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1.
Leukemia ; 29(2): 441-7, 2015 Feb.
Article in English | MEDLINE | ID: mdl-24962016

ABSTRACT

We examined risk of second cancer and late mortality in a population-based Australian cohort of 717 pediatric allogeneic stem cell transplant (HSCT) recipients treated for a malignant disease during 1982-2007. Record linkage with population-based death and cancer registries identified 17 second cancers at a median of 7.9 years post HSCT; thyroid cancer being the most common malignancy (n=8). The cumulative incidence of second cancer was 8.7% at follow-up, and second cancers occurred 20 times more often than in the general population (standardised incidence ratio 20.3, 95% confidence interval (CI)=12.6-32.7). Transplantation using radiation-based conditioning regimens was associated with increased second cancer risk. A total of 367 patients survived for at least 2 years post HSCT and of these 44 (12%) died at a median of 3.1 years after HSCT. Relapse was the most common cause of late mortality (n=32). The cumulative incidence of late mortality was 14.7%. The observed rate of late mortality was 36 times greater than in the matched general population (standardised mortality ratio 35.9, 95% CI=26.7-48.3). Recipients who relapsed or who had radiation-based conditioning regimens were at higher risk of late mortality. Second cancers and late mortality continue to be a risk for pediatric patients undergoing HSCT, and these results highlight the need for effective screening and survivorship programs.


Subject(s)
Hematologic Neoplasms/epidemiology , Hematopoietic Stem Cell Transplantation/adverse effects , Neoplasm Recurrence, Local/epidemiology , Neoplasms, Second Primary/epidemiology , Adolescent , Australia , Child , Child, Preschool , Cohort Studies , Female , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Humans , Incidence , Infant , Male , Neoplasm Recurrence, Local/etiology , Neoplasms, Second Primary/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Recurrence , Risk Factors , Time Factors , Transplantation Conditioning/methods , Treatment Outcome
2.
Bone Marrow Transplant ; 49(5): 691-8, 2014 May.
Article in English | MEDLINE | ID: mdl-24535126

ABSTRACT

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992-2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.


Subject(s)
Hematopoietic Stem Cell Transplantation/statistics & numerical data , Leukemia, Myeloid, Acute/epidemiology , Myelodysplastic Syndromes/epidemiology , Neoplasms, Second Primary/epidemiology , Adolescent , Adult , Australia/epidemiology , Cohort Studies , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Incidence , Lymphoma, Non-Hodgkin/epidemiology , Male , Melanoma/epidemiology , Middle Aged , Multivariate Analysis , Population Surveillance , Registries/statistics & numerical data , Risk Factors , Skin Neoplasms/epidemiology , Transplantation, Autologous , Young Adult
3.
Tissue Antigens ; 78(6): 421-7, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22115424

ABSTRACT

Neuroblastoma is the most common solid tumor in children less than 5 years of age. The early onset of neuroblastoma suggests that genes involved in fetal development and pregnancy may have a putative role in the etiology of neuroblastoma. The human leukocyte antigen subtype G (HLA-G) molecule plays an important role in immune response regulation and appears to regulate immune tolerance during early pregnancy as well as tumor immunosurveillance. Elevated levels of soluble HLA-G (sHLA-G) have been detected in a number of malignancies including serum samples from neuroblastoma and have been reported to be predictive of tumor relapse in neuroblastoma. In light of previous investigations suggesting that single nucleotide polymorphisms in the HLA-G gene may impact on protein expression levels and isoform production, we examined the influence of HLA-G polymorphisms on the susceptibility and clinical outcome of neuroblastoma in 163 neuroblastoma patients and 404 healthy controls. The distribution of HLA-G polymorphisms, alleles, or allelic groups did not differ between children diagnosed with neuroblastoma and healthy controls. Our analyses did not detect an association between common HLA-G polymorphisms and clinical outcome in patients treated for neuroblastoma.


