Biomedical subjects
Publications and source records attributed to F Bergmann.
HT-2 toxin was the sole metabolite formed when T-2 toxin was treated with homogenate from brain without its blood content. Homogenate from brain with its full blood content produced--besides HT-2 toxin--T-2 triol, neosolaniol, 4-deacetylneosolaniol and T-2 tetraol, i.e. the same metabolites formed by incubation of T-2 toxin with whole rat blood.
In a 1-year period, 15 of 4048 pregnant women were found to have thrombocytopenia during their first prenatal visit. Their qualitative and quantitative platelet abnormalities were followed up prospectively for 1 to 6 months post partum. Platelet counts returned to normal in 14 of 15 patients 4 to 6 weeks post partum. von Willebrand factor antigen and ristocetin cofactor activity were low in three of 15 patients 4 to 6 weeks post partum, but had been normal during the antepartum period. Two of these three patients had prolonged bleeding times ante partum and post partum. All three patients subsequently were found to have mild type I von Willebrand disease. Six patients had detectable platelet antibodies. Neonatal thrombocytopenia was found in one term infant of a patient with mild thrombocytopenia and negative platelet antibodies. This study suggests that mild, transient, isolated thrombocytopenia can occur in an otherwise normal pregnancy and its incidence may be lower than previously reported. Extensive testing is not indicated unless there is an associated prolonged bleeding time. The possibility of von Willebrand disease or a qualitative platelet disorder should be considered.
The antibiotic cycloheximide inhibits protein synthesis in eukaryotic cells. This overall effect is similar to that of T-2 toxin, but the mechanism of intoxication by these two inhibitors are different. This is shown here by intracerebral injections of mixtures of T-2 toxin and cycloheximide, leading to potentiation of their toxic effects. The histopathology of cerebral intoxication by the two compounds is similar, but after cycloheximide the lesions appear earlier, and repair is faster.
Several protecting group combinations have been investigated to achieve an automated oligoribonucleotide synthesis on a solid support. The use of 2'-O-tert-butyldimethylsilyl-5'-O-monomethoxytrityl-ribonucleoside -3'-(p-nitrophenylethyl, N,N-diethyl)-phosphoramidites in conjunction with beta-eliminating blocking groups at the aglycone gave satisfactory results. An inverse protecting group strategy based upon analogously substituted 5'-O-2-dansylethoxycarbonyl-2'-O-4- methoxytetrahydropyran-4-yl-phosphoramidites can be regarded as another promising approach.
The role of the hypothalamus (HTH) in the pathogenesis of genetic hypertension was studied in spontaneously hypertensive rats (SHR). It is currently believed that, in this strain, the genetic defect manifests itself mainly in the HTH. We examined this hypothesis by grafting HTH neurons from embryos of SHR or control Wistar Kyoto (WKY) rats into the HTH of adult normotensive WKY rats. Changes in host systolic blood pressure (SBP) were monitored, and alterations in vasoactive intestinal polypeptide (VIP) gene expression of the host brain were studied. In rats grafted with HTH tissue from SHR embryos (G-SHR), the blood pressure rose by 31% as compared with that in the grafted control group. The blood pressure climbed gradually over a period of 6 weeks to its highest level, which was maintained for at least 3 months following grafting. Along with the elevated blood pressure, the heart weight increased by 80% compared to controls. Behavioral changes were also evident in the G-SHR rats, and these were similar to those of the native SHR strain. In situ hybridization histochemistry showed a 40% elevation in VIP transcripts in the suprachiasmatic nucleus of the host G-SHR brain compared to controls. These studies demonstrate that transplantation of embryonic SHR HTH tissue into brains of adult normotensive rats results in the development of hypertensive characteristics in the host. It thus appears that the HTH is a prime candidate for the source of changes leading to spontaneous hypertension in mammals.
Three classes of 12,13-epoxytrichothecenes, differing in the number of hydroxy or acetoxy substituents, were implanted or injected into rat brain to establish structure-toxicity relationships. A free 3 alpha-hydroxy group increases toxicity more than 10-fold, when compared to trichothecenes lacking this substituent. The 8 alpha-hydroxy group enhances toxicity about 4-fold.
