Biomedical subjects
Publications and source records attributed to B Hellwig.
There are some reports in the literature about the comorbidity of Darier's Disease (keratosis follicularis) and psychiatric illness (e.g. mental retardation or affective disorders). Here we present evidence that schizophreniform psychosis may also be associated with Darier's Disease.
1. This is a report of a patient who developed an acute organic psychosis due to neurotoxicity of lithium several days after tapering off a long-lasting clozapine therapy. 2. The organic brain syndrome with initial illusionary misperceptions, a confusional state and a lapse into a pre-coma developed three days after the end of clozapine therapy and seven days after the beginning of haloperidol addition. 3. Possible pharmacokinetic and pharmacodynamic factors responsible for the severe neurotoxicity of lithium after withdrawal of clozapine and addition of haloperidol are discussed.
1. The patient, a 59 year old woman, developed a state of acute excitation several hours after the administration of 400 mg of the fluorquinolone pefloxacin in combination with 1000 mg paracetamol. Nine days later, after a total dosage of pefloxacin of 800 mg, she was admitted to our hospital with a psychotic disorder. 2. There was a full remission of symptoms after treatment with perazine up to a dosage of 500 mg/day. 3. Three years ago, the patient had developed a manic state under a medication with corticosteroids. 4. So far, the mechanism of--in this case--long-lasting central nervous side effects of fluorquinolones is not known. In patients with increased vulnerability of the CNS or in advanced age the application of fluorquinolones should be considered critically, in particular in combination with non-steroidal anti-inflammatory drugs.
A 56-year-old female patient had a history of more than 10 years' duration of a bipolar affective disorder manifest mainly as depressive episodes. These episodes used to occur once or twice each year, frequently leading to hospital admission. On average, the episodes lasted for about 2 months, and they tended to be followed by brief periods of hypomania. Only once, in 1986, did a manic episode make hospitalization necessary. Attempted prophylaxis with lithium at therapeutic plasma levels did not prove effective. Treatment with carbamazepine was discontinued because of leukopenia. The most recent stay in hospital became necessary because of a depressive episode that lasted for 5 months and did not respond to therapy. On admission the patient's score on the Hamilton depression scale was 23. When the calcium antagonist nimodipine was given at a dosage quickly escalated to 360 mg daily, the patient could be discharged in a state of complete remission after 26 days. For the first time in many years she has been emotionally stable for almost 1 year with single agent nimodipine therapy at 180 mg daily.
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In this study we investigated the arrangement of synapses on local axon collaterals of Golgi-stained pyramidal neurons in the mouse cerebral cortex. As synaptic markers we considered axonal swellings visible at high magnification under the light microscope. Such axonal swellings coincide with synaptic boutons, as has been demonstrated in a number of combined light and electron microscopic studies. These studies also indicated that, in most cases, one bouton corresponds precisely to one synapse. Golgi-impregnated axonal trees of 20 neocortical pyramidal neurons were drawn with a camera lucida. Axonal swellings were marked on the drawings. Most swellings were 'en passant'; occasionally, they were situated at the tip of short, spine-like processes. On axon collaterals, the average interval between swellings was 4.5 microns. On the axonal main stem, the swellings were always less densely packed than on the collaterals. Statistical analysis of the spatial distribution of the swellings did not reveal any special patterns. Instead, the arrangement of swellings on individual collaterals follows a Poisson distribution. Moreover, the same holds to a large extent for the entire collection of pyramidal cell collaterals. This suggests that a single Poisson process, characterized by only one rate parameter (number of synapses per unit length), describes most of the spatial distribution of synapses along pyramidal cell collaterals. These findings do not speak in favour of a pronounced target specificity of pyramidal neurons at the synaptic level. Instead, our results support a probabilistic model of cortical connectivity.
