Biomedical subjects
Publications and source records attributed to M Koch.
The two novel prodrugs 4 and 11 have been prepared from tetra-O-acetyl-D-galactopyranose and doxorubicin in three and six steps, respectively. Their low cytotoxicity, high stability in plasma and, in the case of 11, efficient hydrolysis in the presence of alpha-galactosidase, fulfill preliminary conditions for their use in combination with monoclonal antibody-enzyme conjugates.
The wide range of severity in facioscapulohumeral muscular dystrophy (FSHD) complicates genetic advice, although onset age is youngest and severity is greatest in isolated cases. From 14 of 16 large FSHD families which are 4q35 linked, and from 25 of 34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; P < 0.001), with the smallest fragments occurring in isolated cases. A 4q35-linked 38-kb fragment in one family supports scapulohumeral presentation without facial involvement as a milder late-onset variant of FSHD, and with apparent "unaffected" recombinants in small families, suggests that nonpenetrance is more likely with large fragment sizes. Our results, predicting a more limited range for severity within families, and suggesting > 85% of FSHD maps to 4q35, will facilitate genetic counseling. We propose that quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.
The present study sought to test the hypothesis that dopamine in the prefrontal cortex exerts an inhibitory influence on subcortical dopamsine systems and that depletion of prefrontal dopamine may affect behaviour via an increase in dopamine release in the basal ganglia. We used prepulse inhibition of the acoustic startle response, i.e. the inhibition of the acoustic startle response by a preceding non-startling stimulus, as the behavioural test, because this phenomenon of sensorimotor gating is modified in opposite directions by dopamine in the prefrontal cortex and in the basal ganglia. Rats were tested for prepulse inhibition before and after injections of the neurotoxin 6-hydroxydopamine into the medial prefrontal cortex. We attempted to differentiate the contributions of prefrontal dopamine and noradrenaline by pretreating the animals with desipramine (6-OHDAMI rats) or bupropion (6-OHDABUP rats), selective inhibitors of noradrenaline and dopamine reuptake respectively. 6-Hydroxydopamine lesion reduced prefrontal dopamine by 90% and noradrenaline by 80% in 6-OHDADMI rats, while prefrontal dopamine was reduced by 54% and noradrenaline by 95% in 6-OHDABUP rats. The ability of an acoustic prepulse (75 dB, 10 kHz) to inhibit the response to a startle pulse (100 dB noise burst) was maintained in sham-lesioned rats and in 6-OHDABUP rats. However, there was a marked reduction of prepulse inhibition (by 26%) in the 6-OHDADMI rats. Systemic administration of the dopamine antagonist haloperidol (0.05 mg/kg), which did not affect prepulse inhibition in sham-lesioned and in 6-OHDABUP rats, antagonized the lesion-induced deficit in prepulse inhibition in 6-OHDADMI rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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The amplitude of the acoustic startle response (ASR) in rats is increased after administration of footshocks, a phenomenon termed sensitization. The neural circuitry underlying this kind of modulation of the ASR is only partly understood. It has been shown that the central nucleus of the amygdala (cA) and its efferent pathway to the caudal pontine reticular nucleus (PnC), an essential part of the primary startle circuit, is important for the sensitization of the ASR. It was unclear, however, whether the amygdaloreticular pathway directly transfers the effects of footshocks onto the PnC, or whether there exists a relay nucleus within this pathway. The present study tested the hypothesis that the midbrain central gray (CG) is important for the sensitization of the ASR. Neuroanatomical tracing experiments indicate that a descending projection from the medial part of the cA might form synapses in the region of the midbrain CG, where a descending projection to the PnC takes its origin. We lesioned the dorsal and lateral part of the CG with the neurotoxin quinolinic acid and measured the effects of this lesion on the sensitization of the ASR by footshocks. Lesions confined to the dorsal and lateral parts of the CG totally blocked the sensitization of the ASR, without affecting the ASR amplitude in the absence of sensitizing stimuli. These findings suggest a crucial role of the CG for the sensitization of the ASR. The present data are reconciled with other findings from our laboratory and from the literature and we discuss possible mechanisms underlying the mediation of the sensitization of the ASR in rats.
