Biomedical subjects

M Koch

Publications and source records attributed to M Koch.

At least 163 records · Page 9Linked to original sources

PubMed1998

Evolution of enzymatic activities in the enolase superfamily: characterization of the (D)-glucarate/galactarate catabolic pathway in Escherichia coli.

The genes encoding the enzymes in the (D)-glucarate/galactarate catabolic pathway have been identified in the Escherichia coli genome. These encode, in three transcriptional units, (D)-glucarate dehydratase (GlucD), galactarate dehydratase, 5-keto-4-deoxy-(D)-glucarate aldolase, tartronate semialdehyde reductase, a glycerate kinase that generates 2-phosphoglycerate as product, and two hexaric acid transporters. We also have identified a gene proximal to that encoding GlucD that encodes a protein that is 72% identical in primary sequence to GlucD (GlucD-related protein or GlucDRP). However, whereas GlucD catalyzes the efficient dehydration of both (D)-glucarate and (L)-idarate as well as their epimerization, GlucDRP is significantly impaired in both reactions. Perhaps GlucDRP is an example of gene duplication and evolution in progress in the E. coli chromosome.

Alcohol Oxidoreductases↗

PubMed1998

Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy.

A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.

Animals↗

PubMed1998

Deficient sensorimotor gating following seizures in amygdala-kindled rats.

BACKGROUND: Human patients with limbic epilepsy may develop a psychosis. We combined animal models for epileptogenesis and schizophrenia to investigate possible mechanisms underlying the occurrence of psychoses in epileptics. Since the dysfunction of sensorimotor gating is the basis of some psychotic symptoms, we tested if epileptogenesis or acute seizures influence sensorimotor gating in rats, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is the reduction of the ASR that is observed when a startling pulse is preceded by a nonstartling prepulse. Reduced PPI was found in schizophrenics and in rats under certain conditions. METHODS: We investigated the effects on PPI of different models of limbic epileptogenesis (repeated stimulation of the basolateral amygdala, treatment with pentylenetetrazole, injection of kainate). RESULTS: PPI was normal in chronic epileptic rats 1 week after the last generalized seizure. Impaired PPI was found in amygdala-kindled rats 10 min after seizures. The ASR amplitude in the absence of prepulses was increased in kainate-treated rats, but not in the other groups. CONCLUSIONS: Chemical epileptogenesis or repeated stimulation of the amygdala per se did not disrupt sensorimotor gating, but the recent occurrence of seizures in amygdala-kindled rats compromised sensorimotor gating in a way compatible with psychotic states in humans.

Acoustic Stimulation↗

PubMed1998

The ventral pallidum mediates disruption of prepulse inhibition of the acoustic startle response induced by dopamine agonists, but not by NMDA antagonists.

Prepulse inhibition (PPI) of the acoustic startle response is observed when the startling noise pulse is preceded by a weak, non-startling stimulus. PPI has been considered as a measure for sensorimotor gating mechanisms. Disruption of PPI can be found in schizophrenic patients as well as after blockade of NMDA receptors or stimulation of dopamine receptors in rats. The neuronal circuitry which regulates PPI consists of cortico-limbic brain structures where the nucleus accumbens (NAC) plays a key role. The NAC exerts its modulating effects on PPI by way of a projection from the ventral pallidum (VP) to the pedunculopontine tegmental nucleus (PPTg). We recently postulated that the reduction of PPI by intra-NAC infusion of glycine-site NMDA antagonists is not mediated by the VP. We tested here this hypothesis in rats with excitotoxic lesions of the VP which were systemically treated with apomorphine or MK-801 or received intraNAC infusions of dopamine or the glycine-site NMDA antagonist 7-chlorokynurenic acid. Lesioned rats showed a marked deficit in PPI after MK-801 and 7-chlorokynurenate treatment but not after apomorphine or dopamine injection, in contrast to sham-lesioned controls showing deficits in PPI under all conditions. These data provide behavioral evidence for the existence of a pathway which does not include the VP for the mediation of sensorimotor gating deficits. We propose that a direct connection between the NAC and PPTg may be responsible for the effects of NMDA/glycine receptor blockade, whereas the VP is an indispensable relay for the disruptive effects on PPI exerted by the NAC dopamine system.

