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Biomedical subjects

J Simon

Publications and source records attributed to J Simon.

At least 91 records · Page 5Linked to original sources
PubMed2001

An elusive receptor is finally caught: P2Y(12'), an important drug target in platelets.

Despite intensive research, the nucleotide P2 receptor that is involved in the aggregation and activation of platelets by ADP has remained elusive. However, now two research groups have independently identified a new platelet receptor of unexpected structure, P2Y(12), that acts with the P2Y(1) receptor to form the site of ADP activation and explains the multiple transduction mechanisms observed in response to ADP in platelets. Recent evidence also suggests that a third component, ATP action on the P2X(1) receptor ion channel, contributes to platelet activation.

Adenosine Diphosphate↗
PubMed2001

A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients.

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Adult↗
PubMed2001

Sensory modulation dysfunction in children with attention-deficit-hyperactivity disorder.

This study investigates the presence of sensory modulation dysfunction (SMD) among children with attention-deficit-hyperactivity disorder (ADHD). Twenty-six children with ADHD (mean age 8.3 years, 18 males, 8 females), and 30 typically developing children (mean age 8.2 years, 21 males, 9 females) were tested using a laboratory procedure that gauges responses to repeated sensory stimulation by measuring electrodermal reactivity (EDR). Parental report measures of limitations in sensory, emotional, and attentional dimensions were administered using the Short Sensory Profile, the Leiter International Performance Scale-Revised, Parent Rating subscales, and the Child Behavior Checklist (CBCL). Compared to the typical sample, the children with ADHD displayed greater abnormalities in sensory modulation on both physiological and parent-report measures. The children with ADHD also displayed more variability in responses. Within the group with ADHD, levels of SMD were highly correlated with measures of psychopathology on the CBCL. Implications of findings relate to the importance of considering sensory processing abilities in a subgroup of children with ADHD.

Adolescent↗
PubMed2001

Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3.

The Bcl-2-related survival proteins confer cellular resistance to a wide range of agents. Bcl-xL-expressing hepatocyte cell lines are resistant to tumour necrosis factor and anti-cancer drugs, but are more sensitive than isogenic control cells to antimycin A, an inhibitor of mitochondrial electron transfer. Computational molecular docking analysis predicted that antimycin A interacts with the Bcl-2 homology domain 3 (BH3)-binding hydrophobic groove of Bcl-xL. We demonstrate that antimycin A and a Bak BH3 peptide bind competitively to recombinant Bcl-2. Antimycin A and BH3 peptide both induce mitochondrial swelling and loss of DeltaPsim on addition to mitochondria expressing Bcl-xL. The 2-methoxy derivative of antimycin A3 is inactive as an inhibitor of cellular respiration but still retains toxicity for Bcl-xL+ cells and mitochondria. Finally, antimycin A inhibits the pore-forming activity of Bcl-x L in synthetic liposomes, demonstrating that a small non-peptide ligand can directly inhibit the function of Bcl-2-related proteins.

Adenosine Triphosphate↗
PubMed2001

Activity of adenosine diphosphates and triphosphates on a P2Y(T) -type receptor in brain capillary endothelial cells.

1. A P2Y (nucleotide) receptor activity in a clonal population (B10) of rat brain capillary endothelial cells is coupled to inhibition of adenylyl cyclase and has functional similarities to the P2Y(T) (previously designated 'P2T') receptor for ADP of blood platelets. However, the only P2Y receptor which was detectable in a previous study of B10 cells by mRNA analysis was the P2Y(1) receptor, which elsewhere shows no transduction via cyclic nucleotides. We have sought here to clarify these issues. 2. The inhibition of forskolin-stimulated adenylyl cyclase induced by purified nucleotides was measured on B10 cells. The EC(50) value for 2-methylthioADP (2-MeSADP) was 2.2 nM and, surprisingly, 2-MeSATP was an almost equally strong agonist (EC(50)=3.5 nM). ATP and 2-ClATP were weak partial agonists (EC(50)=26 microM and 10 microM respectively) and under appropriate conditions could antagonise the activity on 2-MeSADP. 3. A known selective antagonist of the platelet P2Y(T) receptor, 2-propylthioadenosine-5'-(beta,gamma)-difluoromethylene) triphosphonate (AR-C 66096), was a competitive antagonist of this B10 cell receptor, with pK(B)=7.6. That ligand is inactive at the P2Y(1) receptor in the same cells. Conversely, the competitive P2Y(1) receptor antagonists, the 3', 5'- and 2', 5'-adenosine bis-monophosphates, are, instead, weak agonists at the adenylyl cyclase-inhibitory receptor. 4. The inhibition of adenylyl cyclase by 2-MeSADP was completely abolished by pertussis toxin. 5. In summary, these brain endothelial cells possess a P2Y(T)-type receptor in addition to the P2Y(1) receptor. The two have similarities in agonist profiles but are clearly distinguishable by antagonists and by their second messenger activations. The possible relationships between the B10 and platelet P2Y(T) receptors are discussed.

