests, medical boards were less likely to ask questions about mental conditions, substance abuse, and physical illnesses than on the original applications. Among boards that asked about mental illness on renewal forms, the proportion of boards that asked about the effect of mental conditions on ability to practice medicine increased from 60 percent in 1993 to 90 percent in 1996. CONCLUSIONS: Medical boards commonly ask questions about mental illness on licensure application and renewal forms. In many states, such questions changed between 1993 and 1996 to emphasize impairment resulting from mental illness and to use similar wording for mental disorders and physical conditions.

Changes in public psychiatric hospitalization in Oregon over the past two decades.

OBJECTIVE: In 1988 a governor's commission in Oregon recommended dramatic changes in the state's approach to public psychiatric hospitalization. To evaluate the effect of the recommendations, this study examined characteristics of hospitalization for patients with schizophrenia and bipolar disorder in public psychiatric facilities between 1981 and 1984 and between 1991 and 1994. METHODS: Patients with schizophrenia and bipolar disorder (N=621) were identified as part of a larger study that examined civil commitment in one of Oregon's state hospitals in 1986. Data on the patients' hospitalizations were obtained from a statewide computerized mental health information system. RESULTS: The legal status of hospitalized patients differed between the two time periods, with voluntary hospitalizations overrepresented in 1981-1984 and civil commitments overrepresented in 1991-1994. The locus of hospitalization varied greatly between the two time periods. All hospitalizations in 1981-1984 took place in one of Oregon's three state hospitals. In 1991-1994, subjects were hospitalized in 13 different institutions, including state and community hospitals and specially designed nonhospital inpatient facilities. CONCLUSIONS: Patterns of inpatient hospitalization for public psychiatric patients changed dramatically from 1981-1984 to 1991-1994. The extensive use of community and nonhospital facilities raises questions about monitoring of quality of care in these diverse and decentralized facilities.

Homicide or suicide: the killing of suicidal persons by law enforcement officers.

This paper presents 15 deaths of suicidal persons in Oregon and Florida who, by their behavior, sufficiently provoked law enforcement officers into killing them. Four deaths were certified as suicide, one as undetermined and ten as homicide. All of the deaths are individually described in detail and their case characteristics are presented in a table. The method of study is a descriptive analysis of the case characteristics, including 21 variables which are determined to be relevant to the classification of death. The variables were grouped into six categories: (a) personal information; (b) criminal behavior during the fatal incident; (c) dangerous behavior during the fatal incident; (d) toxicological data; (e) mental illness information; and (f) certification data. From the analysis, reasons for the opinions on manner of death classification are presented. All incidents were perceived as life-threatening to law officers, family members, or hostages. All victims were male except one, and all were Caucasian except two. All victims resisted arrest and verbally threatened homicide during the fatal incident. Two-thirds of the victims took hostages. All victims possessed an apparent handgun or other weapon (knife, iron bar). All victims posed their weapon and threatened others during the incident, 60% of victims actually used the weapon with apparent intent to inflict damage to others. 40% of victims were intoxicated with alcohol but other drug-involvement was uncommon. Seven of 15 had previous suicide attempts, 40% had medically documented psychiatric diagnoses and 60% had reasonable historical evidence of psychiatric diagnoses, most commonly depression or substance abuse. One of the co-authors presents the case for some of the deaths to be certified as suicides, whereas two present the case for all to be certified as homicide. A brief discussion of psychiatric issues is also presented concerning individuals who use others to commit suicide and who may engage in dangerous and/or criminal behavior to do so. A major conclusion is that there is lack of a unified opinion on death certification procedures for individuals who have provoked law enforcement officers to kill them. For such cases, it is recommended that professional organizations of medical examiners/coroners develop guidelines to promote consistency in death certification practices including manner of death classification and selection of death certificate wording so that "police-assisted suicide" may be appropriately reported and studied.

Treatment refusal procedures and service utilization: a comparison of involuntarily hospitalized populations.

This article examines treatment refusal in a large group of hospitalized civilly committed patients. Comparison is made between those subjects whose refusal was reviewed by Oregon's administrative procedures for treatment refusal (override group) and those committed patients who more readily accepted treatment and were not evaluated by this procedure. The objective was to examine the override process and to explore potential differences between these groups in their utilization of hospital and community mental health services before and after the index hospitalization. We reviewed hospital charts on all subjects who went through the administrative override procedure and collected state hospital and community mental health services information from the statewide computerized information system on all subjects in the study. Several key differences were found between the groups. The override sample had significantly more women, and these patients spent significantly more time in the index hospitalization and had had more past hospitalizations. There were no differences between the groups in their utilization of community services before or after the index hospitalization and no difference in hospitalization rates after the index hospitalization. The conclusion is that the Oregon override procedure is functioning consistently, without undue delay in decision making. More investigation is necessary to determine whether override subjects represent a distinct subpopulation within the larger group of chronically mentally ill patients.

