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Biomedical subjects

J Wagner

Publications and source records attributed to J Wagner.

At least 163 records · Page 9Linked to original sources
PubMed1996

Validity of the rapid buffering approximation near a point source of calcium ions.

In the presence of rapid buffers the full reaction-diffusion equations describing Ca2+ transport can be reduced using the rapid buffering approximation to a single transport equation for [Ca2+]. Here we simulate the full and reduced equations, exploring the conditions necessary for the validity of the rapid buffering approximation for an isolated Ca2+ channel or a cluster of channels. Using a point source and performing numerical simulations of different durations, we quantify the error of the rapid buffering approximation as a function of buffer and source parameters as well as the time and spatial scale set by the resolution of confocal microscopic measurements. We carry out simulations of Ca2+ "sparks" and "puffs," both with and without the indicator dye Ca2+ Green-1, and find that the rapid buffering approximation is excellent. These calculations also show that the traditional calculation of [Ca2+] from a fluorescence signal may grossly underestimate the true value of [Ca2+] near a source. Finally, we use the full model to simulate the transient Ca2+ domain near the pore of an open Ca2+ channel in a cell dialyzed with millimolar concentrations of 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid or EGTA. In this regime, where the rapid buffering approximation is poor. Neher's equation for the steady-state Ca2+ profile is shown to be a reliable approximation adjacent to the pore.

Biophysical Phenomena↗
PubMed1996

Using clinical and functional data for quality improvement in outcomes measurement consortia.

BACKGROUND: Using standardized measures, American Group Practice Association care providers compiled a national database from which patients could be tracked, allowing for epidemiologic comparisons among treatments, sources of care, and results. Within five years, the consortia expanded from 6 to 55 clinics and from a focus on total hip replacement surgery to eight different health conditions. DATA COLLECTION PROCESS: Reflecting areas of significant public concern, high prevalence, high cost, or research needs, both patient- and provider-source data are collected at group practices at standardized intervals: 6 months, 12 months, and annually thereafter. OUTCOMES DATA MANAGEMENT AND REPORTING: A readily adaptable database infrastructure allows data-collection tools to adapt individual questions to changing conditions in the health care environment while maintaining the integrity of the whole structure. Aggregate-level reports complement individual clinics' own internal analysis efforts by providing a context for the interpretation of results. CASE STUDIES: In a total hip replacement consortium (including more than 2,300 patients), early findings have shown that patients do not fully recover from surgery as quickly as they themselves anticipated. In the cataract consortium, data scores on near, distant, day, night, glare, and overall vision scales improve considerably after cataract surgery, giving clinics a new tool to monitor and improve performance. In the asthma consortium, one clinic reevaluated the distribution of peak flow meters and the reasons for their underuse after noting the low number of patients in the clinic that had peak flow meters. LESSONS LEARNED: Provider participation in study design, instrumentation, data analysis, and feedback is important, and physician buy-in and support are critical to the success of any outcomes initiative. Missing data are the greatest limitations of a longitudinal data set and are difficult to collect through follow-up. There is still much to be learned about what functional status and well being measures can show about the relationship between health care services and patient health.

Asthma↗
PubMed1996

Human Cart-1: structural organization, chromosomal localization, and functional analysis of a cartilage-specific homeodomain cDNA.

Homeoproteins control cell fates during development, specifying pattern formation and the ontogeny of specific tissues and organs in embryogenesis. Cart-1 cDNA was recently cloned from a rat chondrosarcoma tumor and it encodes a protein containing a paired-like homeodomain that is selectively expressed in cartilage during early chondrocyte differentiation. Here we report the molecular cloning of the human Cart-1 cDNA from a HeLa cervical carcinoma cDNA library. The human Cart-1 cDNA sequence is 88% identical and the deduced amino acid sequence is 95% identical to the rat sequence, indicating that Cart-1 structure is highly conserved. Northern and reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed Cart-1 mRNA expression in HeLa cervical carcinoma cells and human cervical tissue, but Cart-1 mRNA was not detected in GH3 rat pituitary cells and murine 10T1/2 one-half fibroblast cells. The Cart-1 gene was localized to human chromosome 12 and regionally mapped to the 12q21.3-q22 by PCR analysis of rodent-X-human somatic cell hybrid DNA and the CEPH megabase-insert YAC DNA pools, respectively. The Holt-Oram syndrome, characterized by upper limb and atrial septal dysplasias, also maps to the 12q21.3-q22 region. Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. Taken together, these data indicate that Cart-1 may also influence cervix development, identify a putative DNA binding site for Cart-1, and, begin to define its functional role as modulator of gene expression.

Amino Acid Sequence↗
PubMed1996

Immune functions of cord blood cells before and after transplantation.

