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Biomedical subjects

R Schaub

Publications and source records attributed to R Schaub.

At least 19 recordsLinked to original sources
PubMed2006

Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens.

Clozapine-induced agranulocytosis (CA) is still among the least understood adverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case-control study, we performed human leukocyte antigen (HLA) genotyping and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N=42) suffering from CA and 75 non-Jewish Caucasian schizophrenic patients treated with clozapine without developing CA. While controlling for age (P<0.0001) and sex (P=0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P=0.085, odds ratio (OR)=0.36, 95% confidence interval (CI): 0.08-1.23), Cw7 (P=0.058, OR=2.0, 95% CI: 0.87-4.63) and DRB5*0201 (P=0.005, adjusted OR=22.15). For haplotype analysis, we obtained significant association results with CA for the two-locus haplotypes HLA-Cw-B (P=0.022) and HLA-DRB5-DRB4 (P=0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P=0.030). The complex nature of CA implies that many genes might play a role, but currently, only HLA associations with CA are identified as clinically relevant.

Adult↗
PubMed2006

Formation and splitting of paired hydroxyl groups on reduced TiO2(110).

A combination of high-resolution scanning tunneling microscopy and density functional theory is utilized to study the interaction of water with the reduced TiO2(110)-(1 x 1) surface. As the direct product of water dissociation in oxygen vacancies, paired hydroxyl groups are formed. These pairs are immobile and stable unless they interact with adsorbed water molecules. As a result of these interactions, protons are transferred to adjacent oxygen rows, thereby forming single hydroxyl groups. Additionally, we show that hydroxyl groups facilitate the diffusion of water molecules over the oxygen rows.

Journal Article↗
PubMed2004

Assessing dimensional and categorical aspects of depression: validation of the AMDP Depression Scale.

BACKGROUND: A new observer depression scale which is based on the descriptive operationalized classification principles of ICD-10 is introduced. The AMDP Depression Scale (AMDP-DS), a 22-item clinician-rated inventory, provides the opportunity of dimensional as well as categorical depression severity assessment. METHODS: A sample of 50 patients with depressive symptoms were assessed with the AMDP-DS by two raters in a joint rater session. A number of widely used depression scales were applied separately by an independent rater. The ICD-10 symptom checklist was used for categorical assessment of depressive disorders. RESULTS: The inter-rater reliability for the total score of the AMDP-DS was excellent (Intraclass coefficient: 0.97). There were high correlations with the sum scores of the other scales under study. The correlations between the ICD-10 symptom-checklist and the AMDP-DS ranged from 0.75 to 0.89 for the total sample and 0.44 to 0.51 for patients with acute depressive episode. LIMITATIONS: The results are limited by the method of a joint rater setting and the relatively small subsample of patients with depressive episode. CONCLUSIONS: The AMDP-DS satisfies the requirements of psychometric criteria with a sufficient degree. A new depression scale designed to cover dimensional as well as categorical aspects has successfully been developed.

Adult↗
PubMed2004

Prenatal origin of separate evolution of leukemia in identical twins.

Several studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) frequently arises before birth. A prenatal origin of childhood leukemia was further supported by the detection of clonotypic immunoglobulin gene rearrangements on neonatal blood spots of children with various other subtypes of ALL. However, no comprehensive study is available linking these clonotypic events. We describe a pair of 5-year-old monozygotic twins with concordant TEL-AML1-positive ALL. Separate leukemic clones were identified in the diagnostic samples since distinct IGH and IGK-Kde gene rearrangements could be detected. Additional differences characterizing the leukemic clones included an aberration of the second, nonrearranged TEL allele observed in one twin only. Interestingly, both the identical TEL-AML1 fusion sequence and distinct immunoglobulin gene rearrangements were identified on the neonatal blood spots indicating that separate preleukemic clones evolved already before birth. Finally, we compared the reported twins with an additional 31 children with ALL by using the microarray technology. Gene expression profiling provided evidence that leukemia in twins harbours the same subtype-typical feature as TEL-AML1-positive leukemia in singletons suggesting that the leukemogenesis model might also be applicable generally.