T-2 toxin has been found previously to be markedly more toxic upon intracerebral than upon systemic administration. In order to study the generality of this difference, we have applied to brain and liver of albino rats two different types of trichothecenes: T-2 toxin as a representative of 'simple' and myrotoxin B as a representative of 'macrocyclic' members of this series. Myrotoxin B, when applied intracerebrally, was about 100 times more poisonous than T-2 toxin. In contrast, upon intrahepatic injection both compounds exhibited similar degrees of toxicity. The different behavior of the two trichothecenes in the organs tested may be due to local metabolic factors.
Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.
Intravenous injection of the synthetic TRH analog, MK-771, to anesthetised cats raised the blood pressure by a central mechanism, i.e. by activating the outflow of sympathetic stimuli from the CNS to the periphery and raising the plasma concentration of adrenaline and noradrenaline. In contrast, noradrenaline in the CSF was lowered by intravenously injected MK-771. The concentration of 5-HT in the CSF was increased and the pressor action of the peptide was correspondingly enhanced by 5-HT antagonists. These findings suggest that the release of 5-HT into the CSF lowers blood pressure and thus reduces the hypertensive effect of MK-771. Methysergide acts synergistically with MK-771 to combat the sudden fall in pressure induced by acute hemorrhage in the anesthetised cat. Combination of the two drugs enhanced and accelerated recovery from this hypotensive state.
Fourteen patients diagnosed as having thrombotic thrombocytopenia purpura (TTP) were studied. Those who survived have been followed during a 1 to 7 year period. The clinical diagnosis was based on changing neurological findings, thrombocytopenia and evidence of microangiopathic hemolytic anemia. Laboratory tests included the determination of von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (RiCof) and the electrophoretic mobility of von Willebrand factor (CIE VWF:Ag). The ratio of RiCof to VWF:Ag was then calculated. Control individuals included healthy subjects and patients with thrombocytopenia of several etiologies. Statistical differences between the values of RiCof, the ratio of RiCof:VWF:Ag and the CIE of VWF:Ag were found for samples comparing active disease and remission phase. The recovery from thrombocytopenia paralleled the correction of abnormal parameters. Similarly, significant differences were found when above parameters were compared between thrombocytopenia of TTP with other thrombocytopenic states. We suggest that these abnormal tests could be useful in distinguishing TTP from other disorders, and may have prognostic significance in patients already diagnosed as having TTP.
T-2 toxin and its metabolites (resulting from enzymatic hydrolysis by rat brain homogenate) were applied to the midbrain of albino rats, either in solid form or dissolved in dimethyl sulfoxide (DMSO). Solid implants of HT-2 toxin and of T-2 triol were lethal in the range of 10-20 micrograms per rat, i.e. similar to the effect of T-2 toxin itself. For four further trichothecenes, the following decreasing order of toxicities was found: T-2 tetraol = iso-T-2 toxin greater than T-2 tetraol tetraacetate greater than T-2 toxin acetate. Implants of the last compound were the least toxic in the present series of trichothecenes; its LD50 value was nearly ten times higher than that of T-2 toxin. A similar gradation of toxicity was observed upon intracerebral injection of the compounds dissolved in DMSO. Here the only exception was the markedly reduced toxicity of T-2 toxin itself. From these data, the role of free 3 alpha- and 4 beta-hydroxyl groups has been evaluated. For subcutaneous applications, the largest ratio of LD50 values was 5, i.e. for the pair T-2 triol-T-2 tetraol tetraacetate. Among the signs of central intoxication, convulsions, adipsia and aphagia were marked. Pathological changes in the brain tissue, mainly involving necrotic, hemorrhagic and inflammatory lesions at the sites of application, were similar for all trichothecenes tested in this study.
Rats were injected intraperitoneally with T-2 toxin and their aortas were studied by light and electron microscopy. The growth of smooth muscle cell explants taken from the tunica media of aortas of similarly treated animals was observed. A single large dose (2 mg/kg) or four injections of 0.3 mg/kg T-2 toxin caused damage and occasional necrosis of endothelial cells, accumulation of basement membrane-like material in the intima, and swelling and activation of smooth muscle cells in the tunica media. Three or more weeks after the last injection of 0.3 mg/kg T-2 toxin the endothelial cells were normal but an excess of fragmented intimal basement membrane-like material persisted and smooth muscle cells were still activated. Outgrowths from explants of aortic tunica media taken within 1 week of the last dose of T-2 toxin showed marked inhibition of smooth muscle cell growth. Three or more weeks after the toxin, the explants showed significantly increased outgrowths. These findings suggest that T-2 toxin causes early endothelial and smooth muscle cell injury accompanied by inhibition of smooth muscle cell growth in culture. This is followed by stimulation of the proliferative capacity of smooth muscle cells in vitro. If a similar mechanism is operative in vivo, it could explain the chronic vascular changes observed after limited exposure to T-2 toxin.
