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Biomedical subjects

J Albrecht

Publications and source records attributed to J Albrecht.

At least 37 records · Page 2Linked to original sources
PubMed2001

An analysis of acute changes in interleukin-6 levels after treatment of hepatitis C with consensus interferon.

Cytokine production has been implicated in the antiviral response to interferon-alpha (IFN-alpha) in hepatitis C and in the development of IFN-alpha-related side effects. We characterized acute changes in serum cytokine levels following administration of a single dose of consensus IFN (IFN-con1) and during continuous treatment of chronic hepatitis C patients. Serum samples were collected at baseline, at multiple times early after IFN administration, and weekly thereafter. Viral RNA titers were assessed by RT-PCR, and viral kinetics were followed. ELISA assays were used to measure IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-16. Serum cytokine levels were low at baseline. IL-6 was detected in patients with hepatitis C but not in healthy control subjects by either ELISA or RT-PCR, indicating that low levels of circulating IL-6 were associated with hepatitis C infection. None of the cytokines measured increased significantly after IFN administration except for IL-6. IL-6 levels rose rapidly, peaked at 6-15 h in a dose-dependent manner, and returned to baseline by 48 h in both patients receiving a single dose of IFN and those receiving continuous treatment. This was confirmed by RT-PCR. Pretreatment IL-6 levels were directly correlated with area under the curve (AUC) for IL-6 during the 24 h after IFN dosing (r = 0.611, p = 0.007). Viral titers decreased within 24-48 h after a single dose of IFN-con1. Changes in hepatitis C RNA titers were not significantly associated with pretreatment IL-6 levels or with changes in IL-6 levels. In conclusion, (1) baseline serum cytokine levels, except for IL-6, were low or within the normal range in patients with hepatitis C, (2) IL-6 levels were detected in some patients with hepatitis C before treatment but not in healthy controls, (3) IL-6 levels increased acutely after a single dose of IFN-alpha, and IL-6 induction was related to baseline IL-6 level, and (4) changes in IL-6 levels did not correlate with the early virologic response to IFN.

Antiviral Agents↗
PubMed2001

[Preventive therapy of HNPCC--a study concept].

Due to different pattern of penetrance and heterogeneity, the role of prophylactic surgery must be individually defined for every hereditary cancer predisposition. For HNPCC (hereditary nonpolyposis colorectal cancer) subtotal colectomy at the time of colorectal cancer diagnosis is being recommended by the Cancer Genetics Studies Consortium Recent Guidelines from the DGVS (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) state that to date no general recommendation favouring this approach can be made. The open question is: how effective is segmental resection and endoscopic surveillance in given time intervals compared with the reduction of risk by performing extended (prophylactic) surgery. Also the issue of dealing with rectal cancer as the first primary in HNPCC patients must be addressed. In order to answer these questions and after the lessons learned from BRCA mutation carriers and prophylactic mastectomies, quality of life measurement is mandatory for this study.

Colectomy↗
PubMed2001

[Coordination centers for clinical studies--structure and integration of non-university hospitals].

The Integration of non-university hospitals in clinical trials is absolutely necessary to ensure patient availability and generalisation. In our survey we observed significant problems with the conduction of clinical trials in non-university hospitals. Important aspects of these problems are caused by the lack of infrastructure and personnel as well as by rising standards for clinical conduction. The establishment of Coordination Centres for Clinical Trials (KKS) has significantly improved the ability to support clinical trials in non-university hospitals in the future.

Academies and Institutes↗
PubMed2000

Is an "a la carte" combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group.

