Autism, inflammatory bowel disease, and MMR vaccine.
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Causality↗
Biomedical subjects
S J O'Brien
Publications and source records attributed to S J O'Brien.
CCR-5 genotype and sexual transmission of HIV-1.
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Adult↗
Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)
Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.
Acquired Immunodeficiency Syndrome↗
Phylogeographic patterns and evolution of the mitochondrial DNA control region in two neotropical cats (Mammalia, felidae).
The ocelot (Leopardus pardalis) and margay (L. wiedii) are sister-species of Neotropical cats which evolved from a lineage that migrated into South America during the formation of the Panamanian land bridge 3-5 million years ago. Patterns of population genetic divergence of each species were studied by phylogenetic analyses of mitochondrial DNA (mtDNA) control region sequences in individuals sampled across the distribution of these taxa. Abundant genetic diversity and remarkably concordant phylogeographic partitions for both species were observed, identifying parallel geographic regions which likely reflect historical faunal barriers. Inferred aspects of phylogeography, population genetic structure, and demographic history were used to formulate conservation recommendations for these species. In addition, observed patterns of sequence variation provided insight into the molecular evolution of the mtDNA control region in closely related felids.
Animals↗
Osteonecrosis of the knee: current clinical concepts.
Osteonecrosis of the knee should be differentiated into two main categories: (1) primary, spontaneous, or idiopathic osteonecrosis and (2) secondary osteonecrosis (e.g., secondary to factors such as steroid therapy, systemic lupus erythematosus, alcoholism, Caisson decompression sickness, Gaucher's disease, hemoglobinopathies, etc.). Spontaneous or primary osteonecrosis of the knee presents with an acute knee pain in elderly patients. It is three times more common in women than in men. Traumatic and vascular theories have been proposed as a causative factor of osteonecrosis of the knee, but the precise etiology still remains speculative. High index of clinical awareness and a good history and physical examination are essential to make an early, accurate diagnosis. Plain radiographs are often normal during the early course of the disease and, in such instances, radioisotope bone scan and magnetic resonance imaging may be helpful. In the early stage of the disease, nonoperative treatment is indicated and many patients, if diagnosed early, have a benign course with a satisfactory pain relief and a good knee function. In patients with advanced stage of the disease, treatment options include arthroscopic debridement, curettage or drilling of the lesion, bone grafting, high tibial osteotomy, use of osteochondral allograft, and unicompartmental or total knee arthroplasty. The choice of treatment should be based on factors such as age of the patient, severity of symptoms, activity level and functional demands on the knee, site and stage of the lesion, and extent of deformity and secondary osteoarthritis. The clinical features and treatment of steroid-induced osteonecrosis of the knee are briefly discussed. In recent years, "postmeniscectomy" osteonecrosis has been reported, but at present its prevalence and pathophysiology remain unknown. It is possible that this may be a preexisting condition that was not recognized at the time of initial consultation or osteonecrosis may develop after meniscectomy in occasional cases.
Adrenal Cortex Hormones↗
Cloning and mapping of cat (Felis catus) immunoglobulin and T-cell receptor genes.
Molecular cloning and chromosomal mapping of the cat immunoglobulin (Ig) and T-cell receptor (TcR) genes were carried out to provide basic information for genetic analysis of immunologic diseases including leukemias and lymphomas in cats. We cloned two Ig constant genes, IGHM and IGHG and three TcR constant genes, TRAC, TRGC, and TRDC, by polymerase chain reaction (PCR) amplification of cDNA from cat peripheral blood mononuclear cells. For chromosomal mapping of the Ig and TcR loci including the IGK, IGL, and TRB on the cat genome, we performed PCR screening of DNAs from 37 cat x rodent somatic cell hybrids by using specific primers for the given genes. Consequently, three loci for IGH, TRA, and TRD, and two loci for TRB and TRG were found to be syntenic and assigned to cat chromosomes (FCA) B3 and A2, respectively. Further, IGK and IGL loci were mapped on FCA A3 and D3, respectively. These findings support the notion that the genetic linkages between the Ig and TcR genes are extensively conserved between humans and cats.