Adenine Nucleotides↗
PubMed2001

A population study of the influence of beer consumption on folate and homocysteine concentrations.

OBJECTIVE: Mild hyperhomocysteinemia is a significant and independent risk factor for vascular diseases. Blood total homocysteine concentration (tHcy) is considered to be the product of an interaction between genetic and nutritional factors notably intake of folate, vitamin B12 and pyridoxine. The aim of the study was to determine whether regular intake of beer containing large amount of folate and other vitamins influences the tHcy blood concentrations. DESIGN: Cross-sectional population-based survey. SETTING: Adult population, residents of Pilsen (Czech Republic) and vicinity. SUBJECTS: Population series included 292 males and 251 females aged 35-65 y, mean age 53.4 y. All subjects were examined by a standard protocol for clinical, anthropometrical and laboratory estimations. MAIN OUTCOME MEASURES: tHcy was measured by high-pressure liquid chromatography with fluorescent detection, blood folate and B12 levels immunochemically using commercial kits. RESULTS: Beer intake was associated with blood folate and vitamin B12 concentrations positively and with tHcy concentration negatively. By categories of beer intake, subjects with intake of 1 l daily or more had significantly lower tHcy and higher folate concentrations than those reporting lower daily beer intake. CONCLUSION: Moderate beer consumption may help to maintain the tHcy levels in the normal range due to high folate content. Folate from beer may thus contribute to the protective effect of alcohol consumption on cardiovascular disease in population with generally low folate intake from other nutrients. SPONSORSHIP: Supported by grant 301/00/P089 Grant Agency of Czech Republic and Internal Grant Agency of the Ministry of Health.

Adult↗
PubMed2001

The tetraheme cytochrome c NrfH is required to anchor the cytochrome c nitrite reductase (NrfA) in the membrane of Wolinella succinogenes.

The electron-transport chain that catalyzes nitrite respiration with formate in Wolinella succinogenes consists of formate dehydrogenase, menaquinone and the nitrite reductase complex. The latter catalyzes nitrite reduction by menaquinol and is made up of NrfA and NrfH, two c-type cytochromes. NrfA is the catalytic subunit; its crystal structure is known. NrfH belongs to the NapC/NirT family of membrane-bound c-type cytochromes and mediates electron transport between menaquinol and NrfA. It is demonstrated here by MALDI MS that four heme groups are attached to NrfH. A Delta nrfH deletion mutant of W. succinogenes was constructed by replacing the nrfH gene with a kanamycin-resistance gene cartridge. This mutant did not form the NrfA protein, probably because of a polar effect of the mutation on nrfA expression. The nrfHAIJ gene cluster was restored by integration of an nrfH-containing plasmid into the genome of the Delta nrfH mutant. The resulting strain had wild-type properties with respect to growth by nitrite respiration and nitrite reductase activity. A mutant (stopH) that contained the nrfHAIJ locus with nrfH modified by two artificial stop codons near its 5' end produced wild-type amounts of NrfA in the absence of the NrfH protein. NrfA was located exclusively in the soluble cell fraction of the stopH mutant, indicating that NrfH acts as the membrane anchor of the NrfHA complex in wild-type bacteria. The stopH mutant did not grow by nitrite respiration and did not catalyze nitrite reduction by formate, indicating that the electron transport is strictly dependent on NrfH. The NrfH protein seems to be an unusual member of the NapC/NirT family as it forms a stable complex with its redox partner protein NrfA.