Subject(s)
Alleles , Genetic Predisposition to Disease , HLA-G Antigens/genetics , Neoplasm Proteins/genetics , Neuroblastoma/genetics , Polymorphism, Single Nucleotide , Child, Preschool , Female , Gene Expression Regulation, Neoplastic/genetics , HLA-G Antigens/biosynthesis , Humans , Infant , Infant, Newborn , Male , Neoplasm Proteins/biosynthesis , Neuroblastoma/metabolism , Neuroblastoma/mortality , Pregnancy , Protein Isoforms/biosynthesis , Protein Isoforms/genetics
4.
Sex Transm Infect ; 86(3): 207-11, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20522633

ABSTRACT

OBJECTIVE: To evaluate a sensitive and specific, real-time PCR assay with internal control for Chlamydia trachomatis and Neisseria gonorrhoeae DNA detection in urine specimens. METHODS: The diagnostic performance of a laboratory-developed quadruplex assay (LDQA) targeting the cryptic plasmid and MOMP genes of C trachomatis, the porA pseudogene of N gonorrhoeae and a synthetic internal control was assessed using 1028 urine specimens. The LDQA was compared with the Roche COBAS Taqman CT test and the COBAS Amplicor NG assay with supplemental confirmation tests. The subsequent performance of the LDQA in detecting N gonorrhoeae was monitored in comparison with bacterial culture from swabs. RESULTS: 88 (8.6%) urines were determined as C trachomatis positive in the diagnostic evaluation. LDQA sensitivity and specificity were calculated to be 100% and 99.9%, respectively, for C trachomatis. The LDQA showed high specificity with isolates of other Neisseria species and gave complete concordance with resolved data for N gonorrhoeae detection. However, the incidence of N gonorrhoeae infection was low, with 17 (1.7%) positive patients. A post-implementation audit of 14 316 patients gave the LDQA N gonorrhoeae urine PCR protocol (porA, OPA, 16s rDNA) a sensitivity of 96.9% and specificity of 99.8% in comparison with bacterial culture from swabs. CONCLUSIONS: The LDQA was found to be an effective method for the detection of C trachomatis and N gonorrhoeae DNA in urine samples, and the PCR protocol has replaced bacterial culture for the screening of N gonorrhoeae in asymptomatic men and women in the laboratory.


Subject(s)
Chlamydia Infections/diagnosis , Chlamydia trachomatis/isolation & purification , DNA, Bacterial/urine , Gonorrhea/diagnosis , Neisseria gonorrhoeae/isolation & purification , Polymerase Chain Reaction/methods , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Polymerase Chain Reaction/standards , Sensitivity and Specificity , Young Adult
6.
HIV Med ; 3(2): 91-6, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12010355

ABSTRACT

OBJECTIVE: To determine the association between CCR5 and CCR2b genotype and the clinical manifestation of first and subsequent AIDS-defining illnesses (ADIs). METHODS: The distribution of ADIs was examined by CCR5 and CCR2b genotype in a subset of homosexual men enrolled in the Sydney AIDS Prospective Study. The expected number of ADIs was calculated from rates observed in the same tertiary hospital over the same period. RESULTS: Information on initial ADI was collected for 117 homosexual men diagnosed with AIDS before January 1998. Of these individuals, 17 were heterozygous for the CCR5-Delta32 mutation and 11 were heterozygous for CCR2b-64I. The number of observed cases of Pneumocystis carinii pneumonia (PCP), toxoplasmosis, Mycobacterium avium complex (MAC) and cryptosporidiosis reported as a first ADI was substantially fewer in people heterozygous for the CCR5-Delta32 mutation than for those without the mutation, despite similar age, CD4 T-cell count at AIDS diagnosis, year of AIDS diagnosis and receipt of antiretroviral treatment. In addition, among individuals heterozygous for CCR5-Delta32 there were fewer cases of PCP, toxoplasmosis, MAC, and cryptosporidiosis observed as subsequent ADIs compared to the number expected, based on rates measured in the same hospital during the same period (seven observed vs. 24 expected, RR = 0.3, 95% CI = 0.01-0.6). The distribution of first and subsequent ADIs did not differ from the number expected in individuals heterozygous for the CCR2b-64I mutation. CONCLUSION: Results from this study show that heterozygosity for CCR5-Delta32 but not CCR2b-64I appears to protect against opportunistic infections.