Acoustic Stimulation↗

PubMed1998

Elucidation of the mechanism enabling tumor selective prodrug monotherapy.

Elucidation of the mechanism enabling tumor selective PMT in vivo with appropriate glucuronyl-spacer-doxorubicin prodrugs, such as HMR 1826, is important for the design of clinical studies, as well as for the development of more selective drugs. Enzyme histochemistry, immunohistochemistry, and the terminal deoxytransferase technique were applied using human cryopreserved cancer tissues, normal human, monkey, and mouse tissues, and human tumor xenografts to examine mechanisms underlying the selectivity of successful PMT with HMR 1826. It could unambiguously be shown by enzyme histochemistry that necrotic areas in human cancers are the sites in which lysosomal beta-glucuronidase is liberated extracellularly in high local concentrations. The cells responsible for the liberation of the enzyme are mainly acute and chronic inflammatory cells, as shown by IHC. Furthermore, it could be demonstrated that beta-glucuronidase liberated in necrotic areas of tumors can activate HMR 1826, resulting in increased doxorubicin deposition in human tumor xenografts or in human lung cancers subjected to extracorporal perfusion, compared to chemotherapy with doxorubicin. Additionally, the doxorubicin load to normal tissues was significantly reduced compared to chemotherapy with doxorubicin. Surprisingly, the increased doxorubicin deposition in tumors also resulted in strong antitumor effects also in cancers resistant to maximum tolerated doses of systemic doxorubicin. Finally, toxicity studies in mice and monkeys revealed an excellent tolerability of HMR 1826, up to a dose of 3 g/m2 (monkeys). These data suggest that HMR 1826 is a promising candidate for clinical development.

Animals↗

PubMed1998

Non-invasive temperature imaging of muscles with magnetic resonance imaging using spin-echo sequences.

The application of spin-echo magnetic resonance imaging sequences on non-invasive temperature imaging for temperature mapping of human limbs is investigated. In an in vitro experiment performed on a meat sample, the equilibrium magnetisation P and the spin-lattice relaxation time T1 are calculated from the values for the repetition time TR and the signal intensities obtained by a spin-echo sequence at different tissue temperatures as measured by a fibre-optic probe. T1 is linearly correlated to the tissue temperature, and P is linearly correlated to the reciprocal value of the absolute temperature. Both effects, taken together, lead to a non-linear dependency of the signal intensity on temperature. Therefore a TR leading to maximum temperature dependency of the signal intensity is calculated and used in the further experiments. In the in vivo experiments, the lower legs of two volunteers are cooled from outside. Images are acquired with a spin-echo sequence (1.5 T, TR = 1200 ms, TE = 10 ms). A rise in signal intensity in the muscle with falling skin temperature is observed, particularly in more peripheral muscle layers. This study shows that spin-echo sequences can be used to monitor temperature changes and temperature differences in living muscle tissue.

Animals↗

PubMed1998

[Thoracoscopic excision of an uncertain intramural esophagus tumor (granular cell tumor/Abrikossoff tumor)].

A granular cell tumor is one of the rare tumors of the esophagus. We present the case of a 65-year-old male patient, who was admitted to our hospital for an elective cholecystectomy. In the routine diagnostic gastroscopy an intramural tumor in the distal esophagus was incidentally found. Repeated endoscopic biopsies did not reveal the histologic diagnosis, although endoscopic ultrasound invasion to the tunica muscularis could not be excluded. After indicating the operative therapy, the tumor was removed through a thoracoscopic approach. The histologic specimen showed a granular cell tumor of the esophagus (tumor of Abrikossoff). Since the tumor grade was unknown, our therapy seemed to be justified because of the low risk involved in minimally invasive operative procedures. There has been much discussion and controversy in the literature on this subject, including the potential for malignancy and the correct therapy regime, with a general shift to conservative or minimally invasive treatment. The case is discussed with a review of the literature.

