Showing papers by "Stephen J. O'Brien published in 1998"
TL;DR: 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.
Abstract: 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.
733 citations
TL;DR: A prospective study was performed on 318 patients to determine the specificity, specificity, and positive and negative predictive values of the test, which differentiated labral tears and acromioclavicular joint abnormalities on physical examination using a new diagnostic test.
Abstract: Labral tears and acromioclavicular joint abnormalities were differentiated on physical examination using a new diagnostic test. The standing patient forward flexed the arm to 90 degrees with the elbow in full extension and then adducted the arm 10 degrees to 15 degrees medial to the sagittal plane of the body and internally rotated it so that the thumb pointed downward. The examiner, standing behind the patient, applied a uniform downward force to the arm. With the arm in the same position, the palm was then fully supinated and the maneuver was repeated. The test was considered positive if pain was elicited during the first maneuver, and was reduced or eliminated with the second. Pain localized to the acromioclavicular joint or "on top" was diagnostic of acromioclavicular joint abnormality, whereas pain or painful clicking described as "inside" the shoulder was considered indicative of labral abnormality. A prospective study was performed on 318 patients to determine the sensitivity, specificity, and positive and negative predictive values of the test. Fifty-three of 56 patients whose preoperative examinations indicated a labral tear had confirmed labral tears that were repaired at surgery. Fifty-five of 62 patients who had pain in the acromioclavicular joint and whose preoperative examinations indicated abnormalities in the joint had positive clinical, operative, or radiographic evidence of acromioclavicular injury. There were no false-negative results in either group.
546 citations
University of Oxford1, Science Applications International Corporation2, Hochschule Hannover3, Boston Children's Hospital4, New York University5, University of Sheffield6, National and Kapodistrian University of Athens7, Edith Cowan University8, Russian Academy9, University of Ljubljana10, Centre national de la recherche scientifique11, National Institutes of Health12, QIMR Berghofer Medical Research Institute13
TL;DR: The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event, driving its frequency upward in ancestral Caucasian populations.
Abstract: 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.
515 citations
TL;DR: Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, C CR5P1, progress to AIDS more rapidly than those with other CCR 5 promoter genotypes, particularly in the early years after infection.
Abstract: The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.
473 citations
TL;DR: In this paper, transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated Factor VIII concentrate from plasma during 1980-1985 before the development of the HIV blood test.
Abstract: Exposure to HIV type 1 (HIV-1) does not usually lead to infection. Although this could be because of insufficient virus titer, there is now abundant evidence that some individuals resist infection even when directly exposed to a high titer of HIV. This protection recently has been correlated with homozygous mutations of an HIV-1 coreceptor, namely CCR5, the receptor for the β-chemokines. Moreover, earlier results already had shown that the same chemokines markedly suppress the nonsyncitial inducing variants of HIV-1, the chief virus type transmitted from person to person. CCR5 mutation, as a unique mechanism of protection, is, however, suspect because HIV-1 variants can use other chemokine receptors as their coreceptor. Moreover, recent results have established that infection can indeed sometimes occur with such mutations. Here, we report on transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated Factor VIII concentrate from plasma during 1980–1985 before the development of the HIV blood test. Furthermore, and remarkably, 14 subjects remain uninfected to this date, and in these subjects we found homozygous CCR5 mutations in none but in most of them overproduction of β chemokines. In vitro experiments confirmed the potent anti-HIV suppressive effect of these chemokines.
214 citations
TL;DR: It is reported 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.
Abstract: Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding both to CD4 (14, 33, 40) and to one of the seven transmembrane G-protein-coupled chemokine receptors recently discovered to act as coreceptors (2, 6, 8, 11, 16, 19, 20, 24, 46). Viruses able to infect cultured T-cell lines (T tropic) are syncytium inducing (SI), are frequently found in late-stage HIV disease, and utilize the chemokine receptor CXCR4; macrophage-tropic (M-tropic) viruses are non-SI (NSI) in T-cell lines, are found throughout disease, and utilize CCR5 (2, 6, 8, 11, 16, 19, 20, 24, 46). Two other chemokine receptors, CCR2B and CCR3, function as minor HIV-1 entry coreceptors (11, 19, 48), with CCR3 likely playing a role in central nervous system HIV-1 infection (27). Recently, two seven-transmembrane receptors with extensive sequence homology to CCR5 and CXCR4—Bonzo (3, 17) and BOB (17, 22)—have been shown to mediate entry of simian immunodeficiency virus (SIV), as well as some M-tropic HIV-1 and HIV-2 strains. Another seven-transmembrane receptor, GPR1, mediates the entry of SIV but not HIV-1 (22). The CC chemokines RANTES, MIP-1α, and MIP-1β are natural ligands for CCR5 (49, 51), and the CXC chemokine stromal-cell-derived factor 1 (SDF-1) is the only known natural ligand for CXCR4 (8, 46, 49, 51). Ligand binding to both receptors is associated with G-protein-coupled signal transduction and leukocyte chemoattraction (8, 46, 49, 51), as well as partial viral-entry antagonism (2, 8, 11–13, 16, 20, 29, 46, 58). Viral entry and signal transduction are separable in vitro functions for CCR5 (4, 23, 26), but the two may be biologically related to viral pathogenesis in vivo.