Base Sequence↗
PubMed2004

cAMP signalling in the kinetoplastid protozoa.

Several species of kinetoplastid protozoa cause major human infectious diseases. Trypanosoma cruzi is responsible for the fatal Chagas disease in large parts of South America, the various species of Leishmania cause a number of different human diseases with millions of patients world-wide, and the African trypanosome Trypanosoma brucei is the agent of human sleeping sickness, a disastrously re-emerging epidemic of fatal infections in Sub-Saharan Africa. Chemotherapy of all of these infections is in a very unsatisfactory state. cAMP signalling pathways in humans have provided interesting drug targets for a number of clinical conditions, from asthma to impotency. Similarly, cAMP signalling in kinetoplastids might offer useful targets for the development of novel antiparasitic drugs, which makes their exploration an urgent need. Current knowledge suggests that cAMP signalling proceeds along very similar pathways in all kinetoplastid pathogens (T. cruzi, the Leishmanias and T. brucei). Their adenylyl cyclases are structurally very different from the human enzymes and appear to function as enzyme-linked cell surface receptors. They might represent the major sensory apparatus of the kinetoplastids, guiding much of their environmental sensing and host/parasite interaction. The cAMP-specific phosphodiesterases of the kinetoplastids are rather similar to those of human cells and might function in similar ways. Essentially nothing is known on downstream effectors of cAMP in the kinetoplastids. Homologues of protein kinase A and its regulatory subunits have been identified, but their biochemical properties seem to be disctinct from that of mammalian protein kinase A.

Adenylyl Cyclases↗
PubMed2003

Bonding of gold nanoclusters to oxygen vacancies on rutile TiO2(110).

Through an interplay between scanning tunneling microscopy (STM) and density functional theory (DFT) calculations, we show that bridging oxygen vacancies are the active nucleation sites for Au clusters on the rutile TiO2(110) surface. We find that a direct correlation exists between a decrease in density of vacancies and the amount of Au deposited. From the DFT calculations we find that the oxygen vacancy is indeed the strongest Au binding site. We show both experimentally and theoretically that a single oxygen vacancy can bind 3 Au atoms on average. In view of the presented results, a new growth model for the TiO2(110) system involving vacancy-cluster complex diffusion is presented.

Journal Article↗
PubMed2001

Oxygen vacancies as active sites for water dissociation on rutile TiO(2)(110).

Through an interplay between scanning tunneling microscopy experiments and density functional theory calculations, we determine unambiguously the active surface site responsible for the dissociation of water molecules adsorbed on rutile TiO(2)(110). Oxygen vacancies in the surface layer are shown to dissociate H(2)O through the transfer of one proton to a nearby oxygen atom, forming two hydroxyl groups for every vacancy. The amount of water dissociation is limited by the density of oxygen vacancies present on the clean surface exclusively. The dissociation process sets in as soon as molecular water is able to diffuse to the active site.

Journal Article↗
PubMed2001

cAMP signalling in Trypanosoma brucei.

Cyclic AMP was the first second messenger to be identified. After five decades of research, much is currently known about its biological functions and clinical implications. Several components of the cAMP signalling pathways, such as the G-protein coupled receptors and the phosphodiesterases, have become sensitive and specific drug targets for a host of clinical applications. Surprisingly, very little effort has been invested so far into the study of cAMP signalling in parasites, and its significance in host/parasite interaction. Our laboratory has embarked on a study of cAMP signalling in Trypanosoma brucei. A newly identified adenylyl cyclase, GRESAG4.4B, a member of a small family of closely related genes, is being used as a model molecule for investigating the mechanisms which control cyclase activity in the T. brucei cell. On the other hand, a number of genes for different families of cAMP-specific phosphodiesterases have been identified and characterised. One enzyme, TbPDE1, is coded for by a single-copy gene. Knock-outs of this gene display an almost normal phenotype in culture, indicating that TbPDE1 is not an essential enzyme under culture conditions. A second phosphodiesterase which is being studied in detail, TbPDE2A, is clearly different from TbPDE1, and it is coded for by a member of a small gene family containing about six similar, but non-identical genes. TbPDE2A, as TbPDE1, is specific for cAMP. In its N-terminal, it contains a GAF domain which may represent an allosteric cGMP-binding site. The other members of the TbPDE2 family all exhibit strongly conserved catalytic domains, but vary widely in their N-terminal regulatory domains. With regard to downstream signalling by the cAMP generated through the interplay of adenylyl cyclases and phosphodiesterases, we have recently identified a single-copy gene (TbRSU1) which codes for a putative regulatory subunit of the cAMP-regulated protein kinase A. This protein exhibits considerable similarity with its mammalian counterparts. Immunoprecipitation co-precipitates a protein kinase activity with the characteristics of protein kinase A.

