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Biomedical subjects

H Steiner

Publications and source records attributed to H Steiner.

At least 37 records · Page 2Linked to original sources
PubMed2001

Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins.

Presenilin (PS) proteins facilitate endoproteolysis of selected type I transmembrane proteins such as the Alzheimer's disease (AD) associated beta-Amyloid precursor protein (beta APP) and Notch. beta APP is cleaved within its transmembrane domain by an aspartyl protease activity termed gamma-secretase, which may be identical with PS1 and PS2. Notch also undergoes a PS-dependent intramembraneous proteolysis. A similar gamma-secretase-like cleavage may also occur with IRE1 and ATF6, two signaling molecules of the unfolded protein response (UPR) that may require PSs for their activation. Here, we have analyzed whether ATF6 cleavage requires a PS-dependent gamma-secretase activity and whether inhibition of gamma-secretase activity would affect the UPR. Endoproteolysis of ATF6 was observed in the presence of the highly potent gamma-secretase inhibitor L-685,458. ATF6 processing also occurred in the presence of functionally inactive dominant negative mutants of PS1 (PS1 D385N) and PS2 (PS2 D366A) that do not support endoproteolysis of beta APP and Notch. Our results therefore demonstrate that ATF6 is not a substrate for PS mediated gamma-secretase-like endoproteolysis. This finding indicates that gamma-secretase inhibitors, which are currently developed as therapeutic agents to lower the A beta burden in brains of AD patients, do not interfere with the UPR response.

Activating Transcription Factor 6↗
PubMed2001

Intrauterine blood flow and long-term intellectual, neurologic, and social development.

OBJECTIVE: To study the long-term effects of severely abnormal (absent or reversed diastolic) blood flow in the umbilical artery associated with fetal growth restriction on postnatal intellectual, neurologic, and social development. METHODS: Absence or reversal of diastolic blood flow in the umbilical artery was found in 38 consecutive growth-restricted fetuses as determined by biometry and Doppler ultrasound between 1988 and 1992. The 23 infants surviving the prenatal and perinatal period who could be tested were compared at school age with a group of children born at the same gestational age after normal intrauterine growth. They were tested for intellectual, neurologic, and social development by a test battery including the Kaufmann Assessment Battery for Children, Man-Drawing Test, Child Behavior Checklist, Zürich Neuromotor Test, and neuropediatric testing. RESULTS: Intellectual development was significantly better in the control group compared with the study group. In addition, Zürich Neuromotor testing and neuropediatric testing showed significantly better development of control children compared with the study group in 20% of the items tested. There was no detectable difference in social development as measured by the Child Behavior Checklist. CONCLUSION: Severely reduced blood flow to the fetus associated with growth restriction was followed by long-term impairment of intellectual development and partial neurodevelopmental delay.

Adult↗
PubMed2001

The Child Abuse Potential Inventory and pregnancy outcome in expectant adolescent mothers.

OBJECTIVE: The study explores the prenatal Child Abuse Potential (pCAP) scores derived from the Child Abuse Potential Inventory administered to expectant adolescent mothers. The aim of the study was to assess the association of the pCAP scores with maternal negative prenatal behaviors, and evaluate the contribution of the pCAP scores to neonatal morbidity. METHOD: The pCAP scores, demographic data, and self-report on prenatal behaviors were obtained during the second half of the pregnancy in a sample of 45 poor single adolescent mothers. A pediatrician blind to the prenatal data reviewed the neonatal records to assess neonatal morbidity. Maternal prenatal records were reviewed for obstetric risk assessment by an obstetrician who was blind to the rest of the data. The relations among the pCAP scores, prenatal behaviors, and neonatal morbidity were analyzed. RESULTS: In the prenatal period, the pCAP scores were positively correlated with self-reported prenatal smoking and substance use. The multiple linear regression analysis showed that the pCAP scores significantly contributed to neonatal morbidity independently of obstetric risk factors. CONCLUSIONS: The Child Abuse Potential scores obtained during pregnancy in poor single adolescent mothers reflect domains of maternal functioning that are associated with negative prenatal behaviors and appear to be important for predicting neonatal morbidity. Further studies are warranted to validate the prenatal use of the Child Abuse Potential Inventory.

Adolescent↗
PubMed2001

The cell biology of Alzheimer's disease: uncovering the secrets of secretases.

Progress has been made in characterizing the secretases involved in endoproteolytic processing of the beta-amyloid precursor protein - the precursor of the amyloid beta-peptide (Abeta), which is the main constituent of amyloid plaques that form in the brains of patients with Alzheimer's disease. It is now thought that Abeta is pivotal in the pathogenesis of Alzheimer's disease, and that reducing brain Abeta levels may help to treat or prevent the disease. Two essential factors for the proteolytic generation of Abeta have been identified, beta-secretase and the presenilins, which might aid the design of drugs against this disease.

