Gene polymorphisms of interleukin-1alpha influence the course of Alzheimer's disease.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
S Schmitz
Publications and source records attributed to S Schmitz.
[Quality management and certification in oncology].
Explore the source record for details and available documents.
Accreditation↗
Genetic and environmental influences on the associations between attention problems and other problem behaviors.
Problem behavior in children shows a high degree of co-occurrence, both within the domains of internalizing and externalizing behaviors and across domains. Maternal ratings of 207 same- and opposite-sex twin pairs on the Child Behavior Checklist (CBCL/4-18; Achenbach, 1991) were used to determine the etiology of these associations. In the current sample of 4- to 11-year-old children (mean age: 7.6 years) phenotypic correlations were .68 between Internalizing and Externalizing, between .41 and .66 within the internalizing scales, and between .58 and .71 within the externalizing scales. Correlations across domains on the scale level were of similar magnitude. Genetic and shared environmental correlations were generally high, with the exception of the somatic complaints scale which showed low genetic correlations with other scales. These findings of uniformly high shared etiology was seen within and across domains. For example, Attention Problems showed genetic correlations of .65 with Delinquent Behavior and .76 with Aggressive Behavior; the genetic correlations of Attention Problems with internalizing scales were .71 for Anxious/Depressed and .79 for Withdrawn; a low genetic correlation was only shown for the Somatic Complaints scale (r(g) = .16). Although the magnitude of shared environmental contributions was lower, the environmental correlations were close to unity, indicating that the same family environmental factors were involved in aspects of problem behavior when assessed across domains. Results for the Attention Problems scale were similar to other disruptive behavior, justifying its inclusion with the externalizing scales.
Attention Deficit Disorder with Hyperactivity↗
[In vitro permeability studies as a substitute for in vivo studies--which requirements have to be met?].
In order to reduce costs and shorten time-to-market, the permeability of drug substances can be characterized by in vitro techniques including the use of cell and tissue models. It is required to apply appropriate quality standards similar to those used in animal or clinical studies. The Caco-2 cell model is a well-established and recognized in vitro technique in research, industry and in the drug discovery sector. However, the lack of standardized operating is reflected in the heterogeneity of the data acquired using this model. Using the Caco-2 cell model as an example, this paper demonstrates how to test the suitability of a cell culture model for conducting drug permeability studies. The procedures involve not only the characterization of cell morphology but also functional assessment of the model and the periodic testing of monolayer permeability. Both the useful comparison of permeability data and the reliable prediction of in vivo permeability require prior classification of the in vitro permeability in accordance with the FDA"s Biopharmaceutics Classification System (BCS).
Animal Testing Alternatives↗
[Marker transport across biological barriers in vitro: comparison of cell culture models for the gastrointestinal barrier, the blood-brain barrier and the alveolar epithelium of the lung].
In order to respond to the flood of new active ingredients currently being generated by combinatorial chemistry or molecular biological synthesis, selection procedures able to filter out rapidly and economically those drug candidates with the highest development potential are required. This necessitates the measurement of fundamental biopharmaceutical parameters very early in the drug development process. Any pharmaceutically active agent must be able to overcome the body's natural protective mechanisms. A broad variety of biological barriers can be simulated in the laboratory by cell monolayer models. Apart from ethical aspects, the advantage of these in vitro test systems is that permeability studies can be performed at high throughput rates under controlled and reproducible conditions. The validity of such a model is ultimately reflected in its ability to accurately predict the behaviour of an active ingredient at the corresponding in vivo barrier.
Animal Testing Alternatives↗
Identical distribution of the alpha 2-macroglobulin pentanucleotide deletion in subjects with Alzheimer disease and controls in a German population.
Recently, an association between a deletion polymorphism in the alpha 2-macroglobulin gene (A2M) and Alzheimer disease (AD) has been reported. The aim of the present study was to corroborate this association in a German population of 102 AD patients and two control samples of 191 healthy subject and 160 depressed patients. The frequency of the A2M genotype in AD patients was almost identical to that in both control samples. Logistic regression analysis revealed an effect of age and the APOE genotype on AD risk, but no effect of the A2M genotype. Our findings do not support the fact that the previously reported positive association between A2M deletion polymorphism and AD modifies the disease risk in the studied population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:775-777, 2000.
Aged↗
Familial association between allergic disorders and depression in adult Finnish twins.
