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Biomedical subjects

N J Nagelkerke

Publications and source records attributed to N J Nagelkerke.

At least 19 recordsLinked to original sources
PubMed2006

Host genetics of Bordetella pertussis infection in mice: significance of Toll-like receptor 4 in genetic susceptibility and pathobiology.

The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-gamma) production. TNF-alpha expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-beta, TNF-alpha, and IFN-gamma response; efficient clearance of bacteria from the lung; and reduced lung pathology.

Animals↗
PubMed2005

Genetic control of Bordetella pertussis infection: identification of susceptibility loci using recombinant congenic strains of mice.

Susceptibility to and severity of Bordetella pertussis infection in infants and children vary widely. The spectrum of clinical symptoms ranges from subclinical infection to mild disease, severe whooping cough, and death. The aims of this study were to examine genetic susceptibilities of mice to B. pertussis and to identify genetic loci in the mouse genome that are involved in susceptibility to B. pertussis infection. For this purpose we screened two sets of recombinant congenic strains (RCS) of mice, HcB and CcS, for differences in the numbers of bacteria in the lung 7 days after inoculation. For both CcS and in HcB mice, a wide range in numbers of bacteria in the lung was found, suggesting that the course of infection is under multigenic control. From both RCS sets of mice, we selected one strain to identify possible susceptibility loci in F(2) hybrid mice. The degree of lung colonization 7 days postinoculation in these F(2) mice was evaluated in relation to genetic markers by linkage analysis. We found three novel loci that are involved in the control of B. pertussis infection. One locus, designated B. pertussis susceptibility locus 1 (Bps-1), was identified on chromosome 12. The presence of the C57BL/10 genome on this locus instead of the C3H genome significantly decreased the number of B. pertussis bacteria in the lung. Bps-1 has a dominant-positive effect on the clearance of B. pertussis from the lung. The function of most genes in this region is unknown. Two other loci, Bps-2 and Bps-3, showed genetic interaction and are located on chromosomes 5 and 11. We aim to identify the gene(s) in these regions which modify susceptibility to B. pertussis.

Animals↗
PubMed2001

Transmission of Mycobacterium tuberculosis depending on the age and sex of source cases.

This study estimated to what extent tuberculosis transmission in the Netherlands depends on the age and sex of source cases. DNA fingerprints of Mycobacterium tuberculosis isolates were matched to patient information in the Netherlands Tuberculosis Register for 1993-1998. