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Biomedical subjects

S Lucas

Publications and source records attributed to S Lucas.

At least 37 records · Page 2Linked to original sources
PubMed2001

Evidence towards the role of arylamine N-acetyltransferase in Mycobacterium smegmatis and development of a specific antiserum against the homologous enzyme of Mycobacterium tuberculosis.

Arylamine N-acetyltransferase (NAT) in humans inactivates the anti-tubercular drug isoniazid (INH). Homologues of human NAT are present in Mycobacterium tuberculosis and Mycobacterium smegmatis, where they can acetylate, and hence inactivate, INH. The in vivo role of mycobacterial NAT is not known but heterologous expression of the M. tuberculosis gene increases the INH resistance. The 0.85 kb nat gene is part of a gene cluster in M. smegmatis. The gene is transcribed as a large, 7.5 kb mRNA as demonstrated by Northern analysis. A nat knockout strain of M. smegmatis was generated by targeted disruption. The new strain was confirmed to be devoid of NAT activity. The growth of the knockout strain is considerably delayed compared with the wild-type, due to an extended lag phase. The knockout mutant has an increased sensitivity to INH as would be predicted. The NATs from M. smegmatis and M. tuberculosis have a high degree of homology, except in the region of the C terminus. A specific polyclonal antiserum raised against recombinant NAT protein from M. tuberculosis is described that recognizes a stretch of about twenty residues within the C terminus of M. tuberculosis NAT. This highly specific antiserum will enable comparison of nat expression between isolates of M. tuberculosis.

Acebutolol↗
PubMed2001

Necropsies in African children: consent dilemmas for parents and guardians.

BACKGROUND: Necropsy examination provides a good index of the accuracy of clinical diagnosis and the quality of treatment, but its use in sub-Saharan Africa is limited. AIMS: To identify the main reasons for parents'/guardians' refusal of consent for necropsy and to explore the issues affecting their decision. METHODS: A sequential necropsy study of Zambian children between 2 months and 15 years dying of respiratory disease. When the parent/guardian refused permission for necropsy, the main reason given was recorded, after encouragement to express their specific concerns in their own words. RESULTS: Parents/guardians of 891 of 1181 children (75.4%) refused to give permission, and 290 (24.6%) consented. Of those who refused, 43% did so on the grounds that it would be a "waste of time," as the diagnosis should have been made in life and the findings would now be of no benefit to them. More than one quarter of those who refused did so because a death certificate had already been issued and arrangements to transport the body had been made and could not be delayed. Traditional beliefs that ancestral spirits forbade the mutilation of dead bodies were cited by 77 (8.6%). Other reasons included the child not being their own or that they must seek permission from other family members who were not available (6%). Religious beliefs were not a major cause of refusal. CONCLUSIONS: It is possible to achieve a rate of necropsy consent sufficient to undertake valuable clinical pathology studies on children in sub-Saharan Africa. The wide range of reasons cited for refusal points to the diverse and complex interaction of social and cultural factors affecting attitudes to necropsy examination. Medical staff need training and support to improve the uptake of clinical pathology services.

Adolescent↗
PubMed2000

Tc1, from Tityus cambridgei, is the first member of a new subfamily of scorpion toxin that blocks K(+)-channels.

A new peptide, Tc1, containing only 23 amino acids closely packed by three disulfide bridges was isolated from the Amazonian scorpion Tityus cambridgei. It blocks reversibly the Shaker B K(+)-channels with a K(d) of 65 nM and displaces binding of noxiustoxin to mouse brain synaptosome membranes. It is the shortest known peptide from scorpion venom that recognizes K(+)-channels and constitutes a new structural subfamily of toxin, classified as alphaKTx 13.1.

Amino Acid Sequence↗
PubMed2000

Medical migration.

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Africa South of the Sahara↗
PubMed2000

MAGE-B5, MAGE-B6, MAGE-C2, and MAGE-C3: four new members of the MAGE family with tumor-specific expression.

