JIP1 regulates neuronal apoptosis in response to stress

We examined if the relative expression of JNK-interacting protein 1 (JIP1) and phosphorylated c-Jun N-terminal kinase (JNK) regulates cell signaling and contributes to selective neuronal vulnerability in response to environmental stress. In clonal neuroblastoma cultures, stresses such as hypoxia, ischemia, Abeta peptides, and UV irradiation rapidly reduced JIP1 expression. JIP1 mRNA expression was also down-regulated by UV stress and was accompanied by increased JNK and c-Jun activation and cell death. JIP1 protein reduction was partially reversed both by inhibitors predominantly of caspase 3 and of the JNK pathway and resulted in significantly increased cell survival. Conversely, overexpression of JIP1 decreased both nuclear translocation of activated-JNK, and c-Jun phosphorylation induced by either UV irradiation, or the JNK upstream activators, MKK7 or MEKK1. Cell death was reduced about 50% compared to GFP-transfected controls. JIP1 overexpression did not facilitate either JNK expression or activation. In the normal, non-stressed human hippocampus and rat hippocampal organotypic cultures, JIP1 and JNK3 were inversely expressed with more JIP1 in CA2 and CA3 and less in CA1 neurons. In the human hippocampus, transient hypoxia/ischemia selectively spares neurons in CA2 and CA3 and induces death of neurons in the hippocampal CA1 subregion. In the cultures, ischemia reduced JIP1 expression and activated JNK, c-Jun, and caspase 3. Inhibitors of the JNK pathway, JNK activation directly and of caspase 3 activation each partially reversed these effects. Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor.     

Teneurin proteins possess a carboxy terminal sequence with neuromodulatory activity

We have previously shown that a bioactive neuropeptide-like sequence is present at the carboxy-terminus of the teneurin transmembrane proteins. We have subsequently called this peptide 'teneurin C-terminal associated peptide' (TCAP). The sequence encodes a peptide 40 or 41 amino acids long flanked by a cleavage motif on the amino terminus and an amidation motif on the carboxy terminus, characteristic of bioactive peptides. This sequence is highly conserved in all vertebrates. A TCAP-like sequence is encoded by each of the four teneurin genes. We have therefore examined the neurological role TCAP-1 may play in mice and rats. In situ hybridization studies showed that the teneurin-1 mRNA containing the TCAP-1 sequence is expressed in regions of the forebrain and limbic system regulating stress and anxiety. A synthetic version of amidated mouse/rat TCAP-1 was prepared by solid-phase synthesis and used to investigate the in vitro and in vivo activity. TCAP-1 induces a dose-dependent change in cAMP accumulation and MTT activity in immortalized mouse neurons. Administration of synthetic TCAP-1 into the basolateral amygdala significantly increases the acoustic startle response in low-anxiety rats and decreases the response in high-anxiety animals in a dose-dependent manner. When 30 pmol TCAP-1 is administered into the lateral ventricles each day for 5 days, the sensitization of the rats to the acoustic startle response is abolished. These data indicate that TCAP may possess functions that are independent of the teneurin proprotein and together, the teneurins and TCAP, may represent a novel system to regulate neuronal function and emotionality.     

Motivational interviewing in community-based research: Experiences from the field

Motivational Interviewing (MI) has been established as an effective psychotherapeutic treatment for problem drinking in clinical settings. Consequently, there is a growing interest in applying MI to facilitate change across other health behaviors, such as tobacco use, eating habits, and physical activity in a variety of community-based research settings. These extended applications pose new challenges regarding implementation and evaluation. For instance, investigators must consider how best to train intervention counselors; implement strategies for preserving the MI spirit, despite limited client contact time; incorporate adjunctive strategies that support brief MI sessions; and develop a plan for monitoring and evaluating MI treatment fidelity. This article highlights specific examples of how several behavior change research projects applied MI across a variety of settings and populations, provides lessons learned from our experience as a collaborative workgroup, and offers strategies for consideration in future community-based research. Funding for this multisite project was provided by RO1 HL62165, 1AR01 45901, 5M01 RR00334, 1 R01 HD37368-01, 1 R01 DE13093-01, 1 R01 MH59594-01 We express our appreciation of the contributions made by the MI workgroup of the BCC, with specific assistance from Judy Salkeld. Special thanks go to Karen Emmons, Diane Elliot, Esther Moe, and Patricia Jordan who offered substantive comments and guidance on earlier drafts of this article.     

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.     

Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders

OBJECTIVE: This study ascertained the incidence of complications during pregnancy, labor, and delivery and the neonatal characteristics of infants born to women with schizophrenia, bipolar disorder, or major depression in a population-based cohort. METHOD: Based on records linkage across a psychiatric case register and prospectively recorded obstetric data, the study comprised women with schizophrenia or major affective disorders who had given birth to 3,174 children during 1980-1992 in Western Australia. A comparison sample of 3,129 births to women without a psychiatric diagnosis was randomly selected from women giving birth during 1980-1992. Complications were scored with the McNeil-Sj?str?m Scale. Odds ratios were calculated for specific reproductive events. RESULTS: Both schizophrenic and affective disorder patients had increased risks of pregnancy, birth, and neonatal complications, including placental abnormalities, antepartum hemorrhages, and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth population decile, and to have children with cardiovascular congenital anomalies. Neonatal complications were significantly more likely to occur in winter; low birth weight peaked in spring. Complications other than low birth weight and congenital anomalies were higher in pregnancies after psychiatric illness than in pregnancies preceding the diagnosis. CONCLUSIONS: While genetic liability and gene-environment interactions may account for some outcomes, maternal risk factors and biological and behavioral concomitants of severe mental illness appear to be major determinants of increases in reproductive pathology in this cohort. Risk reduction in these vulnerable groups may be achievable through antenatal and postnatal interventions.     

Differences between early-phase primary psychotic disorders with concurrent substance use and substance-induced psychoses

CONTEXT: The distinction between a substance-induced psychosis and a primary psychotic disorder that co-occurs with the use of alcohol or other drugs is critical for understanding illness course and planning appropriate treatment, yet there has been little study and evaluation of the differences between these 2 diagnostic groups. OBJECTIVE: To identify key demographic, family, and clinical differences in substance-induced psychosis and primary psychotic disorders diagnosed according to DSM-IV criteria using a research diagnostic instrument for psychiatric and substance use comorbidity. DESIGN: Data on demographic, family, and clinical factors were gathered at baseline as part of a 3-year longitudinal study of early-phase psychosis and substance use comorbidity in New York, NY. SETTING: Psychiatric emergency department admissions. PARTICIPANTS: The study is based on a referred sample of 400 subjects interviewed at baseline. Participants had at least 1 psychotic symptom assessed during administration of the research protocol, had used alcohol and/or other drugs within the past 30 days, and had no psychiatric inpatient history before the past 6 months. Subject race included 43.5% black, 42.0% Hispanic, and 14.5% white or other. MAIN OUTCOME MEASURE: Psychotic disorders defined by the DSM-IV. RESULTS: Overall, 169 (44%) were diagnosed as having substance-induced psychosis and 217 (56%), as having primary psychosis. Significant differences were observed in all 3 domains. Multivariate analysis using logistic regression identified the following 3 key predictors as being greater in the substance-induced group: parental substance abuse (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.00-2.85), a diagnosis of dependence on any drug (OR, 9.41; 95% CI, 5.26-16.85), and visual hallucinations (OR, 2.13; 95% CI, 1.10-4.13). The key predictor of total positive and negative symptom score was greater in the primary psychosis group (OR, 0.96; 95% CI, 0.94-0.97). CONCLUSIONS: Differences in demographic, family, and clinical domains confirm substance-induced and primary psychotic disorders as distinct entities. Key predictors could help emergency clinicians to correctly classify early-phase psychotic disorders that co-occur with substance use.     

Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers

BACKGROUND: Sham surgery is used in neurosurgical clinical trials in Parkinson disease (PD) but remains controversial. The controversy may be compounded when gene-transfer technologies are tested in sham surgical trials. OBJECTIVE: To determine the perspective of PD clinical researchers on the science and ethics of sham-surgery controls when used to test novel interventions such as gene transfer for PD. DESIGN: Internet survey eliciting both quantitative and qualitative responses. PARTICIPANTS: Investigator members of the Parkinson Study Group. RESULTS: Overall response rate was 103 (61.3%) of 168 researchers. A large majority (97%) of PD clinical researchers believe sham-surgery controls are better than unblinded controls for testing the efficacy of neurosurgical interventions such as gene transfer for PD. Half of the researchers believe an unblinded control efficacy trial would be unethical because it may lead to a falsely positive result. A minority (less than 22%) believe that an invasive sham condition that involves penetration of brain tissue is justified. CONCLUSION: It appears unlikely that the PD clinical research community will perceive future neurosurgical interventions for PD, such as gene-transfer therapies, as truly efficacious unless a sham-control condition is used to test it.     