UNLABELLED: Randomized trials have shown the enhancement of efficacy with interferon alfa-2b and ribavirin (IFN-R) in comparison with interferon monotherapy (IFN) as first line treatment of chronic hepatitis C. Further definition of response based on disease, patient, and treatment characteristics is needed to determine the degree of benefit for the various patient subgroups. The aim of this study was to answer this question by analyzing the data from 1,744 naive patients included in trials that compared 24- or 48-week IFN-R treatment. Response factors were identified by logistic regression and receiver operating characteristics curves. Five independent characteristics were associated with a sustained loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or portal fibrosis, female gender, and age younger than 40 years. There was a significant advantage for IFN-R in comparison with IFN alone whatever the combination of factors. The most efficient strategy is to treat all patients for 24 weeks. If the 24-week polymerase chain reaction (PCR) is positive, treatment can be stopped. If the 24-week PCR is negative, patients with fewer than 4 favorable factors should be treated for an additional 24 weeks. CONCLUSION: The combination of IFN-R is better as first line treatment than IFN monotherapy. For patients who are PCR negative after 24 weeks of treatment, genotyping and baseline viral load, fibrosis stage, gender, and age are useful predictive factors in determining whether to continue an additional 24 weeks of treatment.

Adult↗
PubMed2000

[Dubowitz syndrome and atopic eczema. Case report of monozygotic twins].

Autosomal recessive inheritance, intrauterine growth retardation, short stature, microcephaly, distinct facial dysmorphism, psychomotoric retardation, and often uncharacterized eczematous skin lesions distinguish the rare Dubowitz syndrome. Here a pair of monozygotic twins with Dubowitz syndrome and clear-cut atopic eczema is presented.

Child↗
PubMed2000

Modulation of glutamine uptake and phosphate-activated glutaminase activity in rat brain mitochondria by amino acids and their synthetic analogues.

Uptake of L-[14C]Gln and phosphate-activated glutaminase (PAG) activity were measured in nonsynaptic mitochondria isolated from rat cerebral hemispheres, in the presence of protein and nonprotein amino acids and their synthetic structural analogues and derivatives. The uptake was inhibited by > 50% in the presence of a 10-fold excess of His, homocysteine (Hcy), Trp, Leu, Tyr, Ile, Thr, Ala, Phe, Met, Ser, by > 20% in the presence of a 10-fold excess of Val, Arg, Glu, and was not affected by a 10-fold excess of Orn, alpha-ketoglutarate, Tau and Pro. Uptake of L-[14C] Leu differed from Gln uptake by its resistance to Arg, Glu, and a relatively high sensitivity to the reference inhibitor of the plasma membrane transport of large neutral amino acids (L-system)--BCH (2-aminobicyclo[2.2.1]heptane-2-carboxylic acid), and a number of natural L-system substrates. A newly synthesized alanine analogue, 2'-cyano-(biphenyl) alanine, referred to as MRC01, was the only compound tested that inhibited Gln uptake more strongly than Leu uptake. The strongest Gln uptake inhibitors: MRC01, His, Hcy and Leu, inhibited PAG activity by > 50% when added at the inhibitor/Gln concentration ratio of 1:2. PAG activity was not affected by Tau, Lys or Pro, compounds which did affect Gln uptake. The results suggest that a number of natural amino acids function as common endogenous modulators of cerebral mitochondrial Gln uptake and its degradation. MRC01, because of its inhibitory potency towards both mitochondrial Gln uptake and PAG activity, may become a convenient tool in studying the role of Gln transport in its mitochondrial metabolism in intact CNS cell and tissues.

Alanine↗
PubMed2000

Effects of somatosensory input on central fatigue: a pilot study.

OBJECTIVE: Depression of motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS) may be a sign of central motor fatigue. As a pilot study, we have examined whether post-exercise MEP depression can be compensated by application of sensory stimuli prior to TMS. METHODS: We studied 15 healthy volunteers (aged 21-28 years) who were required to perform an exercise protocol of ankle dorsiflexion until force fell below 66% of maximum force. MEPs were recorded from the right tibialis anterior muscle. Prior to TMS, electrical stimuli were applied to the ipsilateral sural nerve with an individual interstimulus interval between 50 and 80 ms. RESULTS: MEP areas decreased after exercise. When a sensory stimulus was administered MEPs did not change. CONCLUSION: We conclude that the effects of central fatigue may be influenced by application of sensory stimuli.

Adult↗
PubMed2000

Extracellular concentrations of taurine, glutamate, and aspartate in the cerebral cortex of rats at the asymptomatic stage of thioacetamide-induced hepatic failure: modulation by ketamine anesthesia.

