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Biomedical subjects

K Uberla

Publications and source records attributed to K Uberla.

At least 19 recordsLinked to original sources
PubMed2002

Complexity of biomedical data models in cardiology: the Intranet-based AF registry.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with major complications. Ongoing research is focused on new pacing devices for alternative treatment of this disease. The objective of an AF registry is to store prospectively all relevant data covering clinical information, quality of life and device parameters and by this means provide a platform for long-term follow-up. For statistical analysis, categorical and numerical items are required, thus a high-granular data structure must be defined and implemented in the clinical setting. Facing the limits of formalization, we developed an XML-based documentation scheme consisting of 619 items in eight tables and implemented it with state-of-the-art Intranet technology. At present detailed information on 88 patients is recorded. The pacing device generates per patient and follow-up visit a file consisting of approximately 400-500 parameters provided on a floppy disk, which are transferred by means of a specific interface into the database. Success factors for integration of a complex research database into the routine workflow of a busy university hospital are interfaces between data sources to enable non-redundant data entry, intensive fine tuning by iterative software engineering and benefit for the clinical users in form of clinical reports and patient-specific summaries. Data quality must be assured by plausibility checks. To get an overview of this complex dataset we developed a dedicated visualization tool. Due to the high number of items a large patient collective must be recruited for statistical evaluation. Interinstitutional cooperation is required for a consensus on common minimal documentation schemes to enable pooling of data.

Atrial Fibrillation↗
PubMed2002

[Evalutation of health monitoring in Bavaria by computer-assisted telephone interviews (CATI) in comparison to the German National Health Examination Survey conducted in 1998 by the Robert Koch Institute].

Between June 1999 and May 2000, 2051 residents of Bavaria were interviewed on health and health-related behaviour. The objective of the study was to assess the representativeness and validity of data acquired by computer-assisted telephone interviewing (CATI) as compared to results of the German National Health Examination Survey 1998. The following variables showed excellent agreement: subjective health status, lifetime disease prevalences, such as myocardial infarction, stroke, cancer, asthma, diabetes, hypertension, hypercholesterolaemia, utilisation of medical services, and smoking habits (prevalence of present and former smoking, average cigarette consumption per day). Minor differences were found with respect to the frequency of consulting naturopathic doctors. Self-reported anthropometric data from the present study differed considerably from the results of the objective measurements during the German Health Survey. We conclude that, in terms of data quality, CATI compares well with traditional methods such as face-to-face interviewing or mailed questionnaires. In view of several practical advantages of the method, we recommend CATI as a future basic methodology of a German health surveillance system consisting of different coordinated health data collections.

Adolescent↗
PubMed2001

Generation of replication-defective helper-free vectors based on simian immunodeficiency virus.

A systematic study on generating simian immunodeficiency virus (SIV)-based vectors was carried out. The goal was to generate helper-free, replication-defective SIVmac-based vectors at high titers. The general approach was to cotransfect into human 293T cells a plasmid carrying the vector construct along with two helper plasmids that together expressed the SIVmac virion proteins. Initial vectors carried the bacterial beta-galactosidase gene (beta-gal). These vectors had a technical difficulty: "pseudotransduction" of beta-gal protein produced during the 293T cell transfections. As a result, infection of cultures with these vector stocks also resulted in passive transfer into, and X-gal staining of, cells that had not actually been infected by the vector. A second generation of vectors expressing the enhanced jellyfish green fluorescence protein (EGFP) was not subject to this artifact. A systematic study of the SIVmac-based EGFP vectors was carried out. Helper-free vector stocks were obtained when helper plasmids lacking the SIVmac packaging signals were used. By employing envelope helper plasmids derived from different SIVmac isolates, it was possible to generate SIVmac-based vectors pseudotyped with envelope proteins of different cell tropism. Optimization of vector and helper plasmid structures, transfection conditions, and infection procedures ultimately yielded vector titers in excess of 10(6)/ml.

Animals↗
PubMed2001

[Population-based health monitoring via computer-assisted telephone interviews in Bavaria].

From June 1999 until May 2000, 2051 computer-assisted telephone interviews concerning health and health related behaviours were assessed in Bavarian households. The aim of the study was the evaluation of the validity and representativity of this data by a comparison of selected variables from the Bavarian Mikrozensus-survey 1999. The distribution patterns of the marital status, the size of the households, the gainful employment, the household-netto-income, the school qualification and of the smoking status correspond well with those of the Mikrozensus 1999. As often found in questionnaire based surveys, a disproportionately high rate of participation of highly educated persons was observed. This led to an effect only in terms of a too small rate of persons with a low household-netto-income. Within the study, two different designs were compared. The commitment of the telephone numbers to a gender for an equal quotation of men and women led to an under-representation of single-households and therefore also of unmarried persons, but it had no effect on the other characteristics. The results of this study show, that the method of computer assisted-telephone interviews is a valid and cheap basis for the establishment of an exhaustive health surveillance system in Germany.

Adolescent↗
PubMed2001

Transfer of primer binding site-mutated simian immunodeficiency virus vectors by genetically engineered artificial and hybrid tRNA-like primers.

Simian immunodeficiency viruses (SIV) harbor primer binding sites (PBS) matching tRNA or tRNA. To study determinants of primer usage in SIV, a SIVmac239-based vector was impaired by mutating the PBS to a sequence (PBS-X2) with no match to any tRNA. By cotransfection of a synthetic gene encoding a tRNA(Pro)-like RNA with a match to PBS-X2, the activity of this vector could be restored to a transduction efficiency slightly lower than that of the wild-type vector. A vector with a PBS matching tRNA(Pro) was functional at a level slightly below that of the wild-type vector, but higher transduction efficiency could be obtained by cotransfection of a gene for an engineered tRNA(Pro)-tRNA hybrid with a match to PBS-Pro. The importance of tRNA backbone identity was further analyzed by complementing the PBS-X2 vector with a gene for a matching x2 primer with a tRNA backbone, which led to three- to fourfold-higher titers than those observed for the x2 primer with the tRNA(Pro) backbone. In summary, our results demonstrate flexibility in PBS and primer usage for SIVmac239, with PBS-primer complementarity being the major determinant, in analogy with previous findings for murine leukemia viruses and human immunodeficiency virus type 1.

Animals↗
PubMed2001

Information processing in healthcare at the start of the third Millennium: potential and limitations.

The 21st century is said to be a century of the information society. We should be aware that continuing progress in information processing methodology (IPM) and information and communication technology (ICT) is changing our societies, including medicine and health care. At the start of the third Millennium we should ask ourselves, what progress can we expect from modern IPM/ICT for healthcare in the coming decade, what concerns does the information society have to face, and what steps have to be taken. These questions were addressed by clinicians, researchers and industrial representatives in a panel discussion at the joint conference ISCB-GMDS-99 of the International Society of Clinical Biostatistics and the German Society for Medical Informatics, Biometry and Epidemiology. Important aspects raised by the panelists and in the subsequent discussion were: (1) the main goal of expanding IPM/ICT should be to further improve quality of care, while maintaining reasonable costs; (2) with the support of modern IPM and ICT the boundaries between inpatient and outpatient care will fade away enabling a more efficient, patient-centered health care; (3) cooperation between health-care professionals will increase; there will be different ways of communication between them and with the patient, including modern ICT and the Internet; (4) society must be concerned with achieving equal opportunities in being informed about and in using new ICT; (5) misuse of data will remain a serious problem and can become an obstacle to progress.

Biometry↗
PubMed2001

XML-based visual data mining in medicine.

Medical databases in general are characterized by a high degree of complexity in terms of quantity of items, number of parameter values and data types (free text, categorical, numerical and other). Substantial domain knowledge is required for adequate formalization of medical entities. In this context we developed medical database plot (mdplot), a data mining tool to visualize both structure and quality of data in medical databases to identify items suitable for evaluation. Data models are provided in XML format. Missing data is identified to enable targeted efforts to improve data quality prior to analysis. Database items are classified as 1:1- related to the patient (i.e. variables are collected once per patient) and 1:n related. mdplot provides a list of all classes contained in a database, the number of records each and a condensed bar chart for semi-quantitative description of completeness according to four types of items: categorical, numerical, text and other. All items in a category are grouped from left to right, the height of each bar represents the proportion of non-missing values with respect to the total number of records in the class; thus the amount of content in a specific class is visualized. By selection of a specific class, a detailed description of it is provided including mean completeness in each item category as well as number of values per item. The new methodology was applied to a cardiological research database consisting of 619 items on 88 patients.

Atrial Fibrillation↗
PubMed2000

Rev-independent expression of synthetic gag-pol genes of human immunodeficiency virus type 1 and simian immunodeficiency virus: implications for the safety of lentiviral vectors.

The safety of lentiviral vectors for clinical applications is still a major concern. The gag-pol expression plasmids and the lentiviral vectors used in previous studies contain homologous regions, which constitute a risk for recombination events. Synthetic gag-pol genes of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) were therefore constructed, in which the codon usage was optimized for expression in human cells without altering the amino acid sequences. The synthetic gag-pol genes allowed efficient expression of these genes in the absence of Rev and the 5' untranslated leader region. Both the HIV-1 and the SIV synthetic gag-pol expression plasmids could mediate transduction of an SIV vector into nondividing human cells with titers of about 10(6) transducing units/ml. Similar titers were obtained with a four-plasmid vector-packaging system based on HIV-1. Using a biological assay, homologous recombination events between the synthetic gag-pol expression plasmids and an SIV vector were undetectable and in comparison with a previously used gag-pol expression plasmid at least approximately 100-fold less frequent. By eliminating regions of homology and sequences involved in packaging, synthetic gag-pol genes should improve the safety profile of lentiviral vectors.

5' Untranslated Regions↗
PubMed2000

Simple algorithm derived from a geno-/phenotypic database to predict HIV-1 protease inhibitor resistance.

BACKGROUND: Resistance against protease inhibitors (PI) can either be analysed genotypically or phenotypically. However, the interpretation of genotypic data is difficult, particularly for PI, because of the unknown contributions of several mutations to resistance and cross-resistance. OBJECTIVE: Development of an algorithm to predict PI phenotype from genotypic data. METHODS: Recombinant viruses containing patient-derived protease genes were analysed for sensitivity to indinavir, saquinavir, ritonavir and nelfinavir. Drug resistance-associated mutations were determined by direct sequencing. geno- and phenotypic data were compared for 119 samples from 97 HIV-1 infected patients. RESULTS: Samples with one or two mutations in the gene for the protease were phenotypically sensitive in 74.3%, whereas 83.6% of samples with five or more mutations were resistant against all PI tested. Some mutations (361, 63P, 71V/T, 771) were frequent both in sensitive and resistant samples, whereas others (241, 30N, 461/L, 48V, 54V, 82A/F/T/S, 84V, 90M) were predominantly present in resistant samples. Therefore, the presence or absence of a single drug resistance-associated mutation predicted phenotypic PI resistance with high sensitivity (96.5-100%) but low specificity (13.3-57.4%). A more specific algorithm was obtained by taking into account the total number of drug resistance-associated mutations in the gene for the protease and restricting these to certain key positions for the PI. The algorithm was subsequently validated by analysis of 72 independent samples. CONCLUSION: With an optimized algorithm, phenotypic PI resistance can be predicted by viral genotype with good sensitivity (89.1-93.0%) and specificity (82.6-93.3%). The reliability and relevance of this algorithm should be further evaluated in clinical practice.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Development of a self-inactivating, minimal lentivirus vector based on simian immunodeficiency virus.

In contrast to oncoviruses, lentiviruses do not require target cell division for integration into the host genome. Lentiviral vectors can therefore expand the spectrum of target cells susceptible to retroviral gene transfer. To analyze whether vectors based on simian immunodeficiency viruses (SIVs) could be used for gene transfer, a three-plasmid vector-packaging system was developed, in which Gag-Pol and the vector itself are of SIV origin, while Env is derived either from SIV, amphotropic murine leukemia virus (MuLV), or the G glycoprotein of vesicular stomatitis virus (VSV-G). To increase the safety of the SIV vector system, a self-inactivating SIV vector was constructed. After optimization of the SIV gag-pol expression plasmid, a minimal SIV vector, which contained only SIV sequences present on the multiply spliced nef transcript, could still be produced at titers of 2 x 10(5) infectious units/ml. Growth-arrested cells could be transduced with this vector even if vif, vpr, vpx, and nef had been deleted from the packaging construct and the vector.

