Soluble factors guide gonadotropin-releasing hormone axonal targeting to the median eminence.

Axons of GnRH neurons terminate at the median eminence in the medial basal hypothalamus (MBH) of the brain early in development. Similarly, GnRH neurons in grafts of preoptic area (POA) tissue within the third ventricle of hypogonadal mice preferentially innervate the median eminence. Organotypic cocultures of POA explants with other neural tissues suggest that a soluble substance(s) derived from the MBH may be directing this targeting. To begin to identify diffusable chemoattractants, we used preincubated heparin-coated acrylic beads to present specific solutes to POA explants on collagen- and laminin-coated membranes in insert chambers. GnRH axons grew on the membrane in greater number and with longer axons toward conditioned medium from MBH cultures than on the side away from the beads (P < 0.01). In contrast, GnRH axons showed no preferential outgrowth when incubated with beads soaked in control, defined medium. The attraction of MBH-conditioned medium was not generalizable to all neuroendocrine neurons, as it was not seen for galanin immunoreactive outgrowth from POA explants. There also were more GnRH axons toward conditioned medium from mouse brain microvascular endothelial cells, but no difference in axon length. Basic fibroblast growth factor (bFGF), a component of both endothelial cells and ventricular tanycytes, significantly attracted more and longer GnRH axons. Thus, bFGF may be one of the soluble factors directing GnRH outgrowth to the median eminence. However, as with so many other redundancies in the reproductive system, it is unlikely that it is the only targeting factor, as bFGF knockout mice are reported to be reproductively competent.

Adoption studies of schizophrenia.

The observation that schizophrenia is more commonly observed among the relatives of individuals with schizophrenia than in the general population does not indicate the mechanism that produces such familiality occurs. Adoption designs permit evaluation of the role of genetic factors in schizophrenia independently of the influence of family environments. Results from studies of adoptees with schizophrenia and their biological and adoptive relatives indicate that genetic factors play a highly significant role in the risk for schizophrenia. This genetically mediated risk to relatives includes an increased prevalence of both schizophrenia and a nonpsychotic syndrome analogous to schizophrenia, but does not represent a general liability to other forms of psychopathology. Although adoption studies have convincingly demonstrated an important role for genetic factors in schizophrenia, the necessity and specificity of such factors, their precise identity, and their interaction with environmental influences remain unknown.

Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease.

Gaucher disease, an inherited glycolipid storage disorder, is caused by a deficiency of the catabolic enzyme glucocerebrosidase (EC 3.2.1.45). The gene for human glucocerebrosidase is located on chromosome 1q21 and has a highly homologous pseudogene situated 16 kb downstream. We report two novel polymorphic sequences in the glucocerebrosidase gene region: the first consists of a variable number of dinucleotide (CT) repeats located 3.2 kb upstream from the glucocerebrosidase gene, and the second is a tetranucleotide (AAAT) repeat found between the glucocerebrosidase gene and its pseudogene, 9.8 kb downstream from the functional gene. These polymorphic sequences, along with a previously reported PvuII polymorphism in intron 6 of the glucocerebrosidase gene, were analyzed in patients with Gaucher disease (n=106) and in two normal control populations, one of Ashkenazi Jewish ancestry (n=72) and the second comprising non-Jewish individuals (n=46). In these samples, strong linkage disequilibrium was found between mutations N370S, c.84-85insG, and R463C and specific haplotypes; no significant linkage disequilibrium was found when examining haplotypes of patients with the L444P mutation. Studies of these polymorphic sites in several instances also led to the recognition of genotyping errors and the identification of unusual recombinant alleles. These new polymorphic sites provide additional tools for mutational screening and founder effect studies of Gaucher disease.

A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

Is there psychopathology in the coparents of schizophrenic adoptees' half-siblings?

An excess of schizophrenia has been observed in the biological relatives of adoptees with schizophrenia. The present analysis examined the possibility that illness observed among 90 half-siblings may have been influenced by assortative mating resulting in excess illness in the biological parents of the half-siblings not biologically related to the adoptees (the coparents). We found no difference in the prevalence of mental illness between 44 index and 26 control coparents.

Neuropsychological assessment of attention and its pathology in the Israeli cohort.

We assessed attention in 63 of the 98 traceable living subjects of the original 100 in the National Institute of Mental Health (NIMH) joint study of schizophrenia by the United states and Israel, known as the Israeli High-Risk Study cohort; their mean age was 32 years. These data were supplemented, for comparative purposes, with those obtained on 31 normal control and 17 schizophrenia subjects studied at NIMH. The results suggest that attention skills of the adult children of a parent with schizophrenia fall between those of schizophrenia patients and controls, and that measures of sustained attention and the ability to focus and execute provide the best discrimination among groups. Post hoc analyses revealed that poor scores on simple tests of attention obtained in childhood were associated with the development of disorders in adulthood. Low scores on a digit cancellation test at age 11, but not at age 17, predicted which of the children at genetic risk would develop schizophrenia spectrum disorders diagnosed at ages 26 and 32.

