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Biomedical subjects

D Levinson

Publications and source records attributed to D Levinson.

At least 19 recordsLinked to original sources

A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry.

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty-nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non-parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter-p36, 5q35, and 18p11) exhibited evidence of linkage with non-parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter-p36 region. Under the narrow model, the same three loci showed (non-significant) evidence of linkage. These linkage findings (1pter-p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries.

Central America↗

Automated neuropsychological assessment metrics (ANAM) measures of cognitive effects of Alzheimer's disease.

Eight individuals with Alzheimer's disease, and eight age-matched controls, were administered the MMSE, the Yesavage GDS, and a customized subset of the Automated Neuropsychological Assessment Metrics (ANAM) Battery. Accuracy (percent correct) and efficiency (number of correct responses per minute) of performance on six ANAM tasks were assessed. The patients' GDS scores indicated no depression. Although their MMSE scores (mean approximately 25) were significantly lower than those of the controls, they nonetheless indicated that the patients were still functioning at a fairly high level. Analysis of ANAM accuracy scores indicated that the patients were significantly impaired on three tasks measuring working memory. A discriminant function analysis revealed 93.8% correct classification. Analysis of ANAM efficiency scores revealed that except for simple reaction time, the patients were significantly impaired on all tasks. A discriminant function analysis correctly classified 100% of the participants. Given the small size of the groups in the present study, this finding especially underscores the sensitivity of ANAM to the cognitive effects of Alzheimer's disease, as indicated by the large effect sizes. The findings further indicate that ANAM might be capable of detecting more subtle effects of the disease at an earlier stage in its progress.

Aged↗

Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

Allergens↗

T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function.

T helper (Th) cells can be categorized according to their cytokine expression. The differential induction of Th cells expressing Th1 and/or Th2 cytokines is key to the regulation of both protective and pathological immune responses. Cytokines are expressed transiently and there is a lack of stably expressed surface molecules, significant for functionally different types of Th cells. Such molecules are of utmost importance for the analysis and selective functional modulation of Th subsets and will provide new therapeutic strategies for the treatment of allergic or autoimmune diseases. To this end, we have identified potential target genes preferentially expressed in Th2 cells, expressing interleukin (IL)-4, IL-5, and/or IL-10, but not interferon-gamma. One such gene, T1/ST2, is expressed stably on both Th2 clones and Th2-polarized cells activated in vivo or in vitro. T1/ST2 expression is independent of induction by IL-4, IL-5, or IL-10. T1/ST2 plays a critical role in Th2 effector function. Administration of either a mAb against T1/ST2 or recombinant T1/ST2 fusion protein attenuates eosinophilic inflammation of the airways and suppresses IL-4 and IL-5 production in vivo following adoptive transfer of Th2 cells.

Animals↗

Ambulatory mental health treatment under universal coverage: policy insights from Israel.

Untested assumptions concerning ambulatory treatment have shaped mental health policies for decades. Three opinions prevail: (1) all use is alike; (2) any use leads to high use; and (3) all high use is discretionary and therefore excessive. These assumptions were tested, using data from a nationwide survey of ambulatory utilizers in Israel, a country that has universal coverage. The findings, based on detailed clinical and treatment records, challenge all three assumptions. Moreover, they document a diversity of clinical needs while also verifying substantial variations in the type, frequency, and duration of treatment provided to meet those needs. In brief, Israeli data do not confirm continuing concerns by policy makers about uncontrollable use of services with expanded mental health coverage. Special policy limitations on mental health treatment should be reconsidered in light of empirical evidence from a system without the restrictions that exist in the United States.

Ambulatory Care↗

The new genetics and women.

The U.S. Human Genome Project (HGP) is a federally funded effort to produce a detailed genetic and physical map of all human chromosomes. Because of their central role in reproduction and caregiving, women are likely to be affected differently, and more significantly, by the information the HGP generates. It is important to identify inequities that may emerge from gender differences and to consider ways in which they may be avoided, reduced, or overcome. Although this type of analysis is one of the goals of the Ethical, Legal, and Social Issues Program of the National Center for Human Genome Research, few studies have focused explicitly on the impact of the HGP on women. This article describes the potential impact of the "new genetics" on women. Identification of gender differences as they affect both research and clinical practice and the psychosocial, legal, and ethical implications of the HGP should evoke and inform public discussion and policies that may be generated by these issues.

