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Biomedical subjects

K J Robson

Publications and source records attributed to K J Robson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Multicentric origin of hemochromatosis gene (HFE) mutations.

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </=6 Mb, suggesting that this mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </=700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

Alleles↗
PubMed1999

Improving the visibility of radio-opaque markers in mammography.

Owing to the high mean film optical densities used in breast screening mammography, and the very high maximum optical densities that can be obtained using modern mammographic film, it is often found that for larger exposures the nominally radio-opaque markers used to identify views, left and right etc., cannot be seen using a normal illuminator. A simple solution to this problem is to back the radio-opaque markers with a thin metal filter chosen to keep the marker information visible over a wide range of exposures. A convenient material for this is copper foil in the form of self-adhesive tape. The improvement in marker contrast produced by this modification is illustrated using point optical density measurements on marked test films produced at the extremes of the mammographic exposure range.

Breast Neoplasms↗
PubMed1999

Thrombospondin related adhesive protein (TRAP), a potential malaria vaccine candidate.

We have investigated whether naturally induced immunity to Plasmodium falciparum thrombospondin related adhesive protein contributes to protection against malaria in humans. We have carried out a case control study in children living in an endemic region of West Africa to reveal associations between PfTRAP seroprevalence and the risk of cerebral malaria. Sera collected from the case and control groups were analysed by ELISA to compare their serum reactivity against PfTRAP, the circumsporozoite protein and the merozoite surface protein 1. Children with uncomplicated malaria had a significantly higher PfTRAP seroprevalence when compared to children with cerebral malaria. The risk of developing cerebral malaria appeared to depend on the reciprocal relationship between sporozoite inoculation rates and humoral immunity against PfTRAP. Our results suggest that naturally induced humoral immunity against PfTRAP contributes to the development of protection against severe malaria. Experimentally induced immunity against TRAP in different rodent models has consistently proven to elicit a high degree of protection against malaria. This together with the functional properties of TRAP and data describing CD4 and CD8 epitopes for PfTRAP indicate that this molecule could increase the protective efficiency of available sporozoite malaria vaccines.

Africa, Western↗
PubMed1998

Rapid mapping of markers applying vectorette technology to YAC fragmentation allows easy assembly of a high-density STS bacterial clone contig spanning the markers D6S1260-D6S1918.

We have generated a detailed physical map of the 6p21.3/p22.1 boundary, using a combination of yeast artificial chromosome (YAC) fragmentation and high-resolution sequence tagged site (STS) content mapping. YACs from the CEPH, St. Louis, and ICRF libraries have been used to construct a 4.5-Mb contig spanning the markers D6S306 to D6S1571. YAC insert sizes were determined by pulsed field gel electrophoresis (PFGE). Chimerism of YACs was determined by fluorescent in situ hybridization (FISH), and their integrity was determined by fingerprinting with Alu-PCR. We have identified 10 new CA repeat loci in this region as well as over 50 novel STSs, several tRNA genes, a new histone H2B gene and the phospholipase D gene. Using these new markers, we have rapidly generated a bacterial clone contig of over 250 kb, spanning the markers D6S1260 to D6S1918 (WI-3111) with STSs spaced on average every 6 kb.

Animals↗
PubMed1998

Cutaneous manifestations of systemic diseases.

Many aspects of dermatologic diagnosis are either of importance or interest to the nondermatologist, and there are many excellent textbooks available for guidance. This article focuses on four categories of conditions that are the source of frequent queries from the primary care setting: (1) common skin diseases that frequently mimic systemic illness, (2) common skin diseases that have important systemic associations, (3) common systemic diseases that have prominent cutaneous findings, and (4) the seldom seen but frequently raised concerns regarding cutaneous signs of internal malignancy.

Cellulitis↗
PubMed1998

The Thrombospondin-related Protein Family of Apicomplexan Parasites: The Gears of the Cell Invasion Machinery.

A number of severe diseases of medical and veterinary importance are caused by parasites of the phylum Apicomplexa. These parasites invade host cells using similar subcellular structures, organelles and molecular species. Proteins containing one or more copies of the type I repeat of human platelet thrombospondin (TSP1), are crucial components of both locomotion and invasion machinery. Members of this family have been identified in Eimeria tenella, E. maxima, Toxoplasma gondii, Cryptosporidium parvum and in all Plasmodium species so far analysed. Here, Andrea Crisanti and colleagues discuss the structure, localization and current understanding of the function of TSP family members in the invasion of target cells by apicomplexan parasites.

