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Biomedical subjects

J J Shaw

Publications and source records attributed to J J Shaw.

At least 37 records · Page 2Linked to original sources
PubMed1997

Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study.

In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.

Animals↗
PubMed1997

Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA.

SETTING: A study of multicase tuberculosis pedigrees from Northern Brazil. OBJECTIVE: To determine the model of inheritance for genetic susceptibility to tuberculosis, and to test the hypothesis that TNFA and NRAMP1 are candidate susceptibility genes. DESIGN: The study sample included 98 pedigrees, 704 individuals and 205 nuclear families. Segregation analyses were performed using the programs POINTER and COMDS. Combined segregation and linkage analysis was carried out within COMDS. Non-parametric linkage analyses were performed using BETA. RESULTS: A sporadic model for disease distribution in families was strongly rejected, as were polygenic and multifactorial models. A codominant single gene model provided the best fit (P < 0.001) to the data using POINTER. COMDS extended the analysis to compare single-gene and two-gene models. A general two-locus model for disease control was marginally favoured (0.01 < P < 0.05) over the codominant single-gene model. No evidence was found for linkage between susceptibility to disease per se and the TNF gene cluster. Weak linkage was observed using COMDS for genes (IL8RB, P = 0.039; D2S1471, P = 0.025) tightly linked (< 150 kb) to NRAMP1, but not for NRAMP1 itself. CONCLUSIONS: Tuberculosis susceptibility in this region of Brazil is under oligogenic control. Although a minor role for TNFA and NRAMP1 cannot be excluded, our data suggest that neither is a major gene involved in this oligogenic control.

Adolescent↗
PubMed1996

High frequency deletion of the tumour suppressor gene P16INK4a (MTS1) in human thyroid cancer cell lines.

p16INK4a (MTS1) is an important negative regulator of mammalian cell proliferation, acting via inhibition of CDK4/cyclin D-dependent phosphorylation of pRb to prevent progression through the G1 phase of the cell cycle. Loss of p16 activity by either gene deletion, mutation or transcriptional inactivation has now been found in a wide range of human cancers of both epithelial and mesenchymal origin, at a frequency rivalling that of p53 mutation. As a first step towards investigating its possible role as a tumour suppressor gene in thyroid tumorigenesis, we have carried out a Southern blot analysis of the p16 gene locus in a series of cell lines derived from differentiated human thyroid cancers. Homozygous deletion of the entire p16 coding sequence was observed in two of three follicular and two of four papillary cancer cell lines, but not in normal tissue or normal cells immortalised by SV40 T antigen. Given the co-existence of p16 abnormalities in primary tumours and cell lines observed in other tumour types, this high frequency of deletion suggests that p16 is a key tumour suppressor gene in the genesis of differentiated thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed1994

Evidence against involvement of APC mutation in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is one of several tumours associated with familial adenomatous polyposis (FAP), an inherited tumour syndrome which appears to result from germ-line mutation of the APC tumour suppressor gene. Here we investigate the possibility that somatic mutation of APC might play a role in sporadic PTC. 16 cases of PTC together with matched normal tissue were examined by single-strand conformation polymorphism (SSCP) analysis, concentrating on the mutation cluster region (MCR) of the APC gene (codons 1286-1513). No evidence of mutation was observed in any sample. We conclude that APC mutation, at least in the MCR, is not a significant causal mechanism in sporadic PTC.

Adolescent↗
PubMed1994

Epidemiology of canine leishmaniasis: a comparative serological study of dogs and foxes in Amazon Brazil.

The paper describes a longitudinal field study of canine leishmaniasis in sympatric domestic dog and crab-eating fox (Cerdocyon thous) populations. Dogs were studied in house-to-house surveys, and foxes were studied by live-trapping and radio-telemetry. Because serological tests (IFAT in this case) for leishmaniasis are often of uncertain sensitivity and specificity, we draw conclusions comparatively. Both cross-sectional (age-prevalence) and longitudinal analyses indicate that incidence in dogs was highest in the dry season. Seasonal changes in the age-prevalence relationship for dogs suggest that serological conversion and recovery rates decline with prior exposure to infection, where 'recovery' may be due to loss of a positive antibody titre or death from leishmaniasis. The mean incidence in dogs was higher in the rural than in the urban population and higher in hunting dogs than pet dogs. Cross-sectional and longitudinal analyses of fox serological data suggest that foxes remain positive for longer than dogs on average, either because detectable antibody is more persistent or because they experience a lower mortality rate due to leishmaniasis.

