Biomedical subjects
K Schmidt
Publications and source records attributed to K Schmidt.
Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.
We have conducted a comprehensive study of the molecular basis of cystic fibrosis (CF) in 350 German CF patients. A screening approach based on single-strand conformation analysis and direct sequencing of genomic polymerase chain reaction products has allowed us to detect the molecular defects on 95.4% of the CF chromosomes within the coding region and splice sites of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The spectrum of sequence changes comprises 54 different mutations, including 17 missense mutations, 14 nonsense mutations, 11 frameshift mutations, 10 splice site variants and two amino acid deletions. Eleven of these mutations have not previously been described. Our results reflect the marked mutational heterogeneity of CF in a large sample of patients from a non-isolated population.
[High dosage intravenous gamma globulin therapy in juvenile dermatomyositis].
In the last few years high-dose intravenous therapy with gammaglobulin in juvenile dermatomyositis with steroid resistant myopathy has been discussed as an alternative to cytostatic therapy. The 12-year-old Filipinogirl suffered from dermatomyositis with pronounced weakness of the limbs and masticatory muscles; creatinine-kinase was increased 22-fold. After 5 weeks of therapy with prednisolone (1.5 mg/kg body/weight/daily), the creatinine kinase decreased to sixfold of its standard value; the muscular weakness, however, progressed to almost complete paralysis of the scapular abductors and rotators and the coxofemoral flectors and rotators. Additional therapy with gammaglobulin at a dose of 1 g/kg body weight on two consecutive days at 4-week intervals led to complete restoration of muscular strength, normalization of muscle enzymes, and stabilization of these results after 12 courses of gammaglobulin and discontinuation of the steroid medication after 8 courses. This observation suggests that high-dose intravenous application of gammaglobulin represents an efficient therapy with minimal side effects in steroid-resistant juvenile dermatomyositis.
Molecular mechanisms of inhibition of porcine brain nitric oxide synthase by the antinociceptive drug 7-nitro-indazole.
7-Nitro-indazole (7-NI) has been described as novel nitric oxide synthase (NOS) inhibitor with in vivo selectivity for the neuronal isozyme [Moore et al. Br. J. Phaarmac. 110, 219-224 (1993)]. In the present study we have used purified porcine brain NOS to investigate the molecular mechanisms of enzyme inhibition by 7-NI. The drug was competitive with L-arginine, exhibited a kinetic KI of 2.8 microM, and additionally induced a slight reduction in Vmax. As a cytochrome P-450, NOS catalyzes a heme-mediated reduction of molecular oxygen, resulting in the formation of H2O2 in the absence of L-arginine. 7-NI turned out as a potent inhibitor of H2O2 formation (IC50 = 0.28 +/- 0.096 microM) but did not affect flavin-mediated electron transfer. Thus, 7-NI resembled imidazole, a known heme-site inhibitor of NOS. We found that imidazole was a purely competitive inhibitor of L-citrulline formation (KI = 263 microM) and blocked H2O2 formation at similar concentrations (IC50 = 280 +/- 38 microM). In accordance with their L-arginine-competitive effects in the citrulline assay, both drugs antagonized binding of radiolabeled NG-nitro-L-arginine (L-NNA), a high affinity probe for reversible labelling of the substrate site of NOS [Klatt et al., J. Biol. Chem. 269, 14781-14787 (1994)]. The calculated KI values for 7-NI and imidazole were 0.09 +/- 0.024 microM and 200 +/- 63 microM, respectively. Finally, binding of radiolabelled tetrahydrobiopterin, a NOS cofactor with unknown function, was also antagonized by 7-NI with a KI of 0.12 +/- 0.023 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term compliance of intensified insulin therapy.
Results of the DCCT trial (N. Engl. J. Med. 329, 977-986) demonstrate that therapy in insulin-dependent diabetes mellitus (IDDM) should aim at near-normoglycemia. For reaching this standard, intensified insulin therapy--either intensified conventional therapy (ICT) or continuous subcutaneous insulin infusion (CSII)--is mandatory. These regimes demand much long-term motivation and discipline from the diabetics. With > 95%, long-term compliance of ICT is good, according to the few published data available and our own experience. For CSII, on the other hand, cumulated studies reveal discontinuation rates ranging from 0% to 36%, averaging 20.4% and being significantly correlated with metabolic control before start of CSII in terms of glycosylated hemoglobin levels (r = 0.66; P < 0.05). The major reasons for discontinuation of CSII were skin problems (22.1%), inconvenience of the pump (21.4%) and lack of metabolic improvement (9.6%). A conclusion drawn from these meta-analytical data is that a stepwise approach to CSII is recommended for increasing compliance. A period of ICT long enough to gain experience with blood glucose self-control and self-adjustment of meal-related insulin should precede CSII. Furthermore, a general increase of CSII among IDDM patients is necessary to come closer to the standard of near-normoglycemia for these diabetics. Therefore, diabetes treatment and education resources must be improved, especially concerning psychosocial problem solving and cooperation between diabetologists and general practitioners.
