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Biomedical subjects

C M Müller

Publications and source records attributed to C M Müller.

At least 19 recordsLinked to original sources

Pathology associated with sporadic Parkinson's disease--where does it end?

Parkinson's disease (PD) is a multisystem disorder in which predisposed neuronal types in specific regions of the human peripheral, enteric, and central nervous systems become progressively involved. A staging procedure for the PD-related inclusion body pathology (i.e., Lewy neurites and Lewy bodies) in the brain proposes that the pathological process begins at two sites and progresses in a topographically predictable sequence in 6 stages. During stages 1-2, the inclusion body pathology remains confined to the medulla oblongata, pontine tegmentum, and anterior olfactory structures. In stages 3-4, the basal mid- and forebrain become the focus of the pathology and the illness reaches its symptomatic phase. In the final stages 5-6, the pathological process is seen in the association areas and primary fields of the neocortex. To date, we have staged a total of 301 autopsy cases, including 106 cases with incidental pathology and 176 clinically diagnosed PD cases. In addition, 163 age-matched controls were examined. 19 of the 301 cases with PD-related pathology displayed a pathological distribution pattern of Lewy neurites and Lewy bodies that diverged from the staging scheme described above. In these cases, olfactory structures and the amygdala were predominantly involved in the virtual absence of brain stem pathology. Most of the divergent cases (17/19) had advanced concomitant Alzheimer's disease-related neurofibrillary changes (stages IV-VI).

Animals↗

Seasonal changes in astrocytes parallel neuronal plasticity in the song control area HVc of the canary.

In the song control area HVc of the canary, intercellular dye-coupling among astrocytes was studied by intracellular injection of neurobiotin into identified single astrocytes. Injection of individual astrocytes into acute slices resulted in dye spread to neighboring astrocytes, covering a sphere of up to 1 mm in diameter. The astrocytic nature of the dye-coupled cells was verified by double labeling of neurobiotin-filled cells with antisera for the astrocytic filament proteins GFAP or vimentin. The similarity in the number of dye-coupled cells and the total number of astrocytes labeled by immunocytochemical markers indicate that dye-coupling is specific for astrocytes and labels almost the entire local astrocytic population. Within the major nucleus for vocal control (HVc), approximately 25% more astroglial cells were present than in the surrounding forebrain tissue. There is no apparent hindrance of dye spread at the border of the HVc. The density of dye-coupled astrocytes and the expression of cytoskeletal filament proteins differed markedly between the reproductive period in spring and the quiescent period in autumn. While vimentin is the major astroglial filament in autumn, GFAP is strongly expressed in spring. The density of dye-coupled astrocytes reveals a marked increase in the reproductive period, followed by a reduction in autumn. The data indicate that the astrocytic population in the avian forebrain undergoes significant changes coincident with the known functional changes in the vocal control nuclei during periods of song production.

Age Factors↗

Tissue plasminogen activator mediates reverse occlusion plasticity in visual cortex.

Preventing visual input to one eye (monocular deprivation) in early postnatal development reduces cortical responses to stimulation of the deprived eye, with a significant loss of thalamocortical connections. These effects are reversible by opening the deprived eye and closing the previously open eye (reverse occlusion). We show that intracortical blockade of tissue plasminogen activator or plasmin selectively prevents recovery of cortical function and thalamic neuron size during reverse occlusion, without affecting the monocular deprivation response. Therefore, a proteolytic cascade consisting of plasmin generated by tissue plasminogen activator may selectively mediate reverse-occlusion-induced cortical plasticity, perhaps via structural remodeling of axons.

Animals↗

Critical period-dependent reduction of the permissiveness of cat visual cortex tissue for neuronal adhesion and neurite growth.

During postnatal development, the visual cortex undergoes an experience-dependent refinement of its circuitry. This process includes synapse formation, as well as synapse elimination. Both mechanisms appear to be restricted to a limited 'critical period' which lasts for approximately 2 months in cats. We tested whether the termination of the critical period for cortical malleability is paralleled by changes in the growth permissiveness of the tissue. These changes may inhibit progressive reorganization of functional circuitries mediated by axon growth. Embryonic cortical neurons were cultured on unfixed cryostat sections of the visual cortex obtained from cats aged 2-50 weeks. After 2-3 days in vitro the distribution of viable cells and the percentage of neurite-bearing cells were determined and analysed with respect to the developmental age and subdivisions of the underlying tissue substrate. It was shown that cell adhesion and neurite formation are correlated with the developmental age of the substrate tissue and the time period of myelination. While embryonic neurons adhered and survived on grey and white matter tissue from 2- and 4-week-old kittens, there was a significant reduction in cell adhesion on the myelinated white matter regions of the tissue sections of older animals. Quantitative analyses showed that neurite formation by cultured neurons also became successively impaired on grey and white matter areas of tissue substrates, corresponding to the time course of the critical period for cortical malleability. On grey matter tissue this effect was most pronounced between the second and sixth postnatal weeks. The effects were not antagonized by coating the substrate sections with the growth-promoting molecule laminin. It is therefore proposed that neurite growth-inhibiting factors, most probably associated with central nervous system myelin, are gradually expressed postnatally and may contribute to the termination of the critical period in the visual cortex of cats.