Animals↗
PubMed2000

Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors.

The therapeutic success of an antiretroviral salvage regimen containing protease inhibitors (PI) is limited by PI-resistant viral strains exhibiting various degrees of resistance and cross-resistance. To evaluate the extent of cross-resistance to the new PI amprenavir, 155 samples from 132 human immunodeficiency virus type 1-infected patients were analyzed for viral genotype by direct sequencing of the protease gene. Concomitantly, drug sensitivity to indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir was analyzed by a recombinant virus assay. A total of 111 patients had been pretreated with 1-4 PI, but all were naive to amprenavir. A total of 105 samples (67.7%) were sensitive to amprenavir; 25 samples (16.1%) were intermediately resistant, and another 25 samples were highly resistant (4- to 8-fold- and >8-fold-reduced sensitivity, respectively). The mutations 46I/L, 54L/V, 84V, and 90M showed the strongest association with amprenavir resistance (P < 0. 0001). The scoring system using 84V and/or any two of a number of mutations (10I/R/V/F, 46I/L, 54L/V, and 90M) predicted amprenavir resistance with a sensitivity of 86.0% and a specificity of 81.0% within the analyzed group of samples. Of 62 samples with resistance against 4 PI, 23 (37.1%) were still sensitive to amprenavir. In comparison, only 2 of 23 samples (8.7%) from nelfinavir-naive patients with resistance against indinavir, saquinavir, and ritonavir were still sensitive to nelfinavir. Amprenavir thus appears to be an interesting alternative for PI salvage therapy.

Carbamates↗
PubMed2000

Suppression of acute viremia by short-term postexposure prophylaxis of simian/human immunodeficiency virus SHIV-RT-infected monkeys with a novel reverse transcriptase inhibitor (GW420867) allows for development of potent antiviral immune responses resulting in efficient containment of infection.

A nonnucleoside reverse transcriptase (RT) inhibitor, GW420867, was tested for postexposure prophylaxis (PEP) in rhesus macaques experimentally infected with 100 50% tissue culture infective doses of a chimeric simian/human immunodeficiency virus (SHIV) containing the RT gene of HIV-1 (SHIV-RT). Animals were either mock treated, or treated for 4 weeks starting at 8 or 24 h postinfection (p.i.) with GW420867. While such therapy led to undetectable plasma viremia in three of six monkeys, a transient plasma viremia was noted in the other three treated animals at 2 to 4 weeks following cessation of therapy. Following this transient viremia all drug-treated animals showed low or undetectable levels of plasma viremia up to the last sample examined at 90 weeks p.i. Despite low and/or undetectable viremia, virus-specific cytotoxic T lymphocyte and viral Env-specific proliferative responses were seen in the peripheral blood mononuclear cells of both mock- and drug-treated animals as early as 3 weeks p.i. Such virus-specific cellular responses, however, were better maintained in the drug-treated animals than the mock-treated animals. In contrast to the virus-specific cellular response, the magnitude and kinetics of virus specific humoral responses appeared to correlate with the detection of viremia. These data support the view that a short-term PEP with GW420867 permits the generation and maintenance of long-lasting virus-specific cell-mediated immune responses while markedly reducing viral loads to undetectable levels for a prolonged period of time (90 weeks) and leads to long-term disease protection. This model provides a unique means to define mechanisms and correlates of disease protection.

Animals↗
PubMed2000

Antiretroviral therapy during primary immunodeficiency virus infection can induce persistent suppression of virus load and protection from heterologous challenge in rhesus macaques.