A number of genes of the MAGE-A, B, and C families have been shown to code for antigens that are recognized on many human tumors by autologous cytolytic T lymphocytes. These antigens ought to be strictly tumor specific because the encoding MAGE genes are not expressed in normal adult cells except for male germline cells, which lack HLA expression. To identify new genes of this type, we performed representational difference analysis on a melanoma cell line by subtraction with a normal skin sample. This led to the identification of MAGE-C2, a new member of the MAGE-C family. A search for nucleotide sequences encoding MAGE-like proteins in public databases led to the identification of three additional MAGE genes, which were named MAGE-B5, MAGE-B6, and MAGE-C3. The four new MAGE genes are not expressed in normal tissues, except for testis, and are expressed in tumors of different histological origins. Therefore, like other MAGE genes expressed specifically in tumors, MAGE-B5, MAGE-B6, MAGE-C2, and MAGE-C3 ought to encode antigens that could be targets for cancer immunotherapy.

Alleles↗
PubMed2000

An optimized set of human telomere clones for studying telomere integrity and architecture.

Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome ( approximately 300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100-200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.

Chromosomes, Artificial, Yeast↗
PubMed2000

Postmortem histological survey of the ocular lesions in a British population of AIDS patients.

AIMS: To study ocular pathology and systemic correlations in a series of 73 postmortem eyes from British patients who died from AIDS before the introduction of a HAART regimen. METHODS: The eyes were studied with conventional histology, special histochemical stainings, and immunohistochemistry. RESULTS: 72.6% of the cases showed chronic uveal inflammation, caused by opportunistic agents in 37.7% of them (cytomegalovirus (CMV) in 30.1%, C neoformans in 5.6%, and Gram positive bacteria in 1.8%). Cytoid bodies were noted in 10/73 eyes, three linked to CMV retinitis. Six retinal haemorrhages, four of which were secondary to CMV, were found. 14 specimens (19. 1%) showed foci of calcification, and a further 11 (15%) calcium oxalate deposits. In no cases were the calcific deposits suspected clinically. Six eyes (8.2%) did not show any abnormality. CONCLUSIONS: CMV retinitis is the most common (28.7%, 21/73) ocular infection in this series and may occur either during or in the absence of systemic dissemination. Conversely, ocular cryptococcosis appears to be an epiphenomenon of systemic and CNS disease. No other opportunistic ocular infections were present in this series. Interesting findings were the presence of intraocular precipitates of calcium oxalate and calcium phosphate or carbonate in a significant number of cases (15% and 19%, respectively), and the high prevalence of idiopathic uveal inflammation (43.8%).

AIDS-Related Opportunistic Infections↗
PubMed2000

Prospective study of the usefulness of sural nerve biopsy.

OBJECTIVE: This study aimed to determine the usefulness of sural nerve biopsy in neurological practice. METHODS: The first prospective study of sural nerve biopsy in 50 consecutive patients was undertaken. The investigating neurologist declared the prebiopsy diagnosis and management plan and after 3 months an independent neurologist evaluated the contribution of the biopsy to diagnosis and management. An independent audit officer sought information from the patient about the adverse effects and value of the biopsy after 6 weeks and 6 months. RESULTS: In seven cases the nerve biopsy changed the diagnosis, in 35 cases the biopsy confirmed the suspected diagnosis, and in eight cases the biopsy was non-contributory. The biopsy either changed or was helpful in guiding patient management in 60%, especially those with demyelinating neuropathy and multiple mononeuropathy. Seven patients reported having had infection and 10 reported increased pain at the biopsy site 6 months later. CONCLUSION: In a consecutive series of 50 cases, sural nerve biopsy altered the diagnosis in 14%, affected management in 60%, and caused persistent increased pain at the biopsy site in 33%.

Action Potentials↗
PubMed2000

Cellular localisation of HHV-8 in Castleman's disease: is there a link with lymph node vascularity?

AIMS: Human herpesvirus 8 (HHV-8) has been identified in multicentric Castleman's disease and in angioimmunoblastic lymphadenopathies. However, the presence of the virus does not necessarily indicate an aetiological role in these conditions. This study investigates the cell types infected by HHV-8 in Castleman's disease and examines the correlation between HHV-8 and Castleman's disease lymph node angiogenesis. METHODS: Sixteen formalin fixed, paraffin wax embedded samples from patients with Castleman's disease (six multicentric, 10 solitary) were examined for the presence of HHV-8 using the polymerase chain reaction (PCR), non-isotopic in situ hybridisation, PCR in situ hybridisation (PCR-ISH), and real time quantitative TaqMan PCR to HHV-8 open reading frame 26 (ORF-26), and viral (v)-cyclin encoding regions. Vascularity was assessed using CD34, CD31, and factor VIII immunocytochemistry, and lymph nodes were scored as "low" or "high". RESULTS: Five multicentric Castleman's disease and two solitary Castleman's disease biopsies were positive for HHV-8. HHV-8 was identified in approximately 10% of intranodal B lymphocytes, in endothelial cells, and in subcapsular spindle cell proliferations. The copy number of HHV-8 was low at 10-50 copies/1000 cells. The highest copy number was in subcapsular spindle cells. There was no correlation between vascularity score and HHV-8 status. CONCLUSION: The preferential localisation of HHV-8 in subcapsular spindle cell proliferations (where early intranodal Kaposi's sarcoma initiates) and endothelial cells in Castleman's disease might finally explain the link between intranodal Kaposi's sarcoma and Castleman's disease.

Adult↗
PubMed1999

Vasculitic neuropathy in association with chronic graft-versus-host disease.

A 43-year-old woman is reported who developed acute and later chronic graft-versus-host disease following an unrelated donor bone marrow transplantation for chronic myeloid leukaemia. Four years later, she developed a sensory multiple mononeuropathy with biopsy features of chronic vasculitis. This is the first report of vasculitic neuropathy in association with graft-versus-host disease.

Adult↗
PubMed1999

A new MAGE gene with ubiquitous expression does not code for known MAGE antigens recognized by T cells.

A number of genes of the MAGE family have been shown to code for antigens that are recognized on many human tumors by autologous CTLs. These antigens should be strictly tumor specific because the encoding MAGE genes are not expressed in normal adult cells, except for male germ-line cells, which lack HLA expression. Here, we report that a distant relative of the previously identified MAGE genes is expressed in many, if not all, normal tissues. This gene, which was named MAGE-D, is located in Xp11. Its exon-intron structure is completely different from that of the other MAGE genes. None of the 20 MAGE antigenic peptides presently known to be recognized by T lymphocytes is encoded by the new MAGE gene. It appears, therefore, that this new finding leaves intact the tumor specificity of the antigens encoded by the MAGE genes that are expressed only in tumor and germ-line cells.

Adult↗
PubMed1999

Isolation and characterization of pyrimidine auxotrophs, and molecular cloning of the pyrE gene from the hyperthermophilic archaeon Pyrococcus abyssi.

Uracil auxotrophic mutants of the hyperthermophilic archaeon Pyrococcus abyssi were isolated by screening for resistance to 5-fluoro-orotic acid (5-FOA). Wild-type strains were unable to grow on medium containing 5-FOA, whereas mutants grew normally. Enzymatic assays of extracts from wild-type P. abyssi and from pyrimidine auxotrophs demonstrated that the mutants are deficient in orotate phosphoribosyltransferase (PyrE) and/or orotidine-5'-monophosphate decarboxylase (PyrF) activity. The pyrE gene of wild-type P. abyssi and one of its mutant derivatives were cloned and sequenced. This pyrE gene could serve as selectable marker for the development of gene manipulation systems in archaeal hyperthermophiles.

Amino Acid Sequence↗
PubMed1999

Effects of a centipede venom fraction on insect nervous system, a native Xenopus oocyte receptor and on an expressed Drosophila muscarinic receptor.

Centipede venoms are complex protein mixtures; very few is known about their pharmacological actions. Application of a Scolopendra sp. venom fraction (SC1) on the cockroach giant axon induced an increase in the leak current correlated with a decrease in the membrane resistance, suggesting the presence in SC1 of components opening non-specific pores in the axonal membrane. On a cockroach central cholinergic synapse, microinjection of SC1 induced a small transient depolarization of the postsynaptic membrane, followed by a slow stable depolarization and a drastic decrease in the evoked subthreshold excitatory postsynaptic potential amplitude. A pretreatment of the ganglion with atropine or scopolamine reduced the amplitude of the SC1-induced depolarizing wave, suggesting a possible cholinergic muscarinic target. On control Xenopus oocytes, SC1 induced an inward oscillatory Ca2(+)-dependent Cl- current mediated through the activation of native lysophosphatidic acid receptors (LPAr). Indeed, pretreatment of oocytes with 1 microM N-palmitoyl-tyrosine phosphoric acid, a selective competitive antagonist of LPAr, decreased responses to SC1 by 70%. Application of SC1 to oocytes expressing a cloned Drosophila muscarinic receptor (Dml) induced a biphasic response comprising: (1) a large fast Cl- current that was abolished by pretreatment with atropine and scopolamine and (2) a slow and small oscillating Cl- current corresponding to the response observed in control oocytes. These observations confirm the presence of muscarinic agonists in SCI and reveal their direct action on an insect muscarinic receptor subtype homologous to mammalian M1-M3 receptors.

