[Pneumococcal preventive vaccination. Consensus report, 3].
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Adult↗
Biomedical subjects
W Huber
Publications and source records attributed to W Huber.
Inherent increase of apoptosis in liver tumors: implications for carcinogenesis and tumor regression.
We quantitatively assessed rates of cell replication and of apoptosis during the development and regression of liver cancer. In rats, apoptotic activity gradually increased from normal liver to putative preneoplastic foci (PPF), to hepatocellular adenoma (HCA), and to hepatocellular carcinoma (HCC). At all stages, rates of cell replication were higher than of apoptosis, allowing a preferential net gain of (pre)neoplastic cells. As in rats, in human HCC, birth and death rates were increased manifold, indicating a species-independent phenomenon. Implications of the increasing cell turnover were studied in rats using the administration and withdrawal of nafenopin (NAF), a liver mitogen and nongenotoxic carcinogen. Prolonged NAF treatment enhanced cell number in normal liver by 25%, while PPF and liver tumors were amplified at least 100-fold. After stopping NAF treatment, cell replication ceased, while cell elimination by apoptosis was increased in normal and (pre)neoplastic liver. HCA and HCC showed the most pronounced shifts from replication toward apoptosis. As a result, 5 weeks after halting NAF, 20% of cells in normal liver, but about 85% of (pre)neoplastic lesions including HCC, were eliminated. The implications of these findings include that nongenotoxic carcinogens can act as survival factors even for malignant cells. Furthermore, tumor cells not only exhibit excessive proliferation, but also undergo apoptosis at rates that far exceed those in normal tissue. Therefore, inhibition of cell death by the survival activity of nongenotoxic carcinogens results in selective growth of (pre)neoplastic lesions. On the other hand, blockade of survival effects leads to excessive apoptosis in (pre)neoplasia and seems promising as a therapeutic concept for the selective elimination of (liver) cancer.
Adenoma, Liver Cell↗
Piracetam as an adjuvant to language therapy for aphasia: a randomized double-blind placebo-controlled pilot study.
OBJECTIVE: To determine whether piracetam 4.8 g/day together with intensive language therapy improved language function more than language therapy alone. DESIGN: Double-blind, placebo-controlled parallel group study. SETTING: Referral speech and language clinic of a university department of neurology. PATIENTS: Sixty-six inpatients with aphasia present between 4 weeks and 36 months. INTERVENTIONS: Intensive language therapy for 6 weeks in all patients. Thirty-two patients received piracetam 4.8 g daily and 34 patients received placebo. MAIN OUTCOME MEASURE: The Aachen Aphasia Test (AAT), a standardized procedure for evaluating the severity of aphasia, was performed at baseline and after 6 weeks' treatment. RESULTS: In 50 patients evaluated for efficacy, a trend toward improvement in the active group was observed in all subtests of the AAT. This trend was statistically significant for absolute differences in recovery of "written language" and "profile level." CONCLUSION: Piracetam appears to have a positive adjuvant effect on the recovery of aphasia in patients receiving intensive language therapy.
Adult↗
Limited sequence polymorphism in the Plasmodium falciparum merozoite surface protein 3.
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Amino Acid Sequence↗
Analysis of multiple Plasmodium falciparum infections in Tanzanian children during the phase III trial of the malaria vaccine SPf66.
In the first phase III efficacy trial of the malaria vaccine SPf66 in Africa, MOIs in SPf66- and placebo-vaccinated children were analyzed by polymerase chain reaction-restriction fragment length polymorphism of the Plasmodium falciparum merozoite surface antigen 2 (MSA2). MOIs were significantly reduced in asymptomatic vaccine recipients compared with those in asymptomatic placebo recipients; however, no differences were observed among symptomatic children in the vaccine and control groups. These results show that immunization with SPf66 modulates the course of naturally occurring infections, as reflected by reduced MOIs. In placebo recipients, however, there was a significant negative correlation between numbers of infecting genotypes, as identified by MSA2, and morbidity. Asymptomatic placebo recipients had an average of 5 concurrent infections, whereas children with clinical cases had an average of 3.4 infections. These data provide further evidence that premunition from concurrent infections is important in immunity against clinical malaria. No such effect of multiple infections was found in the vaccinated group.
Animals↗
Planning kidney surgery in von Hippel-Lindau disease.
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Brain Neoplasms↗
Global aphasia-with and without hemiparesis. A linguistic and CT scan study.