Adenylyl Cyclases↗
PubMed2001

Decorated Ag19 on Pt(111) or the "rare gas necklace".

Ag19 cluster ions are mass selected and deposited on a Pt(111) surface covered by five monolayers of Kr. Almost monodispersed hexagonal shaped Ag islands are observed after Kr evaporation at 125 K. The identification of the island shape and the exact number of atoms has been successful by decorating the clusters with Kr atoms which can be counted by high resolution scanning tunneling microscopy.

Journal Article↗
PubMed2001

Spontaneous dimerization and leucine-zipper induced activation of the recombinant catalytic domain of a new adenylyl cyclase of Trypanosoma brucei, GRESAG4.4B.

In this study, we describe the isolation and characterization of a new adenylyl cyclase from Trypanosoma brucei and its activation by dimerization of the catalytic domain. In agreement with the current nomenclature of trypanosomal adenylyl cyclases, this new gene is termed GRESAG4.4B. The complete ORF of the GRESAG4.4B gene encodes a protein of 1291 amino acids. Its predicted protein structure is consistent with the structure of other trypanosomal cyclases, and with the cyclases of L. donovani. GRESAG 4.4B is constitutively expressed during the life cycle of trypanosomes. GRESAG4.4B is a member of a gene family, which contains at least six members, which are all clustered on chromosome IV. The catalytic domain of GRESAG4.4B is able to dimerize spontaneously. However, these spontaneously formed, stable dimers only show minimal enzymatic activity. The addition of a leucine zipper (LZ) derived from the S. cerevisiae GCN 4 gene to the N-terminus of the catalytic domain of GRESAG4.4B strongly activated its enzymatic activity. The LZ appears to enforce a distinct conformation of the dimer, which leads to an increased enzymatic activity, and thus may mimic the effect of ligand-induced dimerization of adenylyl cyclase in vivo.

Adenylyl Cyclases↗
PubMed2001

P-selectin antagonism causes dose-dependent venous thrombosis inhibition.

Inhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 microg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p<0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extravasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.

Animals↗
PubMed2000

Maternal serum levels of macrophage colony-stimulating factor are associated with adverse pregnancy outcome.

OBJECTIVE: The aim of this study was the measurement of maternal serum levels of M-CSF throughout pregnancy, in a low risk obstetrical population, to examine the relationship of M-CSF and pregnancy outcome. STUDY DESIGN: Maternal serum was obtained at various stages of pregnancy and post partum, M-CSF levels were measured by ELISA, pertinent clinical data tabulated, and pregnancy outcome was determined. RESULTS: In 564 pregnancies studied, 22% of 260 nulliparous pregnancies and 10% of 304 multiparous pregnancies were hypertensive. Preeclampsia occurred in 1.5% of nulliparous and in 1% of the multiparous women. In apparently normal pregnancies with good outcome, M-CSF levels rose throughout pregnancy. No cases of preeclampsia occurred if maternal serum M-CSF levels increased more than 100% throughout pregnancy. CONCLUSIONS: This study suggests that absolute levels and relative changes in maternal serum M-CSF levels during pregnancy are associated with adverse pregnancy outcomes.

Birth Weight↗
PubMed2000

Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy.