Base Sequence↗
PubMed2001

Neurofibromatosis involving the urinary bladder.

We present two interesting cases of a 24-year-old man and a 14-year-old boy, uncle and nephew, with lower urinary tract symptoms, café au lait patches and subcutaneous nodules. Ultrasonography and computed tomography scans showed a large, irregular lobulated soft tissue mass between the bladder and sacrum. Cystoscopy, laparotomy and biopsies revealed neurofibromatosis involving the urinary bladder. No enlargement of the tumor or upper urinary tract obstruction has occurred during the long-term follow up. We recommend meticulous follow up of patients with giant intrapelvic neurofibromatosis.

Adolescent↗
PubMed2001

[Allergen immunotherapy - a position paper of the German society for allergology and clinical immunology].

Mechanisms of allergen immunotherapy (AIT) are complex inducing numerous immunological effects. Successful AIT is most likely based on a functional switch of and tolerance induction in specific T cells downregulating allergic hypersensitivity and inflammation. Subcutaneous AIT for allergic rhinoconjunctivitis and allergic asthma has been successfully assessed in controlled studies with several clinically important allergens (i. e. birch-, grass- and mugwortpollen, dust mites, animal dander) and has shown convincing clinical efficacy. Considered as the only causal treatment besides allergen avoidance at present, AIT can alter the natural course of allergic diseases. Hymenopteravenom hypersensitivity (to bee- and wasp venom) treated with AIT gives the best results compared to AIT with other allergens. AIT is indicated in patients with IgE-mediated sensitizations and corresponding clinical symptoms to allergens, which do not or hardly permit allergen avoidance and which are available as suitable extracts. Decisions about indication and allergen selection should only be made by a physician with certified training or qualified knowledge and skills in allergology. AIT is administered by physicians experienced in this therapy. After addressing tolerability and present status of health the recommended or individually adjusted does is injected and precisely documented, followed by a mandatory waiting period of 30 minutes. Indication for and application of AIT in children are quite similar compared to the treatment of adults. Children tolerate AIT very well and benefit especially from its immunomodulatory effects. Risk factors for and results of unwanted systemic effects can effectively be minimized by training of the staff members involved, adhering to safety standards and immediate emergency treatment. Modified allergens, recombinant proteins and immunomodulatory adjuvants created by basic research are promises for an improved efficacy of AIT with reduced unwanted effects in the future.

Allergens↗
PubMed2001

In vitro and in vivo activities of syn2836, syn2869, syn2903, and syn2921: new series of triazole antifungal agents.

The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC(90)s) for the four test compounds for strains of Candida spp. ranged from <0.048 to 0.78 microg/ml. All compounds were also active against FLC-resistant Candida albicans and other Candida sp. strains. Moreover, MIC(90)s for strains of Cryptococcus neoformans, Aspergillus spp., Trichophyton spp., and Microsporum spp. were also low and ranged from <0.048 to 0.39 microg/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated that all four test compounds have good efficacies against C. albicans in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing.

Animals↗
PubMed2001

Insulin-like growth factors and body growth in chickens divergently selected for high or low growth rate.

Insulin-like growth factors (IGFs) stimulate growth rate in a number of animal species and are likely to contribute to genetic variations of growth potential. The present study was designed to link levels of IGF-I and IGF-II mRNA and peptides with growth rate in divergently selected genotypes of chickens with high (HG) or low (LG) growth rates. Circulating IGF-I and -II and hepatic mRNA levels were measured under ad libitum feeding conditions from 1 to 12 weeks of age, and at 6 weeks of age under three different nutritional conditions (fed, fasted for 16 or 48 h, re-fed for 4 or 24 h after a 48-h fast). IGF binding proteins (IGFBPs) were also measured. Circulating IGFs increased with age and were higher in HG chickens from 1 to 6 weeks. They decreased with fasting and only IGF-II was fully restored after 24 h of re-feeding, while IGF-I remained low. A significant decrease in steady state IGF-I mRNA levels was also observed with fasting. Across the nutritional study, hepatic IGF-I mRNAs were significantly higher in HG chickens. Variations of IGF-II mRNA levels with nutritional state or genotype exhibited a similar trend. IGFBP (28, 34 and 40 kDa) levels increased with age, while only faint differences were observed between genotypes. IGFBP-28 transiently increased with fasting and was inversely related to blood glucose and insulin levels, suggesting that it is equivalent to mammalian IGFBP-1. In HG chickens, IGFBP-28 and IGFBP-34 levels decreased markedly following re-feeding. Therefore, high and low growth rates were respectively associated with high and low IGF-I and -II levels, supporting the hypothesis of a stimulatory role for both IGFs during post-hatching growth of chickens.

