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Biomedical subjects

A Rump

Publications and source records attributed to A Rump.

At least 19 recordsLinked to original sources
PubMed2003

Evaluation of a didanosin-containing regimen including genotypic resistance testing: an open-label, multicenter study.

PURPOSE: To show Didanosin in a new formulation as a once-a-day capsula as a well-tolerated and effective HIV-therapy when used in a protease sparing regimen including genotypic resistance pattern in blood, semen and cerebrospinal fluid before and during treatment. METHOD: Two groups of 58 patients, each containing 9 patients who had not been previously treated with any antiretroviral medication, and 49 patients heavily pretreated for 3,7 (DDI group) and 2,8 (non-DDI group) years, have been followed up for at least half a year. A group of 24 patients taking a special combination of Didanosin plus Efavirenz and Stavudine have been analysed with genotypic resistance testing concerning viral load response and resistance pattern under therapy. RESULTS: Suppression of plasma HIV-1 RNA to <50 copies/mL and <500 copies/mL in the DDI group was achieved in 74% and 84% of the pretreated patients, respectively, and in 100% of the naive patients after 24 weeks. In the non-DDI group suppression was achieved in 59% and 69% of the pretreated patients, respectively, and in also 100% of the naive patients. The viral load reduction in the DDI containing regimen at week 24 was 1.7 log subset 10 for the pretreated and 3,4 log subset 10 for the naive patients. In the non-DDI group, the reduction was 1.5 for the pretreated and 4,0 for the naive patients. CD4 cell counts increased from 440 to 517 cells/microL at week 24 for the pretreated, and from 171 to 289 for the naive patients in the DDI containing regimen. In the other group, cells increased from 396 to 406 for the pretreated and from 155 to 321 for the naive patients. In each group, 12 patients discontinued treatment; 4 patients in the DDI group and 7 patients in the non-DDI group because of adverse events. There were no AIDS-defining events in the antiretroviral-treated patients in both groups. 16 patients of the special combination group (DDI, D4T and EFV) were evaluated for more than 24 weeks. Suppression of HIV-1 RNA to <50 copies /mL were found in 75% of the naive and 43% of the pretreated patients. No relevant mutations were found during treatment. CONCLUSION: The new formulation of Didanosin as a once-a-day capsula in a protease sparing regimen was well-tolerated, effective in reducing viral load and in preventing AIDS-defining events. The combination of DDI, D4T and EFV proved to be a potent therapy without developing relevant mutations.

Anti-HIV Agents↗
PubMed2001

Gene structure and regulation of the murine epithelial calcium channels ECaC1 and 2.

The recently discovered epithelial calcium channels ECaC1 and ECaC2 are thought to play an important role in active calcium absorption in the intestine and kidney. Vitamin D-responsive elements (VDRE) were detected in the promoter sequence of human ECaC1 and regulation of ECaC by the steroid hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) has been postulated. In this study we describe the structure of two murine ECaCs genes, each consisting of 15 exons localized on chromosome 6. Murine ECaC2 expression was found in many target tissues of 1,25-(OH)(2)D(3), including skin and osteoblastic cells, while ECaC1 expression is confined to the kidney. By screening the murine promoter sequences, we detected a putative VDRE in ECaC1 and an estrogen response element in ECaC2. However, experiments in mice with a mutant, nonfunctioning vitamin D receptor showed that expression of ECaC1 in the kidney and of ECaC2 in duodenum is regulated by calcium levels, but not by 1,25-(OH)(2)D(3). Also, estrogen-deficient ovariectomized (OVX) mice and OVX mice supplemented with estradiol showed unchanged duodenal ECaC2 expression compared with control mice. We conclude that ECaC expression in the kidney and the intestine is regulated by extracellular calcium but not by vitamin D or estrogen in vivo in mice.

Amino Acid Sequence↗
PubMed2001

Complex arrangement of genes within a 220-kb region of double-duplicated DNA on human 2q37.1.

Gene duplication events are followed by divergence of initially identical gene copies, due to the subsequent accumulation of mutations. These mutations tend to be degenerative and may lead to either nonfunctionalization or subfunctionalization of the gene copies. Here we report the molecular characterization of a 220-kb genomic DNA fragment from human 2q37.1, in which a double duplication and a partial triplication event has taken place. As a result, this region contains four copies of alkaline phosphatase (P), four copies of the ECEL1 gene (X), two copies of a newly identified gene (N), and two copies of a cholinergic receptor subunit (R), in the order N-P-X-P-X-P-X-N-P-X-R-R. While three of the four ECEL1 copies, one copy of the phosphatase gene and one copy of the newly identified gene have lost their function, three phosphatase gene copies and the two receptor subunits are still functionally active and thus may provide an example for subfunctionalization of duplicated genes.

Alkaline Phosphatase↗
PubMed2001

A high-resolution genetic, physical, and comparative gene map of the doublefoot (Dbf) region of mouse chromosome 1 and the region of conserved synteny on human chromosome 2q35.