Amino Acid Sequence↗
Pretibial cyst formation after anterior cruciate ligament surgery with soft tissue autografts.
Four cases of subcutaneous pretibial ganglion, with direct communication to the tibial tunnel after autologous reconstruction of the anterior cruciate ligament (ACL) with hamstrings or iliotibial band, are reported. Tibial graft fixation was with a staple in three cases, and with a screw and soft tissue washer in one. The average time to ganglion development was 44 months, and all occurred more than 2 years after ACL surgery. At the time of cyst development, no patient had subjective or objective knee instability. No patient had evidence of tibial tunnel enlargement. All ganglion communicated with the tibial tunnel. This communication was shown with magnetic resonance imaging in two cases, which showed the origin at the joint. Three patients elected to have the ganglion removed; in each of these there was a direct communication with the tibial tunnel. Additionally, hardware was removed in all cases, and local autologous bone grafting of the tibial tunnel aperture was done in two. Minimum follow-up after surgical excision was 2 years, without evidence of recurrence.
Adult↗
Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.
The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.
Acquired Immunodeficiency Syndrome↗
Patterns of Y and X chromosome DNA sequence divergence during the Felidae radiation.
The 37 species of modern cats have evolved from approximately eight phylogenetic lineages within the past 10 to 15 million years. The Felidae family has been described with multiple measures of morphologic and molecular evolutionary methods that serve as a framework for tracking gene divergence during brief evolutionary periods. In this report, we compare the mode and tempo of evolution of noncoding sequences of a large intron within Zfy (783 bp) and Zfx (854 bp), homologous genes located on the felid Y and X chromosomes, respectively. Zfy sequence variation evolves at about twice the rate of Zfx, and both gene intron sequences track feline hierarchical topologies accurately. As homoplasies are infrequent in patterns of nucleotide substitution, the Y chromosome sequence displays a remarkable degree of phylogenetic consistency among cat species and provides a highly informative glimpse of divergence of sex chromosome sequences in Felidae.
Animals↗
A primary care perspective of meningococcal disease.
BACKGROUND: It is generally agreed that pre-admission benzyl penicillin improves the outcome in infection by Neisseria meningitidis. Even so, only a minority of cases in Birmingham received such treatment. The aim of this study was, therefore, to determine the views of general practitioners (GPs) in Birmingham on the early management of meningococcal disease, including the use of parenteral antibiotics. METHODS: A standard semi-structured confidential questionnaire was posted to GPs on the list of Birmingham Family Health Services Authority. The questions covered the GPs' clinical experience of meningococcal infection and their views on the pre-hospital management of suspected cases of Neisseria meningitidis. RESULTS: Completed questionnaires were received from 372 GPs, a response rate of 70 per cent. Nearly all GPs said they carried benzyl penicillin in their on-call bag (353; 95 per cent) and would give it to a patient they suspected had meningococcal disease (361; 97 per cent). A total of 208 GPs (56 per cent) would not give parenteral chloramphenicol to a patient they suspected had meningococcal disease and a penicillin allergy, and only 25 (7 per cent) carried it as an alternative antibiotic. The most common reason for not giving chloramphenicol was unfamiliarity with dosages (132; 63.5 per cent). CONCLUSIONS: The vast majority of GPs in Birmingham would apparently give benzyl penicillin to a patient they suspected had meningococcal infection. No single issue emerged to explain why pre-admission administration of benzyl penicillin was so low. Further work is being carried out locally to help translate positive attitudes into a change in behaviour.
Adult↗
Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32.
Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.
Acquired Immunodeficiency Syndrome↗
Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4.
The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism in CCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heterozygotes had normal levels of CCR2b and CCR5 but slightly reduced levels of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 coreceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection regardless of viral tropism. The MCP-1-induced calcium mobilization mediated by CCR2b signaling was unaffected by the polymorphism, but MCP-1 signaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resulted in heterologous desensitization (i.e., limiting the signal response of other receptors) of both CCR5 and CXCR4. The heterologous desensitization of CCR5 and CXCR4 signaling by both CCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of CCR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.
