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R Koch

Publications and source records attributed to R Koch.

At least 91 records · Page 5Linked to original sources
PubMed2000

Single nucleotide polymorphisms in wild isolates of Caenorhabditis elegans.

Caenorhabditis elegans (isolate N2 from Bristol, UK) is the first animal of which the complete genome sequence was available. We sampled genomic DNA of natural isolates of C. elegans from four different locations (Australia, Germany, California, and Wisconsin) and found single nucleotide polymorphisms (SNPs) by comparing with the Bristol strain. SNPs are under-represented in coding regions, and many were found to be third base silent codon mutations. We tested 19 additional natural isolates for the presence and distribution of SNPs originally found in one of the four strains. Most SNPs are present in isolates from around the globe and thus are older than the latest contact between these strains. An exception is formed by an isolate from an island (Hawaii) that contains many unique SNPs, absent in the tested isolates from the rest of the world. It has been noticed previously that conserved genes (as defined by homology to genes in Saccharomyces cerevisiae) cluster in the chromosome centers. We found that the SNP frequency outside these regions is 4.5 times higher, supporting the notion of a higher rate of evolution of genes on the chromosome arms.

Animals↗
PubMed2000

Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines.

We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNgamma), tumor necrosis factor alpha (TNFalpha), and IFNalpha/beta. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNgamma (IFNgammaKO), the TNFalpha receptor (TNFalphaRKO), or the IFNalpha/beta receptor (IFNalpha/betaRKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNgammaKO and IFNalpha/betaRKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNgamma mediates most of the antiviral effect of the CTLs while IFNalpha/beta is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNalpha/beta observed after injection of poly(I. C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNalpha. We also compared the relative sensitivity of LCMV and adenovirus to control by IFNgamma, TNFalpha, or IFNalpha/beta in these animals. Importantly, IFNalpha/betaRKO mice, and to a lesser extent IFNgammaKO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.

Adenoviridae↗
PubMed2000

Expression of secretory group IIA phospholipase A(2) in relation to the presence of microbial agents, macrophage infiltrates, and transcripts of proinflammatory cytokines in human aortic tissues.

Recent seroepidemiological and immunohistochemical studies have demonstrated an association between microbial infections and atherosclerosis. However, the mechanisms underlying this association are widely unknown. In the present study, arterial specimens obtained at autopsy after sudden death were analyzed concerning (1) the presence of Chlamydia pneumoniae, cytomegalovirus, herpes simplex virus, and Helicobacter pylori; (2) the expression of secretory group IIA phospholipase A(2) (sPLA(2)-IIA) and of proinflammatory cytokines; and (3) the stage of atherosclerosis. Genomic DNA of microbial pathogens was determined by the polymerase chain reaction technique. The expression of sPLA(2)-IIA was studied immunohistochemically by using monoclonal antibodies against human sPLA(2)-IIA. Transcripts specific for sPLA(2)-IIA, interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma were identified by reverse transcription-polymerase chain reaction. In 18 of 102 analyzed specimens, DNA of microbial pathogens was found. Thirteen sections were positive for C pneumoniae, whereas 2 specimens were positive either for cytomegalovirus or for herpes simplex virus. One section contained genomic DNA of all 3 pathogens simultaneously. None of the analyzed tissues exhibited nucleic acids specific for H pylori. In addition to macrophage infiltrates, the presence of microbial DNA was closely associated with the occurrence of transcripts specific for proinflammatory cytokines and sPLA(2)-IIA. Pathogens as well as sPLA(2)-IIA and cytokines were found to be present not only in advanced but also in early stages of atherosclerosis. In tissues negative for sPLA(2)-IIA and cytokine expression, none of the pathogens could be identified. Because macrophages exposed to phospholipase A(2)-treated lipoproteins are transformed into foam cells in vitro, the results of this study suggest an alternative mechanism by which microbial infections may act in a proatherogenic fashion in vessel walls.

Adolescent↗
PubMed2000

Short- and long-term results of abciximab versus aspirin in conjunction with thrombolysis for patients with peripheral occlusive arterial disease and arterial thrombosis.

