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Biomedical subjects

M Schuster

Publications and source records attributed to M Schuster.

At least 19 recordsLinked to original sources
PubMed1999

Mosaicism in a fragile X male including a de novo deletion in the FMR1 gene.

In most cases the fragile X syndrome is caused by an amplification of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene, in combination with the hypermethylation of the proximal CpG island. Recently, also a few cases with deletions or a mosaic of a deletion and a full mutation in the FMR1 gene, leading to the same phenotype, have been described. Here we report the molecular analysis of a patient with typical fragile X phenotype and mosaicism of the FMR1 genomic region consisting of a premutation, a full mutation of the CGG repeats, and a 215 bp deletion, diagnosed by Southern blot hybridisation and polymerase chain reaction (PCR). Sequence analysis of the deletion demonstrated that the 5' breakpoint of the deletion is located within a putative hotspot region 75-53 bp proximal to the CGG repeat.

Adult↗
PubMed1999

Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

BACKGROUND: In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. METHODS: We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. RESULTS: The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001). CONCLUSIONS: Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.

Adolescent↗
PubMed1998

CD95 ligand-induced apoptosis of human medulloblastoma cells.

CD95 ligand (CD95L) is a cytotoxic cytokine that induces apoptosis in susceptible target cells. Medulloblastoma is the most common non-glial intrinsic malignancy of the brain. In this study, we have studied CD95-mediated apoptosis of human medulloblastoma cell lines. We found that DAOY, MED-1 and D-283 cells are susceptible to CD95L-induced apoptosis when RNA and protein synthesis are inhibited. Preexposure of D-283, but not DAOY or MED-1 cells, to interferon-gamma or tumor necrosis factor-alpha enhances CD95 expression and primes these cells for CD95-mediated apoptosis. Inhibitors of interleukin 1-converting enzyme (ICE)-like protease (caspase) activity block CD95L-induced cytotoxicity, suggesting that caspases mediate the death signal induced by CD95L in human medulloblastoma cells. Interestingly, medulloblastoma cells belong to an increasing number of tumor cell types that coexpress CD95 and CD95L. We conclude that CD95 may be a promising target of immunochemotherapy for human medulloblastoma.

Animals↗
PubMed1998

Acetylation at Lys-92 enhances signaling by the chemotaxis response regulator protein CheY.

When Escherichia coli cells lacking all chemotaxis proteins except the response regulator CheY are exposed to acetate, clockwise flagellar rotation results, indicating the acetate stimulus has activated signaling by CheY. Acetate can be converted to acetyl-CoA by either of two different metabolic pathways, which proceed through acetyl phosphate or acetyl-AMP intermediates. In turn, CheY can be covalently modified by either intermediate in vitro, leading to phosphorylation or acetylation, respectively. Either pathway is sufficient to support the CheY-mediated response to acetate in vivo. Whereas phosphorylation of Asp-57 is a recognized mechanism for activation of CheY to stimulate clockwise flagellar rotation, acetylation of CheY is less well characterized. We found evidence for multiple CheY acetylation sites by mass spectrometry and directly identified Lys-92 and Lys-109 as acetylation sites by Edman degradation of peptides from [14C]acetate-labeled CheY. Replacement of CheY Lys-92, the preferred acetylation site, with Arg has little effect on chemotaxis but completely prevents the response to acetate via the acetyl-AMP pathway. Thus acetylation of Lys-92 activates clockwise signaling by CheY in vivo. The mechanism by which acetylation activates CheY apparently is not simple charge neutralization, nor does it involve enhanced binding to the FliM flagellar switch protein. Thus acetylation probably affects signal generation by CheY at a step after switch binding.

Acetate-CoA Ligase↗
PubMed1998

Surviving social assistance: 12-month prevalence of depression in sole-support parents receiving social assistance.

BACKGROUND: Although it is generally recognized that poverty and depression can coexist among single parents receiving social assistance, there is insufficient research on this topic. The goals of this study therefore were to investigate the prevalence, correlates and health care expenditures associated with depression among sole-support parents receiving social assistance. METHODS: Sole-support parents who had applied for social assistance in 2 regions of southwestern Ontario were included in the study. Depression was diagnosed with the 1994 University of Michigan Composite International Diagnostic Interview short forms. RESULTS: The 12-month prevalence rate of depressive disorder among the parents interviewed was 45.4% (345/760). A total of 247 (32.5%) had major depressive disorder alone, 19 (2.5%) had dysthymia, and 79 (10.4%) had both major depressive disorder and dysthymia ("double depression"). Those with major depressive disorder, particularly double depression, had significantly higher rates of coexisting psychiatric disorder than those without depressive disorders. Parents with depression reported higher rates of developmental delay and behaviour problems in their children than parents without depression. Expenditures for health care services were higher for parents with depression and for their children than for parents without depressive disorder and their children. INTERPRETATION: Single parents receiving social assistance have high rates of depression. Such parents with depression also have higher rates of other psychiatric disorders and higher expenditures for health care services, and their children have higher rates of developmental delay and behaviour problems.