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The superior colliculus (SC) is important for the processing of sensory information of different modalities and for the mediation of adequate motor responses in mammals. The present study investigated the effects of excitotoxic lesions of the SC on two different modulations of the acoustic startle response (ASR) in rats. Modulations of the ASR (i.e. increase or decrease of the response strength) represent useful models for the study of sensorimotor integration phenomena. Lesions of the SC decreased the prepulse inhibition of the ASR without affecting the baseline startle amplitude or the enhancement of the ASR by footshock sensitization. These results suggest a crucial role of the SC in the prepulse inhibition of the ASR, a model of sensorimotor gating.
The acoustic startle response (ASR) can be enhanced by administration of footshocks (sensitization). The neural mechanisms underlying this effect are largely unknown. A previous electrophysiological study (Kungel et al., Brain Res., 643 (1994) 29-39) has shown that the neuropeptide substance P (SP) increases the responsiveness to acoustic stimuli of neurons in the caudal pontine reticular nucleus (PnC). Since the PnC is an important part of the primary acoustic startle circuit, we hypothesized that SP is involved in the enhancement of the ASR by electric footshocks. We tested this hypothesis in different experiments by locally injecting SP and SP-antagonists into the PnC of freely moving rats. The present data show that SP (0.5 pmol-1 nmol) locally injected into the PnC dose-dependently increases the amplitude of the ASR in rats. This effect was antagonized by pretreatment with the SP-antagonist CP-96,345. Furthermore, we show that the sensitization of the ASR by 0.6 mA-footshocks can be blocked by local microinjections of the SP-antagonists CP-96,345 (5 pmol-10 nmol) or CP-99,994 (0.5 nmol-100 nmol) into the PnC. Possible pathways relevant for the sensitization of the ASR are discussed.
MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.
Prepulse inhibition (PPI) of the acoustic startle response (ASR) is impaired by dopamine (DA) overactivity in the nucleus accumbens and anteromedial striatum. Since there is evidence that DA in the medial prefrontal cortex exerts an inhibitory control on striatal DA systems, it was investigated whether depletion of prefrontal DA reduces PPI. Rats were tested for PPI both before and after injections (2 x 1 microliter per side) of vehicle, a low (3.0 microgram/microliter) or a high (6.0 microgram/microliter) dose of 6-hydroxydopamine hydrobromide (6-OHDA) into the prefrontal cortex. Only the high dose of 6-OHDA, leading to an 87% depletion of prefrontal DA, impaired PPI. The ability of an acoustic prepulse (75 dB, 10 kHz) to reduce the response to a startle pulse (100 dB noise burst) was maintained in sham lesioned rats, but was significantly disturbed in rats lesioned with the high dose of 6-OHDA. The 6-OHDA treatment did not affect the ASR amplitude in the absence of a prepulse. The reduction of PPI in lesioned rats correlated with the extent of DA depletion. These results suggest that the DA innervation of the prefrontal cortex is involved in the modulation of the ASR and they provide further evidence for opposite actions of prefrontal and subcortical DA systems in the control of behaviour. The present findings are discussed with regard to the potential role of prefrontal DA in schizophrenia.
The present study examined the role of noradrenaline (NA) in the central nucleus of the amygdala (cA) in the sensitization of the acoustic startle response (ASR) in rats. In the first experiment, local microinjections of 0, 0.5, 1, 2 nmol of the alpha 2-adrenergic antagonist yohimbine into the cA increased the magnitude of the ASR in a dose-dependent way. In the second experiment, foot shocks were applied to increase the ASR amplitude (sensitization). Local microinjections of 0, 4, 8, 16 nmol of the alpha 2-adrenergic agonist ST-91 into the cA dose dependently decreased the sensitizing effects of foot shocks on the amplitude of the ASR. It is conjectured that yohimbine increases and ST-91 decreases local NA release by acting at presynaptic autoreceptors. The present data suggest that the release of NA in the cA is involved in the mediation of the sensitizing effects of foot shocks on the ASR.