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.

Ocular blastomycosis in dogs: 73 cases, 108 eyes (1985-1993).

OBJECTIVE: To evaluate clinical signs of ocular blastomycosis in dogs, to determine response of blastomycosis-infected eyes to treatment with systemically administered amphotericin B and ketoconazole, and to identify prognostic indicators of successful antifungal treatment. DESIGN: Retrospective study. ANIMALS: 73 dogs. PROCEDURE: Medical records were reviewed for all dogs with confirmed blastomycosis and ocular disease seen at our hospital between 1985 and 1993. RESULTS: 6 eyes had anterior segment disease, 24 had posterior segment disease, and 78 had endophthalmitis. 40 eyes were treated with a combination of amphotericin B and ketoconazole, and 16 of the 40 responded favorably. However, 16 of the 24 eyes that were not severely affected responded favorably, but none of the 16 eyes that were severely affected did. CLINICAL IMPLICATIONS: Dogs with blastomycosis had posterior segment disease, without complete retinal separation, had a good prognosis for retaining vision. Results of histologic examination suggested that secondary glaucoma was a manifestation of endophthalmitis and was indicative of a grave prognosis for response to antifungal and antiglaucoma treatment.

Psychiatry: three models in search of a future.

The author proposes three models for the future of psychiatry. The public health psychiatry model is rooted in psychiatry's participation in community mental health care for the past 50 years. It emphasizes ideological similarities between community mental health care and managed care. The clinical neuroscience model melds the specialties of neurology and psychiatry to form a clinical brain science, yielding the nonmedical care of mentally ill persons to nonmedical mental health professionals. In the primary care model, more intensive medical training would allow the psychiatrist to function either as a primary care physician or as a "primary care specialist."

Substance-impaired physicians probationary and voluntary treatment programs compared.

We compared the characteristics and treatment outcomes of substance-impaired physicians monitored by two different programs in Oregon: a probationary program administered by the Oregon Board of Medical Examiners and the confidential, voluntary Diversion Program for Health Professionals. Demographic, substance use, and treatment outcome variables were obtained by a retrospective medical record review from 41 physicians monitored by the Oregon board and 56 physicians monitored by the diversion program during a 3-year study period. Compared with physicians monitored by the Oregon board, physicians in the diversion program were younger, more likely to be in training programs and less likely to be in hospital-based practice settings, more often reported by immediate rather than third-party contacts, more likely to choose in-state inpatient treatment than out-of-state treatment, and less likely to have concurrent mental illness diagnoses (P < .05 for all comparisons). Short-term relapse rates did not differ statistically between the groups (22.0% for the Oregon board group, 14.3% for the diversion program group). The higher number of younger physicians and physicians in training and tendency toward increased reporting by immediate contacts in the diversion program suggested earlier intervention than in the Oregon board group.

Flavins inhibit human cytomegalovirus UL80 protease via disulfide bond formation.

Among the most potent inhibitors of human cytomegalovirus protease identified by random screening of a chemical library was 1,4-dihydro-7,8-dimethyl 6H-pyrimido[1,2-b]-1,2,4,5-tetrazin-6-one (1) (PTH2). The oxidized form (2), PT, which is present in solutions of PTH2, was shown to be the actual inhibitory species which irreversibly inactivates the protease; recycling of PTH2 by dissolved oxygen results in complete inhibition of the protease at substoichiometric amounts of compound. No evidence for a covalent adduct between the protease and the inhibitor was obtained, and protease activity was restored by incubation of the inactivated enzyme with the reducing agent bismercaptoethyl sulfone, suggesting that disulfide bond formation was responsible for the observed inhibition. The five cysteines of the protease are normally in the reduced state; analysis of tryptic peptides from inhibited protease indicated that disulfide bonds Cys84-Cys87 and Cys138-Cys161 were formed. Using site-directed mutagenesis, the disulfide pair induced between Cys138 and Cys161 disulfide is dependent upon interaction of PT with the protease and does not form spontaneously, unlike that of the Cys84-Cys87 pair which can form in the absence of inhibitor. The inhibitor's redox chemistry is analogous to that of flavin, and, in fact, flavin inhibits the protease by the same mechanism, causing formation of a disulfide bond between Cys138 and Cys161. That the cysteines are dispensable, but can regulate protease activity by formation of a unique disulfide pair, suggests a plausible mechanism for control of proteolysis during the viral life cycle.

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.