Subject(s)
AIDS-Related Opportunistic Infections/prevention & control , Heterozygote , Receptors, CCR5/genetics , Receptors, Chemokine/genetics , AIDS-Related Opportunistic Infections/genetics , Cohort Studies , Genetic Predisposition to Disease , Homosexuality, Male , Humans , Male , Mutation , Receptors, CCR2
7.
Ann Intern Med ; 135(9): 782-95, 2001 Nov 06.
Article in English | MEDLINE | ID: mdl-11694103

ABSTRACT

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.


Subject(s)
Chemokines, CXC/genetics , HIV Infections/genetics , HIV-1 , Receptors, CCR5/genetics , Receptors, Chemokine/genetics , Acquired Immunodeficiency Syndrome/genetics , Acquired Immunodeficiency Syndrome/mortality , Alleles , Chemokine CXCL12 , Disease Progression , HIV-1/genetics , Heterozygote , Humans , Proportional Hazards Models , RNA/metabolism , Receptors, CCR2 , Regression Analysis
9.
AIDS ; 14(2): 103-8, 2000 Jan 28.
Article in English | MEDLINE | ID: mdl-10708279

ABSTRACT

OBJECTIVE: To determine the influence of CCR5 promoter polymorphisms on HIV-1 progression to AIDS and to evaluate the interaction between CCR5 structural polymorphisms and those occurring in the regulatory region of the same gene. PARTICIPANTS: Seventy-one HIV-1-infected long-term non-progressors with a CD4+ T cell count of > 500 x 10(6)/I more than 8 years after infection were compared with 75 HIV-1-infected individuals who had progressed to AIDS and/or death within 8 years and with a further 119 HIV-1-positive patients who had CD4+ T cell counts of 200-500 x 10(6)/l. An additional 92 HIV-negative individuals were also studied. METHODS: CCR5 delta32 genotype was determined by PCR with primers spanning the 32 base pair deletion. CCR2-64I, CCR5 59029A/G and CCR5 59353C/T genotypes were determined by PCR followed by restriction fragment length polymorphism analysis. RESULTS: Strong linkage disequilibrium between the CCR5 59029A and CCR5 59353C polymorphic variants was identified. CCR5 59029A and CCR5 59353C homozygotes were found to be significantly under-represented in the long-term non-progressor group as compared with the other HIV-1-positive groups, with the effect being more marked in the absence of the CCR5 delta32 and CCR2 64I mutations. CONCLUSIONS: This study provides the first evidence for an association between CCR5 promoter polymorphisms and long-term asymptomatic HIV-1 infection, with individuals lacking the CCR5 59029A/CCR5 59353C homozygous genotype likely to progress more slowly towards AIDS and/or death.


Subject(s)
Acquired Immunodeficiency Syndrome/genetics , HIV-1 , Receptors, CCR5/genetics , Receptors, Chemokine , Genotype , HIV Long-Term Survivors , Heterozygote , Homozygote , Humans , Mutation , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Promoter Regions, Genetic , Prospective Studies , Receptors, CCR2 , Receptors, Cytokine/genetics
10.
Hum Immunol ; 61(2): 172-6, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10717811