Animals↗
PubMed1992

Host preferences of the phlebotomine sandfly Lutzomyia longipalpis in Amazonian Brazil.

Experiments were undertaken to determine the relative attractiveness of humans, dogs and chickens to Lutzomyia longipalpis, the principal vector of Leishmania chagasi causing American visceral leishmaniasis. Field experiments in two villages on Marajó Island, Pará State, Brazil, showed that one boy attracted significantly more flies than one dog or chicken, and slightly fewer flies than a group of six chickens. Experiments with laboratory-bred female flies showed that a significantly greater number of flies engorged on a single human than on either a single dog or chicken, and man-biting catches demonstrated the willingness of flies to bite in the field. It appears that Lu.longipalpis has catholic feeding habits, the attractiveness of different hosts being largely a function of their relative sizes. These results are discussed with reference to the epidemiology of visceral leishmaniasis in Brazil.

Adolescent↗
PubMed1992

Use of bioluminescence for detection of genetically engineered microorganisms released into the environment.

The persistence and movement of strain JS414 of Xanthomonas campestris pv. campestris, which was genetically engineered to bioluminesce, were monitored during a limited field introduction. Bioluminescence and traditional dilution plate counts were determined. Strain JS414 was applied to cabbage plants and surrounding soil by mist inoculation, by wound inoculation, by scattering infested debris among plants, and by incorporating bacteria into the soil. Bioluminescent X. campestris pv. campestris was detected in plant samples and in the rhizosphere up to 6 weeks after inoculation. Movement to uninoculated plants was detected on one occasion, but movement from the immediate release area was not detected. Strain JS414 was detected in soil samples beneath mist- and wound-inoculated plants only at intentionally infested locations and in aerial samples only on the day of inoculation. Our bioluminescence methods proved to be as sensitive as plating methods for detecting the genetically engineered microorganisms in environmental samples. Our results demonstrate that transgenic incorporation of the luxCDABE operon provides a non-labor-intensive, sensitive detection method for monitoring genetically engineered microorganisms in nature.

Containment of Biohazards↗
PubMed1991

Cutaneous leishmaniasis of man due to Leishmania (Viannia) shawi Lainson, de Souza, Póvoa, Ishikawa & Silveira, in Pará State, Brazil.

Leishmania (Viannia) shawi Lainson, Braga, de Souza, Póvoa, Ishikawa & Silveira, 1989, was originally recorded from monkeys (Cebus apella and Chiropotes satanas), sloths (Choloepus didactylus and Bradypus tridactylus) and coatis (Nasua nasua) and the sandfly, Lutzomyia whitmani. With a panel of Leishmania specific monoclonal antibodies, it was found that 30.5% of the Leishmania strains from patients, who had contracted cutaneous leishmaniasis in Pará State, were similar, but not identical to L. (V.) guyanensis. The enzyme profiles of 18 of these strains were determined, and it was found that 12 isolates belonged to the same zymodeme as the type strain of L. (V.) shawi. The other 6 belonged to a second L. (V.) shawi zymodeme that only differed from the other by having a slightly faster PEP band. These results are the first records of infections of L. (V.) shawi in man and suggest that this parasite is probably common in areas of Pará State to the south of the Amazon River.

Animals↗
PubMed1991

Monoclonal antibodies that react with Leishmania (Viannia) naiffi.

Monoclonal antibodies were raised against Leishmania (Viannia) naiffi, which recently has been characterized as a new species. BALB/c mice were immunized with membrane-enriched fractions of a mixture of L. (V.) naiffi isolates. Subsequent fusion of immunized splenocytes with NS-1 myeloma cells resulted in the production of 5 Mabs (N1-N5). Screening by ELISA and indirect immunofluorescence against an extensive cross-panel of Leishmania strains revealed that N3 was species-specific and could thus be used to identify L. (V.) naiffi. N2 and N5 reacted only with strains of L. (V.) naiffi and Leishmania (Viannia) braziliensis, and therefore could be used in conjunction with N3 to identify L. (V.) braziliensis parasites. These species-specific Mabs will therefore be useful additions to the panel of antibodies already available for the identification of Leishmania species. N1 and N4 were found to recognize a small, glycosylated molecule present on all L. (V.) naiffi and L. (V.) braziliensis isolates that is related to the GIPL family of membrane glycophospholipids previously described for Leishmania (Leishmania) major.

Animals↗
PubMed1990

Production of a specific monoclonal antibody for the identification of Leishmania (Leishmania) venezuelensis.

