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Biomedical subjects

D Meyer

Publications and source records attributed to D Meyer.

At least 19 recordsLinked to original sources
PubMed2006

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.

AIMS/HYPOTHESIS: Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. METHODS: We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors. RESULTS: rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11-1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27-0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. CONCLUSIONS/INTERPRETATION: We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

Albuminuria↗
PubMed2006

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.

von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high-molecular-weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.

ADAM Proteins↗
PubMed2006

Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals.

Metabonomics, the study of metabolites and their role in various physiological states, is a novel methodology arising from the post-genomics era and has extensive biomedical application. This technology has exhibited vast success in the identification and study of human diseases and may find further application in the study of HIV/AIDS. Specifically, the wide range of clinical and metabolic abnormalities associated with the use of antiretroviral (ARV) treatment may be investigated. To this end, this preliminary study evaluated whether metabonomic techniques could distinguish between HIV-1 positive/AIDS patients utilizing antiretroviral therapy and HIV-1 negative individuals. Serum metabolic profiles determined by 1H nuclear magnetic resonance (NMR) spectroscopy combined with pattern recognition analysis of the data showed that this distinction was attainable; suggesting that ARV-associated side-effects could be monitored utilizing NMR metabonomic techniques.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2.

ATP-sensitive potassium (K(ATP)) channels are expressed in various tissues and cell-types where they act as so-called metabolic sensors that couple metabolic state to cellular excitability. The pore of most K(ATP) channel types is built by Kir6.2 subunits. Analysis of a general Kir6.2 knockout (KO) mouse has identified a variety of different functional roles for central and peripheral K(ATP) channels in situations of metabolic demand. However, the widespread distribution of these channels suggests that they might influence cellular physiology and animal behavior under metabolic control conditions. As a comprehensive behavioral description of Kir6.2 KO mice under physiological control conditions has not yet been carried out, we subjected Kir6.2 KO and corresponding wild-type (WT) mice to a test battery to assess emotional behavior, motor activity and coordination, species-typical behaviors and cognition. The results indicated that in these test situations Kir6.2 KO mice were less active, had impaired motor coordination, and appeared to differ from controls in their emotional reactivity. Differences between KO and WT mice were generally attenuated in test situations that resembled the home cage environment. Moreover, in their home cages KO mice were more active than WT mice. Thus, our results suggest that loss of Kir6.2-containing K(ATP) channels does affect animal behavior under metabolic control conditions, especially in novel situations. These findings assign novel functional roles to K(ATP) channels beyond those previously described. However, according to the widespread expression of K(ATP) channels, these effects are complex, being dependent on details of test apparatus, procedure and prior experience.

Analysis of Variance↗
PubMed2006

Mutations C1157F and C1234W of von Willebrand factor cause intracellular retention with defective multimerization and secretion.

The D3 domain of von Willebrand factor (VWF) is involved in the multimerization process of the protein through the formation of disulfide bridges. We identified heterozygous substitutions, C1157F and C1234W, in the VWF D3 domain in two unrelated families with unclassified and type 2A von Willebrand disease, respectively. VWF was characterized by a low plasmatic level, an abnormal binding to platelet GPIb and a high capacity of secretion from endothelial cells following DDAVP infusion. Using site-directed mutagenesis and expression in mammalian cells, we have investigated the impact of these mutations upon the multimerization, secretion and storage of VWF. Using COS-7 cells both mutated recombinant VWF (rVWF) displayed only lower molecular weight multimers. Pulse-chase analysis and endoglycosidase H digestion experiments showed the intracellular retention of mutated rVWF in pre-Golgi compartments. Study of hybrid rVWF obtained with a constant amount of wild-type (WT) DNA and increasing proportions of mutated plasmids established that both substitutions reduced the release of WT VWF in a dose-dependent manner and failed to form high molecular weight multimers. Using transfected AtT-20 stable cell lines, we observed similar granular storage of the two mutants and WT rVWF. Our data suggest that cysteines 1157 and 1234 play a crucial role in the early step of the folding of the molecule required for a normal transport pathway, maturation and constitutive secretion. In contrast, their substitution does not prevent the storage and inducible secretion of VWF.

Adolescent↗
PubMed2006

Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD.

BACKGROUND: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. OBJECTIVES: To estimate the proportion of type 1 VWD that is linked to the VWF gene. PATIENTS AND METHODS: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. RESULTS: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. CONCLUSIONS: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.

Adolescent↗
PubMed2006

A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD).

BACKGROUND: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. OBJECTIVES: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. PATIENTS AND METHODS: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. RESULTS: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. CONCLUSIONS: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.

ABO Blood-Group System↗
PubMed2005

Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice.

BACKGROUND: The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet-tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis. OBJECTIVES: To investigate whether VWF is involved in metastasis development. METHODS: In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells. RESULTS: In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis. CONCLUSION: These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated.

Animals↗
PubMed2005

GC-IR based two-dimensional structural group analysis of petroleum products.

To characterize petroleum products, a method based on the combination of IR-spectrometric structural group analysis, GC-simulated boiling analysis and multivariate regression techniques (PLS, PCR) has been developed. The best performance was achieved by a PLS regression model with six aliphatic and aromatic structural groups. Thereby, structural group distribution related to the boiling temperature could be obtained in order to quantify product-specific distribution parameters and to control material-conversion processes caused by biodegradation.