Aged↗

PubMed1998

Spontaneous regression of hepatocellular carcinoma confirmed by surgical specimen: report of two cases and review of the literature.

Two cases with spontaneous regression of a histologically confirmed hepatocellular carcinoma (HCC) are presented. This rarely seen phenomenon of a spontaneous tumor involution is discussed and compared with the current literature. The clinical symptoms were very similar to that of a liver abscess. A 56-year-old male suffered from a multicentric, highly differentiated, trabecular HCC. First symptoms were epigastric pain, septic fever and arthritis. The tumor marker AFP was constantly normal and no hepatitis could be verified. A resection of the tumor was performed. In patient 2, a 74-year-old male, a multicentric, clear cell HCC was found. The patient had completely recovered from hepatitis type B and within the liver tissue no viruses could be identified. Clinical symptoms were mainly characterized by upper abdominal pain and septic fever. AFP was excessively elevated (3850 ng/ml) but returned to normal preoperatively. In both cases, the specimen showed a subtotal necrotic HCC with insignificant amounts of vital tumor cells. Neither patient had a liver cirrhosis macroscopically, however patient 2 had local periportal fibrosis histologically. After 24 and 41 months of follow-up, respectively, both patients are in good health

Aged↗

PubMed1998

Stability and cellular studies of [rac-1,2-bis(4-fluorophenyl)-ethylenediamine][cyclobutane-1,1- dicarboxylato]platinum(II), a novel, highly active carboplatin derivative.

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).

Breast Neoplasms↗

PubMed1998

Association between angiotensin I-converting enzyme genotypes, extracranial artery stenosis, and stroke.

The insertion(I)/deletion(D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been associated with an increased risk of myocardial infarction, lacunar stroke, and with an increased intimal-medial thickness in several populations. The aim of this study was to evaluate whether the ACE I/D genotype is associated with stenosis of extracranial arteries and stroke in middle-aged and aged men and women. We studied 388 patients (247 male, 141 female) using Doppler and Duplex ultrasound of the extracranial arteries. Patients' history was obtained by standard questionnaire and by the hospital case records. Genomic DNA was analyzed by polymerase chain reaction (PCR) to identify the I/D polymorphism, with a second insertion specific PCR in samples classified as homozygous DD genotypes to prevent mistyping. The ACE genotype groups (DD 132, ID 164, II 92) were well matched for the basic characteristics. The DD genotype was more common in patients with extracranial artery stenosis > or = 50%, compared with patients without stenosis (59/147 versus 73/241, odds ratio 1.54, 95%-CI 1.01-2.37), but was not associated with a history of stroke (30/91 versus 102/297, odds ratio 0.94, 95%-CI 0.57-1.54). The association of the DD genotype with extracranial artery stenosis was also present in hypertensive subjects (n = 206, odds ratio 1.76, 95%-CI 0.99-3.17). In the whole group multiple logistic regression analysis revealed that the association of the DD genotype with extracranial artery stenosis was independent of age, gender, hypertension, hyperlipidemia, and diabetes. In conclusion, the ACE DD genotype is a weak risk factor for hemodynamically relevant stenosis of extracranial arteries, but not for stroke.

Adult↗

PubMed1998

Sensorimotor gating changes across the estrous cycle in female rats.

Sensorimotor gating deficits are considered to be among the factors that cause schizophrenic symptoms in humans, a fact that has fostered the research interest into sensorimotor gating phenomena in experimental animals. A measure for sensorimotor gating deficits in humans and animals is the disruption of prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is the reduction of the ASR that is normally observed when the startling pulse is preceded by a weak prepulse. In humans PPI is lower in women than in men and varies across the menstrual cycle in women. The present study assessed PPI in female and male rats to possibly provide an animal model for the investigation of the neuronal basis of sex differences in sensorimotor gating in humans. No differences in PPI between males and females (diestrous or estrous) were observed. However, PPI was significantly reduced in female rats during proestrous compared to diestrous or estrous or compared with male rats. No significant effect of 1 mg/kg of apomorphine on PPI was found in either sex. The magnitude of the ASR in the absence of prepulses was not affected by the gender, the drug, or the phase of the estrous cycle. Because a prominent role for dopamine and serotonin in the regulation of PPI in rats has been shown, and because there is evidence for a strong interaction between estrogen and the monoaminergic systems, the present data are consistent with the hypothesis that estrogen regulates PPI through an interaction with the dopaminergic and/or serotonergic systems.