Caregivers↗

[Patterns of service utilization of mental health outpatients].

In light of the forthcoming implementation of national health reform, it is important to review and analyze data regarding the degree and pattern of outpatient, mental-health service utilization in Israel. The main questions this study addressed were: to identify the main groups of users of mental health care, and to determine the utilization patterns of these groups (by length, frequency, and type of treatment) and the profession of the caregivers. This study is based on the findings of the national survey of all adult users of ambulatory mental health services in 1 week in May 1986, and of a 1-week survey in 1994 of similar data from 7 mental health clinics. When patients were grouped into 2 main clinical categories according to the severity of their psychopathology (psychotic, major affective and organic disorders, vs. neurotic, adjustment and personality disorders) they showed different patterns of service utilization. The pattern of the first group was associated with the severity of the psychopathology, whereas the pattern of utilization of the second group was also associated with sociodemographic factors, which may reflect awareness of psychological problems and readiness to turn to mental health services. These factors may also affect the willingness of the caregiver to treat them.

Adult↗

CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.

Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of CBAVD in the other males and its association with CF remained unclear. We undertook this study to test the hypothesis of commonality of CBAVD and CF by haplotype analysis, in the CFTR locus, of males suffering from CBAVD and of their families. According to the hypothesis of commonality of CBAVD and CF, two brothers with CBAVD are expected to carry the same two CFTR alleles, while their fertile brothers are expected to carry at least one different allele. Eleven families were studied, of which two families, with unidentified CFTR mutations, did not support this hypothesis. In these families two brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. These results provide evidence for genetic heterogeneity in CBAVD. Though in some families CBAVD is associated with two CFTR mutations, we suggest that in others it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.

Congenital Abnormalities↗

Angular induction as a function of the length and position of segments and gaps.

The perceptual distortions which are manifested in the Poggendorff illusion can be studied with the use of a more restricted set of stimulus elements. Experiments were designed in which angular induction effects between two line elements, known respectively as the test segment and induction segment, were evaluated. In some stimulus configurations the induction 'segment' consisted of a tandem pair of segments. Previous studies had shown that the induction segment will bias operant judgments of collinearity for a test segment, this effect being a function of the relative angle between the two. Six experiments are reported, in which the length and position of segments in relation to the tip of the test segment were varied. It was found that substantial induction is produced by a very short segment, and that this can bias judgment even when its displacement spans more than 10 deg of visual angle. Several aspects of the data suggest that the strength of effect is a log-linear function of segment position. However, the results from displacement of single or tandem segments do not conform to predictions based on length/response summation, and thus do not support a linear-systems approach. Neural substrates for these interactions are given brief attention.

Adult↗

Altered platelet protein kinase C activity in bipolar affective disorder, manic episode.

Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.

Adult↗

Psychiatric hospitalization of immigrants to Israel from the former USSR: assessment of demand in future waves of immigration.

In the years 1970-1990 approximately half a million immigrants from the former USSR arrived in Israel. Experts predict that new waves of immigration are likely to happen. This paper presents an attempt to forecast the need for appropriate psychiatric services in future waves of immigration. The study compares hospitalization patterns of immigrants arriving in Israel between 1972-1980 with those arriving in 1990. The rates of admission were compared to the rates for Israelis in the specified periods and an estimate for the future need for psychiatric services was calculated. The central finding in this study was that former Soviet immigrants were admitted to psychiatric hospitals within the first year of their arrival at a higher rate than Israelis in the 1970s and in 1990. In the 1970s the admission rate for immigrants was 33 per 10,000, while the rate for Israelis was 20 per 10,000. In 1990 the admission rate for immigrants was 31 per 10,000, while the rate for Israelis was 20 per 10,000. The forecast for the next years is for 320 first admissions within a year after arrival for every 100,000 immigrants. Planning for new waves of immigrations from the former USSR should therefore include a serious consideration of the provision of appropriate psychiatric services.

Adult↗

Prevention of hospitalization by a community intensive mental health care unit.