Clinical studies have shown a relationship between allergic disorders and depression, panic disorder, attention deficit/hyperactivity disorder, and social anxiety for a significant subset of patients with these disorders. The nature of the relationship, whether due to shared environmental or biologic vulnerabilities or as a result of the stress of chronic illness, has been less clear. By examining the covariance of atopic disorders and depressive symptoms in a community sample of monozygotic (MZ) and dizygotic (DZ) twins, the contribution of genetic and/or shared environmental etiological factors can be established. A Finnish sample of 1337 MZ and 2506 DZ twin pairs, ages 33-60 years, was sent questionnaires inquiring about history of asthma, eczema, and atopic rhinitis, as well as the Beck Depression Inventory (BDI). The nature of the covariation between twins of these symptoms was investigated by fitting competing genetic and environmental models. Within-person correlation between atopic symptoms and BDI was 0.103 (P < 0.001) for the total sample. Using the Mx statistical modeling program to fit the data to competing quantitative genetic models, the best fitting model estimated that 64% of the association between atopy and BDI was due to shared familial vulnerability, primarily additive genetic influences. Although the measures for allergic disorders and depression are crude, this study supports the hypothesis that there is a small shared genetic risk for atopic and depressive symptoms, and if replicated, may open research for common mechanisms between allergic and depressive disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:146-153, 2000.
Adult↗
Drosophila ACT88F indirect flight muscle-specific actin is not N-terminally acetylated: a mutation in N-terminal processing affects actin function.
Many eukaryotic proteins are co and post-translationally modified at their N termini by removal of one or two amino acid residues and N(alpha)-acetylation. Actins show two different forms of N-terminal processing dependent on their N-terminal sequence. In class II actins, which include muscle actins, the common primary sequence of Met-Cys-Asp-actin is processed to acetyl-Asp-actin. The functional significance of this in vivo is unknown. We have studied the indirect flight muscle-specific actin, ACT88F, of Drosophila melanogaster. Our results show that ACT88F is N-terminally processed in vivo as a class II actin by removal of the first two amino acid residues (Met and Cys), but that uniquely the N terminus is not acetylated. In addition we show that ACT88F is methylated, probably at His73. Flies carrying the mod(-) mutation fail to complete post-translational processing of ACT88F. We propose that the mod gene product is normally responsible for removing N-acetyl-cysteine from actin. The biological significance of this process is demonstrated by observations that retention of the N-acetyl-cysteine in ACT88F affects the flight muscle function of mod(-) flies. This suggests that the extreme N terminus affects actomyosin interactions in vivo, a proposal we have examined by in vitro motility assays of ACT88F F-actin from mod(-) flies. The mod(-) actin only moves in the presence of methylcellulose, a viscosity-enhancing agent, where it moves at velocities slightly, but significantly, reduced compared to wild-type. These data confirm that N-acetyl-cysteine at the N terminus affects actomyosin interactions, probably by reducing formation of the initial actomyosin collision complex, a process known to involve the actin N terminus.
Acetylation↗
Acute hematologic toxicity and practicability of dose-intensified BEACOPP chemotherapy for advanced stage Hodgkin's disease. German Hodgkin's Lymphoma Study Group (GHSG).
BACKGROUND: Evidence is recently accumulating that the novel BEACOPP (bleomycin (B), etoposide (E), adriamycin (A), cyclophosphamide (C), vincristine (O), procarbazine (P), prednisone (P)) chemotherapy is a highly effective treatment for advanced stage Hodgkin's disease. Two dose variants of BEACOPP are currently tested in a phase III randomized multicenter trial of the GHSG. To enable more extensive testing of BEACOPP we characterized its practicability regarding schedule adherence, acute hematotoxicity and need for supportive treatment. PATIENTS AND METHODS: Data of 858 patients (6592 therapy cycles) from 184 participating institutions were evaluated. Planned total drug doses of the baseline variant (arm 1) were 80, 2400, 200, 5200, 11.2, 5600 and 4480 mg/m2 for B, E, A, C, O, P and P, respectively. Compared to arm 1, the doses of E, A and C in the dose-intensified variant (arm 2) were escalated by factor 2.0, 1.4, 1.92, respectively, using G-CSF assistance. Stepwise dose reductions were specified in case of dose-limiting toxicities. Both variants are given in eight three-weekly courses. RESULTS: Median dose adherence (dose actually given relative to planned arm 1 dose) in arm 1 was 1.0 for all drugs. Relative dose escalation of E, A, and C actually maintained in arm 2 was 1.83, 1.37 and 1.77 (medians), respectively, and 70% of patients maintained elevated dose levels throughout the entire treatment. Dose-limiting toxicities occurred in 25% of cycles in arm 2, most frequently due to leukocytopenia and thrombocytopenia. Time courses of leukocytes in arm 2 showed more severe but not more prolonged leukocytopenia compared with arm 1. WHO grades 3-4 infections were documented in 2.1% (arm 1) and 3.1% (arm 2) of all cycles. Erythrocytes were transfused in 61% (arm 1) and 28% (arm 2), platelets in < 1% (arm 1) and 6% (arm 2) of all cycles. CONCLUSIONS: Both BEACOPP schemes are practicable in a large multicenter setting. Despite increased hematotoxicity, moderate dose escalation is safe for the majority of the patients with G-CSF assistance and standard supportive treatment.