The location and size of brain lesions were compared between two groups of patients showing persisting global aphasia according to the criteria of the Aachen Aphasia test (AAT). The first group comprised 8 patients suffering from severe hemiparesis for more than 18 months. The 10 patients of the second group showed either no hemiparesis at all, or motor disturbance at the onset of the disorder with complete remission within 1 year. The sizes of the brain lesions were determined by means of CT scans. The location of the lesions was defined by a statistical model of the brain with labelled anatomical structure, which allowed an interindividual comparison. In the CT scans, the infarcted areas of the brains of patients with hemiparesis always extended to the wall of the lateral ventricle, thus including the whole corona radiata with the pyramidal tract. The infarcted areas of the patients without hemiparesis and with transient hemiparesis spared parts of the deep white matter. The data obtained via CT scans are of prognostic value for patients with transient hemiparesis, since determination of the extent of the lesion by means of CT permits an initial estimate on the possible later degree and quality of the motor recovery.
Aphasia↗
Prediction of graft dysfunction by analysis of liver biopsies after cold storage.
Failure of the hepatic allograft continues to be a serious life-threatening risk for the recipient. Because no effective method of extracorporeal support is available for these patients, early retransplantation is the only alternative that offers the potential for survival. The aim of this prospective analysis was to search for a predictor of primary non-function of hepatic allografts before reperfusion. From March to June 1993 we investigated 19 liver biopsies which were obtained during the preparation of the donor liver in the back table bath immediately before the implantation of the organ. All organs were preserved by UW solution. Biopsies were stored at -80 degrees C, the working-up process was started by dividing the biopsy into several portions for the determination of fat (petrol-ether extraction), water (weighing before thawing and after drying) and free amino acids (OPA-HPLC method). Graft function was categorized into three groups: (1) good function; (2) fair function; (3) primary non-function (PNF). In addition to known risk factors for delayed graft function such as a long stay of the donor in intensive care and a prolonged anhepatic period of the recipient, we were able to demonstrate that organs with malfunction had a higher fat and water content. Donor livers developing PNF showed a trend towards higher total and subdivided amino acids, which could be explained by the incapacity of the liver to utilize available substrates for gluconeogenesis.
Biopsy↗
beta-Endorphin and adrenocorticotrophin after incremental exercise and marathon running--female responses.
Investigations of exercise-induced increases in beta-endorphin, adrenocorticotropic hormone (ACTH) and cortisol concentration have been carried out mainly in men. Data concerning the female reaction are sparse and less clear. In a comparison between incremental exercise and marathon running 14 experienced female marathon runners volunteered to run to exhaustion according to an incremental treadmill protocol. They ran a marathon 4 weeks later. Blood was analysed for beta-endorphin, ACTH and cortisol concentration immediately prior to the laboratory treadmill test, 3, 30 and 60 min later, as well as prior to the marathon, after 60 min and 120 min of running and 3, 30 min, and 24 h after completion of the run. At each blood collection, lactate concentration, heart frequency and perceived exertion were determined. The mean marathon running time was 3.22 h. Baseline concentrations for beta-endorphin of 22 pmol.l-1 before the marathon and 19 pmol.l-1 before the treadmill exercise increased 1.4-fold 30 min after the marathon and 1.9-fold after the treadmill exercise; for ACTH the baseline of 4.7 and 4.0 pmol.l-1 was increased by 8.3- and 10.3-fold, respectively. Cortisol concentration rose exponentially from a baseline 17 micrograms.dl-1 and peaked at 2.2-fold 30 min after the run, when the maximal concentration also had been reached after the treadmill test, increasing 1.3-fold from a baseline of 21 micrograms.dl-1. The maximal values for cortisol concentration after both exercises differed from each other, while the maxima of ACTH and beta-endorphin concentrations were similar. The ACTH and beta-endorphin concentration declined more slowly during the recovery after the marathon than after the treadmill. Cortisol concentration was below baseline 24 h later. In comparison with men studied earlier, female marathon runners showed higher baseline concentrations and lesser increases in beta-endorphin and lower baseline concentrations and larger increases in ACTH concentration after both types of exercise. The delayed decrease in concentration of the hormones after the marathon was similar in male and female runners.
Adrenocorticotropic Hormone↗
Specific antigen/antibody interactions measured by force microscopy.
Molecular recognition between biotinylated bovine serum albumin and polyclonal, biotin-directed IG antibodies has been measured directly under various buffer conditions using an atomic force microscope (AFM). It was found that even highly structured molecules such as IgG antibodies preserve their specific affinity to their antigens when probed with an AFM in the force mode. We could measure the rupture force between individual antibody-antigen complexes. The potential and limitations of this new approach for the measurement of individual antigen/antibody interactions and some possible applications are discussed.
Antigen-Antibody Complex↗
Fast Monte Carlo algorithm for nonequilibrium systems.
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Journal Article↗
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↗
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↗
[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↗
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↗
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↗
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↗
[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↗