Animals↗

PubMed1998

Differential effects of two motor tasks on ERPs in an auditory classification task: evidence of shared cognitive resources.

The aim of the study was to assess cognitive demands and fatigue during the execution of two different motor tasks. Event-related brain potentials (ERPs) were recorded from 15 healthy subjects while they concurrently performed, (1) one of two motor tasks, and (2) a three stimulus (70% standard tones, 15% target tones, 15% novel stimuli) auditory classification task. Both motor tasks required the externally paced adduction of the right thumb with the force task requiring a precise movement (feedback given) with about 50% of maximum force output (6 s on task, 4 s rest) while the displacement task required the same precise movement with only minimal force requirements. In separate sessions, both tasks were performed for about an hour with the subjects concurrently paying attention to the auditory task with button presses required for the target stimuli. This provided a dual task situation with trade-offs in P3b amplitude as a function of difficulty of the primary (motor) task. The P3b to the auditory target stimuli was reduced during the force session compared to the displacement session, indicating that the force-task placed a higher demand on cognitive resources. No differential effect of fatigue (time on task) could be ascertained over six consecutive parts of the session. The P3a component, a putative correlate of orienting of attention, showed a rapid attenuation over time but, attesting to its automatic nature, no effect of concurrent motor task. ERP components recorded timelocked to the movements showed a marked difference between the two tasks with the displacement task giving rise to higher amplitudes. Moreover, only for the force task an influence of time on task (fatigue) on the MP was found. The dual task methodology is a potentially useful tool to disentangle cognitive and motor components of central fatigue.

Acoustic Stimulation↗

PubMed1998

Induction of Fos-protein in the forebrain and disruption of sensorimotor gating following N-methyl-D-aspartate infusion into the ventral hippocampus of the rat.

Several neuropsychiatric disorders, including schizophrenia, are characterized by sensorimotor gating deficits. Prepulse inhibition of the acoustic startle response is an operational measure assessing sensorimotor gating and has been found to be reduced in schizophrenic patients. Much attention has therefore been paid to the neuronal mechanisms underlying the disruption of prepulse inhibition. The activity of limbic forebrain structures such as the septohippocampal system, the prefrontal cortex, and the nucleus accumbens has been the main focus of recent research into the regulation of prepulse inhibition in rats. We here provide a functional anatomical picture of forebrain structures probably involved in the regulation of prepulse inhibition. Stimulation of the ventral hippocampus with a subconvulsive dose of N-methyl-D-aspartate caused a significant and long-lasting disruption of prepulse inhibition. Immunostaining of the c-Fos protein revealed a characteristic pattern of neuronal activity in various forebrain areas, including the nucleus accumbens and different frontal cortical areas after hippocampal stimulation. Based on the present findings, we conclude that the overactivity within a network of cortico-limbic forebrain structures compromises the normal processing of sensory stimuli by disrupting a neuronal filter mechanism. Interestingly, there is a considerable overlap between the pattern of neuronal activity observed in our study and the brain pathology in schizophrenics reported in the literature.

Animals↗

PubMed1998

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene is associated with coronary artery plaque calcification as assessed by intravascular ultrasound.

