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Biomedical subjects

W Huber

Publications and source records attributed to W Huber.

At least 91 records · Page 5Linked to original sources
PubMed1995

Structure of octreotide, a somatostatin analogue.

Octreotide, a synthetic somatostatin analogue, is an octapeptide with one disulfide bridge. Crystals of octreotide are orthorhombic, space group P2(1)2(1)2(1), a = 18.458 (5), b = 30.009 (7), c = 39.705 (27) A, with three molecules of octapeptide, one ordered oxalate dianion and 52 water molecules in the asymmetric unit. Complete protonation of the NH(2) groups (as assumed in the refinement) would require three oxalate dianions in the asymmetric unit for charge neutrality; a chemical analysis indicated that four are present. In either case they are so disordered that they cannot be distinguished from the water molecules. The 18 951 unique reflections (R(sym) = 0.026) used for structure solution and refinement were recorded with the EMBL imaging-plate scanner using synchrotron radiation. The structure was solved by Patterson interpretation, locating the three disulfide bridges, followed by tangent phase expansion and E-Fourier recycling. The anisotropic refinement against all F(2) data between 1.04 and 10.0 A resolution by blocked restrained full-matrix least-squares techniques converged to a conventional R index based on F of 0.084 [I > 2a(I) and 10.0 > d > 1.04 A] and wR2, the weighted R-index on F(2), of 0.246 (for all data). One peptide molecule adopts a flat beta-sheet structure; the other two possess different irregular backbone conformations, but are similar to each other. All three molecules have a distorted type II' beta-turn around the D-Trp-Lys region, but exhibit different side-chain conformations. The crystal structure is stabilized by a network of inter- and intramolecular hydrogen bonds.

Journal Article↗
PubMed1995

Recovery from Wernicke's aphasia: a positron emission tomographic study.

Changes in the organization of the brain after recovery from aphasia were investigated by measuring increases in regional cerebral blood flow (rCBF) during repetition of pseudowords and during verb generation. Six right-handed patients who had recovered from Wernicke's aphasia caused by an infarction destroying the left posterior perisylvian language zone were compared with 6 healthy, right-handed volunteers. In the control subjects, strong rCBF increases were found in the left hemisphere in the posterior part of the superior and middle temporal gyrus (Wernicke's area), and during the generation task in lateral prefrontal cortex (LPFC) and in inferior frontal gyrus (Broca's area). There were some weak right hemisphere increases in superior temporal gyrus and inferior premotor cortex. In the patients, rCBF increases were preserved in the frontal areas. There was clear right hemisphere activation in superior temporal gyrus and inferior premotor and lateral prefrontal cortices, homotopic to the left hemisphere language zones. Increased left frontal and right perisylvian activity in patients with persisting destruction of Wernicke's area emphasizes redistribution of activity within the framework of a preexisting, parallel processing and bilateral network as the central mechanism in functional reorganization of the language system after stroke.

Aged↗
PubMed1995

The three-loop model: a neural network for the generation of saccadic reaction times.

This paper presents a computer simulation of the three-loop model for the temporal aspects of the generation of visually guided saccadic eye movements. The intention is to reproduce complex experimental reaction time distributions by a simple neural network. The operating elements are artificial but realistic neurones. Four modules are constructed, each consisting of 16 neural elements. Within each module, the elements are connected in an all-to-all manner. The modules are working parallel and serial according to the anatomically and physiologically identified visuomotor pathways including the superior colliculus, the frontal eye fields, and the parietal cortex. Two transient-sustained input lines drive the network: one represents the visual activity produced by the onset of the saccade target, the other represents a central activity controlling the preparation of saccades, e.g. the end of active fixation. The model works completely deterministically; its stochastic output is a consequence of the stochastic properties of the input only. Simulations show how multimodal distributions of saccadic reaction times are produced as a natural consequence of the model structure. The gap effect on saccadic reaction times is correctly produced by the model: depending only on the gap duration (all model parameters unchanged) express, fast-regular, and slow-regular saccades are obtained in different numbers. In agreement with the experiments, bi- or trimodal distributions are produced only for medium gap durations (around 200 ms), while for shorter or longer gaps the express mode disappears and the distributions turn bi- or even unimodal. The effect of varying the strength of the transient-sustained components and the ongoing activity driving the hierarchically highest module are considered to account for the interindividual variability of the latency distributions obtained from different subjects, effects of different instructions to the same subject, and the observation of express makers (subjects who produce exclusively express saccades). How the model can be extended to describe the spatial aspects of the saccade system will be discussed as well as the effects of training and/or rapid adaptation to experimental conditions.