A limited period of chemotherapy during primary immunodeficiency virus infection might provide a long-term clinical benefit even if treatment is initiated at a time point when virus is already detectable in plasma. To evaluate this strategy, we infected rhesus macaques with the pathogenic simian/human immunodeficiency virus RT-SHIV and treated them with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for 8 weeks starting 7 or 14 days postinfection. PMPA treatment suppressed viral replication efficiently in all of the monkeys. After chemotherapy ended, virus replication rebounded and viral RNA in plasma reached levels comparable to that of the controls in four of the six monkeys. However, in the other two animals, virus loads peaked only moderately after withdrawal of the drug and then declined to low or even undetectable levels. These low levels of viremia remained stable for at least 31 weeks after cessation of therapy. At this time point, these two monkeys were challenged with SIV(8980) to evaluate whether the host responses which were able to keep RT-SHIV replication under control were also sufficient to protect against infection with a highly pathogenic heterologous virus. Both monkeys proved to be protected against the heterologous virus. In one of the two animals, low levels of SIV(8980) replication were detected. Thus, by chemotherapy during the acute phase of pathogenic virus replication, we could achieve not only persistent virus load suppression in two out of six monkeys but also protection from subsequent heterologous challenge. By this chemotherapeutic attenuation, the replication kinetics of attenuated viruses could be mimicked and a vaccination effect similar to that induced by live attenuated simian immunodeficiency virus vaccines was achieved.

Adenine↗
PubMed2000

Evidence for recombination of live, attenuated immunodeficiency virus vaccine with challenge virus to a more virulent strain.

Live, attenuated immunodeficiency virus vaccines, such as nef deletion mutants, are the most effective vaccines tested in the simian immunodeficiency virus (SIV) macaque model. In two independent studies designed to determine the breadth of protection induced by live, attenuated SIV vaccines, we noticed that three of the vaccinated macaques developed higher set point viral load levels than unvaccinated control monkeys. Two of these vaccinated monkeys developed AIDS, while the control monkeys infected in parallel remained asymptomatic. Concomitant with an increase in viral load, a recombinant of the vaccine virus and the challenge virus could be detected. Therefore, the emergence of more-virulent recombinants of live, attenuated immunodeficiency viruses and less-aggressive wild-type viruses seems to be an additional risk of live, attenuated immunodeficiency virus vaccines.

Animals↗
PubMed2000

Phenotypic HIV-1 resistance correlates with treatment outcome of nelfinavir salvage therapy.

In order to analyse whether drug sensitivity testing would be beneficial for clinical decision-making in heavily pretreated patients, we retrospectively studied viral genotype and phenotypic drug resistance in 12 HIV-1-infected patients, each of them with a history of failing at least one therapeutic regimen including one or two protease inhibitors (PIs). The salvage therapy included nelfinavir as new PI in all cases. Four patients showed a sustained and five patients a transient viral load decrease. Three patients failed to show a significant decline of plasma HIV-1 RNA. In the baseline samples of these cases, resistance against all components of their combination therapy could be detected, whereas at least one antiretroviral drug was still active in the cases with transient treatment response. All patients with sustained therapy response harboured viruses that were either fully sensitive or resistant to only one of the drugs administered. In our study, phenotypic drug resistance was predictive for the success of antiretroviral salvage regimens.

Amino Acid Sequence↗
PubMed2000

MedIDok--an Intranet tool for XML-based data modelling in medicine.

Integration of administrative, clinical and scientific documentation in medicine is a challenge because of the complexity and dynamics of the underlying data models. At least 50 items per procedure are necessary for clinically adequate documents. Extensive fine tuning is required to achieve acceptance by physicians, thus rapid prototyping is important. The results of this modelling process should be provided independently of specific implementations for reasons of portability. To address these needs we developed MedIDok (Medical Intranet-based Documentation), a set of intranet tools to generate and maintain specific documentation systems (generated programs, no manual coding) and the associated data models. The data structures are provided in XML format and therefore can be reused with other software architectures. The feasibility of non-redundant Intranet systems for both clinical and scientific information management is assessed covering the following domains at a major university hospital: hip ultrasound, endoscopic cholecystectomy, ESWL (extracorporeal shock wave lithotripsy) and implantable cardiac defibrillators. With the programs generated by MedIDok so far more than 10,000 patient contacts have been documented.

Computer Communication Networks↗