Adaptation, Psychological↗
PubMed1998

Increasing immunization rates among inner-city, African American children. A randomized trial of case management.

CONTEXT: Immunization rates in the inner city remain lower than in the general US population, but efforts to raise immunization levels in inner-city areas have been largely untested. OBJECTIVE: To assess the effectiveness of case management in raising immunization levels among infants of inner-city, African American families. DESIGN: Randomized controlled trial with follow-up through 1 year of life. SETTING: Low-income areas of inner-city Los Angeles, Calif. PATIENTS: A representative sample of 419 African American infants and their families. INTERVENTIONS: In-depth assessment by case managers before infants were 6 weeks of age, with home visits 2 weeks prior to when immunizations were scheduled and additional follow-up visits as needed. MAIN OUTCOME MEASURES: Percentage of children with up-to-date immunizations at age 1 year, characteristics associated with improved immunization rates, and cost-effectiveness of case management intervention. RESULTS: A total of 365 newborns were followed up to age 1 year. Overall, the immunization completion for the case management group was 13.2 percentage points higher than the control group (63.8% vs 50.6%; P=.01). In a logistic model, the case management effect was limited to the 25% of the sample who reported 3 or fewer well-child visits (odds ratio, 3.43; 95% confidence interval, 1.26-9.35); for them, immunization levels increased by 28 percentage points. Although for the case management group intervention was not cost-effective ($12022 per additional child immunized), it was better ($4546) for the 25% of the sample identified retrospectively to have inadequate utilization of preventive health visits. CONCLUSIONS: A case management intervention in the first year of life was effective but not cost-effective at raising immunization levels in inner-city, African American infants. The intervention was demonstrated to be particularly effective for subpopulations that do not access well-child care; however, currently there are no means to identify these groups prospectively. For case management to be a useful tool to raise immunizations levels among high-risk populations, better methods of tracking and targeting, such as immunization registries, need to be developed.

Black or African American↗
PubMed1998

Reducing missed opportunities to vaccinate during child health visits. How effective are parent education and case management?

BACKGROUND: At child health visits, immunizations that are due are frequently not given. Increased parent understanding of and demand for immunizations may influence providers to not miss these opportunities. OBJECTIVE: To assess, as part of a larger study of effectiveness of parent education and case management (CM) in raising immunization rates, the intervention's effectiveness at reducing missed opportunities to vaccinate during child health visits. METHODS: A representative sample of African American newborns and their families from south central Los Angeles, Calif, were randomly assigned to a control or a CM group and observed during the first year of life. Case managers visited and telephoned parents, educating them on the benefits and safety of immunizations, and encouraging them to request immunizations from providers. When the children were at least 1 year of age, parents were interviewed and provider records were abstracted. RESULTS: Complete records were abstracted for 126 controls and 129 CM group children. For these children, 1092 visits were documented where immunizations were due. Missed opportunities to vaccinate occurred at more than 50% of visits. Case management was associated with a modest reduction in the percentage of visits with missed opportunities in the bivariate analysis but not after adjustment for other covariates. In a logistic regression model, missed opportunities were more frequent at visits with private than public physicians and at acute illness than well-child visits. Missed opportunities were less frequent among children with a history of at least 1 cancelled appointment, and for visits of children with mothers who smoked. CONCLUSIONS: Missed opportunities were minimally influenced by a home visitation and parent education program. They are primarily determined by issues under the control of the provider. Family- and child-related characteristics, however, do influence the likelihood of a missed opportunity occurring independent of provider factors.

Black or African American↗
PubMed1998

Solvent production by Clostridium beijerinckii NRRL B592 growing on different potato media.

Very good solvent formation rates were observed when Clostridium beijerinckii NRRL B592 was cultivated on different whole potato media. The increase in whole potato concentration contributed to the increased final solvent concentrations, while the addition of yeast extract or mineral salts gave negative effects. To obtain good solvent productivities and high final solvent concentrations during batch fermentation, no enzymatic hydrolysis of the potato starch was necessary, indicating high activity of the clostridial amylases produced by the strain applied.

Amylases↗
PubMed1998

Massachusetts Weapon-Related Injury Surveillance System.

