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Biomedical subjects

Christoph Schmitz

Publications and source records attributed to Christoph Schmitz.

At least 19 recordsLinked to original sources
PubMed2006

Protection of nigral cell death by bilateral subthalamic nucleus stimulation.

In Parkinson disease (PD), the subthalamic nucleus (STN) becomes hyperactive (disinhibited), which is reported to cause excitotoxic damage to midbrain dopaminergic neurons. Here, we examined whether silencing of the hyperactive STN by chronic bilateral deep brain stimulation (DBS) increased the survival of midbrain dopaminergic neurons in a rat model of PD. High-precision design-based stereologic examination of the total number of neurons and tyrosine tydroxylase (TH) immunoreactive neurons in the substantia nigra pars compacta revealed that STN DBS resulted in a significant survival of these neurons. These data provide the first evidence in vivo that bilateral STN DBS is useful for protecting midbrain dopaminergic neurons from cell death in PD.

Adrenergic Agents↗
PubMed2006

Wolfram syndrome 1 (WFS1) protein expression in retinal ganglion cells and optic nerve glia of the cynomolgus monkey.

Wolfram syndrome (WFS1, OMIM 222300) is a rare genetic disorder associated with multiple organ abnormalities, most prominently optic nerve atrophy and diabetes. Mutations in the WFS1 gene coding for wolframin have been identified. The pathogenesis for optic nerve atrophy remains elusive. We here tested the hypothesis that wolframin is expressed in glial cells of the optic nerve and in retinal ganglion cells in the cynomolgus monkey. Paraffin sections through the retina and optic nerve were examined with immunohistochemistry using affinity-purified antibodies to wolframin. Retinal ganglion cells and optic nerve glial cells were found to be strongly labeled. Dual dysfunction of wolframin in optic nerve glial cells and retinal ganglion cells may explain the progressive optic nerve atrophy in Wolfram syndrome.

Animals↗
PubMed2006

Motor and cognitive improvement by deep brain stimulation in a transgenic rat model of Huntington's disease.

Altered activity of the globus pallidus externus (GPe) is responsible for at least part of the cognitive and motor symptoms of Huntington's disease (HD). In this study, we tested the hypothesis that bilateral globus pallidus (GP; equivalent of GPe in primates) deep brain stimulation (DBS) improves cognitive and motor symptoms in the first transgenic rat model of HD (tgHD rats). GP DBS with clinically relevant stimulation parameters resulted in a significant improvement of cognitive dysfunction and reduced the number of choreiform movements. This data indicate that GPe DBS can be used to treat cognitive and motor dysfunction in HD.

Animals↗
PubMed2006

Minicolumnar abnormalities in autism.

Autism is characterized by qualitative abnormalities in behavior and higher order cognitive functions. Minicolumnar irregularities observed in autism provide a neurologically sound localization to observed clinical and anatomical abnormalities. This study corroborates the initial reports of a minicolumnopathy in autism within an independent sample. The patient population consisted of six age-matched pairs of patients (DSM-IV-TR and ADI-R diagnosed) and controls. Digital micrographs were taken from cortical areas S1, 4, 9, and 17. The image analysis produced estimates of minicolumnar width (CW), mean interneuronal distance, variability in CW (V (CW)), cross section of Nissl-stained somata, boundary length of stained somata per unit area, and the planar convexity. On average CW was 27.2 microm in controls and 25.7 microm in autistic patients (P = 0.0234). Mean neuron and nucleolar cross sections were found to be smaller in autistic cases compared to controls, while neuron density in autism exceeded the comparison group by 23%. Analysis of inter- and intracluster distances of a Delaunay triangulation suggests that the increased cell density is the result of a greater number of minicolumns, otherwise the number of cells per minicolumns appears normal. A reduction in both somatic and nucleolar cross sections could reflect a bias towards shorter connecting fibers, which favors local computation at the expense of inter-areal and callosal connectivity.

Adolescent↗
PubMed2006

Neuroglobin mRNA expression after transient global brain ischemia and prolonged hypoxia in cell culture.

Neuroglobin is a nerve-specific respiratory protein that has been proposed to play an important role in the protection of brain neurons from ischemic and hypoxic injuries. Here, we investigated the regulation of neuroglobin expression after transient global ischemia in the rat brain using mRNA in situ hybridization and under hypoxic stress in cultured neuronal cell lines (PC12, HN33) by quantitative RT-PCR. While neuroglobin mRNA expression was significantly enhanced in cell culture after severe prolonged hypoxia (0-1% O2 for 24 h), we did not find any significant increases in neuroglobin mRNA levels in the rat brain after transient global ischemia. Vegf and Glut1 mRNAs showed increases in the hippocampus as expected. Therefore, it is unlikely that neuroglobin is instrumental in the acute response of neurons to hypoxic or ischemic insults, for which the mammalian brain is not adapted.