Acute peripheral occlusive arterial disease is an important cause of morbidity and mortality, particularly among older persons. Catheter-directed thrombolytic therapy is the treatment of choice but has limitations: long lytic times, occlusions refractory to thrombolysis, and a high rate of restenosis. We conducted a pilot study to evaluate the use of the platelet GP IIb/IIIa receptor antagonist abciximab versus aspirin in conjunction with thrombolysis in patients with acute peripheral occlusive arterial disease associated with arterial thrombosis. A total of 84 patients were randomized into two equal groups to receive 5 mg recombinant tissue plasminogen activator intravenously and 500 IU heparin/hour along with either 500 mg acetylsalicylic acid or a bolus of 0.25 mg/kg abciximab followed by 10 microg/min abciximab over 12 hours (heparin reduced to 250 IU/hour). Primary efficacy criteria included the number of rehospitalizations, reinterventions, and amputations during the following 6 months. Secondary endpoints were the changes in the Fontaine stage, Bollinger index (vessel occlusion), ankle-to-brachial ratios, distance to claudication after 6 months, and the duration of the initial local lysis treatment. Adjunctive use of abciximab reduced the rates of rehospitalization, reinterventions, and amputations versus results with the use of aspirin (10 vs 14 occurrences, respectively; 9 vs 11; 3 vs 5; when summed, intergroup difference p < 0.05). Secondary peripheral occlusive arterial disease variables became highly significant versus aspirin (p < 0.001 or greater) at 3 and 6 months after treatment. The duration of lysis was markedly shorter upon addition of abciximab versus aspirin (75 vs 110 min; p < 0.001). No major bleeding complications or embolisms occurred. These preliminary results indicate that abciximab may have a useful role when used adjunctively with a thrombolytic agent in older persons with acute peripheral occlusive arterial disease and arterial thrombosis.

Abciximab↗
PubMed2000

Blood-brain phenylalanine relationships in persons with phenylketonuria.

OBJECTIVES: Clinicians caring for persons with phenylketonuria (PKU) have been perplexed by the occasional normal individual with the classical biochemical profile consistent with the diagnosis of PKU. Usually untreated subjects with the biochemical profile of blood phenylalanine (Phe) levels >1200 micromol/L are severely mentally retarded and may have neurological findings. Preliminary reports have recently appeared suggesting that low brain Phe levels, in comparison with elevated blood Phe levels, account for the occurrence of these occasional unaffected individuals with the biochemical profile consistent with PKU. METHOD: Magnetic resonance imaging/magnetic resonance spectroscopy was used to measure brain Phe content compared with simultaneously obtained blood Phe levels determined on the amino acid analyzer. This comparison was obtained in 5 normal non-PKU persons, 4 carriers of the gene causing PKU, and in 29 individuals with the proven form of the disorder. RESULTS: Blood-brain measurements in 5 normal persons ranged from.051 to.081 mmol/L, with a mean of.058 mmol/L. Their simultaneously measured brain levels of Phe ranged from.002 to.15 mmol/L, with a mean of.09 mmol/L. Similar measurements were obtained in 4 carriers of the gene causing PKU. Their blood levels varied between.068 and.109 mmol/L, with a mean of.091 mmol/L and simultaneously obtained brain levels of Phe varied between.06 and.21 mmol/L, with a mean of.11 mmol/L. Twenty subjects with a mean IQ of 104 exhibited a mean blood level of 1.428 mmol/L and a simultaneous mean brain level of.23 mmol/L, whereas 9 persons with a mean IQ of 98.7 exhibited a mean blood Phe level of 1.424 and a mean brain Phe level of.64 mmol/L. The correlation between blood and brain levels was not significant. CONCLUSION: In usual cases, intellectually normal persons who have never been treated but who have a biochemical profile consistent with classical PKU exhibit lower brain levels of Phe. Such individuals are exceptional and may not need the vigorous restriction of their blood Phe levels that is required by the majority of persons with PKU.

Adolescent↗
PubMed2000

[Measurement of thyrotropin receptor antibodies (TRAK) with a second generation assay in patients with Graves' disease].