Relationship between Maternal Clinical Factors and Mother-Reported Child Problems

Maternal depression has been associated with mothers’ elevated reports of child problems. However, it is unclear the extent to which elevations in mother ratings reflect having a depression diagnosis, having any mental illness diagnosis, or having a diagnosis vs. symptom levels. As part of a NIMH-funded, longitudinal study of mothers with serious mental illness (N=379), we examined the relationship between mother-reported adolescent behavior problems (N=78) and maternal depression vs. other diagnoses, as well as the effects of depression diagnosis vs. symptom levels. Mothers were recruited from the public mental health system in an urban area, and are primarily African-American and low income. We found that maternal psychiatric symptoms made a unique and significant contribution to explaining the variance in mother-reported child problems, independent of controls (e.g., teacher reports and child demographics), while maternal diagnosis did not. Implications of findings are discussed. This study was funded by NIMH grants awarded to Carol T. Mowbray (#R01MH54321) and Daphna Oyserman (#R01MH57495).     

Glial restricted precursors protect against chronic glutamate neurotoxicity of motor neurons in vitro

We have examined the expression of glutamate transporters in primary and immortalized glial precursors (GRIPs). We subsequently transduced these cells with the GLT1 glutamate transporter and examined the ability of these cells to protect motor neurons in an organotypic spinal cord culture. We show that glial restricted precursors and GRIP-derived astrocytes predominantly express glutamate transporters GLAST and GLT1. Oligodendrocyte differentiation of GRIPs results in downregulation of all glutamate transporter subtypes. Having identified these precursor cells as potential vectors for delivering glutamate transporters to regions of interest, we engineered a line of GRIPS that overexpress the glutamate transporter GLT1. These cells (G3 cells) have a nearly fourfold increase in glutamate transporter expression and at least a twofold increase in the V(max) for glutamate transport. To assess whether G3 seeding can protect motor neurons from chronic glutamate neurotoxicity, G3s were seeded onto rat organotypic spinal cord cultures. These cultures have previously been used extensively to understand pathways involved in chronic glutamate neurotoxicity of motor neurons. After G3 seeding, cells integrated into the culture slice and resulted in levels of glutamate transport sufficient to enhance total glutamate uptake. To test whether neuroprotection was related to glutamate transporter overexpression, we isolated GRIPS from the GLT1 null mouse to serve as controls. The seeding of G3s resulted in a reduction of motor neuron cell death. Hence, we believe that these cells may potentially play a role in cell-based neuroprotection from glutamate excitotoxicity.     

Associations between the impact of terrorism and health perceptions of patients

OBJECTIVE: Previous studies have demonstrated the effects of the September 11th 2001 terrorist attacks on anxiety and anxiety-related conditions in Americans. However, data regarding associations between the attacks and patients' health perceptions are lacking. The objective of this study was to explore associations between the personal impact of the September 11th attacks and patients' perceptions of health and illness. METHOD: We performed a cross-sectional survey of 303 adult African-American, Caucasian, and Hispanic patients at primary care clinics in Houston, Texas. Data were collected between October 15, 2001 and March 1, 2002. We developed items to measure the impact of the September 11th attacks and patients' quality of life. Previously validated scales were used to measure health status, health locus of control, preferences regarding the patient-physician relationship, and patients' explanatory models of illness. RESULTS: Twenty-two percent of patients reported no impact from the attacks, 41% reported mildly negative impact, 22% reported moderately negative impact, and 15% reported extremely negative impact in their lives. In multivariate analysis, demographic characteristics were not associated with impact from the attacks. However, patients who perceived a more external locus of control with respect to health and patients who reported greater meaning of illness in their lives also reported more negative impact from the September 11th attacks. CONCLUSIONS: The September 11th terrorist attacks had at least a somewhat negative impact for a majority of patients far from the site of the nearest attack, and regardless of their demographic backgrounds. The amount of negative impact that patients perceived as a result of the terrorist attacks correlates with certain illness perceptions, including an external health locus of control and a perception of greater meaning of illness in one's life. Such correlations may indicate an effect of terrorism on patients' illness behaviors. Further research is needed to better understand effects of the threat of terrorism on the general health and illness behaviors of patients.