Adolescent↗
Intracranial haemorrhage and use of selective serotonin reuptake inhibitors.
AIMS: In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs. METHODS: We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression. RESULTS: We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10. 8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0. 8 (0.3,2.3). The estimate for 'other antidepressants' was 0.7 (0.3,1. 6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid). CONCLUSIONS: Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.
Adolescent↗
Gender-specific characteristics of 5-year-olds' play narratives and associations with behavior ratings.
OBJECTIVES: To examine the content and structure of children's play narratives in a large sample of 5-year-olds in order to replicate previous findings, explore the role of gender differences, and identify a pattern that can provide useful information about children's behavior. METHOD: The MacArthur Story Stem Battery and coding system was used to code content themes and coherence from play narratives of 652 twins in a nonclinical sample. To measure behavior problems, parents completed the Child Behavior Checklist when their children were aged 5 and 7 years; teachers completed the Teacher's Report Form when the children were aged 7 years. RESULTS: Girls told more coherent narratives with less aggression than boys. Aggressive themes were found to correlate with behavior problems as in previous studies. Upon further examination, this correlation held for girls but not boys. Children who told repeated aggressive/incoherent narratives had more behavior problems than those who did not show this narrative pattern. CONCLUSIONS: The Story Stem methodology is useful for gaining access into the young child's inner world. The gender of the child, content of the story, and coherence of the story all provide useful information in identifying narratives that may indicate more risk for behavior problems.
Aggression↗
Contrast sensitivity and glare disability by halogen light after monofocal and multifocal lens implantation.
BACKGROUND: Standard examination of contrast sensitivity under conditions of glare disability is performed with incandescent light. A new halogen glare test that simulates glare as seen with oncoming vehicle headlights was used to measure glare disability in patients implanted with multifocal and monofocal intraocular lenses (IOLs). METHODS: 28 patients with an average age of 69 years (SD 12 years) were implanted with a monofocal IOL (SI-40NB, Allergan) and 28 patients with an average of 66 years (12 years) were implanted with a refractive multifocal IOL (Array-SA-40N, Allergan). All patients were followed for 5 months postoperatively. Contrast sensitivity at four spatial frequencies (3, 6, 12, and 18 cycles per degree, cpd) with and without a glare source were measured using the halogen glare test (CSV-1000 HGT). Statistical analysis was performed using the two sample Wilcoxon test. The local significance level was set at 0.05. RESULTS: When tested at the lowest spatial frequency (3 cpd) without halogen glare, contrast sensitivity was lower in the multifocal group than in the monofocal group (p=0.0292). With additional glare, there was no difference between both groups. At all other spatial frequencies (6, 12, and 18 cpd), when tested without halogen glare (6 cpd, p=0.5250; 12 cpd, p=0.8483; 18 cpd, p=0.9496) and with moderate (3 cpd, p=0.7993; 6 cpd, p=0.4639; 12 cpd, p=0.7456; 18 cpd, p=1.0) and high halogen glare (3 cpd, p=0. 1513; 6 cpd, p=0.2016; 12 cpd, p=0.3069; 18 cpd, p=0.9933), there was no statistically significant difference between groups. Patients in both groups of age 70 or older had reduced contrast sensitivity without halogen glare and with moderate and strong glare. When monofocal and multifocal patients older than 70 years of age were analysed separately, there was no statistically significant difference in contrast sensitivity with and without glare. Astigmatism >1 dioptre had no significant influence on contrast sensitivity and glare disability when monofocal and multifocal eyes were compared. CONCLUSION: Reduced contrast sensitivity was found in the multifocal group only at the lowest spatial frequency without halogen glare. The monofocal and multifocal groups had no statistically significant differences in contrast sensitivity with moderate and strong glare. These results suggest no difference in glare disability induced by halogen light similar to oncoming vehicle headlights for patients implanted with monofocal and multifocal IOLs.