Animals↗
PubMed2006

Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia.

Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.

Animals↗
PubMed2006

Progressive deterioration of reaction time performance and choreiform symptoms in a new Huntington's disease transgenic ratmodel.

We tested the hypothesis that a recently developed transgenic rat model of Huntington's disease (tgHD rats) showed an age-and genotype-dependent change in psychomotor performance and in the frequency of choreiform movements similar to HD patients. Wild type and tgHD (homozygotic and heterozygotic) rats were behaviorally tested at an age of 15 and 20 months. Our results show that tgHD rats exhibit an age-, and genotype-dependent deterioration of the psychomotor performance and choreiform symptoms, closely mimicking the clinical time course changes of psychomotor symptoms of HD patients. These data provide further experimental evidence that the tgHD rat can be considered as a relevant animal model of HD.

Age Factors↗
PubMed2006

Functional investigations into the role of dopamine and serotonin in partial bilateral striatal 6-hydroxydopamine lesioned rats.

In Parkinson's disease (PD), several neurotransmitter systems, such as the dopaminergic and serotonergic system, show signs of degeneration. This led to the suggestion that alterations in the serotonergic system play a role in the pathophysiology of PD. Partial bilateral dopaminergic lesions of the caudate putamen complex (CPu) of rats induced by 6-hydroxydopamine (6-OHDA) produce behavioral symptoms mimicking PD. In the present study, the role of serotonin and dopamine was investigated both behaviorally and neuroanatomically. In a reaction time task, motor initiation and motor performance were impaired in the lesioned animals compared to controls. The performance of rats treated with d-amphetamine or serotonergic ligands (DOI and ketanserin) in the reaction time task indicated that 5-HT and DA appear to be agonistically related in the CPu. The relation was the same in both control and 6-OHDA lesioned rats. 12 weeks after lesioning, motor initiation recovered, whereas motor performance did not. Parallel to the behavioral study, a second group of animals was lesioned and, at 3 days, 6 weeks and 12 weeks after lesioning, a subgroup was killed to obtain a qualitative indication of the degree of 6-OHDA lesion. Over the three time points, a substantial recovery of tyrosine hydroxylase staining in the CPu was visible. Taken together, since serotonergic ligands have the same effect as dopaminergic ligands on reaction time responding indicated that 5-HT and DA release are agonistically linked in control and 6-OHDA lesioned rats.

Animals↗
PubMed2006

Selective striatal neuron loss and alterations in behavior correlate with impaired striatal function in Huntington's disease transgenic rats.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by selective striatal neuron loss and motor, cognitive and affective disturbances. The present study aimed to test the hypothesis of adult-onset neuron loss in striatum and frontal cortical layer V as well as alterations in behavior pointing to impaired striatal function in a recently developed transgenic rat model of HD (tgHD rats) exhibiting enlarged ventricles, striatal atrophy and pycnotic pyramidal cells in frontal cortical layer V. High-precision design-based stereological analysis revealed a reduced mean total number of neurons in the striatum but not in frontal cortical layer V of 12-month-old tgHD rats compared with age-matched wild-type controls. No alterations in mean total numbers of striatal neurons were found in 6-month-old animals. Testing 14-month-old animals in a choice reaction time task indicated impaired striatal function of tgHD rats compared with controls.

Animals↗
PubMed2006

In vitro comparison of aortic valve movement after valve-preserving aortic replacement.

OBJECTIVE: In aortic valve regurgitation and aortic dilatation, preservation of the aortic valve is possible by means of root remodeling (Yacoub procedure) or valve reimplantation (David procedure). In vivo studies suggest that reimplantation might substantially influence aortic valve-motion characteristics. Evaluation of aortic valve movement in vivo, however, is technically limited and is difficult to standardize. We evaluated the aortic valve-motion pattern echocardiographically in vitro after reimplantation and remodeling. METHODS: By using aortic roots of house pigs (aortoventricular diameter, 22 mm) a Yacoub procedure (22-mm graft; group Y, n = 5) or a David I procedure (24-mm graft; group D, n = 5) was performed. Roots after supracommissural replacement (22-mm graft; group C, n = 5) served as control valves. In an electrohydraulic, computer-controlled pulse duplicator the valves were tested at flows of 2, 4, 7, and 9 L/min. Echocardiographically assessed parameters were rapid valve-opening velocity, slow valve-closing velocity, rapid valve-closing velocity, rapid valve-opening time, rapid valve-closing time, ejection time, maximum valve opening, slow valve-closing displacement, and maximum flow velocity. RESULTS: Mean rapid valve-opening velocity and mean rapid valve-closing velocity at a cardiac output of 2 to 9 L/min were fastest in group D (rapid valve-opening velocity: 69 +/- 10 cm/s [group D] vs 39 +/- 4 cm/s [group Y] vs 42 +/- 4 cm/s [group C], P = .0041; rapid valve-closing velocity: 22 +/- 2 cm/s [group D] vs 16 +/- 2 cm/s [group Y] vs 17 +/- 1 cm/s [group C], P = .0272), and slow valve-closing velocity was slowest in group D (0.2 +/- 0.1 cm/s [group D] vs 1.0 +/- 0.3 cm/s [group Y] vs 0.6 +/- 0.1 cm/s [group C], P = .0063). With increasing cardiac output, the difference in rapid valve-opening velocity between the groups increased, the difference in slow valve-closing velocity remained unchanged, and the difference in rapid valve-closing velocity decreased. CONCLUSIONS: In this standardized experimental setting remodeling of the aortic valve provides significantly smoother valve movements. This might contribute to preservation of a better valve performance during long-term follow-up.