Alzheimer Disease↗
PubMed2001

Poor adolescent expectant mothers: can we assess their potential for child abuse?

PURPOSE: To explore the correlates of high scores on the Child Abuse Potential Inventory in adolescent expectant mothers. METHODS: Child Abuse Potential scores and data on demographics, pregnancy desire, history of maltreatment, psychological functioning, and perceived social support were obtained by self-report and semi-structured interview. The sample consisted of 50 poor single adolescents recruited from prenatal clinics during the second half of the pregnancy. The relationships among the variables were assessed using Pearson product-moment correlation and multiple regression strategies. RESULTS: Higher Child Abuse Potential scores were associated with higher maternal psychological distress, maternal history of psychiatric diagnosis, and lack of perceived support by the father of the baby. Older pregnant teenagers were more likely to report childhood history of maltreatment, higher psychological distress, and perceived and expected less support by the maternal mother. Expectant mothers who were raised by a single parent were more likely to have a history of childhood maltreatment, less likely to live with the father of the baby during their pregnancy and to expect less support from him. CONCLUSIONS: Child Abuse Potential scores, obtained during pregnancy in a sample of poor single adolescents provide a marker of maternal prenatal functioning and perceived social support. Further studies are warranted to validate prenatal use of the Child Abuse Potential Inventory (CAPI), which may help identify populations at particularly high risk for child abuse during pregnancy and inform strategies for early preventive interventions. Adolescent education on family planning, child rearing, and social support programs should address the importance of the fathers' role.

Adolescent↗
PubMed2001

Substance abuse and criminal recidivism: a prospective study of adolescents.

Studies of substance abuse among delinquents have shown mixed results on criminal recidivism. The present study evaluates personality traits associated with substance abuse and recidivism among delinquent boys, and prospectively determines the extent to which these factors are predictive of criminal recidivism. 134 incarcerated boys (x = 15.9 +/- 1.1) completed the Weinberger Adjustment Inventory and the Substance Abuse Screening Inventory. Youth were prospectively followed for up to 4.5 years following release. Among incarcerated delinquents, personality traits are predictive of a positive substance abuse screen and recidivism. A trend indicating a possible interaction between personality and treatment is observed. If these findings are replicated, personality traits may play a role in predicting substance abuse as well as individual delinquent responses to treatment.

Adolescent↗
PubMed2001

Associated health risks of adolescents with disordered eating: how different are they from their peers? Results from a high school survey.

In this study, we compare health risks of adolescents with disordered eating to those of their peers without disordered eating. A self-report health survey from a community sample of 1769 high school students was used to compare emotional, medical, and social behaviors of these two groups. Risk data for disordered eating students was compared within and across genders. Adolescents with disordered eating are at increased risk for emotional and physical health problems compared to their peers. Overall health risks for boys and girls with disordered eating are quite similar. However, boys with disordered eating develop associated health risk profiles that differentiate them from male peers by having increased mental health, sexual and physical abuse, and general health problems. Girls with disordered eating have associated health risks for substance use and sexual risk-taking that distinguished them from their female peers.

Adolescent↗
PubMed2001

Trauma and personality correlates in long-term pediatric cancer survivors.

To explore the relationship between PTSD and trauma-spectrum symptoms, including personality and functional correlates, in long term pediatric cancer survivors (N = 40), we assessed these constructs with a structured interview for PTSD, a clinical interview, and self-report questionnaires. Thirty-five out of 40 participants (88%) currently met at least one trauma symptom at a functionally significant level. These survivors demonstrate high levels of restraint and low levels of distress, representative of a repressive adaptive style. After more than 5 years since treatment completion, the relatively high levels of current trauma-spectrum symptoms may reflect the long-term deleterious impact of childhood cancer.

Adaptation, Psychological↗
PubMed2001

Family environment of children and adolescents with bipolar parents.

OBJECTIVES: The effect of family environment on the development of bipolar disorder (BD) in children is not known. We sought to characterize families with children at high risk for developing BD in order to better understand the contributions of family environment to the development of childhood BD. METHODS: We collected demographic data and parental ratings on the Family Environment Scale (FES) for 56 children (aged 6-18 years) from 36 families with at least one biological parent with BD. The cohort had previously been psychiatrically diagnosed according to semistructured interviews. RESULTS: Statistical comparisons with normative data indicated that parents' ratings were significantly lower on the FES Cohesion and Organization scales and were significantly higher on the FES Conflict scale. Multivariate analyses of variance indicated that families with both parents having a mood disorder had no significantly different FES scores than families with only one parent with a mood disorder (BD). Diagnostic data indicated that while 54% of the children in the sample had an Axis I disorder and 14% had BD, FES scores did not differ significantly for subjects with or without an Axis I disorder, or with or without BD. CONCLUSIONS: Families with a bipolar parent differ from the average family in having less cohesion and organization, and more conflict. Despite this difference, it does not appear that the environment alone of families with a bipolar parent determines the outcome of psychopathology in the children, or that the psychopathology of the children determines the family environment.