Chick embryo fibroblasts cultured on a collagen matrix exert tractional forces leading to the contraction of unrestrained, floating collagen gels and to the development of tension in attached, restrained gels. On a restrained, attached collagen gel the fibroblasts synthesize large quantities of tenascin-C, whereas in a floating, contracting gel tenascin-C synthesis is decreased. This regulation of tenascin-C synthesis can be observed by the secretion of metabolically labeled tenascin-C into the conditioned medium, as well as by the deposition of tenascin-C into the collagen matrix as judged by immunofluorescence. Regulation appears to occur at the transcriptional level, because when cells on attached or floating collagen gels are transfected with promoter constructs of the tenascin-C gene, luciferase expression driven by the tenascin-C promoter parallels the effects measured for endogenous tenascin-C synthesis, whereas luciferase expression under the control of the SV40 promoter does not depend on the state of the collagen gel. The promoter region responsible for tenascin-C induction on attached collagen gels is distinct from the region important for the induction of tenascin-C by serum, and may define a novel kind of response element. By joining this tenascin-C sequence to the SV40 promoter of a reporter plasmid, its activity can be transferred to the heterologous promoter. We propose that the tenascin-C promoter is directly or indirectly activated in fibroblasts generating and experiencing mechanical stress within a restrained collagen matrix. This may be an important aspect of the regulation of tenascin-C expression during embryogenesis as well as during wound healing and other regenerative and morphogenetic processes.
BACKGROUND AND PURPOSE: Falls and immobility are common among community-living elderly persons and result from the accumulated effect of multiple impairments and disabilities as well as environmental hazards. We developed and tested a simple assessment and intervention protocol for use in prevention and treatment programs among community-living elderly persons. This article presents the components of the assessment; the criteria for intervening on diagnosed impairments contributing to falls and immobility; and the recommended treatments, environmental adaptations, training, and exercise programs targeting the diagnosed problems. SUBJECTS: A convenience sample of 11 residents of a senior housing complex who were cognitively intact and ambulatory were chosen for reliability testing of the assessment protocol. A random sample of 20 of the 153 elderly subjects involved in a multiple risk factor trial for fall prevention then were chosen to test the reliability of the intervention recommendations. METHODS: The assessment and intervention protocol was developed by a consensus approach among a group consisting of a geriatric physician, two nurses, and three physical therapists. The interrater reliability of both the assessment and the intervention components of the protocol was determined by comparing the results of two of the study physical therapists. RESULTS: There was excellent agreement in assessment and intervention results by the two physical therapists. The assessment required approximately 45 minutes to complete, suggesting it is feasible for use in clinical practice. CONCLUSION AND DISCUSSION: A simple, standardized assessment and intervention protocol, such as the one described, could aid physical therapists in evaluating and treating community-living elderly persons by improving communication among care providers, providing better documentation for reimbursers, and ensuring a direct linkage between assessment and intervention, thus simplifying the development of a treatment plan for elderly persons with complicated or multiple impairments. The ultimate test of this assessment and intervention protocol will be ascertainment of the goal of the protocol, namely a reduction in falls and improvement in mobility among multiply and chronically ill elderly persons.
The in vitro activities of furo[2,3b]quinoline and acridone alkaloids against Plasmodium falciparum were evaluated by an isotopic semimicrotest. A pyran ring in the furoquinoline nucleus and 2-O-pyranoglycoside and 2-nitro substituents in the acridone nucleus improved the antimalarial activities of the compounds. These findings provide a clue for further chemical modifications.
The advent of new laboratory methods and noninvasive imaging modalities has extended the diagnostic possibilities in normal individuals. This article elaborates the new options for the assessment of stroke risk offered by these techniques. In this context we present the Austrian Stroke Prevention Study, which is the first prospective long-term investigation of normals that includes Doppler sonography, magnetic resonance imaging and single photon emission computed tomography. The design, utility and limitations of this study are discussed.
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We administered the Mattis Dementia Rating Scale (MDRS) to 1,001 healthy volunteers, aged 50 to 80 years, randomly selected from our community. Multivariate regression analysis revealed educational level (p = 0.000004) and age (p = 0.00001), but no other sociodemographic or risk factors for stroke, to be significantly associated with the MDRS score. The age- and education-specific lowest quintile cutoff scores ranged from 140 in subjects aged 50 to 59 years with at least college experience to 130 in subjects aged 70 to 80 years with only 4 to 9 years of schooling. These percentile distributions obtained for decades of age and different levels of education should be useful reference values for clinicians and investigators when applying the MDRS to assess cognitive functioning.