Most viral isolates recovered during primary and early chronic infection are NSI regardless of the route of infection (56, 59). Evolution of coreceptor use from CCR5 to CXCR4 is coincident with viral phenotypic switch from NSI to SI and progression to AIDS in approximately half of all HIV-1-seropositive subjects (31, 32, 34, 43, 54). A 32-bp inactivating deletion in CCR5 (CCR5 Δ32) common to northern European populations (41) has been associated with delayed disease progression in heterozygotes (15, 18, 21, 28, 43, 50, 60) and especially in those harboring NSI virus (18, 43). Subjects homozygous for CCR5 Δ32 (CCR5 −/−) are at a sharply reduced risk for virus transmission (15, 21, 28, 38, 43, 52, 60). However, reports of HIV-1 infected CCR5 −/− individuals, by our group and others, demonstrate that this risk reduction is finite (5, 7, 47, 55). We now report the viral phenotype, replication kinetics, macrophage tropism, and coreceptor usage of viruses derived early and late in disease from an HIV-1-infected CCR5 −/− subject.
192 citations
TL;DR: The heterologous desensitization of CCR5 and CXCR4 signaling by bothCCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of C CR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.
Abstract: 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.
176 citations
TL;DR: Sequence analyses demonstrated that the four Serengeti species carry closely related CDV isolate which are genetically distinct from other CDV isolates from various species and locations, consistent with the conclusions that a particularly virulent strain of CDV emerged among Serengetus carnivores within the last few years.
109 citations
TL;DR: The data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years, suggesting other genetic determinants may be responsible for late protective effects.
Abstract: The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p 8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects.
107 citations
TL;DR: Abundant genetic diversity and remarkably concordant phylogeographic partitions for both species were observed, identifying parallel geographic regions which likely reflect historical faunal barriers.
Abstract: 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.
105 citations
TL;DR: 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.
Abstract: 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.
TL;DR: The mode and tempo of evolution of noncoding sequences of a large intron within Zfy and Zfx, homologous genes located on the felid Y and X chromosomes, are compared.
Abstract: 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.
TL;DR: The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV- 1 RNA plasma viral load during the first 6–12 months following acute infection.
Abstract: BACKGROUND Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms. OBJECTIVES To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection. DESIGN AND METHODS A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death. RESULTS Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64; P < 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04; P = 0.0003), and CD4+ cell count per 100 cell (x 10(6)/l) increase (RH, 0.90; P = 0.02). Multivariate linear regression showed that viral load was 39% lower (P = 0.0001) for each unit increase in HLA score profile and 13% lower (P = 0.002) for each 100 cell (x 10(6)/l) increase in CD4+ cell count. CONCLUSION The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6-12 months following acute infection.
TL;DR: 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.
Abstract: 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.
TL;DR: Age distribution from the 2nd to 8th decade demonstrated a consistent and gradual transition from a flat acromions in the younger decades to a more hooked acromion in the older decades that was significant in both the midsagittal and lateral-sagittal planes.