There have been numerous reports of decreased acute and chronic graft-versus-host disease in patients receiving HLA-matched or HLA-disparate umbilical cord transplants. It has been proposed that this may be due to the unique properties of the neonatal immune system, which permit the development of tolerance to alloantigens. This review discusses experimental evidence contrasting the immune functions of cells derived from cord blood and those from peripheral blood.

Antigens, CD↗
PubMed1996

Chlamydia pneumoniae as a cause of community-acquired pneumonia in hospitalized patients in Berlin.

The incidence of community-acquired pneumonia due to Chlamydia pneumoniae was evaluated in a 1-year prospective study of 236 hospitalized patients with 237 manifestations of pneumonia. The microbiological diagnosis was based on results of cultures of blood and sputum or bronchoalveolar lavage fluid and results of complement fixation tests and indirect immunofluorescence of acute- and convalescent-phase sera for C. pneumoniae, Mycoplasma pneumoniae, Legionella species, Coxiella burnetii, and respiratory viruses. Diagnosis of acute C. pneumoniae infection was made on the basis of the results of microimmunofluorescence of paired serum samples. A microbiological diagnosis was obtained in 160 cases (67.5%). C. pneumoniae was the causative agent in 27 patients (11.4%). The following organisms were the other etiologic agents of pneumonia: Streptococcus pneumoniae, 30 cases (12.7%) (bacteremia occurred in 53.3%); Mycoplasma pneumoniae, 22 (9.3%); respiratory viruses, 22 (9.3%); and Enterobacteriaceae, 18 (7.6%). The prevalence of C. pneumoniae antibody in our study population was 47.5%. As has been increasingly reported in recent years and confirmed by this study, C. pneumoniae appears to be a common etiologic agent of community-acquired pneumonia and upper respiratory tract infection in Germany.

Adolescent↗
PubMed1996

Pharmacokinetics of sparfloxacin and serum bactericidal activity against pneumococci.

Sparfloxacin, a new fluorinated quinolone, exhibits higher in vitro activity against pneumococci than do ciprofloxacin and ofloxacin. Since up to 30% of cases of pneumococcal pneumonia are associated with bacteremia, and since an increasing percentage of pneumococci are resistant against penicillin, we studied the serum bactericidal activity of sparfloxacin against pneumococci in eight healthy, middle-aged volunteers. Pharmacokinetics in serum and urine after a 400-mg oral dose of sparfloxacin were comparable to those described by other authors. Inhibitory and bactericidal activities in serum were measured for four pneumococcal isolates representing penicillin-susceptible (one isolate), intermediately resistant (two isolates), and highly resistant (one isolate) strains. Geometric mean inhibitory titers ranged between 1:2.4 and 1:6.3 and bactericidal titers ranged between 1:1.3 and 1:3.6 during a time period of 1 to 6 h after drug intake. Although such titers were not sufficient to predict a clinical response based on previous pharmacodynamic studies using quinolone antibiotics, data obtained with volunteers may only partially reflect the clinical situation in which a rise of humoral antibodies directed against pneumococcal antigens may help to reinforce the bactericidal action of the antibiotic.

Adult↗
PubMed1996

Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system.

AIMS/BACKGROUND: All components necessary for the formation of angiotensin II, the biologically active product of the renin-angiotensin system (RAS), have been demonstrated in ocular tissue or vitreous and subretinal fluid. The tissue concentrations of renin were too high to be explained by admixture of blood. This raises the possibility of an intraocular RAS, independent of the RAS in the circulation. METHODS: In the present study, gene expression of RAS components in different parts of enucleated human eyes was investigated as evidence for tissue specific production. RESULTS: By using pooled tissue samples renin mRNA could be detected with the RNAse protection assay in retinal pigment epithelium (RPE) choroid, but not in neural retina or sclera. With reverse transcription polymerase chain reaction (RT-PCR), renin mRNA was detected in individual samples of RPE choroid and neural retina, and not anterior uveal tract or sclera. Angiotensinogen and angiotensin converting enzyme (ACE) gene expression could be demonstrated by RT-PCR in individual RPE choroid and neural retina samples and marginally in sclera samples. CONCLUSIONS: These results support the concept of intraocular synthesis of angiotensin II, independent of renin, angiotensin, and ACE in the circulation. Since gene expression was highest in ocular parts, which are highly vascularised, local angiotensin II may be involved in blood supply and/or pathological vascular processes such as neovascularisation in diabetic retinopathy.

Adult↗
PubMed1996

Human renin-dependent hypertension in rats transgenic for human angiotensinogen.