Adult↗
Actin residue glu(93) is identified as an amino acid affecting myosin binding.
Many mutants have been described that affect the function of the actin encoded by the Drosophila melanogaster indirect flight muscle-specific actin gene, Act88F. We describe the development of procedures for purification of this actin from the other isoforms expressed in the fly as well as in vitro motility, single molecule force/displacement measurements, and stop-flow solution kinetic studies of the wild-type actin and that of the E93K mutation of the Act88F gene. We show that this mutation affects in vitro motility of F-actin, in both the presence and absence of methylcellulose, and the ability of the ACT88F actin to bind the S1 fragment of rabbit skeletal myosin. However, optical tweezer measurements of the actomyosin working stroke and the force transmitted from the rabbit heavy meromyosin to and through F-actin are unchanged by the mutation. These results support the proposal (Holmes, K. C. (1995) Biophys J. 68, (suppl.) 2-7) that actin residue Glu(93) is part of the secondary myosin binding site and suggest that myosin binding occurs first at the primary myosin binding site and then at the secondary site.
Actins↗
Expression of neurofilament L-promoter green-fluorescent protein constructs in immortalized Schwann cell-neuron coculture.
The neurofilament L/68 protein (NF-L/68) gene is expressed in the immature Schwann cell phenotype but suppressed after myelin-formation. We have investigated conditions which regulate the activity of the NF-L/68 promoter in green fluorescent protein reporter constructs expressed in the immortal rat Schwann cell strain SCL4.1/F7 in coculture with neurons. Constructs expressed in a plasmid vector containing both the full-length promoter and the 3' proximal 107 bp sequence which includes the cyclic AMP response element (CRE), were active in SCL4.1/F7 cells, but were suppressed as the cells underwent spontaneous growth-arrest. Interaction of SCL4.1/F7 with axons accelerated downregulation of expression from both constructs, however expression of the full-length promoter continued in some cells until the onset of myelin-formation. Expression of the NFL/68 construct recommenced when demyelination was induced in culture by exposure to human sera from patients with paraproteinemic gammopathy. We have demonstrated a method to study the regulation of gene expression patterns in single Schwann cells interacting with neurons and shown that different promoter regions may be controlled by axon-related and -unrelated factors.
Animals↗
Endophthalmitis in cataract surgery: results of a German survey.
OBJECTIVE: To document perioperative prophylactic treatment and to evaluate the risk factors for endophthalmitis after cataract surgery. DESIGN: Cross-sectional study via anonymous survey. PARTICIPANTS: Four hundred sixty-nine centers in Germany were queried. RESULTS: A total of 311 (67%) questionnaires were received, with each center reporting an average of 900 cataract surgeries per year (total, 340,633 surgeries in 1996). Respondents reported a total of 267 cases of endophthalmitis, which resulted in a mean responder-specific endophthalmitis rate of 0.148% versus a median rate of 0%. Statistical analysis via Poisson regression suggested that sclerocorneal incisions were associated with a reduced incidence of endophthalmitis (odds ratio, 0.35; 95% confidence interval, 0.24-0.51). Antibiotics used intraocularly (odds ratio, 0.65; 95% confidence interval, 0.43-0.98) and the preoperative application of diluted povidone-iodine on the conjunctiva (odds ratio, 0.59; 95% confidence interval, 0.36-0.99) were associated with a reduced risk of postoperative infection. Immune deficiencies (66%), diabetes mellitus (62%), occlusion of the lacrimal system (40%), and skin diseases (33%) were regarded as risk factors for endophthalmitis by the respondents. When cataract surgery is performed solely under inpatient conditions, the use of systemic antibiotics as well as the periocular injection of antibiotics at the end of the operation were associated (although not significantly) with a trend toward reducing the incidence of postoperative infection. Conversely, flushing the lacrimal drainage system, using eye shields, and cutting the eyelashes had no demonstrable effect in preventing endophthalmitis. The use of preoperative topical antibiotics (odds ratio, 2.38; 95% confidence interval, 1.21-4.68) and the performance of more than 20% of the surgeries in an outpatient center (odds ratio, 2.0; 95% confidence interval, 1.24-3.21) were associated with a detrimental effect on the development of endophthalmitis. CONCLUSIONS: Although the appropriate antibiotic agent and dosage are not yet established, the administration of intracameral antibiotics and the application of povidone-iodine on the conjunctiva significantly reduced the relative risk of postoperative endophthalmitis in this survey. Because the study was not individual based but rather on aggregate questionnaire, the results have to be interpreted with care.