Reanalysis of SCOR and anxiety measures in the Israeli High-Risk Study.

In an earlier study, skin conductance orienting response (SCOR) and anxiety measures obtained when the subjects of the Israeli High-Risk Study were 11 years old were analyzed, using adult diagnostic information, when the subjects were 26 years old. The present study considers similar data obtained from most of this sample when the subjects were 16 years old. As in the earlier analysis, those subjects who would receive a schizophrenia spectrum diagnosis at 26 had higher anxiety ratings at age 16. Nondiagnosed index subjects also had significantly higher anxiety ratings than the nondiagnosed controls. The subjects who would receive affective spectrum diagnoses at age 26 had the most hyporesponsive SCORs, as predicted, while the subjects who would later be diagnosed in the schizophrenia spectrum had an unexpected hyperresponsive SCOR to the dishabituation tone in a habituation series. Further consideration of the long-term stability of SCORs seems necessary; they may be related to the developing psychopathological processes.

Twenty-five-year followup of the Israeli High-Risk Study: current and lifetime psychopathology.

Current and lifetime psychopathology was assessed in 50 Israeli children of parents with schizophrenia who were either of kibbutz families and raised collectively with the help of child care workers, or of urban families and raised by their parents. Index subjects were compared with 50 matched control children of healthy parents by means of the Schedule for Affective Disorders and Schizophrenia-Israel. Subjects were evaluated in adulthood at a mean age of 31 years; schizophrenia was found exclusively among children of ill parents, and no effect of town or kibbutz rearing on risk for schizophrenia was observed. Major affective illness was more common among kibbutz index subjects. Affective symptomatology observed in some index parents was evenly distributed among town and kibbutz parents and was not related to the diagnosis of affective disorders in at-risk children. Current adult functioning was similar between town-and kibbutz-raised subjects (and in general reflected good adjustment); an excess of personality disorders was found among index subjects. The present findings support the concept that both familial and environmental factors operate in the expression of psychopathology.

Locus of control and mental health in adolescence and adulthood.

Eighty-nine subjects of the original sample of the National Institute of Mental Health joint study by the United States and Israel, known as the Israeli High-Risk Study, were given a clinical interview and a questionnaire measuring locus of control (LOC) during the second phase of the study, when the subjects were adolescents. During phases 3 and 4, approximately 8 and 15 years later, the subjects were psychiatrically assessed and 56 of them repeated the LOC questionnaire. The two measures of LOC were correlated, as were general assessments of mental health (MH). Adolescent LOC was related to lifetime MH, although LOC and MH were not related to each other concurrently in either adolescence or adulthood. The best predictive model for lifetime MH outcomes was a combination of adolescent MH and LOC variables; background variables, including parental schizophrenia, were superfluous. The data suggest that whereas adolescent MH is the best predictor of general MH, adolescent LOC is the better predictor of schizophrenia and major affective disorders.

Overview and summary: twenty-five-year followup of high-risk children.

We report a 25-year followup of a group of 50 children at genetic risk for schizophrenia (by virtue of having a parent with the disorder) and 50 matched controls. The children who eventually developed schizophrenia spectrum disorders, including schizophrenia, were identifiable by cognitive-psychophysiological, neurointegrative, and social/personality traits in the preteenage period. The children at risk were also more likely to develop other Axis I disorders, chiefly affective. Moreover, the risk of Axis I disorders was significantly greater among children raised in the group atmosphere of a kibbutz than among those raised in their own nuclear families in cities and towns in Israel. The study is a unique contribution to knowledge of factors underlying the development of psychopathology.

Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark.

BACKGROUND: Our previous investigation of the prevalence of mental illness among the biological and adoptive relatives of schizophrenic adoptees in Copenhagen, Denmark, showed a significant concentration of chronic schizophrenia (5.6%) and what Bleuler called "latent schizophrenia" (14.8%) in the biological relatives of chronic schizophrenic adoptees, indicating the operation of heritable factors in the liability for schizophrenic illness. METHODS: We now report the results of a replication of that study in the rest of Denmark (the "Provincial Sample"). RESULTS: In this sample, the corresponding prevalences were 4.7% and 8.2%. In the combined "National Sample" of adoptees with chronic schizophrenia, that disorder was found exclusively in their biological relatives and its prevalence overall was 10 times greater than that in the biological relatives of controls. CONCLUSIONS: This study and its confirmation of previous results in the Copenhagen Study speak for a syndrome that can be reliably recognized in which genetic factors play a significant etiologic role. These findings provide important and necessary support for the assumption often made in family studies: observed familial clustering in schizophrenia is an expression of shared genetic factors.

Genetic transmission and improved diagnosis of schizophrenia from pedigrees of adoptees.

