ABSTRACT
S-(3,4-Dichlorobenzyl)isothiourea (A22) disrupts the actin cytoskeleton of bacteria, causing defects of morphology and chromosome segregation. Previous studies have suggested that the actin homologue MreB itself is the target of A22, but there has been no direct observation of A22 binding to MreB and no mechanistic explanation of its mode of action. We show that A22 binds MreB with at least micromolar affinity in its nucleotide-binding pocket in a manner that is sterically incompatible with simultaneous ATP binding. A22 negatively affects both the time course and extent of MreB polymerization in vitro in the presence of ATP. A22 prevents assembly of MreB into long, rigid polymers, as determined by both fluorescence microscopy and sedimentation assays. A22 increases the critical concentration of ATP-bound MreB assembly from 500 nM to approximately 2000 nM. We therefore conclude that A22 is a competitive inhibitor of ATP binding to MreB. A22-bound MreB is capable of polymerization, but with assembly properties that more closely resemble those of the ADP-bound state. Because the cellular concentration of MreB is in the low micromolar range, this mechanism explains the ability of A22 to largely disassemble the actin cytoskeleton in bacterial cells. It also represents a novel mode of action for a cytoskeletal drug and the first biochemical characterization of the interaction between a small molecule inhibitor of the bacterial cytoskeleton and its target.
Subject(s)
Actins/antagonists & inhibitors , Actins/metabolism , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Cytoskeletal Proteins/antagonists & inhibitors , Cytoskeletal Proteins/metabolism , Cytoskeleton/drug effects , Thermotoga maritima/drug effects , Thiourea/analogs & derivatives , Actins/genetics , Bacterial Proteins/genetics , Binding Sites/drug effects , Cytoskeletal Proteins/genetics , Cytoskeleton/genetics , Cytoskeleton/metabolism , Escherichia coli/genetics , Polymers/metabolism , Protein Binding/drug effects , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Thermotoga maritima/metabolism , Thiourea/metabolism , Thiourea/toxicityABSTRACT
The ability of an electrical stimulus to induce a grand mal convulsion during electroconvulsive therapy (ECT) was investigated using four clinical treatment protocols during which the stimulus waveform, the electrical energy and/or the electrode placement were varied. The statistically significant results support the view that a pulsatile square wave stimulus is effective in inducing convulsions, provided that the d'Elia and not the Muller unilateral electrode placement is used. Higher stimulus energy may be required for older patients. The results illustrate successive attempts to remedy a previously reported problem with the effectiveness of the pulsatile waveform as a convulsive stimulus. The benefit of maintaining a database of treatment variables in order to monitor the effect of changes in the protocol under conditions of routine clinical practice is also demonstrated.
Subject(s)
Electroconvulsive Therapy/methods , Electroencephalography , Mood Disorders/physiopathology , Mood Disorders/therapy , Schizophrenia/physiopathology , Schizophrenia/therapy , Schizophrenic Psychology , Adult , Cerebral Cortex/physiopathology , Dominance, Cerebral/physiology , Electrodes , Electroencephalography/instrumentation , Evoked Potentials/physiology , Female , Humans , Male , Middle AgedABSTRACT
The relationship between electric stimulus energy and clinical response was examined in depressed patients receiving electroconvulsive therapy (ECT) under routine clinical conditions with a protocol which dichotomized the stimulus energy by patient age. There was no significant difference in the number of treatments and cumulative seizure duration between groups. The results support the observation that the stimulus energy may contribute to the therapeutic effect of ECT. Reduction of that energy in order to minimize side-effects may compromise the therapeutic effectiveness. The implications for dosage strategies in routine clinical practice are discussed.
Subject(s)
Bipolar Disorder/psychology , Bipolar Disorder/therapy , Depressive Disorder/psychology , Depressive Disorder/therapy , Electroconvulsive Therapy/methods , Electroencephalography , Adult , Bipolar Disorder/physiopathology , Cerebral Cortex/physiopathology , Depressive Disorder/physiopathology , Evoked Potentials/physiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Personality Assessment/statistics & numerical data , Psychiatric Status Rating Scales/statistics & numerical data , PsychometricsABSTRACT
Seventy-seven state psychiatric hospital patients were interviewed six months following discharge in order to examine the relationship between a set of client variables and community length of stay (CLOS), but with a measure of client-perceived general well-being included as a possible mediator of relationships. A study of the relationship between CLOS and general well-being, using hierarchical regression analysis and path analysis, was expected to provide a more complete picture of client community functioning. Results demonstrated a strong relationship between CLOS and general well-being and, also, a number of measures predictive of community success related to CLOS only through general well-being. These findings indicated the importance of considering how clients perceive their general well-being in optimizing chances for community success.
Subject(s)
Community Mental Health Services , Mental Disorders/rehabilitation , Patient Discharge , Social Adjustment , Social Environment , Adolescent , Adult , Female , Hospitals, Psychiatric , Humans , Interpersonal Relations , Male , Mental Disorders/psychology , Middle Aged , Prognosis , Social SupportABSTRACT
This article reports findings obtained in a study that sought to identify factors that influence the willingness of persons associated with and involved in 24-hour residential care to report possible abuse and neglect events. A total of 598 respondents from 33 counties in 5 states were presented with a potentially reportable abuse or neglect situation and were asked to indicate their willingness to report that situation. Characteristics of the event, the resident, staff, and measures of the attitudes of respondents were included in an hierarchical regression model to determine their respective impacts on willingness to report. A model that explained about 45% of the variance in willingness to report was obtained.
Subject(s)
Child Abuse/legislation & jurisprudence , Child Welfare/legislation & jurisprudence , Institutionalization/legislation & jurisprudence , Adolescent , Attitude of Health Personnel , Child , Child Abuse/prevention & control , Child, Preschool , Female , Humans , Male , Risk FactorsABSTRACT
The social problem of homelessness is of increasing concern to mental health professionals. In a large-scale study of homelessness in Ohio, data were collected in face-to-face interviews with 979 homeless people in 19 counties. The median length of homelessness was 60 days. Almost half the respondents cited economic factors, such as unemployment or problems paying rent, as the major reason for their homelessness. Thirty percent had been hospitalized at least once for mental health reasons, and 31 percent showed symptoms serious enough to require mental health services. Findings are also presented in relation to a typology of the homeless--street people, shelter people, and resource people--and urban and rural respondents are compared. These and other findings support the principal conclusions that homelessness is clearly a multidimensional problem and that service strategies must reflect the multiple needs and varying characteristics of homeless people.
Subject(s)
Ill-Housed Persons , Employment , Hospitalization , Income , Mental Disorders/epidemiology , Mental Health , Minority Groups , Ohio , Rural Population , Socialization , Substance-Related Disorders/epidemiology , Transients and Migrants , United States , Urban PopulationABSTRACT
Previous research has reported prevalence rates of mental health problems among homeless individuals that range from 20% to 90%. Attempting to validly verify prevalence rates is important because of the implications concerning both deinstitutionalization and developing an appropriate mental health policy over the next decade. In the present research, which used as its sample the largest homeless sample assessed to date, prevalence was found to fall at the lower range of previously cited data. Despite the fact that the prevalence of mental health problems among the homeless population was found to be relatively low, it was found that homeless people with mental health problems are, at best, only marginally served by the mental health system. Implications for community mental health policymakers and program designers are discussed.