Journal Article↗
PubMed1998

Subacute radiation dermatitis from fluoroscopy during coronary artery stenting: evidence for cytotoxic lymphocyte mediated apoptosis.

A patient with fluoroscopy-induced subacute radiation dermatitis is described. Her biopsy specimen showed vacuolar change and necrotic keratinocytes with lymphocytes in direct apposition, or "satellitosis". Lymphocytes in the dermis and infiltrating the epidermis were predominantly CD8+ and a number of the lymphocytes stained for TIA-1, a cytotoxic granule protein in T-cells and natural killer cells, that appears to be involved in the induction of apoptosis. Our findings suggest cytotoxic lymphocyte mediated apoptosis is involved in the pathogenesis of subacute radiation dermatitis.

Acute Disease↗
PubMed1998

Enhanced immunogenicity for CD8+ T cell induction and complete protective efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara.

Immunization with irradiated sporozoites can protect against malaria infection and intensive efforts are aimed at reproducing this effect with subunit vaccines. A particular sequence of subunit immunization with pre-erythrocytic antigens of Plasmodium berghei, consisting of single dose priming with plasmid DNA followed by a single boost with a recombinant modified vaccinia virus Ankara (MVA) expressing the same antigen, induced unprecedented complete protection against P. berghei sporozoite challenge in two strains of mice. Protection was associated with very high levels of splenic peptide-specific interferon-gamma-secreting CD8+ T cells and was abrogated when the order of immunization was reversed. DNA priming followed by MVA boosting may provide a general immunization regime for induction of high levels of CD8+ T cells.

Animals↗
PubMed1998

The effect of HFE mutations on serum ferritin and transferrin saturation in the Jersey population.

High frequencies of the haemochromatosis-related HFE C282Y mutation have been reported in North European populations, in which a high proportion of patients with the disease are homozygotes. However, the degree of penetrance of this genotype is unknown. We determined the HFE C282Y and H63D genotypes of 411 consenting volunteer blood donors on Jersey, and the serum ferritin and transferrin saturation levels of 204 of these volunteers. The C282Y allele frequency was found to be 8.3% in 822 chromosomes, indicating a homozygote frequency of 1/145. Consistent with this, four C282Y homozygotes were detected in 411 volunteers. As there are only 18 patients presently receiving treatment for haemochromatosis on Jersey, out of a total population of about 85000, there is a large discrepancy between the number of haemochromatosis patients and the number of C282Y homozygotes in this population. In a preliminary study of 204 consenting volunteers we found a correlation between transferrin saturation and HFE H63D/ C282Y genotype (P=0.017) and between serum ferritin and genotype (P = 0.056). We also observed elevated values of transferrin saturation in the two C282Y homozygotes assayed. These results suggest that a large proportion of the many undetected C282Y homozygotes on Jersey and in similar populations could be in the preclinical stages of haemochromatosis, and warrant investigation. However, there may be a wide variation in the expression of the condition, and a more extensive study of the level of disease penetrance encompassing a large number of hitherto undetected C282Y homozygotes is therefore imperative.

Adult↗
PubMed1998

Persistent keratoacanthoma: challenges in management.

BACKGROUND: Keratoacanthoma is a common cutaneous neoplasm, although the persistent form is less common and often more difficult to manage. Multiple treatment approaches have been attempted with variable efficacy. Establishing the diagnosis and selecting a treatment plan for persistent keratoacanthoma is often challenging. OBJECTIVE: Our purpose is to describe the difficulty one may encounter in the diagnosis and treatment of persistent keratoacanthoma. Hopefully, review of this clinical conundrum may facilitate the management of the reader's future patients. METHODS: We describe a case of persistent keratoacanthoma where the diagnosis was initially elusive and the management challenging. Our thought process during each stage of diagnosis and management is described in the form of "issues" with references to the appropriate literature. RESULTS: After several diagnostic and therapeutic interventions, successful treatment was achieved with administration of oral isotretinoin. Long-term remission continued as the dosage was tapered. CONCLUSION: Persistent keratoacanthoma may be challenging to diagnose and manage, presenting a clinical conundrum. Careful review of the clinicopathologic presentation and an understanding of the various treatment options may result in a successful outcome.

Administration, Oral↗
PubMed1998

Natural polymorphism in the thrombospondin-related adhesive protein of Plasmodium falciparum.