Topical applications of various doses of T-2 toxin to rats led to delayed skin reactions. Following a dose-dependent latent period of 12-24 hr, there appeared vascular dilation, stasis, edema and mononuclear cell infiltration, with many degranulating mast cells. These signs were earliest and strongest in the subcutis. Epidermal necrosis occurred 1-2 days later and was probably caused secondarily by ischemia, due to microcirculatory failure. Ultrastructurally, endothelial cells of small vessels were the earliest sites of change. While intercellular junctions remained closed and pinocytosis decreased, the cytoplasm contained many ribosomes, vacuoles, and abnormal mitochondria. Another early effect of topical T-2 toxin was an increase in number and degranulation of mast cells, especially in the subcutis. The resemblance of the skin injury to that produced by irradiation is noted.
In cats anesthetized with pentobarbitone sodium the effect of two types of antiserotonergic agents on cardiovascular recuperation after acute hemorrhage was examined. Methysergide, a competitive inhibitor for 5-HT receptors and p-chlorophenylalanine (PCPA), an inhibitor of tryptophan-5-hydroxylase, improved blood pressure recovery after bleeding. After extensive hemorrhage (40 ml/kg blood), treatment with methysergide improved survival. It is proposed that serotonin participates in the depressor response and survival of acute hypovolemic hypotension.
T-2 toxin was given to rats in three ways: Subcutaneous or intracerebral injection of a solution in dimethyl sulfoxide (DMSO) and by implantation of toxin, adsorbed on talc, into various regions of diencephalon and brain stem. The latter method proved to be most effective. Within a few hours after administration of 10-20 micrograms toxin, the animals became restless, ataxic and dyspneic. These early symptoms were followed by depression and immobility. Prior to death, tachypnea and/or convulsions developed. The rats succumbed to implantation of toxin within 1 - 7 days; no fatalities occurred at later dates. Histologically, the toxin pellets caused necrosis a few days after implantation; at a later stage, the necrotic areas were surrounded by inflammatory infiltrates around small blood vessels. These morphological changes were limited to the application site and were insufficient to explain the lethal effect of intracerebral administration. After intracerebral injections of toxin solutions, the animals died within 24 h. No marked histological changes could be seen after such rapid fatalities.
The time course for the development of morphine tolerance, following prolonged sweet intake, was examined in randomly bred Sabra rats. Exposure to 3% glucose in 6 mM saccharin solution increased drinking by about three times as compared to rats supplied only with water. Suppression of the analgesic effect of morphine was already detectable after 24 h of intake and became progressively more marked within the next 5 weeks. These results support an active interaction between sweet consumption and endogenous opioids in randomly bred rats.
Cats, anesthetized with sodium pentobarbitone, underwent acute hemorrhagic shock by withdrawal of 15 ml blood/kg of body weight. The cerebral ventricular system was perfused with artificial cerebrospinal fluid (CSF). Blood and CSF samples were collected during 2 h, for the analysis of catecholamines (CA) and Leu-enkephalin-like immunoreactivity (LE-ir). The fall of blood pressure immediately after hemorrhage was accompanied by a rise of LE-ir in the CSF and by a decrease of norepinephrine and dopamine below their control values. About half an hour later, the LE-ir returned to its initial low level, while the CA were now markedly elevated. A similar opposite behavior of peptides and CA was observed during subsequent sampling periods, although blood pressure remained constant. These experiments demonstrate an inverse relationship of LE-ir and CA in the CSF, after acute hemorrhagic shock.
Rats of the LC-2-HI strain, selected for high rates of self-stimulation, were supplied with a 3 mM saccharin solution. Within 1 week they developed markedly prolonged latencies to painful stimuli on a hot-plate. In contrast, a similar effect became manifest in LC-2-LO rats only after 3 weeks. Both strains of rats were made diabetic by injection of streptozotocin. LO rats showed more polydipsia and hyperglycemia than HI rats and, when drinking saccharin solution, developed cross-tolerance to morphine within about 2 weeks. It is assumed that saccharin consumption stimulates the release of endogenous opioid peptides, probably via stimulation of gustatory sweet receptors. The opioid peptides exert a biphasic effect: initially they raise the pain threshold, but at a later stage they cause chronic cross-tolerance to morphine.