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H Baron

Publications and source records attributed to H Baron.

At least 19 recordsLinked to original sources
PubMed2006

Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Adolescent↗
PubMed2004

[Mechanisms of transplant vasculopathy].

Cardiac allograft vasculopathy is a diffuse, obliterative form of arteriosclerosis that is characterized by the production of a neointima rich in vascular smooth muscle cells that progressively obstructs the lumen. Pathophysiologically, after heart transplantation, alloantigens (e. g. on donor endothelial cells) are presented by antigen presenting cells to the T-cells of the body's immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T-cell, B-cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Cells of innate immunity, monocyte-derived macrophages, are involved in this process. The inflammatory response culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and migration and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines.

Animals↗
PubMed2003

Improved conformation-dependent immunoassay: suitability for human prion detection with enhanced sensitivity.

The presence of pathogenic prion protein (PrP(Sc)) in lymphoid tissues of variant Creutzfeldt-Jakob disease (vCJD) patients raises questions as to whether prions may be present in bodily fluids as well. Currently, transgenic mice are highly sensitive in vivo tools for the study of prions in tissues or fluids containing high levels of normal prion protein (PrP(C)). We report here an in vitro assay with virtually equivalent sensitivity incorporating a capture antibody into a sandwich conformation-dependent immunoassay (CDI), resulting in 30- to 100-fold increased sensitivity compared with the original, direct CDI. Furthermore, spiking plasma with vCJD prions in different preparations demonstrated that sandwich CDI detects prions with different biophysical properties at high sensitivity, even without proteinase K pretreatment of samples. Thus, sandwich CDI represents a powerful tool to study prions in bodily fluids of CJD/vCJD patients, with a turnaround time of less than 24 h.

Animals↗
PubMed2002

Purity of spiking agent affects partitioning of prions in plasma protein purification.

Prions are not detectable in the blood or plasma of persons afflicted with classical or variant Creutzfeldt-Jakob disease, and they have never been shown to be transmitted by blood or plasma products. Despite the uncertainty as to the presence and biophysical properties of prions in plasma, prion removal studies have been conducted using brain homogenate or microsomes prepared from prion-infected rodent brains as model prions. In this study, we compare the partitioning of different prion spiking agents, having different biophysical properties, in the processes used for plasma protein purification. We have found that membrane-bound prion spiking agents partition similarly, whereas purified, unbound pathogenic prion proteins can have significantly different partitioning properties depending on the conditions in the production process. We conclude that prion spiking studies for the evaluation of prion reduction in plasma protein purification should employ spiking agents with different biophysical properties to mimic partitioning of the theoretical prion contaminant. This will give greater assurance as to the prion safety margins of the life-saving plasma protein therapeutics and excipients.

Animals↗
PubMed2001

Efficient and cost-effective single nucleotide polymorphism detection with different fluorescent applications.

Three methods-5'nuclease assay with TaqMan, minisequencing, and oligonucleotide ligation assay (OLA)-were compared to detectfive single nucleotide polymorphisms (SNPs) in three separate genes. Each method had advantages and disadvantages. The 5' nuclease assay was the fastest and required only a single step. OLA was the most time consuming to optimize, but once running it was the least expensive method. Minisequencing was universal; however, the technique was also the most expensive. All three methods were reliable and highly effective. Investigators must consider their goals in terms of time, sample number, and expense when selecting among these genotyping techniques.

Base Sequence↗
PubMed2001

HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement.

Many aspects of acquired immunodeficiency syndrome (AIDS) have been described in detail in the literature. However, there have been very few articles on the phenomenon of deep vein thrombosis (DVT) in the lower extremities of human immunodeficiency virus (HIV)/AIDS patients. The objective of this communication is to record the incidence of DVT in HIV/AIDS patients and the risks for development of embolic events and to emphasize the need for prevention and for the vigorous treatment of this complication. We conducted a retrospective review of HIV/AIDS-infected patients with DVT admitted to Mount Sinai School of Medicine/Cabrini Hospital in New York during the last 5 years. Analysis includes demographic data; risk factors for HIV/AIDS infection; associated medical problems; recent surgery; and laboratory findings including CD4 counts, platelet counts, prothrombin times, partial thromboplastin times, and plasma albumin levels; and image studies. From January 1995 to January 2000 4752 HIV/AIDS-infected patients were admitted. Of those admitted to the hospital 45 (0.95%) were found to have DVT. There were 36 males and nine females (mean age 43 years). Of the 45 patients 38 had infectious complications and 13 developed a malignancy. The distribution of the thromboses were the femoral vein in 23 patients, the popliteal vein in 20 patients, and the iliofemoral system in 2 patients. Twelve patients had recurrent DVT and three patients developed a pulmonary embolism. HIV/AIDS infection is a considerable risk for development of DVT in the lower extremity. Statistically DVT in HIV/AIDS is approximately 10 times greater than in the general population. Emphasis upon prevention and vigorous treatment of DVT is recommended.

AIDS-Related Opportunistic Infections↗
PubMed2000

Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23 in Chinese and German families.