AIM: The detection of TSH-receptor-antibodies (TRAb) in patients (pts) with Graves' disease (GD) is routinely used in nuclear medicine laboratories. It is performed by commercial, porcine radioreceptorassays (RRA) measuring TSH binding inhibitory activity. A second generation assay using the human, recombinant TSH-receptor was developed during the last years. The manufacturer composed this new assay as a coated tube RRA (CT RRA) and claimed a higher sensitivity for GD. METHODS: TRAb was measured in 207 pts with various thyroid disorders and 205 healthy controls using the new coated tube RRA (Fa. B.R.A.H.M.S. Diagnostica GmbH, Berlin, Germany) as well as a conventional RRA (Fa. Medipan Diagnostica GmbH, Selchow, Germany): 60 pts suffering from GD showing a relapse after antithyroid drug treatment and before radioiodine therapy, 109 pts with disseminated autonomia (DA) and 38 pts suffering from Hashimoto's thyroiditis. A ROC-analysis was performed to find the optimal decision threshold level for positivity. RESULTS: We found 42/60 TRAb-positive pts with GD in the established RRA (threshold 6 U/L) and 52/60 in the CT RRA, respectively. The sensitivity increased from 70% (RRA) to 86.7% (CT RRA). The CT RRA found 2 false positives (one Hashimoto's and one healthy control) and the RRA detected 3 Hashimoto's and 2 healthy controls as false positive. CONCLUSION: The increased sensitivity of CT RRA for GD provides an advantage compared to conventional RRA, especially in GD-patients relapsing after antithyroid drug treatment. Functional sensitivity and Interassay-variation of CT RRA are very precisely compared to conventional RRA. Handling of the new assay is also improved.

False Positive Reactions↗
PubMed2000

[Comparison of rhenium-188, rhenium-186-HEDP and strontium-89 in palliation of painful bone metastases].

AIM: Several radiopharmaceuticals were compared previously with regard to the efficiency in pain palliation of bone metastases. Furthermore, first results were reported on the suitability for such kind of therapy of the generator produced radionuclide rhenium-188. METHOD: Influence of Rhenium-188-HEDP (Re-188), Rhenium-186-HEDP (Re-186) and Strontium-89 (Sr-89) on pain symptoms and bone marrow function were obtained in 44 patients (pts). These were 16 pts. with Re-188 (2943 +/- 609 MBq), 13 pts. with Re-186 (1341 +/- 161 MBq) and 15 pts. with Sr-89 (152 +/- 18 MBq) (6 woman with breast cancer and 38 men with prostata cancer). RESULTS: 81 of pts. after Re-188, 77% after Re-186 and 80% after Sr-89 reported relief of pain. The Karnofsky-Index established by pts. increased from 74 +/- 9% to 85 +/- 11% after Re-188, from 70 +/- 11% to 76 +/- 11% after Re-186 and from 62 +/- 10% to 69 +/- 10% after Sr-89. However, the difference between the pre- and the post-therapeutic value is only statistically significant in the case of Re-188 therapy (p = 0.001). A decrease of platelets of 30 +/- 14% after 2.8 +/- 0.7 for pts. treated with Re-188, of 39 +/- 20% after 3.7 +/- 1.0 weeks for pts. treated with Re-186 and of 34 +/- 26% after 4.4 +/- 1.0 weeks for pts. treated with Sr-89 compared to the value before therapy was observed. The difference was not significant between the 3 groups of pts. (p = 0.125 to 0.862). CONCLUSION: All tried radiopharmaceuticals were effective in pain palliation. The various radionuclides had no significant difference in the pain relief or the bone marrow impairment. If only the Karnofsky-Index after Re-188 HEDP seems to be a little more increase.

Bone Neoplasms↗
PubMed1999

Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte.

We have previously shown that interferon and tumor necrosis factor noncytopathically abolish hepatitis B virus (HBV) replication from the hepatocyte and kidney tubular epithelial cells in vivo. Here we show that a persistent lymphocytic choriomeningitis virus (LCMV) infection is cleared from the hepatocyte noncytopathically when the same cytokines are induced in the liver by antigen-nonspecific stimuli. These results indicate that, like HBV, LCMV is also susceptible to intracellular inactivation by cytokine-induced antiviral mechanisms that are operative in the hepatocyte. In contrast, LCMV is not cleared from intrahepatic nonparenchymal cells or splenocytes, indicating that, unlike the hepatocyte, these cells do not produce the factors required to inactivate LCMV. Antiviral mechanisms like these may have evolved to maintain the functional integrity of vital organs in the face of massive infection.

Adenoviridae↗
PubMed1999

Long-term beneficial effects of the phenylalanine-restricted diet in late-diagnosed individuals with phenylketonuria.

The potential benefits to society of treating late-diagnosed mentally retarded persons with phenylketonuria were investigated. In order to ascertain the effects of late dietary intervention, the charts of 124 adults with PKU seen in the metabolic service at the Childrens Hospital of Los Angeles were reviewed. Fifty-nine were diagnosed later than 3 months of age and were over the age of 18 years. They were followed up with medical, psychological, and nutritional assessments. Genotyping was also performed. Twenty-eight have remained on a phenylalanine-restricted diet during the intervening years. All but 3 of the 28 late-diagnosed PKU persons who remained on a restricted diet showed significant intellectual improvement. Seven are able to attend college, 9 are employed, and 12 are attending workshops and/or day care programs. The result of treatment with the phenylalanine-restricted diet was that these individuals could participate in society and were able to arrest the neurodegenerative course characteristic of persons with mutations classified as severe in the phenylalanine hydroxylase gene. We conclude that society could benefit substantially by providing a phenylalanine-restricted diet for late-diagnosed mentally retarded persons with phenylketonuria. Eighteen of 28 such persons who otherwise would have required residential care are living independently.

Adult↗
PubMed1999

Estimation of wound age and VCAM-1 in human skin.

To estimate the age of skin wounds, the endothelial adhesion molecule VCAM-1 (CD 106) was detected in paraffin sections after autoclaving and using the ABC technique. The percentage of VCAM-1 positive blood vessels was determined after the blood vessels had been marked with PECAM-1 (CD 31). Low positive staining reactions were observed for VCAM-1 on endothelial cells of uninjured skin in 18% of the samples. In injured skin, 51% of the cases investigated showed a VCAM-1 expression. Strong positive staining reactions were observed 3 h at the earliest and 3.5 days at the latest after the time of injury. The immunohistochemical results for VCAM-1 differed significantly between the injured and uninjured skin (P < 0.01). In a few cases VCAM-1 was detected (n = 6) at low intensity in postmortem skin wounds and a moderate to strong expression of VCAM-1 is indicative of the vitality of the wound. The detection of VCAM-1 can be used for estimating the age of wounds in forensic applications if the degree of expression of further adhesion molecules, especially that of selectins, is taken into account.

Forensic Medicine↗
PubMed1999

Objective evaluation of regional left ventricular wall motion during dobutamine stress echocardiographic studies using segmental analysis of color kinesis images.

OBJECTIVES: To test the feasibility of objective and automated evaluation of echocardiographic stress tests, we studied the ability of segmental analysis of color kinesis (CK) images to detect dobutamine-induced wall motion abnormalities and compared this technique with inexperienced reviewers of conventional gray-scale images. BACKGROUND: Conventional interpretation of stress echocardiographic studies is subjective and experience dependent. METHODS: CK images were obtained in 89 of 104 consecutive patients undergoing clinical dobutamine stress studies and were analyzed using custom software to calculate regional fractional area change in 22 segments in four standard views. Each patient's data obtained at rest was used as a control for automated detection of dobutamine-induced wall motion abnormalities. Independently, studies were reviewed without CK overlays by two inexperienced readers who classified each segment's response to dobutamine. A consensus reading of two experienced reviewers was used as the gold standard for comparisons. In a subgroup of 16 patients, these consensus readings and CK detection of wall motion abnormalities were compared with coronary angiography. RESULTS: The consensus reading detected ischemic response to dobutamine in 43 of 1958 segments in 23 of 89 patients. Automated detection of stress-induced wall motion abnormalities correlated more closely with the standard technique than the inexperienced reviewers (sensitivity 0.76 vs. 0.55, specificity 0.98 vs. 0.94 and accuracy 0.97 vs. 0.92). When compared with coronary angiography in a subgroup of patients, analysis of CK images differentiated between normal and abnormal wall motion more accurately than expert readers of gray-scale images (accuracy of 0.93 vs. 0.82). CONCLUSIONS: Analysis of CK images allows fast, objective and automated evaluation of regional wall motion, sensitive enough for clinical dobutamine stress data and more accurate than inexperienced readers. This method may result in a valuable adjunct to conventional visual interpretation of dobutamine stress echocardiography.

