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Biomedical subjects

W Huber

Publications and source records attributed to W Huber.

At least 73 records · Page 4Linked to original sources
PubMed1996

4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

Aminoquinolines↗
PubMed1996

Hepatotoxicity and -carcinogenicity of the fumonisins in rats. A review regarding mechanistic implications for establishing risk in humans.

Cancer induction by the non-genotoxic mycotoxin, fumonisin B1, has been investigated by studying the mechanisms involved during cancer initiation and promotion in rat liver. Cancer initiation is effected through a toxic-proliferative response while the inhibitory effect on hepatocyte cell proliferation appears to be a key aspect determining cancer promotion. Dose-response effects of the fumonisins on the induction of early neoplastic lesions in both long- and short-term animal experiments have been established. The biphasic response of FB1 on hepatocyte proliferation will be discussed in relation to the known mechanisms of cancer induction by the genotoxic hepatocarcinogens. Recent investigations regarding the effect of the fumonisins on lipid biosynthesis and its inhibitory effect on hepatocyte growth stimulatory responses in vitro will be highlighted. Integration of our current knowledge regarding the carcinogenic potential of the fumonisins in setting a realistic and applicable risk assessment model for this non-genotoxic carcinogen will finally be addressed.

Animals↗
PubMed1995

[Hemorrhage caused by duodenal varices].

HISTORY AND CLINICAL FINDINGS: A 53-year-old man had been passing tarry stools and bright red blood per rectum for 6 days. He had a history of pyloroplasty for duodenal ulcers, alcoholic liver cirrhosis, stage B in Child's classification, a Le Veen shunt for ascites, grade I oesophageal varices and several episodes of intestinal bleeding of uncertain cause on repeated endoscopies. Haemoglobin levels was now 4.4 g/dl. Neither oesophago-gastro-duodenoscopy nor colposcopy, radiological examination of the small intestine nor scintigraphy discovered the source of bleeding. Computed tomography revealed varices in the horizontal part of the duodenum, confirmed by arteriography. TREATMENT AND COURSE: At a second endoscopy, this time with a long scope, acute bleedings were seen in the venous convolutions and stopped with 4 ml Polidocanol. Bleeding recurred after 10 days, thought to be due to persisting portal hypertension. A transjugular intrahepatic portosystemic stent shunt (TIPSS) was inserted to lower the pressure. Colour-coded Doppler examination at the time of another bleeding 10 weeks later demonstrated occlusion of the TIPSS. It was re-opened by balloon catheter dilatation, since when there have been no further episodes of bleeding. CONCLUSION: The implantation of a TIPSS is a new causative treatment for recurrent bleeding from ectopic varices due to portal hypertension that cannot be treated by endoscopy.

Angiography↗
PubMed1995

Mutagenesis of immunoglobulin-like domains from the extracellular human interferon-gamma receptor alpha chain and their recognition by neutralizing antibodies monitored by surface plasmon resonance technology.

The extracellular portion of the human interferon-gamma receptor (IFN-gamma R) is predicted to adopt two Ig-like domains each with Ig superfamily type C2 topology. Surface plasmon resonance technology has been used here to compare the equilibrium and kinetic constants for binding reactions between these and several mutant domains, and neutralising anti-IFN-gamma R monoclonal antibodies. The biosensor measurements provide a sensitive method for monitoring the effects of mutations on the functional epitopes recognized by the neutralising antibodies. Thus, using recombinant native-like proteins made in E. coli, the ten N-terminal residues of the receptor were found not to be essential for domain folding, nor for recognition by the antibodies A6, D2 and gamma R38. In a similar way, residues in the interdomain region were found to play an important functional role in the epitope recognized by the antibody gamma R99.

Amino Acid Sequence↗
PubMed1995

Dissection of the extracellular human interferon gamma receptor alpha-chain into two immunoglobulin-like domains. Production in an Escherichia coli thioredoxin gene fusion expression system and recognition by neutralizing antibodies.