Journal Article↗
PubMed2005

Evaluation of a synthetic vaccine construct as antigen for the detection of HIV-induced humoral responses.

Synthetic V3 loop peptides hold numerous benefits for the development of HIV vaccines and in immunodiagnosis; however, their use is limited due to the extensive antigenic variability of this region. The effectiveness of a potential HIV vaccine component, which accounts for V3 loop variability, is evaluated here. A branched peptide construct representing multiple sequences and allowing 1.8 x 10(16) possible permutations was developed to mimic circulating HIV-1 subtype C, V3 loops. The construct was found to be immunogenic, able to induce neutralizing antibodies and sensitive to HIV-1 subtype B/C and HIV-2. This alternative antigen format also incorporates conformational epitopes.

AIDS Vaccines↗
PubMed2005

[Nononcologic abdominal surgery in the elderly].

Due to rising life expectancy of the population, the proportion of elderly patients requiring surgery is rising as well. Present aspects of selected, typical, nononcologic diseases of elderly people are discussed. The key to success in their treatment is not to consider primarily the patient's calendrical age but to assess the individual profile of risk factors on the basis of comorbidities. The kind, extent, and timing of an operation has to be based on this assessment. For the treatment of acute diseases (e.g., complicated ulcera, cholecystitis, appendicitis, mesenteric ischemia, and diverticulitis), a rapid and efficacious diagnostic algorithm is essential that takes into account the reduced functional reserve of old people. Constructive interdisciplinary cooperation and minimally invasive techniques play dominant roles in both diagnosis and therapy. Given these prerequisites, there is no reason to withhold surgical intervention from elderly patients.

Abdomen↗
PubMed2005

A pilot study of deep sclerectomy with implantation of chromic suture material as a collagen implant: medium-term results.

AIMS: A pilot study of the safety and efficacy of deep sclerectomy with a chromic suture implant (DSCI) for open angle glaucoma. METHODS: This prospective trial involved 23 eyes of 16 consecutive patients with uncontrolled open angle glaucoma. The DSCI procedure involved radial suturing of a 2 mm piece of 1/0 chromic suture as an implant. Intraocular pressure (IOP) measurements and eye examinations were performed preoperatively and regularly postoperatively for up to 66 months. RESULTS: The mean follow-up period was 36.3 (SD 19.9) months. The mean preoperative IOP was 26.3 (SD 8.5) mmHg. The mean postoperative IOP was 14.1 (SD 2.8) mmHg at month 12, and 16.5 (SD 2.3) mmHg at 36 months. Complete success rate, defined as an IOP lower than 21 mmHg without medication was 77% of eyes at 36 months. Qualified success rate, defined as an IOP lower than 21 mmHg with medication, was 100% at 36 months. Paired t-test and Wilcoxon test analysis of preoperative vs postoperative IOP at 36 months indicated a significant reduction in IOP. Intraoperative complications included rupture of the trabecular meshwork in seven eyes. Exclusion of these patients from the results analysis revealed a mean follow-up of 37.1 months (SD 9), preoperative mean IOP was 25.9 mmHg (SD 4.1), 12-month mean IOP was 13.4 mmHg (SD 2.8), and 36-month mean IOP 16.6 mmHg (SD 2.1). Early postoperative complications included hyphaema in two eyes and dislocation of implant in one eye. One eye developed a central retinal vein occlusion and cataract progression occurred in one eye. The mean postoperative duration of use of topical dexamethasone was 5.4 months (SD 2). CONCLUSIONS: DSCI using a chromic suture implant provides good control of IOP at medium-term follow-up with few postoperative complications. Prolonged use of postoperative anti-inflammatory medication was necessary.

Aged↗
PubMed2005

Selection and interpretation of clinical pathology indicators of hepatic injury in preclinical studies.

This position paper delineates the expert recommendations of the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology for the use of preclinical, clinical pathology endpoints in assessment of the potential for drug-induced hepatic injury in animals and humans. Development of these guidelines has been based on current recommendations in the relevant preclinical and human clinical trial literature; they are intended to provide a method for consistent and rigorous interpretation of liver-specific data for the identification of hepatic injury in preclinical studies and potential liability for hepatic injury in human patients.

Animals↗
PubMed2005

Prediction of manure and nutrient excretion from dairy cattle.

Accurate estimates of manure excretion are needed for planning manure storage facilities and for nutrient management. Data sets from metabolism studies conducted at several universities were compiled and evaluated for excretion of total manure, N, P, and K. Animal groups included calves weighing up to 204 kg, heifers weighing between 274 and 613 kg, nonlactating cows, and lactating cows. Regression equations were developed to predict excretion of total manure, total dry matter, N, P, and K. Predictors used in the regression equations for lactating cows included milk yield, percentages of protein and fat in milk, dietary concentrations of crude protein and neutral detergent fiber, and intakes of nutrients. The regression equations provide improved predictions of excretion and enable more accurate planning of manure storage and nutrients to be managed at the farm level.

Animal Nutritional Physiological Phenomena↗