Tissue characterization using intelligent adaptive filter in the diagnosis of diffuse and focal liver disease.
In ultrasonic imaging an adaptive two-dimensional filter (ATDF) can suppress randomly generated speckle using the ratio of the local variance to the local mean as the speckle recognition feature (R). The degree of smoothing depends on the difference between the recognition feature in the region to be filtered and the selected reference tissue. We have investigated the clinical application of ATDF for ultrasound B-mode images of liver abnormalities. Using the R values of normal liver as reference values, the ATDF images were displayed. Normal livers (n = 17, R = 2.19 +/- 0.14 M +/- SEM), fatty livers (N = 16, R = 1.89 +/- 0.15) and those with acute hepatitis (N = 10, R = 2.25 +/- 0.18) appeared smooth after application of the adaptive filter, but those diseases with higher R values, such as chronic hepatitis (N = 10, R = 3.04 +/- 0.30), cirrhosis (n = 16, R = 4.44 +/- 0.30), metastases (N = 16, R = 6.43 +/- 0.53) and hepatocellular carcinomas (N = 8, R = 7.92 +/- 0.85), were largely unsmoothed. In conclusion, ATDF allows differentiation of some forms of liver disease and may be helpful in the detection of microfocal echogenic textural lesions.
The use of spectral analysis to determine regional cerebral glucose utilization with positron emission tomography and [18F]fluorodeoxyglucose: theory, implementation, and optimization procedures.
A method for kinetic analysis of dynamic positron emission tomography (PET) data by linear programming that allows identification of the components of a measured PET signal without predefining a compartmental model has recently been proposed by Cunningham and co-workers. The method identifies a small subset of functions from a large input set of feasible functions that best fits the time course of total radioactivity measured by PET. To investigate in detail the properties of this technique, we applied it to PET studies with [18F]fluorodeoxyglucose, a tracer with well-characterized kinetic properties. We examined dynamically acquired data over various time intervals in many brain regions and found that the number of components identified by the method is stable and consistent with the presence of kinetic heterogeneity in every region. We optimized the method for determination of regional rates of glucose utilization; calculated rates were found to be somewhat dependent upon the treatment of noise in the measured tissue data and upon the time interval in which the data were collected. The application of a numerical filter to remove noise in the data resulted in values for regional cerebral glucose utilization that were stable with time and consistent with rates determined by the other established techniques. Based on the results of the current study, we expect that the spectral analysis technique will prove to be a highly flexible tool for kinetic analysis of other tracer compounds; it is capable of producing low-variance, time-stable estimates of physiological parameters when optimized for time interval of application, input spectrum of components, and processing of noise in the data.
Implementation of the AHCPR pain guidelines for children.
Successful implementation of Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines must involve an institutional commitment and an interdisciplinary effort. This article describes how a pediatric nursing research committee took the leadership role in implementing the AHCPR acute pain guidelines for children. Steps toward implementation included assessment of current practice methods, nursing interventions, interdisciplinary interventions, and plans for evaluating the practice change through the institutional quality assessment and improvement program.
First observation of the beta -delayed proton decay of 52Ni.
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Production cross sections and the particle stability of proton-rich nuclei from 58Ni fragmentation.
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Pediatric cancer pain management: a survey of nurses' knowledge.
This study assesses the knowledge base of pediatric nurses in Iowa regarding cancer pain. The Iowa Cancer Pain Relief Initiative surveyed 10,000 nurses in the state of Iowa (representing approximately 25% of all actively licensed nurses in the state). A demographic question allowed pediatric nurses' responses to be separated and analyzed independently. One hundred six of the respondents indicated their primary area of practice to be pediatrics, and it is this group of respondents that was analyzed. Content analysis of questionnaires from pediatric respondents indicated that pediatric nurses cared for cancer patients regularly but had poor understanding of general principles of pain management for the cancer patient. Nurses had exaggerated concerns regarding the risk of addiction and respiratory depression associated with narcotic analgesics. They also had poor understanding of basic pharmacokinetic principles of common analgesic agents.
[Pruritus in internal diseases].
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How to apply the AHCPR's pediatric pain guideline.
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[Fatal diffuse alveolar damage after gold medication].