The extracellular interferon gamma receptor alpha-chain (IFN gamma R) is believed to comprise two discrete approximately 110 amino acid immunoglobulin-like domains, perhaps similar to those seen in the crystal structure of the extracellular human growth hormone receptor [De Vos, A. M., Ultsch, M., & Kossiakoff, A. (1992) Science 255, 306-312], a distant relative in the cytokine receptor superfamily. In accord with this idea, we show that these IFN gamma R immunoglobulin-like domains can be produced separately in a soluble form with a native-like fold. The N-terminal domain (residues 1-108), with a Cys105 to Ser105 mutation, was produced at a high level, in a soluble form, as a thioredoxin-interferon gamma receptor fragment fusion protein in the cytoplasm of Escherichia coli. Upon extraction, the receptor Cys60-Cys68 disulfide bond formed spontaneously, to generate a native-like structure directly without the need for refolding. Cleavage of the fusion protein by enterokinase released the receptor fragment (approximately 12 kDa), which was recognized by several neutralizing antibodies with affinities, measured using surface plasmon resonance technology, that were essentially indistinguishable from those seen with the full length extracellular IFN gamma R produced in eukaryotic cells. Circular dichroism and 1D 1H nuclear magnetic resonance spectra indicated that the receptor fragment adopts a folded state, with mainly beta-sheet and reverse turn secondary structure. The second membrane-proximal Ig-like domain of the IFN gamma R (residues 90-229) was produced, albeit less efficiently, and characterized in a similar way. The production of these two independently folded proteins provides experimental support for the two domain organization of the IFN gamma R and opens new avenues for structural studies on these Ig-like molecules by NMR and crystallographic methods.

Amino Acid Sequence↗
PubMed1995

Determination of kinetic constants for the interaction between the platelet glycoprotein IIb-IIIa and fibrinogen by means of surface plasmon resonance.

The binding reaction between purified human platelet glycoprotein IIb-IIIa and fibrinogen was investigated by real-time measurements using the surface-plasmon-resonance sensor technology. In these experiments, either glycoprotein IIb-IIIa or fibrinogen was immobilized on a sensor surface. The time-dependent change in surface coverage that occurred immediately upon contact with a solution of the complementary protein was then detected. The ability to record this dynamic event from its initiation allowed the collection of kinetic and thermodynamic data over an extended time period. These data indicated that initially, in fast reaction, a reversible low-affinity complex with an equilibrium dissociation constant, Kd, of 155-180 nM was formed. In a subsequent slower reaction this complex was transformed into a more stable high-affinity complex with a Kd of 20-70 nM. Efficient dissociation of the high-affinity complex could only be induced in the presence of a competitive inhibitor such as RGDV. These data demonstrate that the binding between glycoprotein IIb-IIIa and fibrinogen is not a single monophasic reaction, but is composed of at least two consecutive processes both with their own kinetics.

Amino Acid Sequence↗
PubMed1995

[Pyrimethamine-sulfadiazine resistant cerebral toxoplasmosis in AIDS].

A 48-year-old man with known HIV infection for 4 years was admitted with a 2-week history of increasing brachio-facial paraesthesiae of the left side of the body and pains in the head and neck. Physical examination also showed discrete slowing of mental activity and oral candidiasis. Toxoplasmosis serology showed a low titre with a borderline IgM titre. Cranial computer tomography showed two confluent contrast medium concentrating foci in the region of the head of the caudate nucleus and the right internal capsule. Because toxoplasmosis encephalitis was suspected, treatment was started with sulfadiazine (1 g four times daily), pyrimethamine (25 mg four times daily), folic acid (15 mg daily) and dexamethasone (8 mg three times daily). After 19 days of treatment there was no clinical improvement, and a check CT scan showed worsening with increased oedema of the cerebellar medulla, compression of the lateral ventricles and a mid-line shift of 5 mm. Since the Sabin-Feldman test titre had increased, and there was no evidence to suggest a lymphoma or a viral or fungal infection, toxoplasmosis resistant to standard therapy was postulated, and treatment was started with clindamycin (600 mg three times daily) and pyrimethamine (25 mg four times daily). The clinical features subsided within 4 days. A further check CT scan 14 days later showed almost complete resolution.

AIDS-Related Opportunistic Infections↗
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↗