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Biomedical subjects

B Roth

Publications and source records attributed to B Roth.

At least 163 records · Page 9Linked to original sources

A study of the occurrence of HLA DR2 in 124 narcoleptics: clinical aspects.

The authors examined HLA antigens in 124 narcoleptics. In addition to narcolepsy, 122 patients suffered also from cataplexy. The two patients without cataplexy suffered also from sleep paralysis and hypnagogic hallucinations. These two symptoms were also present in many of the other patients. HLA group DR2 was found in 120 patients including all six symptomatic cases. In four patients HLA DR2 was not present. Two of these were fully pronounced narcolepsy-cataplexy cases whereas the two other did not suffer from cataplexy. Since several other cases with negative DR2 have already been published it is necessary to admit the existence of DR2-negative narcolepsy, albeit very rare. Among 5 patients with isolated sleep paralysis HLA DR2 was present in one familial and 1 sporadic case. The authors further discuss some aspects of the classification of narcolepsies in the light of recent HLA studies as well as their delimitation from idiopathic hypersomnia.

Cataplexy↗

BAEPs in hereditary motor-sensory neuropathies. Involvement of central brain-stem parts of the auditory pathway.

Brain-stem auditory evoked potentials (BAEPs) were tested in 34 patients with hereditary motor and sensory neuropathy (HMSN), most of which with HMSN type I with the autosomal dominant type of inheritance. In only a few cases a recessive or sporadic form of the disease was diagnosed, and one patient was rated as HMSN type III. In 44% complicated forms with signs of CNS involvement (cerebellar manifestation, nystagmus or cranial nerve lesions) were ascertained. BAEPs tests revealed slightly, albeit non-significantly prolonged wave III latency while wave V latency was significantly prolonged and so was the interpeak interval of waves III-V. One third of the records showed a prominent decrease in wave V amplitude.

Adolescent↗

Kleine-Levin syndrome ethiopathogenesis and treatment.

The complex of the symptoms of psychic disorders and of the disorders of sleep, appetite, and food intake often forms the basis of the clinical picture of a mental disease. However, it is only rarely conceived in a complex manner as a set of physiologically interdependent functions. A remarkable proof of the interdependence of these functions is their complex disorder, the Kleine-Levin syndrome. The first descriptions of the symptoms of the Kleine-Levin syndrome can be found in the studies of several authors published as early as at the turn of the century. In 1942, the syndrome was designated by Critchley and Hoffmann after Willi Kleine and Max Levin, who defined it precisely in 1925 and 1929. The syndrome of periodic hypersomnia, megaphagia, and psychic disorders, originally described only in young males, was later found in females as well; the original very strict criteria were gradually broadened and complemented to some extent. At present, the most commonly accepted criterion for the diagnosis of the Kleine-Levin syndrome is the existence of the combined sleep disorder (hypersomnia or insomnia lasting from days to weeks), food intake disorders (megaphagia or anorexia), and various psychic abnormalities accompanying or following the attacks of the affection. We term the syndrome typical if the sleep disorder appears in the form of hypersomnia, food disorder in the form of megaphagia, and if psychic abnormalities are clearly expressed. On the other hand, we term the syndrome atypical if one of the main symptoms is opposite. The incomplete syndrome consists of only two main symptoms. The attacks of the affection set on mostly suddenly, lasting from several days to several weeks, ending suddenly again. The interparoxysmal periods last from several days to several months, sometimes even to several years. The etiopathogenesis of the affection is still unknown. A number of reports indicate a disorder of the diencephalon, perhaps only of the hypothalamus. The pathological-anatomical findings following the death of persons suffering from the disorders of sleep and food intake and from psychic abnormalities mostly reveal lesions in the region of the third brain ventricle. The development of the typical syndrome is benign, however, and morphological studies are not available. The typical Kleine-Levin syndrome can hardly escape the attention of clinicians owing to the richness and clarity of symptoms. The atypical or discretely expressed forms, however, often remain unrecognized even after a detailed medical examination and may lead to diagnostic uncertainty.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Exogenous enzymatic modulation of lectin binding sites in human tissue. Development of hemolysis in hemolytic-uremic syndrome (HUS) considering alteration of the glycocalyx in the erythrocyte membrane.