ABSTRACT

The host and viral factors that underlie infection with HIV-1 vary considerably with some individuals progressing to AIDS within 3 to 5 years after infection, whereas others remain clinically asymptomatic for over 10 years. Host factors that may contribute to disease progression include HLA and allelic variants of the chemokine receptors CCR5 and CCR2, which have been shown to influence both long-term survival and rapid progression. In this study, we have examined the contribution of HLA and polymorphisms in CCR5 and CCR2 to long-term survival in transfusion-acquired HIV-1-infected individuals. We have found a higher number of HLA-A32 and -A25 alleles but a lower number of the HLA-B8 allele in the study group compared with the frequencies seen in the HIV-1-negative Australian caucasian population. However, there was no apparent contribution by allelic variants of CCR5 and CCR2 to long-term survival and the combined influence of HLA and CCR polymorphisms could not be evaluated in this relatively small (n = 20) group of study subjects. The results of this work support a role for HLA in long-term nonprogression though the presence in the Sydney Blood bank Cohort of nef-defective HIV-1 may confound associations between certain HLA alleles and long-term survival in the face of infection with HIV-1.


Subject(s)
HIV Infections/virology , HIV-1 , HLA Antigens/genetics , Transfusion Reaction , Adult , Aged , Alleles , CD4-CD8 Ratio , Disease Progression , Female , Genes, MHC Class I/genetics , Genotype , HIV Infections/genetics , HIV Infections/immunology , HIV Long-Term Survivors , HLA Antigens/immunology , Histocompatibility Testing , Humans , Male , Middle Aged , Polymorphism, Genetic , Receptors, Chemokine/genetics , Viral Load
11.
AIDS Res Hum Retroviruses ; 15(17): 1519-27, 1999 Nov 20.
Article in English | MEDLINE | ID: mdl-10580402

ABSTRACT

Members of the Sydney Blood Bank Cohort (SBBC) have been infected with an attenuated strain of HIV-1 with a natural nef/LTR mutation and have maintained relatively stable CD4+ T lymphocyte counts for 14-18 years. Flow cytometric analysis was used to examine the phenotype of CD4+ and CD8+ T lymphocytes in these subjects, including the immunologically important naive (CD45RA+CD62L+), primed (CD45RO+), and activated (CD38+HLA-DR+ and CD28-) subsets. The median values were compared between the SBBC and control groups, comprising age-, sex-, and transfusion-matched HIV-1-uninfected subjects; transfusion-acquired HIV-1-positive LTNPs; and sexually acquired HIV-1-positive LTNPs. Members of the SBBC not only had normal levels of naive CD4+ and CD8+ T lymphocytes, but had primed CD45RO+ CD4+ T lymphocytes at or above normal levels. Furthermore, these primed cells expressed markers suggesting recent exposure to specific antigen. SBBC members exhibited variable activation of CD8+ T lymphocytes. In particular, SBBC members with undetectable plasma HIV-1 RNA had normal levels of activated CD8+ T lymphocytes. Therefore, the result of long-term infection with natural nef/LTR mutant HIV-1 in these subjects suggests a decreased cytopathic effect of attenuated HIV-1 on susceptible activated CD4+ T lymphocyte subsets in vivo, and minimal activation of CD8+ T lymphocytes.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Defective Viruses/genetics , Genes, nef/genetics , HIV Infections/immunology , HIV-1/genetics , Adult , Aged , Aged, 80 and over , Antigens, Surface/analysis , CD4-CD8 Ratio , Cohort Studies , Cross-Sectional Studies , Defective Viruses/immunology , Female , Follow-Up Studies , HIV Infections/virology , HIV-1/immunology , Humans , Longitudinal Studies , Lymphocyte Count , Male , Middle Aged , Polymerase Chain Reaction , RNA, Viral/blood
12.
N Engl J Med ; 340(22): 1715-22, 1999 Jun 03.
Article in English | MEDLINE | ID: mdl-10352163