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In the cerebral cortex two main types of anatomical parcellation have been proposed: cyto- and myeloarchitectonics. Cytoarchitectonics is based on differences in the distribution and the sizes of cell bodies. Myeloarchitectonics relies on the layering and packing density of intracortical myelinated fibres. Thereby attention is mainly focused on those horizontal fibres which are organized in bands known as the stripes of Baillarger. Cyto- and myeloarchitectonics must be somehow related: structural changes from area to area as revealed by the Nissl stain coincide with changes in the myelin picture. In this paper, it is demonstrated that two simple assumptions are sufficient to transform quantitative data on the Nissl picture of a certain area (i.e. layer thicknesses, neuron sizes, neuron densities) into the corresponding myelin picture. The first assumption is that large neurons contribute more to the intracortical myelin content than small ones, and that this relation can be represented by a sigmoid curve. The second assumption is that the average distribution of horizontal axon collaterals of pyramidal neurons with respect to the cell body can be quantified by a simple model. On the basis of these two assumptions, myelin patterns were computed for the whole spectrum of cortical variability, including the primary visual, somatosensory, auditory and motor cortices, the speech centres and a number of association areas. Comparison of the simulations with real myelin preparations revealed remarkable similarities. These findings support the assumption that the horizontal component of the myelin picture is mainly produced by axon collaterals of pyramidal cells, and that nonpyramidal neurons and afferent fibres play a minor role. Moreover, the results suggest that the distribution of horizontal axon collaterals of pyramidal neurons and the principles of their myelination are very similar in different areas. The function of intracortical myelin is discussed. The increase in conduction velocity gained by myelination seems negligible for most intracortical fibres. It is argued that myelination may be related to learning processes during the critical period.
The binding domain of forskolin in the adipocyte/muscle-type glucose transporter (GLUT-4) was localized with the aid of the photoreactive derivative, [125I]IAPS-forskolin (3-[125I]iodo-4-azidophenethylamido-7-O-succinyldeacetyl-forskolin). Plasma membranes from insulin-treated rat adipocytes containing predominantly the GLUT-4 isoform were irradiated with UV light in the presence of [125I]IAPS-forskolin. The covalently labeled glucose transporters were isolated by immunoprecipitation with specific antiserum and partially digested with trypsin and elastase. The fragments were separated by gel electrophoresis, transferred on to nitrocellulose membranes, and identified by direct autoradiography and by immunoassay with antiserum against a peptide sequence corresponding to the C-terminus of GLUT-4. Digestion with a high-purity grade trypsin generated two photolabeled fragments with apparent molecular weights of 21 and 16 kDa. Since the antiserum detected two fragments with identical electrophoretic mobility, both labeled fragments appeared to contain the intact C-terminus of GLUT-4. In contrast, digestion with elastase generated only one photolabeled fragment with intact C-terminus at 21 kDa, and a smaller unlabeled fragment with intact C-terminus at 15 kDa. A less pure trypsin preparation generated two labeled (21 and 17 kDa) and one unlabeled (15 kDa) fragment with intact C-terminus. These data suggest that the site of covalent binding of IAPS-forskolin in the GLUT-4 is located within a region of 1-6 kDa defined by the difference between the unlabeled C-terminal fragment (15 kDa) and the labeled fragments (21, 17 and 16 kDa). Based on a tentative allocation of the fragments to the sequence of the GLUT-4, it is suggested that the covalent binding site of IAPS-forskolin is located between the membrane spanning helices 7-9, possibly in the proximity of helix 9.
The binding affinities of the glucose transporter isoforms GLUT1, GLUT2, and GLUT4 for the inhibitory ligands cytochalasin B, forskolin, dipyridamole, and isobutylmethylxanthine (IBMX) were compared in membranes from human erythrocytes and rat brain containing the erythrocyte-type glucose transporter (GLUT1), in membranes from rat liver containing the liver-type glucose transporter (GLUT2), and in membranes from adipocytes and heart containing predominantly the adipose/muscle-type glucose transporter (GLUT4). The binding affinities of cytochalasin B for GLUT1 and GLUT4 were virtually identical (KD) in membranes from erythrocytes, 190 nM; in brain, 130 nM; in adipocytes, 160 nM; and in heart, 170 nM). In contrast, no specific glucose-inhibitable binding of cytochalasin B was detected in liver membranes. The binding affinity for forskolin of GLUT1 was significantly lower than that of GLUT4 (KD in erythrocytes, 2360 nM; Kl in brain, 4360 nM; and KD in adipocytes, 200 nM; and in heart, 210 nM); specific glucose-inhibitable binding to GLUT2 was not detectable. Like forskolin, the glucose transport inhibitors dipyridamole (Kl in adipocyte membranes, 1.2 microM; in erythrocytes, greater than 40 microM) and IMBX (Kl in adipocyte membranes, 60 microM; and in erythrocytes, greater than 500 microM) bound with higher affinity to GLUT4 than to GLUT1. These data demonstrate striking differences of GLUT1, GLUT2, and GLUT4 with respect to their binding affinity for the inhibitory ligands cytochalasin B, forskolin, dipyridamole, and IBMX. It is suggested that the complex differences result from interaction of more than one heterogeneous binding site at the glucose transporters with the inhibitory ligand.