The mouse doublefoot (Dbf) mutant exhibits preaxial polydactyly in association with craniofacial defects. This mutation has previously been mapped to mouse chromosome 1. We have used a positional cloning strategy, coupled with a comparative sequencing approach using available human draft sequence, to identify putative candidates for the Dbf gene in the mouse and in homologous human region. We have constructed a high-resolution genetic map of the region, localizing the mutation to a 0.4-cM (+/-0.0061) interval on mouse chromosome 1. Furthermore, we have constructed contiguous BAC/PAC clone maps across the mouse and human Dbf region. Using existing markers and additional sequence tagged sites, which we have generated, we have anchored the physical map to the genetic map. Through the comparative sequencing of these clones we have identified 35 genes within this interval, indicating that the region is gene-rich. From this we have identified several genes that are known to be differentially expressed in the developing mid-gestation mouse embryo, some in the developing embryonic limb buds. These genes include those encoding known developmental signaling molecules such as WNT proteins and IHH, and we provide evidence that these genes are candidates for the Dbf mutation.

Animals↗
PubMed2001

Novel strategies to prevent catheter-associated infections in oncology patients.

Aggressive cytotoxic treatment of cancer contributes to the growing number of life-threatening infections. Vascular catheters create predominant risks for staphylococcal, enterococcal and candida blood stream infections. Although the contaminating microorganisms may be few in number, the altered host immune response in the presence of such implants as well as disease-associated immunosuppression implies that even small bacterial counts have to be regarded as highly virulent species. Diagnosis of catheter-related infection (CRI) remains difficult before withdrawal of the suspected catheter. Positive culture of catheter surface, lumen and hub and positive peripheral blood probes (paired quantitative blood culture) are predictive for catheter related bacteremia (CRB). Diligent catheter care and effective antimicrobial catheters may reduce prolonged hospital stay, increased morbidity or mortality and serious economical consequences. The most promising approach features the incorporation of antimicrobial drugs into the polymer matrices that entrap but do not bind the drugs, allowing for extended release. For the efficacious prevention of colonization in the microenvironment of the implantable device the concentration of the antimicrobial substances must exceed usual antibiotic concentrations by a thousand-fold. This is the desired effect--high concentration near the device surface and very low systemic concentration. Incorporation of antimicrobials in the bulk material that constitutes a device can be effective as shown in several in vitro and in vivo studies. In the future, modification of both short-term and long-term catheters by biofilm-active antimicrobials creating slow delivery systems may provide an effective method to protect patients from nosocomial infection in oncology.

Anti-Infective Agents↗
PubMed2000

The DNA sequence of human chromosome 21.

Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1 in 700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumours. Here we report the sequence and gene catalogue of the long arm of chromosome 21. We have sequenced 33,546,361 base pairs (bp) of DNA with very high accuracy, the largest contig being 25,491,867 bp. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 kilobases. Thus, we achieved 99.7% coverage of 21q. We also sequenced 281,116 bp from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes and 59 pseudogenes.

Base Sequence↗
PubMed2000

Comparative genome sequence analysis of the Bpa/Str region in mouse and Man.

The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Elevated DNA sequence diversity in the genomic region of the phosphatase PPP2R3L gene in the human pseudoautosomal region.

The evolution, inheritance and recombination rate of genes located in the pseudoautosomal region 1 (PAR1) is exceptional within the human genome. Pseudoautosomal genes are identical on X and Y chromosomes and are not inherited in a sex linked manner. Due to an obligatory recombination event in male meiosis, pseudoautosomal genes are exchanged frequently between X and Y chromosomes. During the isolation, characterization and sequencing of a novel gene PPP2R3L, which was classified by sequence homology as a novel member of the protein phosphatase regulatory subunit families, it became apparent that cosmids of different origin harboring this gene are highly polymorphic between individuals, both at the nucleotide level and in the number.

Amino Acid Sequence↗
PubMed1998

Efficacy of silver-coated medical devices.

Silver coating of medical devices is believed to prevent device-associated infection. Several in-vitro and in-vivo studies, as well as clinical observations on silver-nylon, silver-intramedullary pins, silver oxide Foley catheters and silver-coated vascular prostheses have been performed during the past 30 years. Nevertheless, randomized clinical studies showing efficacy of such coated medical devices in high-risk patient populations are rare, have dealt with very small numbers of patients or are controversial. Physico-chemical, pharmacological and microbiological data explaining the antimicrobial efficacy of silver in prophylaxis of implants are presented here, as well as the scientific background for the established clinical benefits of silver-preparations in burns.

Blood Vessel Prosthesis↗
PubMed1997

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome.

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX) from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Adolescent↗
PubMed1997

Caffeine in saliva after peroral intake: early sample collection as a possible source of error.