ABSTRACT

BACKGROUND AND METHODS: The Sydney Blood Bank Cohort consists of a blood donor and eight transfusion recipients who were infected before 1985 with a strain of human immunodeficiency virus type 1 (HIV-1) with a deletion in the region in which the nef gene and the long terminal repeat overlap. Two recipients have died since 1994, at 77 and 83 years of age, of causes unrelated to HIV infection; one other recipient, who had systemic lupus erythematosus, died in 1987 at 22 years of age of causes possibly related to HIV. We present longitudinal immunologic and virologic data on the six surviving members and one deceased member of this cohort through September 30, 1998. RESULTS: The five surviving recipients remain asymptomatic 14 to 18 years after HIV-1 infection without any antiretroviral therapy; however, the donor commenced therapy in February 1999. In three recipients plasma concentrations of HIV-1 RNA are undetectable (<200 copies per milliliter), and in two of these three the CD4 lymphocyte counts have declined by 9 and 30 cells per cubic millimeter per year (P=0.3 and P=0.5, respectively). The donor and two other recipients have median plasma concentrations of HIV-1 RNA of 645 to 2850 copies per milliliter; the concentration has increased in the donor (P<0.001). The CD4 lymphocyte counts in these three cohort members have declined by 16 to 73 cells per cubic millimeter per year (P<0.001). In the recipient who died after 12 years of infection, the median plasma concentration of HIV-1 RNA was 1400 copies per milliliter, with a decline in CD4 lymphocyte counts of 17 cells per cubic millimeter per year (P=0.2). CONCLUSIONS: After prolonged infection with this attenuated strain of HIV-1, there is evidence of immunologic damage in three of the four subjects with detectable plasma HIV-1 RNA. The CD4 lymphocyte counts appear to be stable in the three subjects in whom plasma HIV-1 RNA remains undetectable.


Subject(s)
Genes, nef , HIV Infections/immunology , HIV Infections/virology , HIV-1/classification , HIV-1/genetics , Adult , Aged , Aged, 80 and over , CD4 Lymphocyte Count/drug effects , Disease Progression , Female , HIV Infections/mortality , HIV Long Terminal Repeat/genetics , HIV-1/isolation & purification , Humans , Longitudinal Studies , Male , Middle Aged , Mutation , RNA, Viral/blood , Viral Load
13.
AIDS Res Hum Retroviruses ; 14(2): 117-21, 1998 Jan 20.
Article in English | MEDLINE | ID: mdl-9462921

ABSTRACT

It is now apparent that a proportion of individuals (5-8%) remains clinically free of HIV-1 disease with normal levels of CD4+ lymphocytes (> or =500/microl) for more than 8 years following infection. However, the proportion of these individuals who ultimately progress to AIDS remains to be established. We determined the virological and immunological characteristics of a cohort of long-term nonprogressors in Australia and examined the role of these factors in predicting disease progression. Individuals with documented asymptomatic HIV-1 infection for at least 8 years with CD4+ lymphocyte counts >500 cells/microl were recruited from hospital clinics and general practices serving the eastern area of Australia. CD4+ lymphocyte count, rate of CD4+ lymphocyte change, CD8+ lymphocyte count, beta2-microglobulin, immune complex dissociated (ICD) HIV-1 p24 antigen, and plasma HIV-1 RNA were measured at baseline and multiple visits at 6-month intervals over an average period of 2 years. Up to November 1996, 67 study participants were recruited, of whom 72% had been infected with HIV-1 for at least 10 years. HIV-1 RNA correlated with beta2-microglobulin, ICD p24 antigen, and the ability to isolate virus in culture but not with levels of CD4+ or CD8+ lymphocytes. Serum beta2-microglobulin was a stronger predictor of CD4+ lymphocyte decline than HIV-1 RNA and the only factor significantly associated with CD4+ lymphocyte decline. These findings show that the serum concentration of beta2-microglobulin is a strong predictor of immunological progression in people with long-term asymptomatic HIV-1 infection and provides additional prognostic information to HIV-1 RNA in determining the risk of disease progression.