Animals↗

Sevoflurane in paediatric anaesthesia.

Sevoflurane is a potent inhalational agent, combining several advantages of specific interest in paediatric anaesthesia. Rapid and smooth induction, a safe cardiovascular profile, rapid emergence and a short postoperative recovery with minimal side effects are ideal characteristics of this agent for the use in paediatric anaesthesiology. The apparent improvement in management should not obscure the fact that sevoflurane in higher MAC should be used with caution in renal impairment. For the future world of our children, the lack of chlorine in the structure makes sevoflurane theoretically less ozone-depleting than halothane and isoflurane, a substance contributing to environmental protection.

Air Pollutants↗

Sedation and anaesthesia outside the OR.

The sedation of paediatric patients is associated with serious risks such as hypoventilation, apnoea, airway obstruction, and cardiopulmonary impairment; these risks should be avoided or accurately and rapidly diagnosed and appropriately treated. Appropriate management may include ventilation by mask and cardiopulmonary resuscitation, which require special training and skills.

Airway Obstruction↗

Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin.

BACKGROUND: Animals subjected to immunostimulatory conditions (sepsis) exhibit decreased total cytochrome P450 content and decreased P450-dependent drug metabolism. Cytochrome P450 function is of clinical significance because it mediates the metabolism of some opioid and hypnotic drugs. The authors tested the hypothesis that reduced P450 function and decreased drug metabolism in sepsis are mediated by endotoxin-enhanced synthesis of nitric oxide. METHODS: Hepatic microsomes were prepared from male Sprague-Dawley rats in nontreated rats, rats pretreated with phenobarbital and rats receiving aminoguanidine or NG-L-monomethyl-arginine alone. Nitric oxide synthesis was augmented for 12 h with a single injection of bacterial lipopolysaccharides. Nitric oxide synthase was inhibited with aminoguanidine or N(G)-L-monomethyl-arginine during the 12 h of endotoxemia in some animals. Plasma nitrite and nitrate concentrations were measured in vivo, and total microsomal P450 content, and metabolism of ethylmorphine and midazolam in vitro. RESULTS: Administration of endotoxin increased plasma nitrite and nitrate concentrations, decreased total cytochrome P450 content, and decreased metabolism of ethylmorphine and midazolam. Inhibition of nitric oxide formation by aminoguanidine or N(G)-L-monomethyl-arginine partially prevented the endotoxin-induced effects in the nontreated and phenobarbital-treated groups. Aminoguanidine or N(G)-L-monomethyl-arginine alone did not have an effect on either total cytochrome P450 content or P450-dependent drug metabolism. Plasma nitrite and nitrate concentrations correlated significantly negatively with P450 content (nontreated r = -0.88, phenobarbital r = -0.91), concentrations of formed formaldehyde (nontreated r = -0.87, phenobarbital r = -0.95), and concentrations of midazolam metabolites (4-OH midazolam nontreated r = -0.88, phenobarbital r = -0.93, and 1'-OH midazolam nontreated r = -0.88, phenobarbital r = -0.97). CONCLUSIONS: Altered hepatic microsomal ethylmorphine and midazolam metabolism during sepsis is mediated in large part by nitric oxide.

Animals↗

Development of layers, maps and modules.

Developing neuronal cell sheets acquire position-specific features by mechanisms that differ in radial and tangential dimensions. These features include guiding cues for axonal growth and targeting that are used, for example, in map formation. Recent evidence supports the notion that graded distributions of molecules are involved in growth cone navigation and axonal branching. In addition, activity-dependent processes are important determinants of functional architecture, especially with respect to modular organization.

Afferent Pathways↗

Forced-air warming maintains normothermia during orthotopic liver transplantation.

We evaluated the efficacy of forced-air warming to maintain normothermia during liver transplantation. In a prospective, clinical trial 20 patients were randomly assigned to routine thermal management (circulating-water mattress set at 42 degrees C, intravenous fluid warming to 37 degrees C and passive insulation) or routine management with additional forced-air warming of head, chest, and arms. Core temperature was measured in the pulmonary artery. Morphometric and demographic characteristics were similar in each group, as was total administered fluid volume replacement. Core temperatures in each group decreased by about 0.6 degrees C during the first 70 min of anaesthesia and then by 0.9 degree C within 90 to 120 min in the patients given routine thermal management, but only by 0.4 degree C in those warmed with forced-air. Subsequently, core temperatures in the control group increased to only 35.7, SD 0.25 degree C whereas those in the patients given forced-air warming increased to 36.5, SD 0.2 degree C. Despite the relatively high ambient temperature, patients warmed only with a circulating-water mattress and passive insulation became hypothermic during surgery. In contrast, when forced-air warming was added to this routine thermal management, patients were normothermic at the end of surgery. Forced-air warming prevented intra-operative hypothermia during liver transplantation.

Body Temperature↗

[Changes in hemostasis during orthotopic liver transplantation and massive transfusion: a case report].

UNLABELLED: Changes in hemostasis during orthotopic liver transplantation (OLT) and an intraoperative bleeding complication requiring massive transfusion are discussed. DESIGN: The monitoring of hemostasis included bed-sided thromboelastography, measurement of in vitro platelet function with the thrombostat and routine coagulation tests as well as retrospective analysis of coagulation factors. RESULTS: Changes in hemostasis during OLT were documented as reported previously until reperfusion of the donor organ. Due to an incongruence between the caval veins and massive surgical bleeding, the liver had to be clamped again for reconstruction and perfused with University-of-Wisconsin solution. The second reperfusion was technically uncomplicated. However, the coagulation profile deteriorated dramatically: especially a decrease in platelet function and hyperfibrinolysis led to massive oozing. Successful therapeutical intervention included substitution of packed red blood cells. fresh frozen plasma, platelets. concentrates of hemostatic factors, and aprotinin. The patient was discharged from hospital after 5 weeks with a good liver function and a normal coagulation profile. CONCLUSION: During OLT, clinically relevant changes in hemostasis can occur suddenly. Therefore. a close perioperative monitoring of primary and secondary coagulation is mandatory.

Blood Coagulation Tests↗

Astrocytic dye coupling in rat hippocampus: topography, developmental onset, and modulation by protein kinase C.

Previous studies have shown that astrocytes constitute a functional syncytium whereas the cytoplasmata of individual cells are connected via gap junctions. Many studies have used cultured astrocytes and have examined electrical coupling with the help of double electrode techniques. Another approach has been the immunohistochemical detection of gap junction proteins in sections of brain tissue. From the results of these experiments it is difficult to infer the extent of astrocytic coupling in situ. To get an impression of the distribution of coupled astrocytes we took advantage of the hippocampal slice preparation which leaves the topography of neurons and astrocytes intact. We performed injections of low molecular weight dyes into single electrophysiologically identified astrocytes. As these dyes can pass through gap junctions this leads to the staining of all connected cells in a certain area, limited by the diffusional spread of the dye. The results show that there is virtually no border to astrocytic coupling between the diverse hippocampal subdivisions. This widespread coupling could already be detected at postnatal day 4, the earliest age tested. Activation of protein kinase C with phorbol esters showed that it is possible to reduce gap junctional communication by some extent. We conclude that although no compartmentalization was seen with respect to astrocytic coupling, the intercellular communication of these glial cells has the capability of being regulated for example by neuronal signals which activate the phospholipase C pathway in astrocytes.

Animals↗

Potential photosensitizers for photodynamic therapy. IV. Photophysical and photochemical properties of azaporphyrin and azachlorin derivatives.

The photophysical and photochemical properties of a 5-azaprotoporphyrin derivative ([5]AZPP), a zinc-15-azaporphyrin derivative (Zn-[15]AZIDP) and an E-Z isomeric mixture of a 5-azachlorin derivative ([5]AZCH) were studied in various solvents. The quantum yields of fluorescence phi F0, S1-T1 intersystem crossing phi T0 and singlet oxygen (1 delta g) formation phi delta were measured and the Stern-Volmer constants for the quenching of the S1 states by oxygen and the rate constants of quenching of O2(1 delta g) by the different azaporphyrinoid compounds were obtained. The fluorescence quantum yield (phi F0 = 0.23), the strong absorption in the red (lambda max = 674 nm, epsilon max = 66,000 M-1 cm-1) and the high value of the quantum yield for singlet oxygen (1 delta g) formation (phi delta = 0.65) observed for [5]AZCH recommend azachlorin derivatives as potential markers and photosensitizers for tumour therapy.

Deuteroporphyrins↗

Postnatal development and localization of an N-acetylgalactosamine containing glycoconjugate associated with nonpyramidal neurons in cat visual cortex.