Subclinical hepatic encephalopathy (SHE) was produced in rats by two intraperitoneal injections of TAA at 24 h intervals and the animals were examined 21 days later. Concentrations of the neuroactive amino acids taurine (Tau), glutamate (Glu) and aspartate (Asp), were measured in the cerebral cortical microdialysates of thioacetamide (TAA)-treated and untreated control rats. During microdialysis some animals were awake while others were anesthetized with ketamine plus xylazine. There was no difference in the water content of cerebral cortical slices isolated from control and SHE rats, indicating a recovery from cerebral cortical edema that accompanies the acute, clinical phase of hepatic encephalopathy in this model. When microdialysis was carried out in awake rats, dialysate concentrations of all the three amino acids were 30% to 50% higher in SHE rats than in control rats. Ketamine anesthesia caused a 2.2% increase of water content of cerebral cortical slices and increased Asp, Glu, and Tau concentration in microdialysates of control rats. In SHE rats, ketamine anesthesia produced a similar degree of cerebral edema, however, it did not alter Asp and Glu concentrations in the microdialysates. These data may reflect on one hand a neuropathological process of excitotoxic neuronal damage related to increased Glu and Asp, on the other hand neuroprotection from neuronal swelling indicated by Tau redistribution in the cerebral cortex. The reduction of the effects of SHE on Glu and Asp content in ketamine-anesthesized rats is likely to be due to interference of ketamine with the NMDA receptor-mediated component of the SHE-evoked excitatory neurotransmitter efflux and/or reuptake of the two amino acids. By contrast, the SHE-related increase of Tau content was not affected by ketamine anesthesia, indicating that the mechanism(s) underlying SHE-evoked accumulation of Tau must be different from the mechanism causing release of excitatory amino acids. The results with ketamine advocate caution when using this anesthetic in studies employing the cerebral microdialysis technique for measurement of extracellular amino acids.

Anesthetics, Dissociative↗
PubMed2000

The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group.

BACKGROUND & AIMS: Black patients with chronic hepatitis C have lower response rates than white patients to interferon monotherapy. The factors responsible for these differences are unknown, as is the impact of combination antiviral therapy on responsiveness among ethnic groups. We evaluated the impact of race on response to therapy in these patients. METHODS: A total of 1744 patients with chronic hepatitis C were randomized in 2 recent clinical trials to receive 24 or 48 weeks of interferon monotherapy or interferon-ribavirin combination therapy. RESULTS: Sustained virologic responses occurred in 27% of 1600 whites, 11% of 53 blacks (P = 0.01 vs. white), 44% of 32 Asians, and 16% of 27 Hispanics. No black patient had a sustained virologic response to interferon monotherapy, but 20% and 23% had sustained responses to 24 and 48 weeks, respectively, of combination therapy. Among black patients, 96% had hepatitis C genotype 1 compared with 65% of white subjects (P < 0.0001). Sustained response rates were similar for black and white patients with genotype 1 infection (23% vs. 22%, respectively). Compared with whites, black patients were older, weighed more, and had higher median Histologic Activity Index scores but did not differ in sex, baseline alanine aminotransferase or hepatitis C virus (HCV)-RNA levels, degree of fibrosis or percentage with cirrhosis, or other demographic variables. White subjects had a significantly greater reduction in HCV-RNA levels than blacks at weeks 4, 12, 24, and 48 of therapy, but only for black patients treated with interferon monotherapy. The decreased reduction of HCV-RNA reduction among blacks was eliminated by combination therapy. CONCLUSIONS: These observations suggest that the impaired responsiveness of black patients to interferon monotherapy can be overcome partially by combination interferon-ribavirin therapy.

Adult↗
PubMed2000

Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.