The influence of collection time on the correlation of caffeine concentrations in saliva and serum was examined in six healthy adults after peroral administration of 5 mg/kg caffeine citrate. Saliva was obtained from three different salivary glands (sublingual, right parotid, and left parotid) and evaluated separately. Caffeine concentrations in saliva and serum samples were determined by high-performance liquid chromatography. There were no differences in the caffeine concentrations in saliva from the three investigated glands (alpha = 0.05). Saliva samples collected earlier than 2 hours after caffeine intake showed higher caffeine concentrations than could be expected from the corresponding serum samples. Gingiva contamination was shown to be responsible for the higher caffeine concentrations in saliva, and it was concluded that saliva is a feasible matrix for therapeutic drug monitoring of caffeine. If caffeine is administered orally, saliva samples should be taken at least 2 hours after caffeine intake. If caffeine-containing beverages are used as the source of caffeine or if subjects do not cooperate by rinsing the mouth of caffeine contamination, an additional 60 minutes should be added before saliva sampling.

Administration, Oral↗
PubMed1997

New antiinfectious biomaterials. Ciprofloxacin containing polyurethanes as potential drug delivery systems to prevent foreign-body infections.

Device related infections are an increasing problem since foreign materials are used in modern medicine. Ciprofloxacin-HCl salt (CAS 86393-32-0) and lipophilic ciprofloxacin-betaine (Bay o 9867) incorporated into polyurethanes by solvent casting technique were studied in order to develop antiinfectious properties of this biomaterial. Drug release rates, bacterial colonization and morphological features of the polymerciprofloxacin combinations were studied and the physico-chemical mechanisms of the delivery were discussed. Ciprofloxacin salt showed a fast initial release rate, whereas ciprofloxacin-betaine was characterized by a more continuous release behaviour. A higher diffusity of the lipophilic ciprofloxacin-betaine in the polymer could be shown as compared to its salt incorporated into the polyurethane. The high initial burst effect of the hydrochloride antibiotic was caused by its high solubility in the elution medium. Bacterial colonization to the antibiotic-loaded polyurethanes was inhibited effectively only by preparations showing a slower but more sustained drug release. Scanning electron microscopy (SEM) demonstrated that the polyurethane-antibiotic combination was most homogenous for ciprofloxacin-betaine. Polyurethane material loaded with ciprofloxacin salt showed crystals at the surface and a granular structure of the polymeric matrix. Crystalline structure of the drug on polymeric surfaces varied with loading concentration and lipophilicity. Physico-chemical similarity of the polymeric material and the antibodies is important for the homogeneity of the polymer-antibiotic combinations. High homogeneity is required for a sustained and prolonged release and effective inhibition of bacterial colonization.

Anti-Infective Agents↗
PubMed1996

Drug delivery concepts for the efficacious prevention of foreign-body infections.

Several classes of antibiotics released from polyurethanes and silicones were examined for their activity against foreign body colonization by coagulase-negative staphylococci. Beta-lactams, gyrase inhibitors, aminoglycosides, macrolides and rifampicin were used as antimicrobials to impregnate or load the polymers. Coating of polymeric surfaces by precipitation or adsorption techniques lead to a lower and shorter drug release as compared to polymeric devices with incorporated antibiotics. Prolonged drug delivery of matrix-loaded polymers exceeding the microenvironmental minimal bactericidal concentrations (mMBC), ensured the prevention of bacterial colonization. In this study, we have been able to demonstrate the usefulness of a reproducible long-time antimicrobial dosage regime from the internal phase of the implant as compared to surface coated polymers. In addition, pharmacodynamic aspects and the potential of bonded antibiotics for inducing adverse effects such as resistance development and allergic reactions are discussed.

Ciprofloxacin↗
PubMed1996

Editing of GluR2 RNA in the gerbil hippocampus after global cerebral ischemia.

Postischemic delayed neuronal death (DND) in CA1 of the gerbil hippocampus is thought to be caused by an abnormal increase of Ca2+ influx into the cell, mediated by excessive activation of glutamate receptors. One subtype of glutamate receptors, the AMPA receptor, is not permeable to calcium ions as long as an edited form of its GluR2 subunit is present. It is possible that global ischemia interferes with the posttranscriptional editing of the GluR2 mRNA and thus leads to calcium influx via the AMPA receptor. In order to test this hypothesis, we examined the extent of GluR2 RNA editing in CA1 and CA3 microdissected from gerbil hippocampus after 5 min of global ischemia and various recirculation intervals. At each interval tested, quality and quantity of mRNA editing in the vulnerable CA1 region were the same as in CA3. Furthermore, postischemic mRNA editing in both hippocampal regions was indistinguishable from editing in untreated control animals. Our results clearly demonstrate that global ischemia does not cause impairment of GluR2 RNA editing, which is thus not responsible for the abnormal calcium permeability of the postischemic cell membrane.

Animals↗