Animals↗
PubMed2006

In-vitro comparison of aortic valve hemodynamics between aortic root remodeling and aortic valve reimplantation.

BACKGROUND AND AIM OF THE STUDY: Valve-preserving aortic replacement has become an accepted option for patients with aortic valve regurgitation and aortic dilatation. The relative role of root remodeling versus valve reimplantation inside a vascular graft has been discussed, albeit controversially. In the present study, an in-vitro model was used to investigate the aortic valve hemodynamics of root remodeling and valve reimplantation; roots with supracommissural aortic replacement served as controls. METHODS: Aortic roots with aortoventricular diameter 21 mm were obtained from pigs. Root remodeling was performed using a 22-mm graft (group I, n = 6), or valve reimplantation with a 24-mm graft (group II, n = 7). Control roots were treated by supracommissural aortic replacement (22-mm graft; group III, n = 7). Using an electrohydraulic, computer-controlled pulse duplicator, the valves were tested at flows of 2, 4, 5, 7, and 9 I/min at a heart rate of 70 /min and a mean arterial pressure of 100 mmHg. Parameters assessed included: mean pressure gradient, effective orifice area, valve closure and regurgitant volume, and energy loss due to ejection, valve closure and regurgitation. Data were compared using ANOVA. RESULTS: There were no differences between the three groups in terms of regurgitant volume, energy loss due to valve regurgitation, or valve closure. The aortic valve orifice area was largest and systolic gradient lowest in group I at all flow rates (p < 0.001). Ejection energy loss was lowest in group I at all flow rates (9 l/min: group I, 128 +/- 21 mJ; group II, 399 +/- 46 mJ; group III, 312 +/- 27 mJ; p < 0.001). Valve closure volumes were similar in groups I and III, but significantly lower in group II at all flow rates (p = 0.047). CONCLUSION: In this standardized experimental setting, root remodeling--but not valve reimplantation--resulted in physiologic hemodynamic performance of the aortic valve with regard to orifice area, pressure gradient, and systolic energy loss.

Animals↗
PubMed2006

Hemodynamics of high-performance bileaflet valves: comparison to simulated clinical Doppler measurements.

BACKGROUND AND AIM OF THE STUDY: The newly designed, so-called 'high performance' bileaflet heart valve prostheses are suggested to be especially beneficial in small sizes. Herein, valvular energy loss and transvalvular gradients were evaluated using an in-vitro pulsatile flow model for aortic prostheses (St. Jude Medical Regent and On-X, sizes 19-23 mm). Gradients were compared with simulated clinically derived Doppler gradients to determine the extent of pressure recovery. METHODS: Valves were analyzed using a pulsatile circulatory mock loop simulator at heart rates of 70 and 110 bpm, and at cardiac outputs of 2, 4, 5, and 7 l/min, respectively (FDA requirements). Measurements consisted of computed calculation of energy loss and determination of mean pressure gradient by pressure transducers. A Doppler probe was mounted into the device for simultaneous measurement of Doppler gradient according to the Bernoulli equation. RESULTS: The systolic energy loss of the SJM Regent valve averaged 5.0 +/- 4.6% (range: 0.2 to 14.9%) of the effective forward energy, while that for the On-X valve was 6.5% (range: 0.7-22.8%). Total energy loss was 9.9% (range: 4.8-22.1%) for the SJM Regent valve, and 12.7% (range: 6.5-27.7%) for the On-X valve. The average extent of pressure recovery was 64% for both valve types. CONCLUSION: All tested valves were characterized by excellent hemodynamic performance, with overall low systolic and total energy losses, but results were slightly favorable for the SJM Regent valve. Valve performance was concluded to be much better than expected by clinical routine Doppler measurements, which significantly overestimates transvalvular gradients; this effect was explained by pressure recovery. Nevertheless, Doppler gradient remains a valuable follow up technique for patients with heart valve prostheses.

Biomechanical Phenomena↗
PubMed2005

The aging brain: accumulation of DNA damage or neuron loss?

Age-related molecular and cellular alterations in the central nervous system are known to show selectivity for certain cell types and brain regions. Among them age-related accumulation of nuclear (n) DNA damage can lead to irreversible loss of genetic information content. In the present study on the aging mouse brain, we observed a substantial increase in the amount of nDNA single-strand breaks in hippocampal pyramidal and granule cells as well as in cerebellar granule cells but not in cerebellar Purkinje cells. The reverse pattern was found for age-related reductions in total numbers of neurons. Only the total number of cerebellar Purkinje cells was significantly reduced during aging whereas the total numbers of hippocampal pyramidal and granule cells as well as of cerebellar granule cells were not. This formerly unknown inverse relation between age-related accumulation of nDNA damage and age-related loss of neurons may reflect a fundamental process of aging in the central nervous system.

Aging↗
PubMed2005

Stereological studies of capillary length density in the frontal cortex of schizophrenics.

The presence of microvasculature abnormalities in the prefrontal cortex of schizophrenics was proposed in a recent study of molecular signatures of schizophrenia [Prabakaran et al (2004) Mol Psychiat 9:684-697]. To assess this possibility further, we investigated capillary length densities in prefrontal cortex area 9 and anterior cingulate cortex area 24 in postmortem brains from 13 schizophrenics and 13 age- and sex-matched controls. To check that our sample of brains shared cardinal neuropathological features of schizophrenia with previously reported case studies, we also measured cortical gray matter volumes and cortical thickness in areas 9 and 24. The mean cortical gray matter volume was significantly reduced in brains from schizophrenics compared to controls. Mean cortical thickness was significantly reduced in area 24, but not in area 9, in schizophrenics. There were no differences in mean capillary length densities in either area 9 or 24 between the two groups. Thus, alterations in capillary length density in the prefrontal cortex cannot be considered a general feature of schizophrenia. Compromised brain metabolism and occurrence of oxidative stress in the brain of schizophrenics are likely caused by other mechanisms.

Adult↗
PubMed2005

Mean cell spacing abnormalities in the neocortex of patients with schizophrenia.

It has been postulated that the prefrontal cortices of schizophrenic patients have significant alterations in their interneuronal (neuropil) space. The present study re-examines this finding based on measurements of mean cell spacing within the cell minicolumn. The population studied consisted of 13 male schizophrenic patients (DSM-IV criteria) and 13 age-matched controls. Photomicrographs of Brodmann's areas 9, 4 (M1), 3b (S1), and 17 (V1) were analyzed with computerized image analysis to measure parameters of minicolumnar morphometry, i.e., columnarity index (CI), minicolumnar width (CW), dispersion of minicolumnar width (V(CW)), and mean interneuronal distance (MCS). The results indicate alterations in the mean cell spacing of schizophrenic patients according to both the lamina and cortical area examined. The lack of variation in the columnarity index argues in favor of a defect postdating the formation of the cell minicolumn.

Adult↗
PubMed2005

Acute and separate modulation of motor and cognitive performance in parkinsonian rats by bilateral stimulation of the subthalamic nucleus.

The subthalamic nucleus (STN) is involved in motor and cognitive performance through its key role in the basal ganglia-thalamocortical circuits, but how these different modalities (motor and cognition) are controlled (similar vs. dissimilar) has not yet been elucidated. In the present study, the effects of bilateral STN deep brain stimulation (DBS) on motor and cognitive performance were investigated in a rat model of Parkinson disease (PD). After being trained in a choice reaction time (CRT) task, rats received bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width), and varying amplitudes of 1, 3, 30, and 150 microA during the CRT task. Finally, rats were sacrificed and the brains processed for staining to determine the dopaminergic lesion (TH immunohistochemistry) and localization of the electrode tip (HE histochemistry). Bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc) and increased motor time (MT), proportion of premature responding (PR), and reaction time (RT). Bilateral STN stimulation with an amplitude of 3 microA normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 microA reversed the lesion-induced deficits in MT and RT. Our data show for the first time that bilateral STN stimulation differentially affected the 6-OHDA-induced motor and cognitive deficits. This means that basal ganglia-thalamocortical motor and associative circuits responsible for specific motor and cognitive performance, which are processed through the STN, have unique physiological properties that can acutely and separately be modulated by specific electrical stimuli.

Animals↗