Computer Simulation↗
PubMed1995

Variable region cDNA sequences and characterization of murine anti-human interferon gamma receptor monoclonal antibodies that inhibit receptor binding by interferon gamma.

Murine monoclonal antibodies (mAbs) are described that recognize the extracellular human interferon gamma receptor alpha-chain (IFN gamma R) and inhibit the binding to it of interferon gamma. The inhibitory activities (IC50s) of these mAbs, quantified by radioimmunoassay using native receptor on human Raji cells, lie in the range 0.5-24 nM, whereas their relative affinities for the immobilised recombinant extracellular receptor, determined using surface plasmon resonance technology, are in the range 0.6-40.9 nM. Nine mAbs derived from one immunization, were shown by variable region cDNA sequencing to be clonally related, with mAb A6 from this group showing the highest affinity for the receptor. Another two mAbs, gamma R38 and gamma R99, derived from a separate immunization, are clonally unrelated to each other and to those in the A6 family. From the V-region sequences, the L-chains of mAbs A6, gamma R38 and gamma R99 were shown to belong to the V kappa 34C, V kappa 34C and V kappa 1 families, whereas the H-chains belong to the 3069, J606 and J558 families, respectively. The mAbs A6 and gamma R38 recognize overlapping epitopes on the N-terminal Ig-like domain of the IFN gamma R, whereas the gamma R99 epitope is located largely in the membrane proximal Ig-like domain. Sequence comparisons with Ig structures solved by X-ray diffraction allowed deductions concerning likely CDR canonical conformations. These studies provide essential information for crystallographic and mutagenesis experiments aimed at understanding the molecular basis of the interactions of these mAbs with the extracellular IFN gamma R.

Amino Acid Sequence↗
PubMed1995

The functional anatomy of recovery from auditory agnosia. A PET study of sound categorization in a neurological patient and normal controls.

H2(15)O-PET was used to investigate the functional anatomy of recovery in a patient (J.B.) with bilateral perisylvian strokes and auditory agnosia, who partially regained the ability to recognize environmental sounds, but remained clinically word-deaf. The patient and a group of six normal volunteers were scanned in the following three conditions: (i) passive listening to environmental sounds; (ii) categorization of environmental sounds; (iii) at rest. In normal subjects, passive listening as compared with rest was associated with significant activations in the auditory cortices and posterior thalami, and in the inferior parietal lobe and anterior insula/frontal opercular region on the right. In J.B., activations were observed in the spared auditory cortex and inferior parietal lobe of the right hemisphere and in regions adjacent to the perisylvian lesion in the left hemisphere (anterior insula/frontal opercular region, middle temporal gyrus and inferior parietal lobe). The recovered function, as measured by categorization of sounds compared with passive listening, in J.B. was associated with bilateral activation of a distributed network comprising (pre)frontal, middle temporal and inferior parietal cortices, as well as the right cerebellum and the right caudate nucleus. In addition, there was a left-sided activation of the anterior cingulate gyrus. In normal subjects, the same categorization task led to activation of a network comprising (pre)frontal, middle temporal and inferior parietal cortices in the left hemisphere only. These results suggest that bilateral activation (with recruitment of areas homologous to those known to be responsible for normal function), the engagement of peri-infarct regions, and the involvement of a more widespread neocortical network, are mechanisms of functional reorganization after injury that may enable recovery from, or compensation for, cognitive deficits.