Subject(s)
HIV Infections/physiopathology , HIV-1 , Adolescent , Adult , Aged , CD4 Lymphocyte Count , Cohort Studies , Disease Progression , Female , HIV Core Protein p24/analysis , HIV Infections/immunology , HIV Infections/virology , Humans , Male , Middle Aged , Predictive Value of Tests , RNA, Viral , Time Factors , beta 2-Microglobulin/analysis
14.
AIDS ; 11(15): 1833-8, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9412701

ABSTRACT

BACKGROUND: The beta-chemokine receptor CCR-5 is used as a coreceptor by macrophage-tropic strains of HIV-1 to gain entry into CD4+ cells. OBJECTIVE: To determine the effect of a common 32 base-pair deletion mutation in the CCR-5 gene (CCR-5 delta 32) on progression of HIV infection to AIDS, and to assess the level of heterozygosity for this mutation in a well-defined group of long-term non-progressors (LTNP). PARTICIPANTS: Sixty-four HIV-1-infected LTNP (CD4+ T lymphocyte count > 500 x 10(6)/l after 8 years) were compared with 95 individuals infected within a similar period (1983-1986) but who had rapidly progressed to AIDS and death, and with a further 120 HIV-positive individuals with CD4+ counts < 500 x 10(6)/l. METHODS: The presence of the CCR-5 delta 32 mutation was assessed using polymerase chain reaction with primers spanning the 32 base-pair deletion. CD4+ and CD8+ counts, plasma HIV-1 RNA, p24 antigen and beta 2-microglobulin levels in LTNP carrying the CCR-5 delta 32 mutation were compared with LTNP lacking the mutation. RESULTS: A marked increase in the frequency of CCR-5 delta 32 heterozygosity was found among LTNP (35.9%) compared with rapid progressors (12.6%; P = 0.0005) and patients selected on the basis of a CD4+ T-cell count < 500 x 10(6)/l (12.5%; P = 0.0004). LTNP heterozygous for CCR-5 delta 32 had a significantly higher CD8+ T-cell count than those without the mutation (1218 versus 972 x 10(6)/l; P = 0.044). No significant correlation was observed between heterozygosity and CD4 count, viral load, p24 antigen or beta 2-microglobulin within the LTNP group. CONCLUSIONS: This study provides the strongest evidence to date for the importance of a single copy of the CCR-5 delta 32 mutation in long-term non-progression of HIV infection, which may involve, in part, CD8+ T lymphocytes.


Subject(s)
HIV Infections/metabolism , Heterozygote , Receptors, CCR5/genetics , Disease Progression , Gene Frequency , Genotype , HIV Infections/genetics , HIV Infections/physiopathology , Humans , Survivors , Time Factors
15.
Lancet ; 344(8924): 718-20, 1994 Sep 10.
Article in English | MEDLINE | ID: mdl-7915778

ABSTRACT

From a registry of people with transfusion-acquired HIV infection, 25 recipients were identified for whom the dates of HIV infection in the 8 corresponding donors could be established. Longer times to AIDS and to death in recipients were independently associated (p < 0.01) with the receipt of blood from donors who developed AIDS more than 10 years after HIV infection, as well as with older age and fewer transfusions. Sex, zidovudine treatment, and severity of illness at transfusion were not significantly associated with survival.


Subject(s)
Acquired Immunodeficiency Syndrome/physiopathology , Blood Component Transfusion/adverse effects , Blood Donors , Blood-Borne Pathogens , HIV Infections/transmission , Acquired Immunodeficiency Syndrome/mortality , Adolescent , Adult , Female , Follow-Up Studies , HIV Infections/drug therapy , HIV Infections/physiopathology , Humans , Male , Middle Aged , Multivariate Analysis , Prognosis , Survival Analysis , Time Factors , Zidovudine/therapeutic use
16.
Biochem Med Metab Biol ; 47(3): 211-20, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1627351