Aged↗
PubMed1999

Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations.

Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichilemmomas. Several neurological symptoms are also part of CD with megalencephaly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of developing malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found with higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were identified in both familial and sporadic CD patients. We identified eight PTEN mutations, of which seven were novel, in 13 CD patients. Combined with previous data we have identified 17 independent CD mutations. Gross DNA alterations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutations are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical features of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, it is likely that we have identified the majority of CD patients in the Netherlands. From this we estimate that CD has a prevalence of about 1 in 250,000 in the Dutch population with a low mutation frequency.

Female↗
PubMed1999

Molecular correlations in phenylketonuria: mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population.

We studied 133 California phenylketonuria (PKU) patients and one obligate heterozygote to delineate the molecular basis of PKU in a population with greater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latter defined by both the diagnostic pretreatment blood phenylalanine (PHE) level and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR-mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked whether mutation severity, as defined by such expression analysis, correlated with pretreatment PHE levels or with IQ test results. A mutation was identified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles were found; A47E, T81P, I102T, E182G, T328D, Y343P, K371R, Y387H, A389E, E422K, IVS9nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlation between genotype and IQ. We conclude that in samples collected from an ethnically heterogeneous population, there is no correlation of mutation severity with either pretreatment PHE levels or IQ measurement in treated patients. We caution that genetic counseling in PKU should incorporate the notion that prognosis may not be predicted with precision based on mutation analysis in a given patient.

California↗
PubMed1999

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

OBJECTIVE: To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). METHODOLOGY: PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. RESULTS: The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for >6 years showed IQ scores 10 points above average for their group. CONCLUSIONS: The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy.

Female↗
PubMed1999

Lhermitte-Duclos disease as a component of Cowden's syndrome. Case report and review of the literature.

In recent years, 16 cases involving the association between Lhermitte-Duclos disease (LDD), which is a hamartomatous overgrowth of cerebellar tissue, and Cowden's syndrome (CS), an autosomal-dominant condition characterized by multiple hamartomas and neoplasias, have been reported. LDD may be one of the manifestations of CS. Recently, mutations of the PTEN/MMAC 1 gene, a tumor suppressor gene, have been found in families with CS, including four patients in whom LDD was diagnosed. The authors present a case of LDD in a 53-year-old woman who also had the typical mucocutaneous lesions found in CS, as well as goiter and intestinal polyposis. In this case, CS had never been suspected until the diagnosis of LDD was made. The mutation detected in the PTEN/MMAC 1 gene as well as neuropathological results are described.

Cerebellar Neoplasms↗
PubMed1999

[Attention deficit disorders and memory capacity in children with language delay and in normal children].

In order to investigate the hypothesis that language-impaired children also show deficits in memory, 110 language-impaired and 123 children showing no such impairments (average age 10;0 yrs.) were tested for verbal memory and selecting attention through a matching familiar figures test. As an additional measure, teachers assessed the children, using DSM criteria, for both general attentivenesse and attention deficit disorder. The results revealed significant differences between both groups concerning their ability to memorise word lists and difficulties resisting distractions. They also show a significantly diminished stability regarding the retention of memories. Furthermore, the ability to memorise has proved to be greatly independent of both selective attention and the rated attentiveness in class. It is therefore concluded that language-impaired children have difficulties in acquiring information as well as a limited capacity to memorise. These differences in ability to memorise between language-impaired children and children with no impairments are most likely attributable to the meta-cognitive competence of the child.

Attention↗