Agnosia↗
PubMed1993

[Pneumonia due to a rare atypical Mycobacterium in AIDS].

A 38-year-old man, HIV-positive for 6 years, developed fever and cough with deterioration in his general state. Chest radiography demonstrated an infiltration in the left upper lobe and computed tomography showed a septated cavity. Three bronchioalveolar lavages over 4 weeks recovered Klebsiella, Candida, Pseudomonas and Staphylococcus in the lavage fluid. Acid-fast rods were not found in any of the microscopic preparations. His clinical condition and the radiological findings deteriorated despite appropriate antibiotic administration. A further cavity occurred in the right upper lobe and the inflammatory infiltrations extended further. Although no acid-fast organism had been demonstrated, tuberculostatic treatment was begun (daily 300 mg isoniazid, 600 mg rifampicin, 900 mg streptomycin, 2 g pyrazinamide). His general condition and the radiological findings rapidly improved. Four weeks after culturing the lavage fluid atypical Mycobacterium xenopi was isolated. This case illustrates the difficulty of diagnosing an atypical mycobacterial infection. It takes time and effort, but it is of great importance because up to 50% of patients with AIDS contract such infection. Early and appropriate treatment will significantly improve quality of life and life expectancy.

AIDS-Related Opportunistic Infections↗
PubMed1993

Glutathione S-transferase isoenzyme patterns in different subtypes of enzyme-altered rat liver foci treated with the peroxisome proliferator nafenopin or with phenobarbital.

It is known that phenobarbital (PB) and the peroxisome proliferator (PP) nafenopin (NAF) promote tumor formation by stimulating selective growth of different subtypes of liver foci. While PB enhanced the gamma-glutamyltranspeptidase (GGT)-positive eosinophilic-clear cell foci (ECF), NAF amplified the GGT-negative weakly basophilic foci (WBF). These findings provide the possibility of using the occurrence of these foci subtypes as early indicators for the carcinogenic potential of PB- and PP-type promoters. In order to improve the methods for the discrimination between ECF and WBF we studied further differences in their phenotype, as determined by the expression pattern of glutathione S-transferase (GST) subunits. GST subunits of the alpha (Ya, Yc), mu (Yb1, Yb2) and pi family (Yp), which compose different GST isoenzymes, were demonstrated by immunohistochemical methods. ECF were the only foci subpopulation that expressed GST subunit Yp, while this subunit was always absent in WBF and in another focus subtype, the tigroid foci (TF). Neither PB nor NAF changed this pattern. Thus Yp expression was rather a function of the focus type than of the promoter used. Upon PB treatment expression of the GST subunits Yb1 and Yb2 was frequently elevated in ECF, while Ya and Yc remained more or less unchanged. In NAF-treated livers large WBF, however, showed diminished expression of all investigated GST subunits of the alpha and mu family. In conclusion, PB seems to promote mostly ECF with elevated levels of mu and pi class GSTs, while low levels or absence of all GSTs tested may be associated with growth selection of WBF through the PP NAF.

Adenoma↗
PubMed1993

Peroxisomal enzyme induction uncoupled from enhanced DNA synthesis in putative preneoplastic liver foci of rats treated with a single dose of the peroxisome proliferator nafenopin.

Putative preneoplastic foci of spontaneous origin could be detected in the livers of 2 year old, untreated male Wistar rats. The unaltered and preneoplastic hepatocytes showed an identical expression of the peroxisomal marker enzyme acyl-CoA oxidase, as determined by immunohistochemical staining. A single dose of the peroxisome proliferator (PP) nafenopin (NAF) induced the enzyme predominantly in hepatocytes around the central venules and cell replication mainly in the periportal areas. However, upon one NAF application almost all of the preneoplastic foci showed a considerably weaker immunoreaction for peroxisomal acyl-CoA oxidase than the surrounding tissue. Concomitantly NAF elevated replicative DNA synthesis index in foci up to approximately 40%, while replication of hepatocytes in the unaltered portion of the livers increased only slightly to moderately. In conclusion, NAF-induced peroxisomal acyl-CoA oxidase and replicative DNA synthesis seem not to be necessarily coupled within the same liver cell. Furthermore, preneoplastic foci responded rather to the cell replicative than to the peroxisomal effects of NAF, suggesting that the PP-induced growth stimulus is of particular significance for the carcinogenic action of this class of compounds.