ABSTRACT

Mucopolysaccharidosis type I (MPS I: McKusick 25280) is a clinically heterogenous lysosomal storage disorder which is caused by a variable deficiency in alpha-L-iduronidase activity (alpha-L-iduronide iduronohydrolase, EC 3.2.1.76). Cultured fibroblasts from an MPS I patient (cell line 2827) with a severe clinical phenotype (Hurler syndrome) have been characterized using immunochemical and biochemical techniques. Using a specific immunoquantification assay, we have demonstrated that cell line 2827 had an alpha-L-iduronidase protein content (189 ng/mg of extracted cell protein) at least six times greater than the mean level found in normal control fibroblasts (30 ng/mg of extracted cell protein). This was the only MPS I cell line, from a group of 23 MPS I patients, that contained greater than 7% of the mean level of alpha-L-iduronidase protein detected in normal controls. Cell line 2827 had very low alpha-L-iduronidase activity toward the fluorogenic substrate 4-methylumbelliferyl-alpha-L-iduronide, and a radiolabeled disaccharide substrate derived from heparin. Maturation studies of alpha-L-iduronidase in cell line 2827 showed apparently normal levels of alpha-L-iduronidase synthesis with delayed processing to the mature form. Subcellular fractionation experiments demonstrated alpha-L-iduronidase protein in lysosomal-enriched fractions isolated from cell line 2827, suggesting a normal cell distribution and supporting the proposed delayed processing. It is proposed that the MPS I patient described has an alpha-L-iduronidase gene mutation which affects both the active site and post-translational processing of the enzyme. This mutation must be structurally conservative because it does not result in instability either during maturation or in the lysosome.


Subject(s)
Iduronidase/analysis , Mucopolysaccharidosis I/metabolism , Proteins/analysis , Cells, Cultured , Child, Preschool , Fibroblasts/metabolism , Humans , Lysosomes/enzymology , Male , Subcellular Fractions/metabolism
17.
Am J Hum Genet ; 50(4): 787-94, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1550122

ABSTRACT

alpha-L-Iduronidase activity is deficient in mucopolysaccharidosis type I (MPS I; Hurler syndrome, Scheie syndrome) patients and results in the disruption of the sequential degradation of the glycosaminoglycans dermatan sulfate and heparan sulfate. A monoclonal antibody-based immunoquantification assay has been developed for alpha-L-iduronidase, which enables the detection of at least 16 pg alpha-L-iduronidase protein. Cultured human skin fibroblasts from 12 normal controls contained 17-54 ng alpha-L-iduronidase protein/mg extracted cell protein. Fibroblasts from 23 MPS I patients were assayed for alpha-L-iduronidase protein content. Fibroblast extracts from one MPS I patient contained at least six times the level of alpha-L-iduronidase protein for normal controls--but contained no associated enzyme activity--and is proposed to represent a mutation affecting the active site of the enzyme. Fibroblast extracts from 11 MPS I patients contained 0.05-2.03 ng alpha-L-iduronidase protein/mg extracted cell protein, whereas immunodetectable protein could not be detected in the other 11 patients. Four fibroblast extracts with no immunodetectable alpha-L-iduronidase protein had residual alpha-L-iduronidase activity, suggesting that the mutant alpha-L-iduronidase in cultured cells from these MPS I patients has been modified to mask or remove the epitopes detected by two monoclonal antibodies used in the quantification assay. Both the absence of immunoreactivity in a mild MPS I patient and high protein level in a severe MPS I patient present limitations to the use of immunoquantification analysis as a sole measure of patient phenotype. Enzyme kinetic analysis of alpha-L-iduronidase from MPS I fibroblasts revealed a number of patients with either abnormal substrate binding or catalytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Iduronidase/analysis , Mucopolysaccharidosis I/enzymology , Antibodies, Monoclonal , Cells, Cultured , Fibroblasts/enzymology , Humans , Iduronidase/immunology
18.
Am J Hum Genet ; 48(4): 710-9, 1991 Apr.
Article in English | MEDLINE | ID: mdl-1901688