We have analyzed the appearance of N-acetylgalactosamine containing glycoconjugates by staining sections of fixed cat visual cortex with the lectins from Vicia villosa (VVA) and Glycine max (SBA) conjugated to fluorescent labels, horseradish peroxidase, or biotin. The appearance of lectin staining during postnatal development followed an inside-out gradient starting in the deep cortical layers at the fourth postnatal week, successively including more of the superficial layers during the first three postnatal months until labelled cells were present throughout layers II-VI at the seventh postnatal month. Staining was associated with the soma and proximal dendrites of bipolar and multipolar nonpyramidal neurons. Outside layer IV large neurons with basket cell and neurogliaform morphology predominated, whereas small multipolar cells were stained in layer IV. High power observation revealed a lattice-like staining on neuronal surfaces. In the cortical white matter staining was found at the nodes of Ranvier. The ultrastructural localization of lectin binding sites was assessed by a pre-embedding histochemical procedure with biotinylated lectin visualized with HRP-conjugated avidin and diaminobenzidine as the chromogen. The reaction product was found exclusively in close association with synaptic terminals on somata and proximal dendrites of nonpyramidal neurons. There was no preference with respect to the morphology of the synaptic structure, i.e., symmetric synapses with ovoid or asymmetric synapses with round vesicles. In the vicinity of synaptic contacts the staining was associated with membranes of astrocytic processes ensheathing the synapses. In the cortical white matter astrocytic processes running along myelinated axons were strongly labelled at the nodes of Ranvier. Comparison of Western blots from 4-week-old and adult cat cortex membranes revealed one lectin-positive protein band with an apparent molecular weight of about 24 kD in conjunction with the histochemical expression of perisynaptic staining in the adult tissue. It is concluded that the employed lectins selectively visualize distal astroglial processes ensheathing synapses on a subpopulation of cortical interneurons and nodes of Ranvier. On the basis of the developmental appearance and localization we consider and discuss the possibility that the N-acetylgalactosamine containing glycoconjugate is involved in the stabilization of synaptic contacts on GABA-ergic interneurons.

Acetylgalactosamine↗

Reticular facilitation of cat visual cortical responses is mediated by nicotinic and muscarinic cholinergic mechanisms.

Stimulation of the mesencephalic reticular formation facilitates responses in the visual cortex elicited from the optic radiation. Using intravenous administration of cholinergic antagonists we investigated in adult cats and two kittens whether this effect is mediated by cholinergic mechanisms. When administered alone the muscarinic antagonists atropine and scopolamine and the nicotinic antagonist mecamylamine failed to block reticular facilitation and sometimes even enhanced the effects of reticular stimulation. However, when administered in combination muscarinic and nicotinic antagonists eliminated or significantly reduced the facilitation. This was even true when the two antagonists were administered with a time lag of several hours. These results support the notion that reticular facilitation of cortical responses is mediated by cholinergic mechanisms and suggest that this effect is mediated either by a receptor with a mixed pharmacological property or by two independent pathways acting via nicotinic and muscarinic receptors. This hypothesis is discussed in the context of recent evidence on cholinergic transmission and earlier data on the pharmacology of reticular arousal.

Animals↗

Structures mediating cholinergic reticular facilitation of cortical responses in the cat: effects of lesions in immunocytochemically characterized projections.

Cholinergic afferents to the neocortex controlled by the mesencephalic reticular formation (MRF) are known to transiently facilitate cortical excitability. In an attempt to identify the pathway mediating this effect in the cat visual cortex we combined retrograde tracing techniques with immunocytochemical methods to visualize the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT). In addition we examined, in acute electrophysiological experiments, whether local neurotoxin injections into nuclei of the basal forebrain interfered with the reticular facilitation of cortical evoked potentials. Cholinergic projections to area 17 originate from different centers in the homolateral substantia innominata/internal capsule, the septal nuclei, and the nuclei of the diagonal band of Broca. No direct cholinergic projection from the MRF to the visual cortex was observed. Retrogradely labelled cells intermingled with ChAT-positive neurons in the brainstem generally revealed immunopositivity for catecholaminergic markers. Local injections of neurotoxins in the substantia innominata blocked reticular facilitation, whereas local lesions of the septal nuclei and the nuclei of the diagonal band had no effect on MRF-induced facilitation. The blockage of the reticular facilitation of cortical evoked responses after unilateral lesions of the substantia innominata was bilateral, suggesting a cooperative interaction between basal forebrain structures of the two hemispheres. The anatomical and physiological data are discussed with respect to possible mechanisms of transient brainstem influences on cortical excitability.

Animals↗