OBJECTIVE: This study was performed to determine the effectiveness of recombinant P-selectin glycoprotein ligand Ig (rPSGL-Ig) pretreatment to decrease thrombosis and inflammation in experimental venous thrombosis. rPSGL-Ig, a unique mucin-like glycoprotein, has a high affinity for P-selectin. METHODS: Twelve juvenile baboons underwent inferior vena cava (IVC) thrombosis with temporary 6-hour IVC balloon occlusion. Before balloon placement, the animals received rPSGL-Ig (4 mg/kg; n = 8) or saline solution for control (n = 4). The animals underwent evaluation with duplex ultrasound scan imaging, magnetic resonance venography (MRV), phlebography, coagulation profile, and tissue analysis at death for cytokines and vein wall leukocyte morphometrics. With the MRV results, thrombus development, thrombus resolution, and inflammation (gadolinium; square millimeters of enhancement) were assessed. RESULTS: Each animal provided two time points for evaluation (days 2 and 6 after balloon occlusion). A significant decrease in IVC thrombosis between balloons was found in the rPSGL-Ig animals (1 of 16) versus the control animals (5 of 8; P <.01). The MRV results showed significantly less enhancement in the rPSGL-Ig animals at days 2 and 6 (P <.05). Spontaneous thrombus resolution (including balloon sites) was significantly greater from day 2 to day 6 in the rPSGL-Ig animals versus the control animals (23% vs 2%; P <.001), without pulmonary embolism. Lower interleukin-8, platelet factor IV, and monocyte chemotactic protein-1 levels were found in rPSGL-Ig vein walls without significant differences in vein wall leukocyte morphometrics. There were significantly lower D-dimer levels in the rPSGL-Ig-treated animals (P <.05), but there were no differences in measurements of coagulation. Adequate circulating rPSGL-Ig levels were documented. CONCLUSION: Pretreatment with rPSGL-Ig results in: (1) a significant inhibition of thrombosis and vein wall inflammation; (2) a decrease in vein wall cytokine expression; and (3) a promotion of thrombus resolution. Inflammatory inhibition by rPSGL-Ig without anticoagulation therapy provides effective venous thrombosis prophylaxis in experimental venous thrombosis.

Animals↗
PubMed2000

Carotid atherosclerosis, vascular risk profile and mortality in a population-based sample of functionally healthy elderly subjects: the Berlin ageing study.

OBJECTIVES: Studies on extracranial carotid atherosclerosis have predominately been undertaken on middle-aged subjects. This study examines the prevalence of extracranial carotid atherosclerosis, its relation to vascular risk factors and its significance for survival in elderly subjects. DESIGN: Population-based cross-sectional survey. Non-modifiable vascular risk factors examined were family history of atherosclerotic disease, sex and apolipoprotein E (apoE) genotype. Potentially modifiable risk factors assessed were smoking, fibrinogen, fasting lipids, body mass index, hypertension and diabetes. SETTING AND SUBJECTS: Two hundred and twenty-five functionally healthy volunteers of the Berlin Ageing Study, aged 70-100. MAIN OUTCOME MEASURES: Presence of carotid stenosis and plaque ascertained by ultrasound imaging; 5-year mortality. RESULTS: At least one plaque was found in 144 (64%) of the volunteers; 34 (15%) had a stenosis over 50%; and nine (4%) had a stenosis over 75%. Total cholesterol > 6.5 mmol L-1, LDL cholesterol > 4.6 mmol L-1 and total cholesterol/HDL cholesterol ratio > 5 were significantly associated with presence of plaque in 70- to 80-year-old subjects, as was diabetes in subjects over 80 years. Log-linear analyses showed significant three-way interactions for high LDL cholesterol and diabetes with plaques and age. Family history, sex, apoE genotype, smoking and fibrinogen were not related to presence of plaque in the study population. Cox regression analysis revealed increased 5-year mortality rates for subjects with plaques (OR = 2. 88; 95% CI = 1.30-6.35), whereas the vascular risk profile was not associated with mortality. CONCLUSIONS: In a population-based sample of functionally healthy elderly subjects, the significance of the vascular risk profile seemed to be diminished. It had no impact on survival and only modifiable risk factors showed an age-dependent association with carotid disease.