CONTEXT: Surveillance data on nonfatal weapon-related injuries--particularly those treated only in the emergency department (ED)--have been largely unavailable. OBJECTIVE: To develop a surveillance system for fatal and nonfatal gunshot wounds and sharp instrument assaults. DESIGN: The Massachusetts Department of Public Health (DPH) developed an ED-based reporting system for weapon-related injuries. Inpatient discharges and mortality data were linked to ED data, and police data sources were evaluated. SETTING: Statewide. PARTICIPANTS: All 84 acute care hospital emergency departments. Uniform Hospital Discharge Data Set (UHDDS), mortality, and police data were obtained from existing systems. MAIN OUTCOME MEASURES: System sensitivity, predictive value positive (PVP), representativeness, flexibility, usefulness, acceptability, and sustainability. RESULTS: The ED reporting system captured 82% of firearm-related injuries and 74% of reportable sharp instrument wounds from 1994 to 1996. Case reporting by demographic characteristics of the victim was representative and largely complete. Reporting by characteristics of the incident (e.g., type of gun) was less reliable. Police data were used to augment the system. From 1994 to 1996, ED-treated gunshot wounds dropped 41%, from 662 in 1994 to 393 in 1996. Unintentional and self-inflicted gunshot wounds showed no declines. For every firearm-related homicide, 4.7 nonfatal firearm assaults were treated; 85% of self-inflicted gunshot wounds were fatal. CONCLUSIONS: The system has proven timely (1996 ED data were available for release in March 1997), flexible (the reporting form has been revised several times), useful (DPH responds to 150 weapon injury data requests annually), acceptable (reporting is voluntary and no hospital declined participation), and sustainable (state funding is currently supporting the ED reporting system).

Adolescent↗
PubMed1998

Soluble CD95 (Fas/APO-1) in malignant glioma: (no) implications for CD95-based immunotherapy?

CD95 targeting is a novel approach of immunotherapy for malignant glioma that might be antagonized by the release of soluble CD95 by the tumor cells. An alternatively spliced CD95 mRNA that encodes a secreted CD95 variant has been detected in glioma cell lines in vitro and in human tumors in vivo. Here, we report that the levels of soluble CD95 in the serum of malignant glioma patients do not differ from those of lumbar disk disease patients. Soluble CD95 was detected in the CSF in 2 of 20 malignant glioma patients by ELISA. Bioassay studies indicate that these low levels of soluble CD95 in the CSF of some patients with malignant glioma cells are unlikely to interfere with CD95-based immunotherapy of malignant gliomas in vivo.

Apoptosis↗
PubMed1998

Chemotactic response regulator mutant CheY95IV exhibits enhanced binding to the flagellar switch and phosphorylation-dependent constitutive signalling.

CheY, a response regulator protein in bacterial chemotaxis, mediates swimming behaviour through interaction with the flagellar switch protein, FliM. In its active, phosphorylated state, CheY binds to the motor switch complex and induces a change from counterclockwise (CCW) to clockwise (CW) flagellar rotation. The conformation of a conserved aromatic residue, tyrosine 106, has been proposed to play an important role in this signalling process. Here, we show that an isoleucine to valine substitution in CheY at position 95--in close proximity to residue 106--results in an extremely CW, hyperactive phenotype that is dependent on phosphorylation. Further biochemical characterization of this mutant protein revealed phosphorylation and dephosphorylation rates that were indistinguishable from those of wild-type CheY. CheY95IV, however, exhibited an increased binding affinity to FliM. Taken together, these results show for the first time a correlation between enhanced switch binding and constitutive signalling in bacterial chemotaxis. Considering present structural information, we also propose possible models for the role of residue 95 in the mechanism of CheY signal transduction.

Bacterial Proteins↗
PubMed1998

Importance of CD49d-VCAM interactions in human monocyte adhesion to porcine endothelium.

By using a primate model of natural antibody depletion, we have previously shown that delayed rejection of porcine cardiac xenografts in unmodified primate recipients resulted from xenograft infiltration with monocyte/macrophage lineage cells. In the present study, we initially showed that human monocytes/macrophages demonstrated significantly greater adherence to unstimulated pig aortic endothelial cells (PAEC) than to human umbilical vein endothelial cells (HUVEC). Human TNF-alpha augmented monocyte adhesion to HUVEC by 5-fold higher levels than to PAEC. This effect could not be explained on the basis of incompatibility between human TNF-alpha and its receptor on PAEC since porcine VCAM expression increased by 75-85% after stimulation with TNF-alpha. TNF-augmented monocyte adherence was abrogated by either treatment of PAEC with an anti-VCAM Mab or monocytes with an anti-CD49d Mab. These results suggest that VCAM-CD49d interactions are important in adhesion of human monocytes to PAEC but may not be as effective as those between human monocytes and allogeneic endothelium, perhaps because of structural differences across species. Other interactions, as yet undefined, must explain the relative increase in adhesiveness of human monocytes for unstimulated PAEC versus HUVEC. In experiments investigating the functional consequences of this enhanced monocyte adherence, PAEC stimulation induced 10-fold higher levels of macrophage-derived IL-1 beta and 3-fold higher levels of T cell proliferation compared with HUVEC. Using an anti-DR Mab to interrupt antigen presentation by autologous macrophages markedly reduced the T cell proliferative response to PAEC. Together, these results indicate that the enhanced adherence of human monocytes to PAEC contributes to xenograft rejection beyond the hyperacute period by leading to tissue infiltration, elaboration of cytokines, and an augmented indirect pathway of T cell xenoantigen recognition.