The effect of rapid converting enzyme inhibition (CEI) with intravenous enalaprilat on technetium-99m-(99mTc) diethylenetriaminepentaacetic acid (DTPA) and 99mTc-dimercaptosuccinic acid (DMSA) renograms was evaluated in rats with two-kidney, one-clip renovascular hypertension. Rapid sequential DTPA renograms, performed immediately before and five minutes after enalaprilat injection (30 micrograms/kg), demonstrated a selective decrease in clipped kidney DTPA plasma clearance following CEI and no significant effect on unclipped kidney function. Pre- and post-CEI data were obtained with a single injection of DMSA by administering enalaprilat five minutes after the radiopharmaceutical. Enalaprilat slowed the rate of DMSA accumulation in clipped relative to unclipped kidneys, and reduced the clipped/unclipped kidney ratio of absolute DMSA uptake at 10 and 30 min. DTPA and DMSA were equally effective in demonstrating the CEI effect. Enalaprilat was also compared with captopril (3 mg/kg, intraperitoneally), using sequential DTPA renograms. Clipped kidney DTPA plasma clearance was reduced to an identical degree (40%) by both converting enzyme inhibitors. Clinical renographic protocols can probably be devised to take advantage of the rapid, reliable CEI of enalaprilat, thereby shortening total procedure time.
The efficacy of five different radiodiagnostic agents for detecting renal tubular dysfunction induced with cisplatin in rats was compared to controls. Diethylenetriaminepentaacetic acid (DTPA) labeled with 99mTc or 111In was administered simultaneously with each of the other four agents [99mTc]glucoheptonate, [99mTc]dimercaptosuccinic acid, [131I]hippuran and [111In]lysozyme) as a standard to normalize for differences in functional impairment from animal to animal from the same dose of cisplatin. The 2-hr plasma clearance and computer-generated 2- to 3-min uptake in the two kidneys with [99mTc]dimercaptosuccinic acid were significantly inferior to similar measurements with the other agents in differentiating abnormal from normal function. The 2-hr uptake of [99mTc]glucoheptonate and [111In]lysozyme proved of no value in this differentiation. The late renal retention of [99mTc]dimercaptosuccinic acid well separated the cisplatin from control rats, but the greatest difference was observed by the 2-hr uptakes of [131I]hippuran and DTPA.
The efficacy of different radiodiagnostic agents for demonstrating the decline in renal function from cyclosporine (CyA) nephrotoxicity was assessed in rats receiving a standard dose of the drug for 2 wk, compared with control rats. The agents included [99mTc]DTPA, [131I]hippuran, [111In]lysozyme, [99mTc]glucoheptonate (GHA), [99mTc]dimercaptosuccinate (DMS) and [111In]aminated dextran (amdex). A small dose of [99mTc]- or [111In]DTPA was administered simultaneously to normalize the results for variations in drug response from one animal to another. There were statistically significant differences in the detectability of the renal functional impairment by plasma clearance, early and 2-hr renal uptake among the different agents. However, none was clearly superior to DTPA. This conclusion is consistent with previous studies which showed a parallel decline in glomerular filtration rate (GFR) and effective renal plasma flow in acute CyA toxicity probably due primarily to vasoconstriction.
In Goldblatt hypertension in rats produced by implanting a silver clip on the left renal artery, captopril induces a greater difference in the 1-min uptake of diethylenetriaminepentaacetic acid (DTPA) between the two kidneys than in baseline uptakes, similar to the experiences in unilateral renovascular hypertension in man. The combination of captopril and furosemide induces an even greater difference in renal uptakes than with captopril alone in this rat model. In paired experiments, DTPA complexes were used as a standard to compare the differences in renal uptake between the two kidneys after captopril-furosemide with other existing and potential renal radiodiagnostic agents. No statistically significant difference was found between DTPA, glucoheptonate, dimercaptosuccinic acid, aminated dextran, or lysozyme. However, the differences in renal uptake were significantly less with hippuran than with DTPA. Furosemide and captopril caused delayed renal retention of hippuran after one minute. This response appeared to be due to non-specific volume depletion because it occurred in both clipped and unclipped kidneys.