To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed assays to measure both the human and rat renin-angiotensin systems in these rats. We used human and mouse renin, transgenic human angiotensinogen, and the human renin inhibitor Ro 42-5892 to determine human- and rat-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human plasma mixed in known amounts and with plasma from rats transgenic for human renin. We then tested the human angiotensinogen-transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osmotic minipumps. High human angiotensinogen transgene expression was found in the liver, brain, kidney, gastrointestinal tract, and aorta, whereas rat angiotensinogen gene expression was detected in the liver and brain. During human renin infusion, blood pressure increased to >200/150 mm Hg. Before infusion, human angiotensinogen was 100-fold greater than rat angiotensinogen (141 +/- 73 versus 1.2 +/- 0.16 microg angiotensin l/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increased to very high levels (449 +/- 262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable levels. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. However, even at these levels, human angiotensinogen was not rate limiting and angiotensin II was not a significant stimulus for angiotensinogen production. We conclude that these transgenic rats represent a novel model of human renin-dependent hypertension.

Angiotensinogen↗
PubMed1996

Bone marrow transplantation. New strategies for treating malignant disease.

In the years since the world's first successful bone marrow transplant (BMT) was performed at the University of Minnesota in 1968, the field of bone marrow transplantation has evolved rapidly. Stem cells can be obtained from a variety of sources: bone marrow from a matched sibling or unrelated donor (allogeneic transplant), bone marrow or peripheral blood from the patient (autologous transplant), and umbilical cord blood that was collected and stored after delivery for later use by the infant, a matched sibling, or an unrelated patient. Bone marrow transplantation is a widely accepted and successful therapy for treating a variety of malignant and nonmalignant diseases. Continuing research should yield new methods to ensure successful engraftment and to prevent or reduce complications post-BMT. Many patients with cancer have been cured with BMT. However, much work remains to improve survival and to better manage complications. New approaches under investigation may expand the availability of transplantation and improve short- and long-term survival and quality of life.

Adult↗
PubMed1996

Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation.

BACKGROUND: Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists. STUDY DESIGN: 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks. METHODS: Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR. RESULTS: SNX caused a significant (P < 0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01) higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/- 0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P < 0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P < 0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower. CONCLUSION: Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomerulosclerosis by mechanisms which are, at least in part, independent of systemic blood pressure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Characteristics of patients younger than 40 years of age operated for coronary artery disease.

This study reviews data on 126 patients (107 men, 19 women) younger than 40 years of age who underwent coronary artery bypass grafting during an 8-year period. They were matched to a control group which also consisted of 126 operated patients but exceeding the age of 39. The majority of the patients in the study group presented with angina; 85.9% were CCS III or IV compared to 61.9% in the control group. More than 3 fourths of the patients (80.5%) had experienced at least 1 myocardial infarction. There was a high incidence of coronary risk factors, especially hyperlipoproteinemia (88.5%), smoking (85.1%), and hypertension (83.1%), whereas in the control group these risk factors occurred in only 49.2%, 21.4%, and 53.2% of the patients, respectively. Other risk factors like diabetes mellitus or family history of coronary artery disease were found in 10.3% and 48.6% of the young patients. While 23.0% of the patients had varying degrees of left main stenosis, 9.5%, 18.3%, and 72.2% had single, double, and triple vessel disease, respectively. Left ventriculograms showed serious functional impairment (ejection fraction less than 40%) in 22.2% of the patients. A total of 286 saphenous vein grafts (2.3 grafts per patient) and 126 internal mammarian grafts were implanted, whereby an internal mammarian graft was always used. In 6 patients we used an intermittent mechanical support system (intraaortic balloon pump in 5 patients and an assist device in 1). In-hospital mortality rate was 1.6% (2 patients); long-term mortality rate 5.2% (mean follow-up interval 54 +/- 20 months). Actuarial survival was 93.0%, 89.8%, and 89.8% at 3,5, and 7 years, respectively. Survival in patients with normal and impaired ejection fraction was significantly different (p < 0.035) for 5-year and 7-year survival (100% vs. 81.8%). We observed encouraging intermediate term results in young adult patients after coronary revascularization. This may have been due to the consistent use of internal mammary artery grafts.

Actuarial Analysis↗
PubMed1996

Knowledge sources for Natural Language Processing.

This paper aims at reviewing the problem of feeding Natural Language Processing (NLP) tools with convenient linguistic knowledge in the medical domain. A syntactic approach lacks the potential to solve a number of typical situations with ambiguities and is clearly insufficient for quality treatment of natural language. On the other hand, a conceptual approach relies on some modelling of the domain, of which the elaboration is d long-term process and where the ultimate solutions are far from being recognised and universally accepted. In-between is the beauty of the compromise. How can we significantly improve the coverage of linguistic knowledge in the years to come?

Artificial Intelligence↗
PubMed1996

[Development of a model of human renin hypertension in rats].