We have developed a typing system using natural sequence variation in the thrombospondin-related adhesive protein (TRAP) gene of Plasmodium falciparum. This method permits a haplotype to be assigned to any particular TRAP gene. We have applied this method to a hospital-based, case control-study in Mali. Previous sequence variation and conservation in TRAP has been confirmed. Particular TRAP haplotypes can be used as geographic hallmarks. Because of the high level of conflict between characters, we have examined the phylogenetic relationships between parasites using a network approach. Having received patient samples from urban and periurban areas of Bamako, the majority of haplotypes were closely related and distinct from TRAP sequences present in other continents. This suggests that the structure of TRAP can only tolerate a limited number of sequence variations to preserve its function but that this is sufficient to allow the parasite to evade the host's immune system until a long-lived immune response can be maintained. It may also reflect host genetics in that certain variants may escape the host immune response more efficiently than others. For vaccine design, sequences from the major regional variants may need to be considered in the production of effective subunit vaccines.

Animals↗
PubMed1997

TRAP is necessary for gliding motility and infectivity of plasmodium sporozoites.

Many protozoans of the phylum Apicomplexa are invasive parasites that exhibit a substrate-dependent gliding motility. Plasmodium (malaria) sporozoites, the stage of the parasite that invades the salivary glands of the mosquito vector and the liver of the vertebrate host, express a surface protein called thrombospondin-related anonymous protein (TRAP) that has homologs in other Apicomplexa. By gene targeting in a rodent Plasmodium, we demonstrate that TRAP is critical for sporozoite infection of the mosquito salivary glands and the rat liver, and is essential for sporozoite gliding motility in vitro. This suggests that in Plasmodium sporozoites, and likely in other Apicomplexa, gliding locomotion and cell invasion have a common molecular basis.

Animals↗
PubMed1997

Cloning and expression of the thrombospondin related adhesive protein gene of Plasmodium berghei.

Sporozoite recognition of host cells is a key step in the life-cycle of malaria parasites. Two sporozoite proteins have so far been characterized in some detail, the circumsporozoite protein (CS) and thrombospondin related adhesive protein (TRAP). We report here the cloning and expression of the TRAP gene homologue from Plasmodium berghei, PbTRAP. The PbTRAP gene encodes a protein of 606 amino acids having a deduced molecular mass of 66 kDa. The overall structure is clearly that of the TRAP family having a signal sequence followed by an integrin A domain, a sulphatide binding motif, followed by a proline based repeat before a transmembrane domain and helical cytoplasmic tail. The observed molecular mass is almost 50% larger than expected, this can be explained almost entirely by the abnormal behaviour in SDS-PAGE of the proline based repeat. As would be expected PbTRAP shows greatest similarity with the P. yoelli TRAP homologue sporozoite surface protein 2 (SSP2) than with PfTRAP, the TRAP gene from P. falciparum. The pattern of expression is similar to that of SSP2.

Amino Acid Sequence↗
PubMed1997

A rapid non-invasive method for the detection of the haemochromatosis C282Y mutation.

We describe the rapid single-step detection, by mutagenically separated polymerase chain reaction (MS-PCR), of the HLE C282Y mutation, for which > 90% of haemochromatosis patients in the U.K. are homozygous. In addition to using purified DNA as a template, whole blood and lysed buccal cell extracts from mouthwash samples can be used. Therefore sample collection may be non-invasive and purification steps kept to a minimum.

Genetic Techniques↗
PubMed1997

Recombinant vaccinia viruses for the characterization of Plasmodium falciparum-specific cytotoxic T lymphocytes: recognition of processed antigen despite limited re-stimulation efficacy.

Cytotoxic T lymphocytes (CTL) have been implicated in immunity to Plasmodium falciparum infection and disease. We have previously described the use of peptides to define malaria-specific CTL epitopes. To determine whether these peptide epitopes are processed intracellularly from the whole antigen we have developed recombinant vaccinia viruses (rVV) expressing three malaria antigens: thrombospondin-related adhesive protein (TRAP), Pfs16 and the C-terminal half of liver-stage antigen (LSA)-1. Target cells infected with recombinant viruses were lysed by malaria-specific CTL from semi-immune African donors. We also tested the ability of cells infected with these recombinant vaccinia viruses to re-stimulate malaria-specific CTL in peripheral blood lymphocytes from malaria immune adults. Two other pox virus recombinants, NYVAC, an attenuated vaccinia virus, and ALVAC, a canarypox virus, both expressing malaria antigens were also evaluated for their ability to stimulate malaria-specific CTL in contrast to peptide, none of these viruses successfully re-stimulated CTL from the peripheral blood lymphocytes of semi-immune donors. The ability of human CTL from naturally exposed individuals to recognize processed antigen supports the relevance of these cells in protective immunity to malaria.

Adult↗