Animals↗
PubMed1998

Computer-aided resolution of an experimental paradox in bacterial chemotaxis.

Escherichia coli responds to its environment by means of a network of intracellular reactions which process signals from membrane-bound receptors and relay them to the flagellar motors. Although characterization of the reactions in the chemotaxis signaling pathway is sufficiently complete to construct computer simulations that predict the phenotypes of mutant strains with a high degree of accuracy, two previous experimental investigations of the activity remaining upon genetic deletion of multiple signaling components yielded several contradictory results (M. P. Conley, A. J. Wolfe, D. F. Blair, and H. C. Berg, J. Bacteriol. 171:5190-5193, 1989; J. D. Liu and J. S. Parkinson, Proc. Natl. Acad. Sci. USA 86:8703-8707, 1989). For example, "building up" the pathway by adding back CheA and CheY to a gutted strain lacking chemotaxis genes resulted in counterclockwise flagellar rotation whereas "breaking down" the pathway by deleting chemotaxis genes except cheA and cheY resulted in alternating episodes of clockwise and counterclockwise flagellar rotation. Our computer simulation predicts that trace amounts of CheZ expressed in the gutted strain could account for this difference. We tested this explanation experimentally by constructing a mutant containing a new deletion of the che genes that cannot express CheZ and verified that the behavior of strains built up from the new deletion does in fact conform to both the phenotypes observed for breakdown strains and computer-generated predictions. Our findings consolidate the present view of the chemotaxis signaling pathway and highlight the utility of molecularly based computer models in the analysis of complex biochemical networks.

Acetates↗
PubMed1998

Improving the quality of healthcare for children: implementing the results of the AHSR research agenda conference.

OBJECTIVE: To describe the rationale, development, content, and results of the AHSR-sponsored conference on developing a research agenda focused on improving the quality of care for children. DATA SOURCES AND METHODS: Planning documents, background papers, and conference proceedings. PRINCIPAL FINDINGS: The conference developed the research agenda focused on (1) monitoring the health of children; (2) evaluating the efficacy and effectiveness of health services for children; (3) assessing the quality of healthcare provided to children; (4) improving the quality of healthcare within health systems; (5) assessing the performance of community systems for children; (6) exploring the impact of different financial incentives on the provision of pediatric healthcare; and (7) developing and disseminating clinical practice guidelines and other information to physicians, families, and consumers. Specific issues and research questions in each area are also presented. Strategies for implementing the research agenda are presented and include: (1) expanding the child health services research workforce; (2) developing child healthcare quality improvement research centers; (3) conducting research in specific high-priority areas; (4) focusing research on improving the health of vulnerable populations; (5) improving child health data and collection systems at the national level; (6) developing better community health monitoring for children; (7) building and supporting research networks and a consortium of research users; and (8) developing a coordinated interagency federal effort to advance this agenda and to provide accountability for its completion. CONCLUSION: The proposed research agenda should be a national priority so that all Americans can be assured that children are receiving the best quality of care that the United States can provide.

Child↗
PubMed1997

Endometrial resection and late reoperation in the treatment of menorrhagia.

STUDY OBJECTIVE: To evaluate the effectiveness of transcervical resection of the endometrium and indications for late reoperation. DESIGN: Retrospective study. SETTING: Central hospital in northern Norway. PATIENTS: Two hundred fifty women (age 30-59 yrs) with dysfunctional bleeding. INTERVENTIONS: Hysteroscopic transcervical resection of the endometrium. MEASUREMENTS AND MAIN RESULTS: Success as measured by patient satisfaction at 3-month follow-up was 97% and at 4 to 48 months was 91.6%. Mean observation time was 24 months. Twenty-one women required further surgery. Repeat resection was performed in eight women (3.2%), of whom 95% were satisfied. Thirteen women (5.2%) had a hysterectomy. Late reoperation was performed in 7 patients (2.8%) due to recurrent unacceptable vaginal bleeding and in 14 (5.6%) due to late onset of pain. CONCLUSION: After endometrial resection, a definite subgroup (8.4%) of women developed late onset of pain or bleeding requiring reoperation.

Adult↗