Age Factors↗
PubMed2000

Self rating of health is associated with stressful life events, social support and residency in East and West Berlin shortly after the fall of the wall.

STUDY OBJECTIVE: To compare the health status and factors influencing the health of populations that had previously lived under different political systems. DESIGN: Cross sectional health and social survey using postal interviews. The relation between self reported health and psychosocial factors (stressful life events, social support, education, health promoting life style and health endangering behaviour) was investigated. To determine East-West differences a logistic regression model including interaction terms was fitted. SETTING: East and West Berlin shortly after reunification 1991. PARTICIPANTS: Representative sample of 4430 Berlin residents aged 18 years and over (response rate 63%). RESULTS: Of all respondents, 15.4% rated their health as unsatisfactory. Residents of East Berlin rated their health more frequently as unsatisfactory than residents of West Berlin (Or(age adjusted)= 1.29, 95%CI 1.08, 1.52), these differences occurred predominantly in the over 60 years age group. Logistic regression showed significant independent effects of stressful life events, social support, education, and health promoting life style on self rated health. The effects of education and health promoting life style were observed to be more pronounced in the western part of Berlin. Old age and female sex showed a stronger association with unsatisfactory health status in the eastern part of Berlin. CONCLUSIONS: For subjects aged over 60 years there was evidence that living in the former East Berlin had an adverse effect on health compared with West Berlin. The impact of education and a health promoting lifestyle on self rated health seemed to be weaker in a former socialist society compared with that of a Western democracy. This study supports an "additive model" rather than a "buffering model" in explaining the effects of psychosocial factors on health.

Adolescent↗
PubMed2000

The spectrum of growth abnormalities in children with 18q deletions.

The objective of this study was to assess the spectrum of growth abnormalities in children with 18q deletions. The growth axis of 50 individuals with a cytogenetically and molecularly confirmed 18q deletion was investigated by determining height, growth velocity, insulin-like growth factor I (IGF-I), IGF-binding protein-3, bone maturation, and response to pituitary stimulants of GH. Children with 18q deletions are short; 64% have a height more than -2 SD below the mean. Affected children also grow slowly; 68% have a growth velocity more than -1 SD below the mean. Half of the individuals have delayed bone maturation. Growth factors are skewed downward; 72% of the IGF-I values and 83% of the IGF-binding protein-3 values are below the mean for chronological age. Similarly, 72% of the children had a reduced or absent response to either of the GH stimulants, arginine and clonidine. In the total group of 50 children only 2 were normal for all parameters evaluated. Short stature and poor growth are common features of individuals with 18q deletions. GH deficiency is common in this cohort of patients and probably plays a role in the short stature seen in many of the affected individuals.

Adolescent↗
PubMed1999

DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries.

We have identified and characterized mouse, rat, and human cDNAs that encode a novel secreted protein of 448 amino acids named DANCE (developmental arteries and neural crest epidermal growth factor (EGF)-like). DANCE contains six calcium-binding EGF-like domains, one of which includes an RGD motif. Overexpression studies of recombinant DANCE protein document that DANCE is a secreted 66-kDa protein. DANCE and recently described protein S1-5 comprise a new EGF-like protein family. The human DANCE gene was mapped at chromosome 14q32.1. DANCE mRNA is mainly expressed in heart, ovary, and colon in adult human tissues. Expression profile analysis by in situ hybridization revealed prominent DANCE expression in developing arteries. DANCE is also expressed in neural crest cell derivatives, endocardial cushion tissue, and several other mesenchymal tissues. In adult vessels, DANCE expression is largely diminished but is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells that lose their ability to proliferate in late stage of injury. DANCE protein was shown to promote adhesion of endothelial cells through interaction of integrins and the RGD motif of DANCE. DANCE is thus a novel vascular ligand for integrin receptors and may play a role in vascular development and remodeling.

Amino Acid Sequence↗