Adolescent↗
PubMed2001

Unilateral striatal dopamine depletion: time-dependent effects on cortical function and behavioural correlates.

Previously, we showed that unilateral blockade of D1 dopamine receptors in the striatum inhibits immediate-early gene expression bilaterally throughout large parts of the cortex, including sensory-evoked expression in the barrel cortex. To further investigate this dopamine regulation of cortical function, we examined the effects of dopamine depletion on cortical gene regulation and behavioural correlates. Two days after unilateral infusion of 6-hydroxydopamine into the midbrain, rats displayed a (to some degree) bilateral reduction in cortical zif 268 expression that was more pronounced on the lesioned side. This decrease was found across motor, somatosensory, insular and piriform, but not cingulate, cortex, similar to the effects of blockade of striatal D1 receptors. Furthermore, whisker stimulation-evoked c-fos and zif 268 expression in the barrel cortex ipsilateral to the lesion was also attenuated by acute dopamine depletion. These cortical deficits were accompanied by a breakdown of spontaneous behaviours in an open-field test. In contrast, 21 days after dopamine depletion, both basal and sensory-evoked gene expression in the cortex were near-normal. This cortical recovery was paralleled by recovery in locomotion and in sensory-guided behaviour (scanning) related to the hemisphere contralateral to the lesion, but not in scanning by the dopamine-depleted hemisphere. Our results suggest that striatal dopamine exerts a widespread facilitatory influence on cortical function that is necessary, but not sufficient, for normal behaviour. Moreover, the mechanisms mediating this cortical facilitation appear to be subject to substantial neuroplasticity after dopamine perturbation.

Animals↗
PubMed2001

Comparison between two- and three-dimensional ultrasound measurements of nuchal translucency.

OBJECTIVE: Fetal nuchal translucency measurement has been introduced as a screening test for the calculation of risk of chromosomal abnormalities. The purpose of this study was to investigate: (1) the feasibility of obtaining nuchal translucency measurements using three-dimensional ultrasound; (2) whether three-dimensional ultrasound could improve and facilitate the required repeated measurements of nuchal translucency; (3) the correlation between two- and three-dimensional nuchal translucency measurement values. SUBJECTS AND METHODS: Between September 1999 and May 2000, in a prospective cohort study, 229 unselected pregnant women with a mean age of 34.6 (range, 20-46) years were examined. The mean fetal crown-rump length was 64.3 (range, 45-84) mm. Nuchal translucency thickness was measured first by two- and then by three-dimensional ultrasound in two planes (three-dimensional mid-sagittal and three-dimensional transverse). An attempt was made to repeat each nuchal translucency measurement three times (totalling nine measurements per patient) and the means of the two- and three-dimensional measurements were compared. The majority (95%) of the measurements were made transabdominally and 5% were made transvaginally. The time limit for each examination was 20 min. RESULTS: With the two-dimensional method, nuchal translucency could be measured in 96.8% of cases. Of these, three measurements could be obtained in 51.7%, two in 23.2% and only one in 25.1%. The three-dimensional examination was successful in 98.6% of cases. Of these, three measurements could be obtained in 60%, two in 22.8% and one in 17.2%. Transvaginally, all examinations were successful. The main reason for the failure of two-dimensional ultrasound was the fetal position, which in some cases precluded the distinction between fetal skin and amnion or the uterine wall. Using two-dimensional ultrasound, 6.3% of the cases of measurement failure were due to an inability to differentiate clearly between fetal skin and amnion, whilst the equivalent value for the three-dimensional method was only 3.3%. For the three-dimensional technique, fetal movement was the main reason for failure. The mean time for both methods was similar (9 min and 10 min for two- and three-dimensional ultrasound, respectively) and the correlation between the measurements obtained by the two- and three-dimensional techniques was very high (r = 0.97). CONCLUSION: The number of fetuses in which nuchal translucency could be measured tended to be higher with three-dimensional ultrasound, although the difference was not statistically significant. The possibility of rotating a stored volume and inspecting it in three orthogonal planes makes three-dimensional ultrasound a useful tool for nuchal translucency measurements, especially in doubtful cases.

Adult↗
PubMed2001

The response evaluation measure (REM-71): a new instrument for the measurement of defenses in adults and adolescents.