Animals↗
PubMed1999

Brittle diabetes characterised by recurrent hypoglycaemia.

There is little information on the clinical characteristics of "brittle" Type 1 (insulin-dependent) diabetic patients with predominantly hypoglycaemic instability. From a total cohort of 381 brittle diabetic patients from various parts of the United Kingdom, 64 (17%) had life-disrupting instability due to recurrent hospital admissions with hypoglycaemia. Compared to brittle patients with recurrent ketoacidosis (DKA), who comprised 59% of the total, those with recurrent hypoglycaemia were characterised by older mean age (34 +/- 20 v 22 +/- 11 y, p < 0.001), and more equal sex distribution (53% v 71% female, p < 0.05). Patients with "mixed brittleness" (24% of total) were intermediate between the other groups, in terms of both age and female predominance. Physicians in charge of patients with hypoglycaemic brittle diabetes considered psychosocial factors to be frequent underlying causes, though organic conditions such as lost hypoglycaemic warnings and alcohol abuse were also mentioned. Factitious insulin overdose was diagnosed in 3 patients. We conclude that hypoglycaemic brittle diabetes is a small but important sub-group of the overall brittle syndrome. It differs in age and sex distribution from the more common syndrome of recurrent DKA.

Adolescent↗
PubMed1998

LAGE-1, a new gene with tumor specificity.

Representational difference analysis was used to identify genes that are expressed in a human melanoma cell line and not in normal skin. A cDNA clone that appeared to be specific for tumors was obtained and the corresponding gene was sequenced. This new gene was named LAGE-I. Using a LAGE-I probe to screen a cDNA library from the same melanoma cell line, we identified a closely related gene, which proved to be identical to NY-ESO-I, a gene recently reported to code for an antigen recognized by autologous antibodies in an esophageal squamous cell carcinoma. Gene LAGE-I maps to Xq28. It comprises 3 exons. Alternative splicing produces 2 major transcripts encoding polypeptides of 210 and 180 residues, respectively. Expression of LAGE-I was observed in 25-50% of tumor samples of melanomas, non-small-cell lung carcinomas, bladder, prostate and head and neck cancers. The only normal tissue that expressed the gene was testis. As for MAGE-AI, expression of LAGE-I is induced by deoxy-azacytidine in lymphoblastoid cells, suggesting that tumoral expression is due to demethylation. The expression of LAGE-I is strongly correlated with that of NY-ESO-I. It is also clearly correlated with the expression of MAGE genes.

Amino Acid Sequence↗
PubMed1998

Identification of a new MAGE gene with tumor-specific expression by representational difference analysis.

Human genes expressed exclusively in tumors and male germ line cells, such as those of the MAGE, BAGE, and GAGE families, encode antigens recognized by T lymphocytes, which are potentially useful for antitumor immunotherapy. To identify new genes of this type, we generated cDNA populations enriched in sequences expressed only in testis and melanoma, using the representational difference analysis approach. A testis cDNA library enriched by subtraction with cDNA from four other normal tissues was hybridized with radiolabeled melanoma cDNA enriched by subtraction with normal skin cDNA. A cDNA fragment sharing significant homology with MAGE genes was identified, and a cosmid containing this new gene, named MAGE-C1, was isolated. MAGE-C1 is composed of four exons and encodes a putative protein of 1142 amino acids. It is about 800 residues longer than the other MAGE proteins due to the insertion of a large number of short repetitive sequences in front of the MAGE-homologous sequence. The MAGE-C1 gene appears to be located on band Xq26, whereas the MAGE-A and MAGE-B genes are located on Xq28 and Xp21, respectively. Like other MAGE genes, MAGE-C1 is expressed in a significant proportion of tumors of various histological types, whereas it is silent in normal tissues except testis. It is probable, therefore, that like other MAGE genes, MAGE-C1 encodes antigens that may constitute useful targets for cancer immunotherapy because of their strict tumoral specificity.

Amino Acid Sequence↗