The extent of liver fibrosis is an important prognostic factor in patients infected with hepatitis C virus. Administration of a combination of interferon and ribavirin produces a superior viral clearance response rate than interferon alone. The effect of this combination regimen on hepatic fibrosis has not been established. To determine the impact of combination regimen or interferon alone on the progression of liver fibrosis we pooled individual data of 1,509 patients with pretreatment and post-treatment biopsies from 3 randomized trials. Fibrosis progression and regression rates between biopsies were calculated by the Kaplan-Meier method and by the fibrosis progression rate per year. The percentage of patients without significant fibrosis (stage 0 or 1) at 96 weeks was 68 +/- 4% (mean +/- SE) when treated by combination regimen for 48 weeks, 64 +/- 4% by interferon alone for 48 weeks, 42 +/- 7% by combination regimen for 24 weeks (lower than both 48-week regimens P <.001), and 24 +/- 9% interferon alone for 24 weeks (lower than the combination regimen for 24 weeks; P =.02). Three factors were independently associated with fibrosis reduction: sustained viral response, duration of treatment, and baseline fibrosis stage (all P <.001 in proportional hazards regression model). These results show that interferon and ribavirin combination therapy significantly reduces the rate of fibrosis progression in patients with hepatitis C. This effect was most prominent in patients who achieved a virologic response, those receiving 48 weeks of therapy, and in patients with significant fibrosis at baseline.

Adult↗
PubMed2000

Lessons to be learned for gastroenterology from recent issues in clinical trial methodology.

Randomized trials are the preferred tool for patient-oriented research, and their main role is to enable the transfer of results from basic research to routine application. While the need for randomized trials is evident, conducting these trials is becoming increasingly difficult and complex. This article reviews actual and conflicting issues of clinical trials with respect to gastroenterology. Major problems in trial design are neglect of previous research, inadequate sample size calculations and irrelevant outcome criteria. Significant trial management problems include subversion of random allocation, and the design of systems and procedures that are inefficient, ineffective and inflexible. One of the major challenges in conducting randomized, controlled trials is obtaining informed consent because of the differing perspectives and languages of physicians and patients. Recommendations include practical guidance in obtaining informed consent, feedback of trial results to patients and support of research related to obtaining informed consent. Despite statistical guidance, several critical issues persist with respect to trial analysis. The use of confidence intervals is under-represented, the presentation of baseline data is often omitted and postsubgroup analysis is performed. Another controversial but relevant issue is the intention-to-treat analysis. Despite the formulation of standards, there is consistently poor quality of trial reporting, poor registration of unpublished trials and limited registration of ongoing trials. The authors conclude that there is a need for more randomized trials in gastroenterology. While the complexity of trial conduction has increased, so have the means of methodological and practical support. Thus, all problems can be professionally tackled, resulting in good clinical research.

Clinical Trials as Topic↗
PubMed2000

Effect of acute hepatic encephalopathy on [3H]dopamine release from rat cerebral cortex and striatum in vitro: role of Ca2+.

Hepatic encephalopathy (HE) is characterized by motor symptoms associated with disturbed functions of the dopaminergic systems, but the underlying mechanisms are not clear. A previous study from our laboratories revealed that HE, induced in rats by repeated treatment with thioacetamide, enhanced the 50 mM potassium (KCl)-stimulated release of newly loaded [3H]dopamine in both striatal and frontal cerebral cortical slices in the presence of Ca2+. In the present study we compared the effects of HE on dopamine release in striatal and frontal cerebral cortical slices and synaptosomes in the presence and absence of Ca2+. HE enhanced the KCl-stimulated [3H]dopamine release from striatal and frontal cortical synaptosomes in the presence of Ca2+ to the same extent as in slices prepared from the respective brain regions. In the absence of Ca2+ a slight reduction in dopamine release was observed in frontal cortical synaptosomes from HE rats when compared to control rats, while no effect of HE on the release was discernible in frontal cortical and striatal slices and striatal synaptosomes. We conclude that in both brain regions studied HE stimulates dopamine exocytosis triggered by Ca2+ influx without affecting the release mediated by means of plasma membrane transporters or exocytosis involving intraterminal Ca2+.

Acute Disease↗
PubMed2000

Induction of permeability transition and swelling of rat brain mitochondria by glutamine.