Cell Line, Transformed↗
Comparative genomics: tracking chromosome evolution in the family ursidae using reciprocal chromosome painting.
The Ursidae family includes eight species, the karyotype of which diverges somewhat, in both chromosome number and morphology, from that of other families in the order Carnivora. The combination of consensus molecular phylogeny and high-resolution trypsin G-banded karyotype analysis has suggested that ancestral chromosomal fissions and at least two fusion events are associated with the development of the different ursid species. Here, we revisit this hypothesis by hybridizing reciprocal chromosome painting probes derived from the giant panda (Ailuropoda melanoleuca), domestic cat (Felis catus), and man (Homo sapiens) to representative bear species karyotypes. Comparative analysis of the different chromosome segment homologies allowed reconstruction of the genomic composition of a putative ancestral bear karyotype based upon the recognition of 39 chromosome segments defined by painting as the smallest conserved evolutionary unit segments (pSCEUS) among these species. The different pSCEUS combinations occurring among modern bear species support and extend the postulated sequence of chromosomal rearrangements and provide a framework to propose patterns of genome reorganization among carnivores and other mammal radiations.
Animals↗
General outbreaks of infectious intestinal disease in England and Wales: 1995 and 1996.
One thousand nine hundred and nineteen general outbreaks of infectious intestinal disease in England and Wales were reported to the PHLS Communicable Disease Surveillance Centre (CDSC) between 1 January 1995 and 31 December 1996, compared with 1073 in the previous two years. A minimum data set was received for 1568 (82%) of the 1919 outbreaks. Over 40,000 people were affected and about 2% of those who were ill were admitted to hospital. Seventy-one deaths were reported. The duration of outbreaks varied between less than one day and 202 days (median six days) according to the pathogen. Small round structured virus (SRSV) (43%) and salmonellas (15%) were the most commonly reported pathogens. In almost a quarter of the outbreaks (24%) the aetiology was unknown. Over half the outbreaks (64%) were reported to be transmitted from person to person, most of which were due to SRSV and occurred in residential homes and hospitals. Twenty-two per cent of outbreaks were described as mainly foodborne, 51% of which were due to salmonellas. The number of outbreaks reported in each region ranged from 52 in Wales to 512 in Northern and Yorkshire.
Caliciviridae Infections↗
European politicians need epidemiologists.
This paper reviews some of the recent discussions about public health policy in Europe. In particular it points to the interest in communicable diseases and the need to extend this interest into non-communicable fields. It draws attention to the consequential need for trained and continuously updated epidemiologists.
Epidemiology↗
Cloning and chromosome mapping of the feline genes p21WAF1 and p27Kip1.
For investigation of the relation of cell cycle regulation with tumorigenesis in cats, we carried out molecular cloning of feline p21WAF1 and p27Kip1 cDNAs and chromosomal mapping of these genes on the cat genome. The feline p21WAF1 cDNA clone obtained in this study encoded 164 amino acids (aa) showing 83.5% and 76.8% sequence similarity with those of the human and mouse counterparts, respectively. The cat p27Kip1 cDNA clone isolated here encoded 198 aa, showing sequence similarities of 93.4% and 90.4% with its human and mouse counterparts, respectively. Using a panel of feline x rodent somatic cell hybrids, the feline CDKN1A (p21WAF1) and CDKN1B (p27Kip1) loci were assigned to feline chromosomes B2 and B4, respectively. Southern-blot analyses of 17 feline spontaneous leukemia and lymphoma cases using these cDNAs as probes did not reveal any rearrangements in either the p21WAF1 or the p27Kip1 gene. RT-PCR/SSCP (single strand conformation polymorphism) analysis of p27Kip1 cDNA did not uncover any amino acid substitutions in the 10 feline leukemia and lymphoma cases that were examined.
Amino Acid Sequence↗
CCR5-delta 32 gene deletion in HIV-1 infected patients.
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Acquired Immunodeficiency Syndrome↗
Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.
The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.
Acquired Immunodeficiency Syndrome↗