ABSTRACT

A sensitive and specific, monoclonal antibody-based immunoquantification assay has facilitated determination of the N-acetylgalactosamine-4-sulfatase (4-sulfatase) protein content in cultured fibroblasts from normal controls and mucopolysaccharidosis type VI (MPS VI) patients. The assay enabled the quantification of 4-sulfatase protein by using a panel of seven monoclonal antibodies and has shown that fibroblasts from 16 MPS VI patients contained less than or equal to 5% of the level determined for normal controls. Fibroblasts from the most severely affected patients contained the lowest levels of 4-sulfatase protein, usually with few epitopes detected, while fibroblasts from mildly affected patients had higher levels of 4-sulfatase protein, with all seven epitopes detected. The pattern of epitope expression is proposed to reflect the conformational changes in the 4-sulfatase protein that arise from different mutations in the 4-sulfatase gene. Immunoquantification in combination with a specific and highly sensitive 4-sulfated trisaccharide-based assay of enzyme activity in these MPS VI patient fibroblasts enabled the determination of residual 4-sulfatase catalytic efficiency (kcat/Km). The capacity of fibroblasts to degrade substrate (catalytic capacity) was calculated as the product of 4-sulfatase catalytic efficiency and the content of 4-sulfatase in fibroblasts. One patient, 2357, with no clinical signs of MPS VI but with reduced 4-sulfatase activity and protein (both 5% of normal) and dermatansulfaturia, had 5% of normal catalytic capacity. The other 15 MPS VI patient fibroblasts had 0%-1.4% of the catalytic capacity of fibroblasts from normal controls and were representative of the spectrum of MPS VI clinical phenotypes, from severe to mild.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Chondro-4-Sulfatase/metabolism , Mucopolysaccharidoses/genetics , Antibodies, Monoclonal , Cells, Cultured , Chondro-4-Sulfatase/genetics , Chondro-4-Sulfatase/immunology , Dermatan Sulfate/urine , Enzyme-Linked Immunosorbent Assay , Fibroblasts/enzymology , Humans , Kinetics , Mucopolysaccharidoses/enzymology , Phenotype , Reagent Kits, Diagnostic , Substrate Specificity
19.
Am J Hum Genet ; 47(5): 802-7, 1990 Nov.
Article in English | MEDLINE | ID: mdl-2220820

ABSTRACT

The lysosomal hydrolase alpha-L-iduronidase (IDUA) is one of the enzymes in the metabolic pathway responsible for the degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. In humans a deficiency of IDUA leads to the accumulation of glycosaminoglycans, resulting in the lysosomal storage disorder mucopolysaccharidosis type I. A genomic subclone and a cDNA clone encoding human IDUA were used to localize IDUA to chromosome 4p16.3 by in situ hybridization and this was confirmed by Southern blot analysis. This localization is different from that of a previous report mapping IDUA to chromosome 22 and places the gene for IDUA in the same region of chromosome 4 as the Huntington disease gene. Measurement of expressed human IDUA activity in human-mouse hybrid cell lines confirmed that IDUA is on chromosome 4.


Subject(s)
Chromosomes, Human, Pair 4 , Iduronidase/genetics , Animals , Antibodies, Monoclonal/immunology , Cell Line , Chromosome Mapping , Chromosomes, Human, Pair 22 , DNA Probes , Humans , Hybrid Cells/metabolism , Iduronidase/immunology , Mice
20.
Tissue Antigens ; 7(1): 1-14, 1976 Jan.
Article in English | MEDLINE | ID: mdl-56057

ABSTRACT

H-2 alloantisera contain Ia antibodies whose detection is obscured by the presence of serodominant K,D specificities. A method is described whereby Ia antisera can be prepared by absorbing conventional H-2 sera with donor-strain erythrocytes. The analysis of such absorbed antisera has led to the identification of the new specificity Ia.16, and the redefinition of the specificities H-2.34 and H-2.46 as complex Ia specificities which map in the I-A region of the H-2 complex. A number of other so-called H-2 specificities also appear to have Ia-like properties.


Subject(s)
Antibodies/analysis , Blood Group Antigens , Erythrocytes/immunology , Histocompatibility Antigens , I Blood-Group System , Animals , Epitopes , Haploidy , Immune Sera , Mice , Mice, Inbred Strains , Spleen/immunology
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