In previous investigations of the prevalence of schizophrenic illness among the biological relatives of schizophrenic adoptees in Copenhagen and the remainder of Denmark, the operation of heritable spectrum illness was clearly implicated. The findings supporting that conclusion are briefly summarized. Classical chronic schizophrenia was found almost exclusively in the biological relatives of chronic schizophrenic probands and its prevalence was ten times greater than that in the biological relatives of controls. These were global diagnoses, made without knowledge of the relationships and family histories of the subjects, and based upon the descriptions of dementia praecox or schizophrenia by Kraepelin and Bleuler. They showed considerably greater sensitivity and at least equal specificity in comparison with diagnoses made on the same material in accordance with operational criteria as exemplified by DSM-III. The prevalence of a disorder in the biological relatives of adoptees with that disorder in comparison with biological relatives of control adoptees offers a useful test for the expression of genetic factors in the disorder, but also a much needed evaluation of the validity of diagnoses based on clinical observation.

Risk for affective disorder and alcohol and other drug abuse in the relatives of affectively ill adoptees.

We investigated the risk for substance abuse in the biological relatives of adoptees with affective illness, controlling for potential confounds, and additionally assessed risk by probands' and relatives' gender. Our sample consisted of 67 index adoptees with affective illness, matched control adoptees, and their biological and adoptive relatives. Both affective illness and substance abuse were more common in the biological relatives of affectively ill adoptees than in controls' relatives. Affective illness was more common than substance abuse among female index biological relatives, with the opposite pattern observed among male relatives.

Results of extended peptide T administration in AIDS and ARC patients.

We report here the extended Phase I testing of d-ala-Peptide-T-amide (Peptide T) in open trial. The drug was given intravenously in doses ranging from 0.1 to 3.2 mg/kg/day to 14 acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients for 12 weeks. Following a 4-week off-drug period, the first 6 patients finishing the intravenous testing were continued on intranasal drug, 25 mg/day, for 8 weeks. Control subjects were tested on the same neuropsychologic tests, but did not receive drug. Minimal evidence of toxicity was found. Performance increments in cognitive and neuromotor function were observed in patients with moderate neuropsychologic impairment compared with controls. Changes in constitutional symptoms included weight gain averaging 2 kg and reported improved sense of well-being. The latter findings were independent of variation in cognitive and neuromotor function. Measures of immunologic function and antiviral activity did not change significantly during the study. These data provide a scientific rationale for Phase II testing of Peptide T in human immunodeficiency virus-1 (HIV-1) patients focusing on neuropsychiatric outcome.

Central nervous system effects of human immunodeficiency virus type 1.

Following its early entry into the central nervous system (CNS), HIV-1 alters cerebral cell architecture and may subsequently affect higher cognitive functions, leading eventually in some patients to HIV-1 encephalopathy. The CNS may also be the target of opportunistic infections and malignancy secondary to HIV-1 immunosuppression. Studies at the cellular, anatomical, and behavioral levels present evidence for significant involvement of the CNS in HIV-1 disease, while initial reports of treatment strategies hold promise for providing some amelioration in affected individuals.

The shared experience of catastrophe: an expanded classification of the disaster community.

Based on observational and interview data following a major air crash, a classification of individuals affected by catastrophe is proposed in which degree of involvement is used to characterize the dynamic nature of the disaster community. The model encompasses individual and group activities, roles and relationships, and the shared meaning of the traumatic event. Implications for the identification of neglected participants and for preventive community intervention are offered.

Neuropsychological effects of early HIV-1 infection: assessment and methodology.

Studies of neuropsychological performance early in the course of human immunodeficiency virus-type 1, infection are reviewed. The studies differed on reporting the presence and severity of neuropsychological changes, and comparisons among studies are hampered by variations in the study populations, sample sizes, assessment methods, approaches to data analysis, and definitions of thresholds for abnormality. Recommendations that would facilitate comparisons among future studies include using markers for disease state, applying longitudinal designs, using common instruments for assessing neuropsychological status, selecting appropriate controls, controlling for co-factors, reporting raw scores as well as presumed indices of impairment, and relating impairment on neuropsychological tests to affected individuals' daily activities, if possible.

The relationship of occipital skull asymmetry to brain parenchymal measures in schizophrenia.

It has long been hypothesized, but never proven that an organic brain injury early in life predisposes to schizophrenia. Since brain and cranial development are closely linked, if such an event occurred early enough in the premorbid course of schizophrenia, it could conceivably effect skull architecture. To approach this question, the occipital bone depth and the occipitomedian angle were measured in 50 patients with chronic schizophrenia and in 35 medical controls. Strong correlations emerged between the skull asymmetry indices and the occipital and temporal lobe parenchymal asymmetry indices. There were no statistically significant differences in cranial asymmetry measures between the patients with schizophrenia and the medical controls. However, when the comparison was limited to right handed individuals with homolateral sighting dominance, a weak, but statistically significant trend was observed for more symmetrical slanting along the sagittal suture in the schizophrenic patients. In addition, cranial asymmetry was weakly predictive of increased prefrontal markings in the schizophrenic patients. The congruence of skull findings with parenchymal variables suggests that certain aspects of skull and parenchymal architecture are co-determined.