OBJECTIVE: There is widespread agreement that the concept of defense is useful, but large-scale studies with representative cohorts are lacking. Self-report measures capturing conscious derivatives of defense can facilitate such studies. The authors report the design and initial performance of a new self-report measure of specific defenses. METHOD: A 71-item questionnaire based on a developmental model of defenses was created, pilot tested, and refined. The item pool was given to two independent clinical researchers for the classification of items (concordance=98.5%). The instrument was then administered to 1,875 nonclinical subjects drawn from two suburban high schools and from a public waiting area of a local airport (1,038 female subjects; mean age=21.0 years, SD=11.9, range=13-89), who were also assessed with a simple screening measure covering demographic variables and satisfaction with life. RESULTS: The internal consistency of the questionnaire items was good. Two factors emerged from a factor analysis of the items, paralleling Vaillant's theoretical model. Most defenses made unique, significant contributions to these factors. Defenses and factors related in the expected direction with scores on life satisfaction in various domains. CONCLUSIONS: The Response Evaluation Measure is a brief, coherent, and potentially useful screening instrument for the assessment of defenses in adults and adolescents.

Adolescent↗
PubMed2001

Nuclear signaling: a common function of presenilin substrates?

Major progress has recently been made in the characterization of the secretases involved in endoproteolytic processing of the Alzheimer's disease (AD)-associated beta-amyloid precursor protein, betaAPP. betaAPP is the precursor of the amyloid beta-peptide, which is a major constituent of amyloid plaques in the brains of Alzheimer patients. It is now commonly believed that Abeta plays a pivotal role in the pathogenesis of AD, and that inhibiting the production of Abeta may help to treat or to prevent the disease. With beta-secretase and the presenilins, two essential factors in the proteolytic generation of Abeta have now been identified. However, very little is still known about the biological function of the long-known betaAPP. In this review we will discuss a novel putative function of betaAPP in nuclear signaling, an activity, that betaAPP may share with other presenilin substrates such as Notch.

Acetyltransferases↗
PubMed2001

Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.

PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project. MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test. RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013). CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.

Adult↗
PubMed2000

A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells.

The familial Alzheimer's disease-associated presenilins (PSs) occur as a dimeric complex of proteolytically generated fragments, which functionally supports endoproteolysis of Notch and the beta-amyloid precursor protein (betaAPP). A homologous gene, sel-12, has been identified in Caenorhabditis elegans. We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteolytic cleavage in C. elegans similar to the PSs in human tissue. In contrast, SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon expression in human cells, suggesting that SEL-12 is cleaved by a C. elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not associated with a dominant negative activity in human cells, because SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere with Notch1 cleavage. Moreover, both mutant variants increase the aberrant production of the highly amyloidogenic 42-amino acid version of amyloid beta-peptide similar to familial Alzheimer's disease-associated human PS mutants. Our data therefore demonstrate that the C60S mutation in SEL-12 is associated with aberrant endoproteolysis and a loss of function in C. elegans, whereas a gain of misfunction is observed upon expression in human cells.

Amyloid beta-Peptides↗
PubMed2000

First direct measurement of the parity-violating coupling of the Z0 to the s quark

We present the first direct measurement of A(s), the parity-violating coupling of the Z0 boson to the strange quark, using approximately 550 000 e(+)e(-)-->Z0-->hadrons events recorded by the SLC Large Detector with a polarized e(-) beam. We tagged Z0-->s&smacr; events by the absence of B or D hadrons and the presence in each hemisphere of a high momentum K+/- or K(0)(s). Fitting the polar angle distributions of the strangeness-signed thrust axis gave A(s) = 0.895+/-0.066(stat)+/-0.062(syst). The analyzing power and uu+d&dmacr; background were constrained using the data, greatly reducing any model dependence.

Journal Article↗
PubMed2000

A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster.

Peptidoglycans from bacterial cell walls trigger immune responses in insects and mammals. A peptidoglycan recognition protein, PGRP, has been cloned from moths as well as vertebrates and has been shown to participate in peptidoglycan-mediated activation of prophenoloxidase in the silk moth. Here we report that Drosophila expresses 12 PGRP genes, distributed in 8 chromosomal loci on the 3 major chromosomes. By analyzing cDNA clones and genomic databases, we grouped them into two classes: PGRP-SA, SB1, SB2, SC1A, SC1B, SC2, and SD, with short transcripts and short 5'-untranslated regions; and PGRP-LA, LB, LC, LD, and LE, with long transcripts and long 5'-untranslated regions. The predicted structures indicate that the first group encodes extracellular proteins and the second group, intracellular and membrane-spanning proteins. Most PGRP genes are expressed in all postembryonic stages. Peptidoglycan injections strongly induce five of the genes. Transcripts from the different PGRP genes were found in immune competent organs such as fat body, gut, and hemocytes. We demonstrate that at least PGRP-SA and SC1B can bind peptidoglycan, and a function in immunity is likely for this family.

Amino Acid Sequence↗