Exposure of rat cerebral mitochondria to 2-10 mM glutamine (Gln) for 20 min, produced a concentration-dependent, gradual decrease of light scattering reflecting mitochondrial swelling. The light scattering decreasing effect of 5 mM Gln was attenuated by 0.5 microM cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition (mPT) induction. Histidine (His), which is a potent inhibitor of high affinity Gln uptake to mitochondria, attenuated Gln-induced decrease of mitochondrial light scattering when added at equimolar concentration, and abolished the decrease when added at 15 mM concentration shortly before addition of Gln. His inhibited the uptake of 5 mM [14C]Gln in a concentration-dependent manner as measured during 3 min incubation. CsA did neither affect [14C]Gln uptake nor modified its inhibition by His. The effects of 5 mM His and 0.5 microM CsA on mitochondrial light scattering were additive, indicating that mitochondrial swelling represents a cumulative effect of Gln -driven entry of osmotically obligated water and induction of mPT. Addition of ammonium ions at neurotoxic concentrations neither influenced the decrease of light scattering induced by Gln, nor produced any change in light scattering when added alone. The results point to mitochondrial swelling and subsequent activation of mPT, as one of the potential mechanisms by which Gln induces metabolic disturbances in the brain in hyperammonemic conditions.

Animals↗
PubMed2000

A more efficient method of texture use in surgical robot simulation.

Texture mapping is a crucial supplement to modeling in 3D graphic simulation technology. Relatively small objects in a simulation environment can be represented with textures rather than by modeling, which helps economize on precious data storage space. Textures also lend some surfaces a more realistic appearance, both for the user and the viewer. The production of a texture, however, is a very complex process of repeated trial-and-error approximations. This inspired the idea of using mathematical formulas to determine the optimal texture so that the desired simulation environment is achieved with maximum effect and efficiency. In this paper the mathematical formulas for producing optimal texture are described. The results are presented as applied in a surgical robot simulation environment in an operating room.

Computer Graphics↗
PubMed1999

Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome.

Hepatic encephalopathy (HE) and portal-systemic encephalopathy (PSE) are the terms used interchangeably to describe a complex neuropsychiatric syndrome associated with acute or chronic hepatocellular failure, increased portal systemic shunting of blood, or both. Hepatic encephalopathy complicating acute liver failure is referred to as fulminant hepatic failure (FHF). The clinical manifestations of HE or PSE range from minimal changes in personality and motor activity, to overt deterioration of intellectual function, decreased consciousness and coma, and appear to reflect primarily a variable imbalance between excitatory and inhibitory neurotransmission. Pathogenic mechanisms that may be responsible for HE have been extensively investigated using animal models of HE, or cultures of CNS cells treated with neuroactive substances that have been implicated in HE. Of the many compounds that accumulate in the circulation as a consequence of impaired liver function, ammonia is considered to play an important role in the onset of HE. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent overactivation of the ionotropic Glu receptors, mainly the N-methyl-D-aspartate (NMDA) receptors. Hepatic encephalopathy complicating chronic liver failure appears to be associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a net increase of inhibitory neurotransmission, as a consequence of at least two factors. The first is down-regulation of Glu receptors resulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. Liver failure inactivates the Glu transporter GLT-1 in astrocytes. The second factor is an increase in inhibitory neurotransmission by gamma-aminobutyric acid (GABA) due to (a) increased brain levels of natural benzodiazepines; (b) increased availability of GABA at GABA-A receptors, due to enhanced synaptic release of the amino acid; (c) direct interaction of modestly increased levels of ammonia with the GABA-A-benzodiazepine receptor complex; and (d) ammonia-induced up-regulation of astrocytic peripheral benzodiazepine receptors (PBZR). Brain ammonia is metabolised in astrocytes to glutamine (Gln), an osmolyte, and increased Gln accumulation in these cells may contribute to cytotoxic brain edema, which often complicates FHF. Glutamine efflux from the brain is an event that facilitates plasma-to-brain transport of aromatic amino acids. Tryptophan and tyrosine are direct precursors of the aminergic inhibitory neurotransmitters, serotonin and dopamine, respectively. Changes in serotonin and dopamine and their receptors may contribute to some of the motor manifestations of HE. Finally, oxindole, a recently discovered tryptophan metabolite with strong sedative and hypotensive properties, has been shown to accumulate in cirrhotic patients and animal models of HE.

Hepatic Encephalopathy↗