The effective development of human renin inhibitors meets its major obstacle in the absence of a suitable experimental rodent model and the species-specificity of human renin, exclusively cleaving its natural substrate human angiotensinogen. We have reconstructed the human renin-angiotensin system in transgenic rats over expressing the human angiotensinogen gene TGR (hAOGEN) 1623 by chronically injecting i.v. human recombinant renin. We have first established new in vitro enzyme kinetic techniques to measure the various components of the chimeric renin-angiotensin system and distinguished the two human and rat-specific pathways of generating angiotensin I by the human specific renin inhibitor Ro 42-5892 (Hoffmann-La Roche). Male heterozygous TGR had plasma levels of rat angiotensinogen of 1.2 +/- 0.2 mg Ang l/ml while the plasma levels of the transgene were 141 +/- 98 mg Ang l/ml (n = 41; not normally distributed). Transgene expression was found in the liver kidney, aorta, heart and adrenals. Four rats were infused i.v. with human recombinant renin at 50 ng/h over 9 days which chronically increased their blood pressure to > 200 mmHg while total plasma renin activity increased by a factor of 300. Rat renin disappeared form the plasma. This new model of experimental human renin-induced hypertension in rats will facilitate the screening and characterization of human renin inhibitors.

Angiotensinogen↗
PubMed1995

Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes.

Antibodies that catalyze the aldol reaction, a basic carbon-carbon bond-forming reaction, have been generated. The mechanism for antibody catalysis of this reaction mimics that used by natural class I aldolase enzymes. Immunization with a reactive compound covalently trapped a Lys residue in the binding pocket of the antibody by formation of a stable vinylogous amide. The reaction mechanism for the formation of the covalent antibody-hapten complex was recruited to catalyze the aldol reaction. The antibodies use the epsilon-amino group of Lys to form an enamine with ketone substrates and use this enamine as a nascent carbon nucleophile to attack the second substrate, an aldehyde, to form a new carbon-carbon bond. The antibodies control the diastereofacial selectivity of the reaction in both Cram-Felkin and anti-Cram-Felkin directions.

Acetone↗
PubMed1995

Late infections after allogeneic bone marrow transplantations: comparison of incidence in related and unrelated donor transplant recipients.

Infectious complications are a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). We have evaluated the incidence of late infections (beyond day +50) in recipients of related (RD) and unrelated donor (URD) allogeneic BMT, factors associated with increased risks of infection, and the impact of the late infections on survival. Between 1989 and 1991, 249 patients received an RD (n = 151) or URD (n = 98) allogeneic BMT at the University of Minnesota and all late infections were investigated. Three hundred sixty-seven late infectious events developed in 162 patients between 50 days and 2 years after BMT. The incidence of any late infection was greater in URD versus RD recipients (84.7% v 68.2%, respectively; P = .009). In multivariate analysis, advanced graft-versus-host disease (GVHD) was significantly associated with late infections. The effect of GVHD was apparent only in RD recipients (relative risk [RR], 2.29; P = .003), whereas URD recipients, with or without GVHD, had more late infections compared with RD recipients without GVHD. Multivariate analysis showed that late posttransplantation infections were the dominant independent factor associated with increased nonrelapse mortality (RR, 5.5; P = .0001), resulting in improved 3-year survival for RD versus URD recipients (49.9% +/- 8% v 34.4% +/- 10%; P = .004). In this study, we observed that late infections are more frequent in URD recipients, resulting in substantially higher nonrelapse mortality. This prolonged period of increased infectious risk in URD recipients suggests the need for aggressive surveillance and therapy of late infections and perhaps prolonged antibiotic prophylaxis for all URD BMT recipients.

Adolescent↗
PubMed1995

Structure of the murine MPTP-PEST gene: genomic organization and chromosomal mapping.

Protein tyrosine phosphatases comprise a large family of enzymes that are involved in the control of cellular tyrosine phosphorylation. We have used lambda phage analysis to elucidate the complete genomic structure of an intracellular member of this family, the murine MPTP-PEST gene. Eight overlapping lambda phage clones representing the MPTP-PEST locus were isolated from a 129/sv mouse genomic library. The gene spans over 90 kb of the mouse genome and is composed of 18 exons, 10 of which constitute the catalytic phosphatase domain. Detailed comparison of the position of intron/exon boundaries of the phosphatase domain of MPTP-PEST to those of several other protein tyrosine phosphatases indicates that the MPTP-PEST catalytic domain contains additional exons as a consequence of the insertion of novel introns. In addition, this analysis reveals a strong conservation of the genomic organization within the catalytic domain of the protein tyrosine phosphatase gene family. Finally, fluorescence in situ hybridization with MPTP-PEST genomic DNA refines the map position of MPTP-PEST to mouse chromosome 5A3 to B. This result is in agreement with the previous mapping of the human PEST gene to chromosome 7q11.23, a region of synteny with the centromeric portion of mouse chromosome 5.

Amino Acid Sequence↗