FITC-labelled lectins (DBA, PNA, RCAI, UEAI) with different carbohydrate specificity were used to look for possible alterations of the glycocalyx of erythrocyte membrane in patients with hemolytic uraemic syndrome (HUS; n = 34) in comparison with controls (n = 66). These investigations revealed that patients with the blood group A, B and O possess a significantly higher amount of sialic acid covered binding sites for PNA (p less than 0.05) on the membrane of red blood cells than controls, as measured by quantitative fluorescence microscopy. This significant difference was additionally found for sialic acid substituted RCAI binding sites on B erythrocytes (p less than 0.05). Without pretreatment of red blood cells with neuraminidase a significant difference between HUS patients and controls was observed for PNA on A, for RCAI on O and for UEAI on A erythrocytes. The measured values are influenced by contamination of red blood cells with serum glycoproteins as could be assessed by the lower values on washed erythrocytes. As a whole the results indicate that the composition of the glycocalyx in red blood cells of HUS patients seems to be altered and that the pathogenesis of this syndrome is additionally influenced by serum factors. With the exception of UEAI that possesses a significant higher amount of binding sites on washed erythrocytes of blood group O the other lectins used are not suitable for the demonstration of blood group specificity.

Blood Group Antigens↗

Interaction of the antifolate antibiotic trimethoprim with phosphatidylcholine membranes: a 13C and 31P nuclear magnetic resonance study.

The interaction of the bacterial dihydrofolate reductase inhibitor trimethoprim with small unilamellar 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine vesicles was studied using 13C and 31P NMR spectroscopy. In an effort to determine whether trimethoprim passively permeates the vesicle membrane, an impermeant, anionic complex of the paramagnetic ion Dy3+ was added to the extravesicular compartment. Based on the downfield shift that the Dy3+ complex induces in the [2-13C] resonance of trimethoprim in free solution, membrane permeation and movement of the drug into the intravesicular space can in principle be established from observation of the C2 chemical shift alone. In contrast to what is predicted by a two-compartment model separated by a semipermeable barrier, the presence of vesicles virtually reverses the effect of the shift reagent on the [2-13C] carbon resonance. These results suggest that the majority of the trimethoprim might be sequestered within the vesicle membrane. A saturable decrease in the spin-lattice relaxation time and a saturable increase in the line width at half-height of the [2-13C] resonance as a function of vesicle concentration indicated that trimethoprim does in fact bind to the phospholipid matrix of the membrane bilayer. The KD for the interaction calculated from the relaxation data was 9.7 +/- 0.3 X 10(-4) M at a pH of 7.01 and an ionic strength of 0.015 M. The chemical shift of the [2-13C] resonance is unaffected by interaction with the electroneutral membrane, and the pKa increases by only 0.16 upon binding. These results point to an interfacial location for the pyrimidine moiety. Using the paramagnetic shift reagent Pr3+ and the 31P NMR signal from the phosphodiester groups of the membrane lipids, trimethoprim was shown to displace Pr3+ ions from binding sites on the outer membrane surface as would be expected if the polar pyrimidine ring were located at or near the membrane surface. The extent to which trimethoprim and trimethoprim derivatives modified in the 3'- and 4'-positions interact with the exo face of the membrane is strongly dependent on the type of substituent and whether it is in the 3'- or 4'-position. Van der Waals interactions between the 5-benzyl sidechain and the hydrophobic fatty acid region of the membrane interior appear to be necessary for the polar portion of trimethoprim to compete favorably for the membrane-binding site with the polyvalent Pr3+ ion.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Membrane Permeability↗

A modified nicotinic acetylcholine receptor lacking the 'ion channel amphipathic helices'.

Antibodies to a synthetic peptide from the 'amphipathic helix' of the alpha-chain of the nicotinic acetylcholine receptor (nAChR) bound both to detergent-solubilised and membrane-bound nAChR, indicating that this region, suggested as a component of the transmembrane ion channel in one model, is not buried in the membrane. Trypsinisation of membranes prior to affinity purification yielded preparations lacking the amphipathic helices of the alpha- and beta-chains and probably also of the gamma- and delta-chains. Such material should allow direct testing, by reconstitution experiments, of the importance of these regions for channel activity.

Animals↗

Mapping the main immunogenic region and toxin-binding site of the nicotinic acetylcholine receptor.

The alpha-chain of the nicotinic acetylcholine receptor carries the binding sites both for cholinergic ligands and for most experimentally induced or naturally occurring antibodies to the native receptor. By means of expression cloning in Escherichia coli, fusion proteins were derived from specific fragments of a complementary DNA encoding the mouse alpha-chain, allowing the mapping of the toxin-binding site to residues 160-216 and the main immunogenic region to residues 6-85. This approach permits the independent study of different functional domains of a complex receptor molecule and should be generally applicable to other proteins for which complementary DNA clones are available.

Amino Acid Sequence↗

Haemorrhagic shock-encephalopathy syndrome: plasmapheresis as a therapeutic approach.

We present the case of a 4.5-week-old boy with acute encephalopathy, shock, intestinal bleeding and disseminated intravascular coagulation. The clinical course and typical laboratory parameters were compatible with a diagnosis of haemorrhagic shock-encephalopathy syndrome (HSE). Immediate shock treatment, repeated haemodialysis and plasmapheresis did not prevent a fatal outcome 4 days after the onset of clinical symptoms.