We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations >240 mg/dl and triglyceride concentrations >250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two-point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since DIS194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.

Adult↗
PubMed2000

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Adult↗
PubMed2000

[Linkage of familial combined hyperlipidemia to chromosome 1q21-23 in Chinese and German families].

OBJECTIVE: To examine familial combined hyperlipidemia (FCHL) families from nonisolated regions in China and Germany to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. METHODS: We recruited 24 German families with 133 members and 12 Chinese families with a total of 81 members in China. The markers ApoA2, D1S1677, D1S104, and D1S194 were examined by multipoint linkage analysis. RESULTS: Multipoint linkage analysis allowing for heterogeneity gave a maximum LOD score (HLOD) of 1.97 right over D1S194, estimating the proportion of linked families at 17%. This marker was adjacent to D1S104. The evidence for linkage was roughly the same both in the German (13%, HLOD(D1S194) = 1.08) and Chinese families (proportion of linked families 26%, HLOD(D1S194) = 0.97). CONCLUSION: In the light of the relatively small numbers and the heterogeneity our populations represent, we interpret our observations as encouraging support for the recent findings indicating the presence of linkage for FCHL on chromosome 1q21-23.

Apolipoprotein A-II↗
PubMed1998

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr

Computer Communication Networks↗
PubMed1998

Approaches to the genetics of cardiovascular disease through genetic field work.

Successful molecular genetic studies of complex disease require exact, careful phenotypization, which is more difficult than that performed for monogenic diseases. We have developed a family-oriented field working approach, which relies on index patients, their primary care physicians, and a minimum number of field working staff. The patients are responsible for recruiting their family members. Packets containing an explanatory pamphlet, an informed consent statement, a questionnaire, and blood cuvettes are provided. Data are transferred from questionnaire and from the laboratory into a computer program that facilitates construction of the family tree. We have applied this genetic field working approach primarily to patients with lipid disorders. Coupling results from genetic field working with modern DNA diagnostic tests such as the oligonucleotide ligation assay, has enabled us to effectively identify patients with familial hypercholesterolemia in the German population. We are now extending genetic field working to hypertension. Hypertension is much more difficult to study, because the phenotype is more difficult to discern and document. Both complex diseases have the disadvantage that the parents of the index patients are likely to already be dead. Nevertheless, we concentrate on the recruitment of large pedigrees, sibling pairs with parents whenever possible, and trios consisting of index patient and both parents or index patient, parent and sibling. With these constellations we can conduct association studies, linkage analysis, and novel combinations of both approaches.

Automation↗
PubMed1996

Oligonucleotide ligation assay (OLA) for the diagnosis of familial hypercholesterolemia.

More than half of all deaths in Western society are related to arteriosclerotic cardiovascular diseases. Inherited disturbances in the low-density-lipoprotein (LDL) receptor and similar lipid-related defects account for the majority of these deaths. Testing procedures thus far rely on total cholesterol, LDL cholesterol, high-density-lipoprotein cholesterol, and triglyceride determinations. These tests are not able to provide any genetic information. We have developed an oligonucleotide ligation assay (OLA) that enables us to screen for high-risk individuals by testing for 19 common mutations in the LDL receptor and the apolipoprotein B genes using an automated genotyping-based two-step protocol. The novel OLA uses oligomeric pentaethyleneoxide mobility modifiers. The automated test will be useful in screening large populations for genetic data to distinguish relative from absolute risk, as well as for cost-effective familial analysis.

Apolipoproteins B↗
PubMed1995

[aDNA--a new approach to old questions].

aDNA-analyses are presented for ancient bones, teeth, soft tissues and dried body fluids. The implications and perspectives for Historical Anthropology are discussed. Methods are described on examples of molecular sex determination and kinship analysis. Finally, first amplifications of DNA-sequences from pathogenes of tuberculosis and plague from ancient skeletal material are reported.

Anthropology, Physical↗
PubMed1994

Image analysis of neuritic regeneration by adult rat dorsal root ganglion neurons in culture: quantification of the neurotoxicity of anticancer agents and of its prevention by nerve growth factor or basic fibroblast growth factor but not brain-derived neurotrophic factor or neurotrophin-3.

Peripheral neuropathies are a common side effect of chemotherapeutic agents, particularly antineoplastic drugs such as taxol, cisplatin, or vinca-alkaloids (vincristine, vinblastine, vindesine). Using dissociated cultures of adult rat dorsal root ganglion (DRG) neurons and video image analysis after neurofilament immunostaining, we have designed a system that allows: (i) rapid screening of potential neurotoxic agents, with the establishment of dose-response curves and the calculation of IC50; (ii) quantification of neurotrophic effects; and (iii) demonstration of neuroprotection by trophic factors. In particular, we show that nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) stimulate in vitro neuritic regeneration by adult rat DRG neurons, while brain-derived neurotrophic factor and neurotrophin-3 lack such effects. Furthermore, 24 h of pretreatment by NGF or bFGF drastically decreases the neurotoxic effect of vincristine and cisplatin.

Animals↗