Ambulatory Care↗
Differential memory span--abnormal lateralization pattern in schizophrenic patients and their siblings?
The recurring digit span test is hypothesized to assess consolidation memory and hypothetically addresses neuropsychological left-temporohippocampal functioning, an area of the brain which is presumed to play a crucial role in schizophrenia. The present study applied the recurring digit span memory test and the recurring block span memory test (assumed to be an indicator of right-temporohippocampal functioning) to 106 acute schizophrenic patients (DSM-III-R), 49 siblings of these patients without DSM-III-R lifetime diagnoses as well as 53 non-related control subjects without DSM-III-R lifetime diagnoses. Results of our investigation indicate that schizophrenic patients differ from control subjects regarding recurring digit span in a reduced number of correct reproductions of recurring trials. Since performance of schizophrenic patients was only non-significantly different from control subjects regarding recurring block span memory, our findings point to a task-specific memory impairment in schizophrenia and argue against a generalized deficit in this disease. Furthermore, individuals at risk for schizophrenia also differed from control subjects concerning the recurring digit span memory test but not with regard to the recurring block span test. Therefore we conclude that the reduced cumulative learning curve of verbal material (reduced number of correct reproduction of recurring digit trials) in schizophrenic patients and their healthy siblings might represent a marker for the liability to schizophrenia and parallels neuroimaging findings concerning left-sided temporohippocampal abnormalities in this disease, which presumably play a key role in the etiology of schizophrenia.
Adult↗
How many myeloid post-progenitor cells have to be transplanted to completely abrogate neutropenia after peripheral blood progenitor cell transplantation? Results of a computer simulation.
Although hematopoietic recovery following high-dose chemotherapy (HD-CT) and peripheral blood progenitor cell (PBPC) transplantation is rapid, there is still a 5- to 7-day period of severe neutropenia which, theoretically, might be abrogated by an additional transplantation of more differentiated myeloid post-progenitor cells (MPPC). However, both the number of MPPC required to abrogate neutropenia as well as the optimum scheduling of MPPC infusions are currently unknown. Therefore, these questions were addressed by applying a computer model of human granulopoiesis. First, model calculations simulating varying levels of chemotherapy dose intensity were performed and compared with typical clinical neutrophil recovery curves. Using this approach, the data for HD-CT without PBPC transplantation could be reproduced by assuming a reduction of stem cells, committed granulopoietic progenitors and proliferating precursors to about 0.001% of normal. PBPC-supported HD-CT was reproduced by increasing the starting values to at least 0.1%, which corresponded to about 1 to 2 x 10(5)/kg transplanted CFU-GM. Interestingly, reproduction of PBPC-supported HD-CT data could be observed for a wide range of starting values (0.1%-10% of normal), thus confirming the clinical observation that hematopoietic recovery after PBPCT cannot be improved by increasing the dose of transplanted cells over a certain threshold. Using the same simulation model, we then studied the effects of an additional MPPC transplantation. The results showed, that at least 5.7 X 10(8) MPPC/kg have to be provided in addition to the normal PBPC graft to avoid neutropenia <100/microL, and that MPPC are best transplanted on days 0 and 6 after HD-CT. Assuming a 100- to 120-fold cellular ex-vivo expansion rate and MPPC representing about 70% of total expanded cells, 5.7 X 10(8) MPPC/kg could be generated starting from 1 to 2 leukapheresis preparations with about 7 to 8 x 10(6) CD34+ PBPC/kg. Considering furthermore, that only a fraction of ex-vivo generated cells will seed and effectively produce neutrophils in-vivo, the required number of MPPC is most likely even higher and, therefore, might be difficult to be achieved clinically. However, the validity of the model results remains to be proven in appropriate clinical studies.
Antineoplastic Combined Chemotherapy Protocols↗
A new concept for melatonin deficit: on pineal calcification and melatonin excretion.
Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organs's size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system.
Adolescent↗