Brain Diseases↗

Renal and cerebral necrosis in survivor after in utero death of co-twin.

A newborn with bilateral renal cortical necrosis and severe cerebral damage in association with a macerated stillborn twin is reported. The alterations in the kidneys and brain of the twin born alive suggest that the primary event took place before birth. Thromboplastic material and embolizing particles derived from the dead fetus may have passed the monoamnionic-monochorionic twin placenta and caused disseminated intravascular coagulation in the living twin, followed by infarction in other organ systems.

Brain Diseases↗

Anxiety disorders and psychiatric referral in the general medical emergency room.

A retrospective chart review of patients seen in the medical emergency room between July 1983 and July 1984 indicated that only one third of the patients who received a final diagnosis that included anxiety were referred for psychiatric follow-up. This was in sharp contrast to the referral pattern from the ER of depressed or psychotic patients. In the present study, referred and nonreferred patients were compared on 17 variables to determine those factors that influenced decision to refer. Among the five factors that discriminated between the criterion groups were age, depression, and lack of concomitant medical findings.

Adolescent↗

2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 7. Analysis of the effect of 3,5-dialkyl substituent size and shape on binding to four different dihydrofolate reductase enzymes.

A group of trimethoprim (TMP) analogues containing 3,5-dialkyl(or halo)-4-alkoxy, -hydroxy, or -amino substitution were analyzed in terms of their inhibitory activities against four dihydrofolate reductase (DHFR) isozymes. Although selectivities were lower than with TMP, the activities against vertebrate DHFR were usually at least 2 orders of magnitude less than against enzymes from microbial sources. However, the profiles of activity were remarkably similar for rat, Neisseria gonorrhoeae, and Plasmodium berghei enzymes in all three series, although somewhat different for Escherichia coli DHFR, leading to the conclusion that the hydrophobic pockets are similar for the first three isozymes. Optimal substitution was reached with 3,5-di-n-propyl or 3-ethyl-5-n-propyl groups. Branching of chains at the alpha-carbon, which resulted in increased substituent thickness, was detrimental to E. coli DHFR inhibition in particular. MR is an inadequate parameter for use in correlating such substituent effects. Conformational changes of the more bulky inhibitors can be invoked to explain some differences in inhibitory pattern. Although log P explains simple substituent effects with the vertebrate DHFRs very well, it is insufficient in the more complex cases described here, where shape is clearly involved as well. Solvent-accessible surface areas were measured for TMP in E. coli and chicken DHFRs, where the coordinates are now known. The environment is more hydrophobic in the latter case; this can also be postulated for rat DHFR, which has a very similar activity profile. As with the mammalian isozymes, N. gonorrhoeae DHFR contains an active site phenylalanine replacing Leu-28 of E. coli DHFR, thus creating a more hydrophobic pocket. A similar replacement may also occur in the P.berghei isozyme. Selectivity for bacterial DHFR is dependent on the nature of the 4-substituent, being low for polar 4-hydroxy compounds but high for polar 4-amino analogues, possibly as a result of solvation differences. With complex substituents, the environment of each atom in the active site must be taken into account to adequately explain structure-activity relationships.

Animals↗

2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 8. The 3,4,5-triethyl isostere of trimethoprim. A study of specificity.

3,4,5-Triethylacetophenone was synthesized in 60% yield by a Friedel-Crafts reaction from 4-ethylacetophenone and converted to 2,4-diamino-5-(3,4,5-triethylbenzyl)pyrimidine (2), a trimethoprim (1) isostere, by standard techniques. This compound is more lipophilic than 1 by three log units (log P, octanol/water). Compound 2 was approximately equipotent with 1 in inhibiting Escherichia coli dihydrofolate reductase (DHFR), 2-fold more potent against P. berghei and N. gonorrhoeae DHFR, and 10 and 25 times better an inhibitor of rat and chicken liver DHFR, respectively. Although the 3,4-dimethoxy analogue 19 was 10-fold less inhibitory to E. coli DHFR than 1, it was 3-4 times more potent on the vertebrate isozymes, whereas the diethyl congener 10 followed 19 in its E. coli DHFR binding but was less active on rat and chicken DHFR. Therefore, a significant portion of the selectivity of 1 for bacterial, as opposed to vertebrate, DHFR, involves the methoxy functions. An analysis of the X-ray data on 1 and 2 complexed with chicken DHFR, coupled with kinetic data, led to the conclusion that the difference in binding energies of the methoxy and ethyl compounds probably involve desolvation factors, as well as direct energies of interaction with protein atoms. Thus, one cannot invoke lipophilicity or shape alone in explaining the relationship in properties of 1 and 2.

Animals↗