We report about the case of a 74-year-old woman who suffered diffuse alveolar damage and consecutive lethal pulmonary failure after gold therapy for rheumatoid arthritis. This is the fourth documented case of fatal pulmonary failure following gold therapy. The clinical findings were dominated by severe dyspnoea that warranted respirator therapy shortly after admission. Chest radiographs showed progressing confluent perihilar patchy infiltrates that suggested interstitial involvement. Steroid therapy had only a short-lasting effect on the respiratory failure, the patient died in prolonged hypoxic circulatory failure. Post-mortem examination showed the organotypical findings of diffuse alveolar damage in proliferative stage with advanced pulmonary fibrosis. With the discontinuation of gold medication and early steroid therapy, this disease which is based on immunological pathomechanisms is usually reversible. Both the knowledge of this entity and early diagnosis are essential for a promising therapeutic intervention.
Reversible inactivation of endothelial nitric oxide synthase by NG-nitro-L-arginine.
NG-Methyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA) inhibited NO-induced cGMP accumulation in porcine aortic endothelial cells with half-maximally effective concentrations of 15 and 3.4 microM, respectively. The effects of both compounds were reversible, but the L-NNA-induced inhibition was only reversed by wash-out in the presence of 1 mM L-arginine. In short-term incubations (45 s) of membrane fractions, L-NMA and L-NNA exhibited similar potencies to inhibit endothelial NO synthase, but L-NNA was markedly more potent than L-NMA after prolonged incubation periods (> or = 3 min) due to induction of a pronounced, reversible enzyme inactivation.
Oxygen adsorption on Co(101-bar0): Different reconstruction behavior of hcp (101-bar0) and fcc(110).
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Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-L-arginine as an intermediate.
Brain NO (nitric oxide) synthase contains FAD, FMN, heme, and tetrahydrobiopterin as prosthetic groups and represents a multi-functional oxidoreductase catalyzing oxidation of L-arginine to NO and L-citrulline, formation of H2O2, and reduction of cytochrome c. We show that substrate analogues and inhibitors interacting with the heme block both the reductive activation of oxygen and the oxidation of L-arginine without affecting cytochrome c reduction. We further demonstrate that N omega-hydroxy-L-arginine is an intermediate in enzymatic NO synthesis. The ratio of L-citrulline to free N omega-hydroxy-L-arginine was > or = 50 under various assay conditions, but could markedly be reduced down to 4 by redox active inhibitors. Brain NO synthase is shown to utilize both L-arginine and N omega-hydroxy-L-arginine for the formation of stoichiometric amounts of NO and L-citrulline. Tetrahydrobiopterin equally enhanced reaction rates from either substrate (approximately 5-fold), but its rate accelerating effects were only observed at NADPH concentrations > or = 3 microM. In the absence of L-arginine or tetrahydrobiopterin, brain NO synthase catalyzes the generation of H2O2. We now show that, in contrast to L-arginine, N omega-hydroxy-L-arginine fully blocked H2O2 formation in the absence of exogenous tetrahydrobiopterin, indicating that N omega-hydroxy-L-arginine is a direct inhibitor of enzymatic oxygen activation. Based on these data, a hypothetical mechanism of enzymatic NO formation is discussed.
B-cell lymphoma after angioimmunoblastic lymphadenopathy: a case with oligoclonal gene rearrangements associated with Epstein-Barr virus.
We describe a patient with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), who subsequently developed large-cell immunoblastic lymphoma of B-cell immunophenotype. At the time of the initial diagnosis, histologic examination of an inguinal lymph node showed typical features of AILD, and there was no evidence of a monoclonal B-cell population by immunohistochemical analysis. In situ hybridization and Southern blot analysis for Epstein-Barr virus (EBV) were negative. At autopsy 2 years later, the patient had widespread lymph node and organ involvement by large-cell immunoblastic lymphoma of B-cell immunophenotype. Southern blot analysis performed on DNA extracted from lymph nodes, liver, and spleen showed two patterns of Ig heavy chain and kappa light chain gene rearrangements. The T-cell receptor beta chain gene was in the germline configuration. Analysis with an EBV terminal repeat region probe showed two clonal populations that paralleled the Ig gene rearrangement studies. Double-labeling immunohistochemistry and in situ hybridization confirmed the presence of EBV within the neoplastic B cells. The data support the hypothesis that EBV was not etiologically related to AILD in this case, and that EBV proliferation may occur after the onset of the disease. Further, the data suggest that some B-cell lymphomas that arise in the setting of AILD resemble EBV-associated B-cell lymphomas that arise in other immunodeficiency states.