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  • 1
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Familial hypercholesterolemia (FH), at a prevalence of about 1 in 200 in the French-Canadian population, is caused by a 10-kb deletion in the low-density lipoprotein (LDL) receptor gene in 60% of French-Canadian FH heterozygotes. We genotyped 159 FH patients who carry this common mutation and 221 healthy French-Canadian controls for five DNA restriction fragment length polymorphisms (RFLPs) of the LDL receptor gene. The allele numbers for four of the five RFLPs differed significantly (P 〈 0.001) between FH patients and control subjects. Our results suggest that the 10-kb deletion carrier allele is associated with a single haplotype (called the B haplotype). In a family study including a patient homozygous for the 10-kb deletion, we showed that the B haplotype cosegregates with the deletion in affected members and that the B haplotype is also associated with the normal allele in some members of the family. We identified 15 different haplotypes for the normal allele in 10-kb deletion carrier FH heterozygotes. These results offer strong support, at a molecular level, for the hypothesis of a founder effect for the 10-kb deletion in the French-Canadian population.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-1041
    Keywords: Hyperlipidemia ; dyslipoproteinemia ; treatment algorithm ; lipid-lowering drugs prevention strategy ; atherosclerosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary There is overwhelming evidence from prospective studies that plasma cholesterol levels are exponentially related to coronary artery disease (CAD) risk. Inversely, the beneficial effect of lowering plasma cholesterol is convincingly established from major clinical trials. A consensus has been reached in a large number of countries on the need to lower plasma lipid levels, especially LDL-cholesterol, to delay the onset, slow the progression and induce regression of atherosclerotic lesions in the coronary arteries. This remains the major indication of lipid-lowering therapy. In recent years, the emphasis has been put on target plasma lipid concentrations for dietary and drug therapy. In the process of establishing prevention strategies, however, some confusion arose: target values and criteria for assessing CAD risk and initiating therapy have differed from country to country, as well as among various groups within a country. Population strategies and high-risk case-finding strategies have clashed. Treatment algorithms have emphasized lipid levels rather than lipid transport disorders. With time, these algorithms have become more and more complex and the confused physician in practice, sometimes, has started to treat mg/dL (or mmol/L) rather than patients. This confusion has been compounded by debates on the variability of plasma lipid measurements within as well as across laboratories. In the one to one relationship that exists in the physician's office, much of this confusion can be dispelled if, after a thorough clinical evaluation, the patient's situation is taken in context, a diagnosis is made and the indicated therapy is prescribed. A good algorithm is one that focuses first on diagnosis, separates secondary from primary causes of dyslipoproteinemia, starts with diatary therapy, targets drugs to the metabolic disturbance, takes into account the psycho-social environment and the risk factor context and adjusts the treatment according to the observed response. Within this framework, specific target levels may be given due consideration. Treatment should be individualized and the key lipid transport disorders identified. Today, the physician has the advantage of prescribing drugs that have been proven valuable for the ultimate goal of therapy: prevention of atherosclerotic complications.
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  • 3
    ISSN: 0009-3084
    Keywords: Lp(a) ; Macrophage scavenger receptor ; Oxidation ; Plasminogen binding ; U937 cells
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-0646
    Keywords: spiromustine ; spirohydantoin mustard ; blood-brain barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also enhance alkylating activity against tumors other than brain tumors. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma. Alkylating activity has been demonstrated in an intracerebral glioma in the rat. Spiromustine is a cell cycle non-specific agent. Animal pharmacology studies have shown a biphasic plasma decay curve, with hepatic metabolism and excretion, an enterohepatic circulation of metabolites, and approximately 50% renal excretion of unchanged drug. Toxicology studies in mice, rats and dogs showed that dose-related myelosuppression, and neurotoxicity predominated; other organ toxicities were mild. Spiromustine is currently entering Phase I clinical trials on a variety of schedules.
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  • 5
    ISSN: 1573-7284
    Keywords: Apolipoprotein B ; Familial defective apolipoprotein B-100 ; Familial hypercholesterolemia ; Canadian kindred ; Normolipidemia ; Gene interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg3500→-Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3′ hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuH(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family. The presence of phenotypic heterogeneity among individuals with the same apo B mutation may result from epistatic interaction of the apo B locus with genetic factors regulating cholesterol homeostasis, including possible involvement of the apo E and the LDL-receptor gene loci. This study also confirms that the clinical diagnosis of FH is not necessarily associated with an LDL-receptor defect.
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  • 6
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cellular immune responses are important in the recovery from human cytomegalovirus (HCMV) infection. However, little is known about the CD4+ T cell response and the target antigens (Ag) recognized. In this paper, we have analysed the proliferative T cell response of healthy HCMV seropositive (HCMV+) blood donors to recombinant immediate-early proteins expressed in trans-fected astrocytoma cells and to total HCMV Ags expressed in infected astrocytoma cells. We found that CD4+ T cells were the major cell population that proliferated in the presence of IE or total HCMV Ags. Among healthy HCMV seropositive blood donors with anti-HCMV specific proliferative response, 33–44% also responded to IE Ags. Moreover, in high responders, the precursor frequencies of cells which proliferated in the presence of total HCMV, IE, or IEl Ags were high (1/103 to 1/255, 1/2785 to 1/7744 and 1/5190 to 1/13531, respectively). In some donors, the anti-IE response was variable over time, whereas the anti-total HCMV Ags response remained constant, which suggests regulation of the anti-IE response in immunocompetent subjects. Our results suggest that the CD4+ anti-IEl response represents a significant part of the anti-HCMV proliferative response, both at the population level, and within individual immune systems.
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  • 7
    ISSN: 0163-7827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-0646
    Keywords: tiazofurin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3–16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.
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  • 9
    ISSN: 0005-2760
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0005-2760
    Keywords: LDL ; Macrophage ; Oxidized LDL ; Simvastatin
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Type of Medium: Electronic Resource
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