Aging↗
PubMed2001

A third crystal form of Wolinella succinogenes quinol:fumarate reductase reveals domain closure at the site of fumarate reduction.

Quinol:fumarate reductase (QFR) is a membrane protein complex that couples the reduction of fumarate to succinate to the oxidation of quinol to quinone. Previously, the crystal structure of QFR from Wolinella succinogenes was determined based on two different crystal forms, and the site of fumarate binding in the flavoprotein subunit A of the enzyme was located between the FAD-binding domain and the capping domain [Lancaster, C.R.D., Kröger, A., Auer, M., & Michel, H. (1999) Nature 402, 377--385]. Here we describe the structure of W. succinogenes QFR based on a third crystal form and refined at 3.1 A resolution. Compared with the previous crystal forms, the capping domain is rotated in this structure by approximately 14 degrees relative to the FAD-binding domain. As a consequence, the topology of the dicarboxylate binding site is much more similar to those of membrane-bound and soluble fumarate reductase enzymes from other organisms than to that found in the previous crystal forms of W. succinogenes QFR. This and the effects of the replacement of Arg A301 by Glu or Lys by site-directed mutagenesis strongly support a common mechanism for fumarate reduction in this superfamily of enzymes.

Amino Acid Substitution↗
PubMed2001

[Changes in the risk profile and the development of hypertension in the population of Plzen 1987-1989 and 1995-1996].

OBJECTIVE: To evaluate risk factors and the general risk profile in a longitudinally followed-up cohort of the Plzen population. MATERIAL AND METHODS: The investigation was made in a cohort of 332 men and 280 women selected from the epidemiological study PILS II (Plzen longitudinal study) examined in 1987-1989 and 1995-1995. Both investigations adhered to the standard protocol. Anamnestic data were assessed, anthropometric parameters (BMI). Blood pressure (BP) was assessed by means of a mercury sphygmomanometer using the standard procedure, biochemical parameters were examined from a blood sample on fasting in the routine laboratories of the Faculty Hospital Plzen. Changes of individual factors were evaluated by the paired Wilcoxon test and chi 2 group test resp. The global coronary risk was calculated by means of logistic coefficients from the Framingham study. RESULTS: In the cohort which aged on average by 7.6 years the number of smokers decreased in men by 8.1% and by 3.6% in women. The blood pressure increased significantly in both sexes, there was an increase in the number of hypertensive subjects by 26.8% in men and 21.7% in women. In men there was a significant decrease of non-HDL cholesterol, in women, there was a significant increase of subjects with diabetic dyslipidaemia. The total coronary risk (Framingham score) increased after standard transposition to the age of 60 years only by 0.5% in men and women, which reflects the risk due to increased BP. The standard of treatment of hypertension was quite unsatisfactory. When using criteria SBP > or = 140 and/or DBP > or = 90 mm Hg during the second examination 71% of the patients remained without treatment. The number of subjects not aware of hypertension declined from 54% to 19.3% of subjects. A favourable indicator was the finding that there was a decline of hypertensive subjects with a high coronary risk (> or = 20% from ca 11 to 6%). CONCLUSION: During the investigation period in the cohort which to a certain extent represents the Plzen population a certain improvement of the risk profile occurred in particular as regards smoking and disorders of the lipid spectrum, however not as regards the prevalence and treatment of hypertension. Despite the favourable development in the Czech population in the investigated cohort, obviously at the expense of poor control of hypertension, the average coronary risk did not improve.

Adult↗