We describe a monoclonal antibody (Mab), V1, specific for Leishmania (Leishmania) venezuelensis. Previous Mabs and DNA probes were not specific for this parasite, and so it was not directly possible to distinguish L. (L.) venezuelensis from other Leishmania species. Immunofluorescent staining using Mabs may be performed on very few parasites, whereas other methods of identification usually require far greater numbers of organisms. L. (L.) venezuelensis frequently dies on subculture. Mab V1 can be used to identify this parasite by indirect immunofluorescence and radioimmunoassay.

Animals↗
PubMed1990

Partial transformation of human thyroid epithelial cells by mutant Ha-ras oncogene.

We have previously shown that activation of ras oncogenes by mutation is a frequent early event in human thyroid neoplasia. Using amphotropic retroviral vectors to achieve gene transfer, we demonstrate here that human primary thyroid epithelial cells can be partially transformed by an activated cellular or viral Ha-ras oncogene, in the absence of a cooperating oncogene. The transformation event induced by ras involves temporary rescue from senescence for up to 20 rounds of cell division together with morphological alteration, growth factor independence and anchorage independence. It has therefore been possible to reconstruct in vitro a key early event in the genesis of human epithelial neoplasia.

Cell Transformation, Neoplastic↗
PubMed1990

Cutaneous leishmaniasis of man due to Leishmania (Viannia) naiffi Lainson and Shaw, 1989.

Until recently mammalian hosts of Leishmania (Viannia) naiffi Lainson & Shaw, 1989 have been limited to armadillos, Dasypus novemcinctus, in Amazonian Brazil. Past evidence for human cutaneous leishmaniasis due to this parasite is reviewed, and a recent infection in man reported, with identification of the parasite by isoenzyme profiles and a specific monoclonal antibody. The role of some phlebotomine sandfly species as vectors is discussed.

Adult↗
PubMed1990

A case of multiple lesion mucocutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis infection.

A case of leishmaniasis with multiple lesions due to Leishmania (Viannia) braziliensis infections was diagnosed in a male patient from north-east Brazil. The skin lesions were nodular and pustular and progressed to ulcers. Skin and the oral mucosae were also affected. The behaviour in culture and hamsters of the parasite recovered from a skin lesion was similar to other strains of L. (V.) braziliensis and the strain was characterized by monoclonal antibodies as belonging to serodeme I of this species. The histopathology of the skin lesions of the patient and hamster were of an inflammatory nature which extended through the dermis; leishmania in the tissues were more easily detected by the immunoenzymatic PAP method.

Adult↗
PubMed1989

A tobacco mosaic virus-hybrid expresses and loses an added gene.

An additional open reading frame from the chloramphenicol acetyltransferase (CAT) gene was fused behind a tobacco mosaic virus (TMV) subgenomic RNA promoter and inserted into different positions in the complete TMV genome to examine how much this viral genome can be altered with continued replication. One hybrid virus, CAT-CP, with the insertion between the 30K and coat protein genes, replicated efficiently, produced an additional subgenomic RNA and CAT activity, and assembled into 350-nm virions, compared to 300-nm virions of wild-type TMV. However, during systemic infection of plants, the inserted sequences were deleted. This deletion was exact, resulting in progeny wild-type TMV. Another hybrid virus examined was CP-CAT, which had the insertion between the coat protein gene and the nontranslated 3' region. This virus replicated poorly, produced only minimal levels of CAT activity, and did not systemically invade infected plants. These data show that some extensive modifications of the TMV genome still allow efficient virus replication.

Chloramphenicol O-Acetyltransferase↗
PubMed1989

Leishmania (Viannia) naiffi sp. n., a parasite of the armadillo, Dasypus novemcinctus (L.) in Amazonian Brazil.

A new leishmanial parasite, Leishmania (Viannia) naiffi sp. n., is described from the nine-banded armadillo, Dasypus novemcinctus (Edentata: Dasypodidae), from Para State, north Brazil. The parasite grows luxuriantly in Diffco blood-agar medium (B47), but poorly in the skin of intradermally inoculated hamsters. A comparison of isoenzyme profiles by starch gel electrophoresis separates the parasite from L. (V) braziliensis and L. (V.) guyanensis by the enzymes ASAT, ALAT, PGM, GPI, G6PD, PEP, MPI and GD, and from Leishmania (Leishmania) chagasi, L. (L.) amazonensis and L. (L.) deanei by ASAT, ALAT, PGM, GPI, MPI, G6PD, MDH, PEP and ACON. Finally, L. (V.) naiffi is serologically differentiated from L. (V.) braziliensis, L. (V.) guyanensis and L. (V.) panamensis on monoclonal antibodies specific for these parasites.

Animals↗