Abstract: To more completely describe acromion morphology and its relationship to impingement syndrome, we performed three-dimensional magnetic resonance imaging (N = 111) or computed tomography (N = 27) on 132 symptomatic shoulders. The mean patient age was 46.2 years (range, 14 to 86). Four parameters were evaluated: the angle of anterior slope of the acromion in the midsagittal and lateral-sagittal planes, lateral acromial angulation in the coronal plane, and the presence or absence of medial encroachment in the acromioclavicular joint. Twenty-five asymptomatic age-matched shoulders were used as controls. All imaging data were combined because no significant differences existed between the two imaging techniques. The mean acromion angle was 19.4 degrees in the midsagittal plane and 20 degrees in the lateral-sagittal plane. In the coronal plane, 97 (73%) acromions were neutral and 35 (27%) were downward sloping. Medial encroachment was present in 31 (24%) shoulders. Age distribution from the 2nd to 8th decade demonstrated a consistent and gradual transition from a flat acromion in the younger decades to a more hooked acromion in the older decades that was significant in both the midsagittal and lateral-sagittal planes. Furthermore, a greater percentage of patients were found to have downward angulating acromions with increasing age. Ninety-eight patients (74%) had stage II or III impingement. Of these shoulders, 39 (40%) had type I acromions, 51 (52%) type II, and 8 (8%) type III. Twenty-eight of 33 acromions with coronal lateral downward sloping had impingement, and all 31 shoulders with medial encroachment had impingement.
TL;DR: It is suggested that the Andean mountain cat diverged from a common ancestor with the ocelot (Leopardus paradalis) and margay and exhibits moderate levels of genetic variation.
Abstract: Rarely observed in the wild, the existence of the Andean mountain cat (Oreailurus jacobita) has been established based on only 3 skulls and 14 museum skins The Andean mountain cat's evolutionary relationship to other felids based on morphological characters is largely contradictory, with evidence aligning it with South American small spotted cats (ocelot lineage) or alternatively with pantherine lineage felids Here we describe the phylogenetic distinctiveness and placement of the Andean mountain cat using DNA extracted from pieces of nine independent pelt specimens, including one confiscated from a trapper in 1995 A phylogenetic analysis of DNA sequences from three rapidly evolving mitochondrial genes (16S rRNA, NADH-5, and ATP-8) indicate that the Andean mountain cat is a distinct species belonging to the ocelot lineage Our findings suggest that the Andean mountain cat diverged from a common ancestor with the ocelot (Leopardus paradalis) and margay (L wiedii) and exhibits moderate levels of genetic variation
TL;DR: 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.
Abstract: 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.
TL;DR: A small local population of cats from a rural farm in the United Kingdom had a remarkably high FIV antibody prevalence, but displayed 8-fold less overall diversity of FIV genomic variation compared with FIV from different parts of the world, interpreted as a consequence of a recent monophyletic introduction of Fiv into the population.
TL;DR: The addition of GM-CSF to the treatment with IFn-A in CML patients who are sensitive to IFN-A alone but fail to achieve a major cytogenetic response may be beneficial in some patients and should be further investigated.
Abstract: Patients with chronic myelogenous leukemia (CML) who achieve a major cytogenetic remission when treated with interferon-alpha (IFN-A) have a survival advantage when compared to patients with no cytogenetic response. We investigated the effect of combining granulocyte-macrophage colony-stimulating factor (GM-CSF) with IFN-A in the cytogenetic response of patients with minor responses to IFN-A alone. CML patients were eligible if they had shown sensitivity to IFN-A as determined by achievement of a hematologic or cytogenetic response, but failed to achieve or lost a major cytogenetic response after a minimum of 12 months of therapy with IFN-A alone. Patients received GM-CSF 30 microg/m2 daily, subcutaneously and the dose was escalated to 60 microg/m2 if tolerated. IFN-A was continued at the same dose being received by the patient and escalated when possible. Fourteen evaluable patients were included, 13 in chronic phase and one in accelerated phase. The best response prior to GM-CSF was a transient major cytogenetic response in two patients (14%), minor cytogenetic response in nine (64%), and complete hematologic response in three (22%). The median time on IFN-A prior to the start of GM-CSF was 39 months (range 12-72 months). Four patients achieved a significant cytogenetic response, including two complete (14%) and two partial (14%) cytogenetic remissions during therapy. One partial cytogenetic remission converted to complete shortly after therapy was discontinued. Two other patients had a significant reduction in the percentage of Philadelphia chromosome-positive metaphases. The dose of IFN-A could be escalated in half of the patients treated. No toxicity could be attributed to the addition of GM-CSF. We conclude that the addition of GM-CSF to the treatment with IFN-A in CML patients who are sensitive to IFN-A alone but fail to achieve a major cytogenetic response may be beneficial in some patients and should be further investigated.
TL;DR: Findings in Madagascar suggest a novel therapeutic target: not HIV but the host's cooperation with it, and herald an era in which genomes are seen as having been shaped by the evolutionary pressures of infection, and may thus hold evolution-tested therapies.
Abstract: Suspicion that human genes affect the natural history of AIDS has been confirmed by discoveries of three such genes, one of which confers near-total immunity in about 1% of Caucasians. The findings suggest a novel therapeutic target: not HIV but the host's cooperation with it. They also herald an era in which genomes are seen as having been shaped by the evolutionary pressures of infection, and may thus hold evolution-tested therapies.
TL;DR: The notion that the genetic linkages between the Ig and TcR genes are extensively conserved between humans and cats is supported.
Abstract: 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.
Patent•
10 Aug 1998
TL;DR: The CCR2-64I allele has been found to be associated with a postponement of AIDS outcomes and increased risk for progression from HIV-1 infection to the development of clinical AIDS and death as discussed by the authors.
Abstract: The present invention relates to a CCR2 mutant, designated 'CCR2-64I'. 'CCR2-64I' is a CCR2 gene sequence which has a nucleotide substitution (a G to A substitution) at position 190 (counting from the ATG start codon) such that the valine found position 64 in the wild-type CCR2 amino acid sequence is replaced by an isoleucine. CCR2 is a C-C chemokine receptor and has been implicated as a co-receptor for HIV-1. It has been discovered that the presence of the CCR2-64I allele correlates with a postponement of AIDS outcomes, and that infected individuals who have the CCR2-64I allele are at reduced risk for progression from HIV-1 infection to the development of clinical AIDS and death. Isolated nucleic acid molecule encoding CCR2-64I and the establishment of cell lines that express CCR2-64I provides valuable tools for continuing research on HIV infection. Diagnostic methods for analysis of the allelic frequency of CCR2 wild-type and 64I genes are provided. In addition, antibodies which bind to CCR2-64I, CCR2-64I variants, and CCR2 binding agents represent potential anti-HIV agents.
01 Jan 1998
TL;DR: In 1966, Bruce Wallace, a young but distinguished member of the Cornell University Faculty, accepted me as a graduate student in genetics and I learned important lessons from Bruce about the value of science and scientific investigation.
Abstract: In 1966, Bruce Wallace, a young but distinguished member of the Cornell University Faculty, accepted me as a graduate student in genetics. Under the direction of Bruce and his colleagues, particularly Ross Maclntyre, I studied the principles, theory, and applications of population genetics, the behavior of genes, and genomic diversity. But I also learned important lessons from Bruce about the value of science and scientific investigation.
Patent•
23 Oct 1998
TL;DR: A nucleic acid sequence having a single nucleotide mutation in the 3' untranslated region of the mRNA transcript of the structural gene for stromal derived factor (SDF1-3'A) is provided in this paper.
Abstract: A nucleic acid sequence having a single nucleotide mutation in the 3' untranslated region of the mRNA transcript of the structural gene for stromal derived factor (SDF1-3'A) is provided. The mutation occured at an allele frequency of 6-26 % in various racial groups. SDF-1 is the principal ligand for CXCR4, a 7-transmembrane G-coupled receptor which, with CD4, provides an entry port for T-tropic HIV-1, a variety that frequently develops in AIDS patients just prior to CD4 T-lymphocyte depletion. Also provided in the invention is a method for determining the prognosis of a subject exposed to HIV-1 and a method for determining the susceptibility of a subject to HIV-1 infection.
TL;DR: Nine patients had combined anterior cruciate ligament (ACL) disruption and patella dislocation and underwent surgical reconstruction of one or both of these injuries and had an average grade 1A Lachman and no pivot on all patients who underwent ACL reconstruction.
Abstract: Nine patients had combined anterior cruciate ligament (ACL) disruption and patella dislocation and underwent surgical reconstruction of one or both of these injuries. Six patients had both the ACL reconstructed and the patella realigned, and three had only the ACL reconstructed. Associated injuries were present in eight cases; these included meniscal tears in eight patients and medial collateral ligament injuries in two of these same patients. At final follow-up, at an average 19.7 months, examination revealed an average grade 1A Lachman and no pivot on all patients who underwent ACL reconstruction. No patients had hypermobile patellae or apprehension. One patient had a 4 degrees loss of extension and none had a loss of flexion. Two patients had continued anterior knee pain at final follow-up; one of these patients was the same person who had a loss of extension. None had recurrent instability of the ACL and none had recurrent instability of the patella. Arthroscopy 1998 Jan-Feb;14(1):80-4
TL;DR: All the considered design characteristics showed enhanced expectations for optimum results from the custom design as specified in the six aims, which is considered significant in reducing the incidence of failures of hip arthroplasties and hopefully improves patient outcomes.