The presented study sought to determine the ability of a psycho-social model of intensive care intervention to prevent hospitalization. One hundred and thirteen patients identified as "needing hospitalization" were followed from their first intervention until their exit from the unit, and were checked again, a year after discharge. The results of our follow-up show that within the one year follow-up, the percentage of patients who had been hospitalized among the unit's patients was lower than the percentage of hospitalization common in psychiatric hospitals. This conclusion applies to patients with previous hospitalizations, as well as for patients with no previous hospitalizations. The success of the Intensive Mental Health Care Unit in preventing hospitalization was importantly demonstrated among the group of schizophrenic patients who form the largest subgroup of psychiatric hospital patients. In this study, chances of improvement and of remaining out of the hospital for the follow-up period were higher among patients who were working than when they entered the unit. A cost estimate based on the results indicates that the model tested is also a very cost effective model for intervention.

Adult↗

Effect of fat pre-feeding on bile flow and composition in the rat.

Studies were conducted in rats to determine if the increase in lymph triacylglycerol output on pre-feeding a 20% glyceryltrioleate diet (Mansbach, C.M., II and Arnold, A. (1986) Am. J. Physiol. 251, G263-269) was due to an increase in phosphatidylcholine output into bile. Rats who were fed chow or pre-fed the 20% fat diet were equipped with biliary and duodenal cannulas and infused with glucose-saline while bile was collected hourly. The next day a taurocholate-glyceryltrioleate infusion was given and bile collected for 5 h. Bile flow, bile acid, phosphatidylcholine and cholesterol output were greater in the chow fed group than controls during the 6 h of the glucose saline period. Outputs were low overnight. During the taurocholate-glyceryltrioleate infusion, bile flow, bile acid, phosphatidylcholine and cholesterol output were all greater in the fat pre-fed group than the chow fed controls. We conclude that fat pre-feeding profoundly influences biliary composition and flow. The 2-fold increase in biliary phosphatidylcholine output during duodenal lipid infusion offers a potential explanation for the increased delivery of triacylglycerol into the lymph in rats on a similar fat pre-feeding program.

Animals↗

A bifunctional fusion protein containing Fc-binding fragment B of staphylococcal protein A amino terminal to antidigoxin single-chain Fv.

A bifunctional molecule was genetically engineered which contained an amino-terminal effector domain that bound immunoglobulin Fc (fragment B of staphylococcal protein A) and a carboxyl-terminal domain that bound digoxin [a single-chain Fv (sFv)]. Effector and sFv binding properties were virtually identical with those of the parent molecules, despite the proximity of the FB to the sFv combining site. This finding is unprecedented since in all molecules of the natural immunoglobulin superfamily, the antigen binding domain is amino terminal to the effector domain. The FB-sFv sequence was encoded in a single synthetic gene and expressed as a 33,106 molecular weight protein in Escherichia coli. After purification, renaturation, and affinity isolation, yield of active fusion protein were 110 mg/L of fermented cells (18.5-g cell paste). Bifunctionality was confirmed by the ability of FB-sFv to cross-link IgG to digoxin-bovine serum albumin, as measured by plate assays and by Ouchterlony analysis. Analysis of the expressed fusion protein suggests that the sFv holds promise for the development of multifunctional, targetable single-chain proteins.

Amino Acid Sequence↗

Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli.

A biosynthetic antibody binding site, which incorporated the variable domains of anti-digoxin monoclonal antibody 26-10 in a single polypeptide chain (Mr = 26,354), was produced in Escherichia coli by protein engineering. This variable region fragment (Fv) analogue comprised the 26-10 heavy- and light-chain variable regions (VH and VL) connected by a 15-amino acid linker to form a single-chain Fv (sFv). The sFv was designed as a prolyl-VH-(linker)-VL sequence of 248 amino acids. A 744-base-pair DNA sequence corresponding to this sFv protein was derived by using an E. coli codon preference, and the sFv gene was assembled starting from synthetic oligonucleotides. The sFv polypeptide was expressed as a fusion protein in E. coli, using a leader derived from the trp LE sequence. The sFv protein was obtained by acid cleavage of the unique Asp-Pro peptide bond engineered at the junction of leader and sFv in the fusion protein [(leader)-Asp-Pro-VH-(linker)-VL]. After isolation and renaturation, folded sFv displayed specificity for digoxin and related cardiac glycosides similar to that of natural 26-10 Fab fragments. Binding between affinity-purified sFv and digoxin exhibited an association constant [Ka = (3.2 +/- 0.9) x 10(7) M-1] that was about a factor of 6 smaller than that found for 26-10 Fab fragments [Ka = (1.9 +/- 0.2) x 10(8) M-1] under the same buffer conditions, consisting of 0.01 M sodium acetate, pH 5.5/0.25 M urea.

Base Sequence↗