OBJECTIVES: We evaluated the influence of the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene on coronary plaque morphology and calcification in patients with angiographically documented coronary artery disease (CAD). BACKGROUND: The ACE I/D polymorphism has been associated with an increased risk of myocardial infarction in patients with the DD genotype but not with the presence of native CAD. METHODS: We studied 146 patients undergoing percutaneous transluminal coronary angioplasty for stable angina pectoris by means of preinterventional intravascular ultrasound (IVUS). Qualitative and quantitative criteria were used to classify the target lesions as poorly or highly echoreflective or as calcified. Genomic deoxyribonucleic acid was analyzed by polymerase chain reaction (PCR) to identify the I/D polymorphism, with a second insertion-specific PCR in DD genotypes to prevent mistyping. RESULTS: The ACE genotype groups (DD 46, ID 68, II 32) were well matched for the basic characteristics. Patients with the DD genotype had significantly more calcified lesions (DD 80%, ID 57%, II 66%; unadjusted odds ratio [OR] 2.88, 95% confidence interval [CI] 1.30 to 6.92, p = 0.008) and more calcifications >180 degrees of the vessel circumference (DD 22%, ID 10%, II 6%; OR 2.80, 95% CI 1.05 to 7.63, p = 0.03). The prevalence of myocardial infarction was not significantly associated with coronary calcification (OR 1.44, 95% CI 0.72 to 2.88, p = 0.31). CONCLUSIONS: Patients with CAD and the ACE DD genotype have a significantly higher incidence and greater extent of coronary lesion calcification, as determined by IVUS. This finding indicates that the ACE I/D gene polymorphism is related to the development or progression of atherosclerotic plaque calcification.

Aged↗

PubMed1998

The Mayo Vascular Center experience.

American medicine is trending toward an increasing number of specialty care centers. Cancer centers, transplant centers, and sports medicine centers are only a few common examples. Vascular centers are relatively new entities that are forming for obvious reasons. As the general population ages, peripheral vascular disease has become more prevalent. Several types of medical, surgical, and radiological specialists are involved in the diagnosis and treatment of such patients. Creating multispecialty vascular centers is one method to focus expert care on the patient, to alleviate some of the turf battles between specialties, and to contain burgeoning Medicare costs.

Hospitals, Group Practice↗

PubMed1998

Synthesis and biological activity of esters in the trans-1,2-dihydroxy-1,2-dihydroacronycine series.

Permanganate oxidation of acronycine (1) led to keto alcohol 4 which could be reduced to trans-1,2-dihydroxy-1,2-dihydroacronycine (3) using NaBH4. Acylation of 3 afforded 12, 13, and 14. These esters (12, 13, and 14) were more potent than 1 when tested against L-1210 cells in vitro. Diacetate 12 was evaluated in vivo against murine P-388 leukemia and was markedly active at a dose 16-fold lower than acronycine itself. Comparison of these results with those recently obtained in the cis-1,2-dihydroxy-1,2-dihydroacronycine series is discussed.

Acronine↗

PubMed1998

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting-enzyme gene and diabetic nephropathy in IDDM patients.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been reported to be associated with diabetic nephropathy in IDDM. We studied the relationship between this polymorphism and diabetic nephropathy in 210 IDDM patients. Their DNA was analyzed by polymerase chain reaction to type for the presence (I) or absence (D) of the 287 bp fragment in intron 16 of the ACE gene. The relative frequency of the different genotypes was 33.8% (DD), 43.8% (ID), and 22.4% (II). There were no significant differences between the genotypes in age, body-mass-index, blood pressure, plasma total cholesterol and triglycerides. The prevalence of microalbuminuria or nephropathy was 23.9% in the DD, 16.3% in the ID, and 17% in the II genotypes. The higher percentage of microalbuminuria or nephropathy in the DD genotypes was due to an increasing frequency of DD genotypes in the IDDM patients with long diabetes duration. After matching for diabetic retinopathy, gender, and diabetes duration, there was no association between the ACEI/D polymorphism and diabetic nephropathy. In conclusion, these results suggest that the ACE DD genotype cannot be regarded as a risk factor for diabetic nephropathy, but may even be associated with diabetes duration and thus longevity in IDDM patients.

Adult↗

PubMed1998

Lithium and clozapine-induced neutropenia/agranulocytosis.

Lithium administration was used in a patient with a clozapine-induced neutropenia and in another with complete agranulocytosis to assess whether lithium could stimulate neutrophil production. In both cases, following lithium administration, the neutrophil count was increased to the normal range within 6 days. In the patient who had presented a neutropenia, clozapine treatment was then reinstated in the presence of lithium and continued without the neutrophil count dropping into the yellow-alert range thereafter.

Adult↗