Acyl-CoA Oxidase↗
PubMed1993

Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin.

The peroxisome proliferator (PP) nafenopin (NAF) enhanced tumor development in rat liver through promotion of a subtype of putative preneoplastic cell foci, characterized by weak cytoplasmic basophilia. In order to elucidate the selective growth advantage of these weakly basophilic foci (WBF) we investigated the effects of NAF on their metabolic phenotype and DNA synthesis. In WBF, as well as in other foci subpopulations and in hepatocellular carcinomas the occurrence of five NAF-inducible enzymes, i.e. of peroxisomal beta-oxidation (acyl-CoA oxidase, bifunctional protein and thiolase), catalase and cytochrome P-452 was studied by immunohistochemical methods. In untreated livers almost all foci were stained with the same intensity as the surrounding tissue. When NAF was applied, most of the liver foci showed considerably less staining than the non-focal parenchyma in which pronounced enzyme induction had occurred. However, the subpopulation of WBF showed a more heterogeneous pattern of enzyme expression varying from less to even more than in the adjacent tissue. A similarly broad range of expression of peroxisomal enzymes was found in hepatocellular carcinomas. On average, however, the tumors exhibited less staining and lower activity of peroxisomal beta-oxidation than the surrounding parenchyma. WBF always showed higher rates of DNA synthesis than other foci subtypes and unaltered liver. In approximately one-third of these foci DNA synthesis was found to be enhanced concomitantly with elevated expression of peroxisomal beta-oxidation enzymes. In conclusion, WBF may have a selective growth advantage as they 'overrespond' to the inducing effects of NAF on DNA synthesis and peroxisomal enzymes.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1993

Leukotriene B4 and C4 production in isolated rat gastric mucosal cells.

Dispersed rat gastric mucosal cells (F0) were separated into five fractions (F1-F5) by counterflow elutriation, with F1 representing the smallest and F5 the largest cell diameters. In F0-F5, leukotriene B4 (LTB4) release in response to 10(-5) M calcium ionophore A-23187 was 7.68 +/- 1.26, 51.6 +/- 10.8, 72.4 +/- 10.4, 7.1 +/- 0.7, 5.7 +/- 0.6, and 11.6 +/- 3.4 pg.10(6) cells-1 x 30 min-1. In the identical fractions, sulfidopeptide release in response to A-23187 was 200.6 +/- 20.5, 1,116.0 +/- 166.6, 1,309.4 +/- 163.2, 189.8 +/- 25.8, 108.0 +/- 18.0, and 158.4 +/- 54.0 pg.10(6) cells-1 x 30 min-1. High-pressure liquid chromatography verified the radioimmunologically determined LTB4 and identified LTC4 as the only sulfidopeptide LT released. LT release from F2 cells in response to A-23187 was time and dose dependent, reaching maximal stimulation at 10(-5) M A-23187. This response was blocked by the dual inhibitor of cyclooxygenase and lipoxygenases, BW755C (2 x 10(-5)-2 x 10(-4) M), by the selective 5-lipoxygenase inhibitor L-651,392 (10(-7)-10(-5) M), and by MK-886 (10(-9)-10(-7) M), which blocks translocation of 5-lipoxygenase. The postreceptor stimuli dibutyryl adenosine 3',5'-cyclic monophosphate, forskolin, 12-O-tetradecanoyl-phorbol-13-acetate, and oleyl-acetyl-glycerol failed to induce LT release. However, 10(-4) M arachidonic acid increased basal LT release up to eightfold and increased A-23187-stimulated LT release by an additional 30%.(ABSTRACT TRUNCATED AT 250 WORDS)

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