Plasma lipid and lipoprotein changes in obstructive jaundice: Immunochemical identification of abnormal alpha lipoprotein forms

1. Alpha lipoprotein levels have been variously described as increased or decreased in the plasma of subjects with jaundice due to intra- or extrahepatic biliary obstruction, including biliary cirrhosis, the findings varying with the method used. 2. To resolve this paradox, a chemical and immunochemical study of the changes that occurred in the plasma lipids and lipoproteins of 21 subjects with various types of obstructive jaundice was performed. Three patterns of lipoprotein disturbances were recognised. 3. In 9 subjects an abnormal alpha lipoprotein form was detected by immunoelectrophoretic and immunodiffusion studies within the d 1.006 - 1.063 fraction, together with beta lipoproteino This low density alpha lipoprotein displayed cathodal or retarded electrophoretic mobility in agar and agarose gels respectively, and abnormal features in immunodiffusion studies. These subjects also showed, on paper electrophoresis/electrophoresis of their d 1.006 - 1.063 fraction, an additional lipoprotein hand migrating between the origin and the beta lipoprotein band, or cathodally; this band displayed unusual staining characteristics in that it usually stained for protein but not for lipid although the latter was shown to be present. It is thought to correspond to the abnormal alpha lipoprotein detected on immunoelectrophoresis. These abnormalities disappeared with relief of jaundice. 4. An abnormal alpha lipoprotein form vas also detected at d 1.006 - 1.063 in the plasma of 2 subjects; unlike the previous form it shoved normal electrophoretic mobility in agarose and agar gels, and in paper in which it stained for lipid and for protein. Its immunodiffusion characteristics vere unaltered. 5. In 10 subjects alpha lipoprotein was not identified outwith its normal density class, and in this group/ group elevated levels of beta lipoprotein of altered composition were found establishing the occurrence of a pure hyperbetalipoproteinaemia. 6. Quantitative studies of the plasma lipid and lipoprotein levels, and of lipoprotein composition showed several significant differences between the groups, with the maximum disturbances occurring in the subjects with the low density alpha lipoprotein of altered electrophoretic mobility. 7. On the basis of these findings it is suggested that the appearance of alpha lipoproteir forms of abnormally low density, with or without altered electrophoretic mobility, results from the over-lipidation of alpha lipoprotein secondary to biliary obstruction. 8. The demonstration of an alpha lipoprotein form of low density, altered electrophoretic mobility and unusual staining properties resolves the previous conflicting reports regarding alpha lipoprotein changes/changes in obstructive jaundice. 9. A lipoprotein of beta mobility was found within the d < 1.006 fraction of 11 subjects, similar to the "floating" beta lipoprotein of familial Type III hyperlipoproteinaemia. 10. Subjects with jaundice due to extra- or intrahepatic biliary obstruction could not be distinguished from those with biliary cirrhosis by their lipid and lipoprotein abnormalities

Estudo comparativo da imuno-antigenicidade de 8 amostras de Paracoccidioides brasiliensis

Para se detectar diferenças imuno-antigênicas entre 8 amostras de P. brasiliensis isoladas de diferentes áreas endêmicas (Botucatu: Pb 1, 2 e 3; São Paulo: Pb: 18, 192 e 265; Venezuela: Pb 9 e 73), esutdaram-se: 1. A reatividade antigênica de cada amostra nas reações de imunofluorescência indireta (II) e de imunodifusão dupla em gel de agar (ID) contra painel de 20 soros controles positivos para paracoccidioidomicose; 2. A capacidade de induzir resposta imune humoral (medida por imunodifusão) e celular (medida pelo teste de coxim plantar) em camundongos imunizados com an-tígenos de cada amostra. Observamos: 1. As amostras Pb 265 e Pb 9 mostraram-se mais reativas na II; 2. Os antígenos das amostras Pb 192 e Pb 73 foram significativamente mais reativas na ID; 3. Estes dados demonstram diferenças de antigenicidade entre estas amostras; 4. A amostra Pb 18 mostrou baixo poder indutor de resposta imune celular e alta capacidade de indução de resposta imune humoral em camundongos imunizados, revelando dissociação de sua imunogenicidade. Estas diferenças podem indicar a existência de cepas distintas do fungo ou refletir modificações do parasita no hospedeiro ou du rante seu cultivo

Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate

A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two; hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal Cells

A revised evolutionary history of the CYP1A subfamily : gene duplication, gene conversion, and positive selection

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Molecular Evolution 62 (2006): 708-717, doi:10.1007/s00239-005-0134-z.Members of cytochrome P450 subfamily 1A (CYP1As) are involved in detoxification and bioactivation of common environmental pollutants. Understanding the functional evolution of these genes is essential to predicting and interpreting species differences in sensitivity to toxicity by such chemicals. The CYP1A gene subfamily comprises a single ancestral representative in most fish species and two paralogs in higher vertebrates, including birds and mammals. Phylogenetic analysis of complete coding sequences suggests that mammalian and bird paralog pairs (CYP1A1/2 and CYP1A4/5, respectively) are the result of independent gene duplication events. However, comparison of vertebrate genome sequences revealed that CYP1A genes lie within an extended region of conserved fine-scale synteny, suggesting that avian and mammalian CYP1A paralogs share a common genomic history. Algorithms designed to detect recombination between nucleotide sequences indicate that gene conversion has homogenized most of the length of the chicken CYP1A genes, as well as the 5’ end of mammalian CYP1As. Together, these data indicate that avian and mammalian CYP1A paralog pairs resulted from a single gene duplication event and that extensive gene conversion is responsible for the exceptionally high degree of sequence similarity between CYP1A4 and CYP1A5. Elevated non-synonymous/synonymous substitution ratios within a putatively unconverted stretch of ~250 bp suggests that positive selection may have reduced the effective rate of gene conversion in this region, which contains two substrate recognition sites. This work significantly alters our understanding of functional evolution in the CYP1A subfamily, suggesting that gene conversion and positive selection have been the dominant processes of sequence evolution.Funding for this work was provided by the NIH Superfund Basic Research Program at Boston University (5-P42-ES-07381) and by the Woods Hole Oceanographic Institution

Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients

Preclinical and clinical studies demonstrate the feasibility of treating β-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human β-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients

History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts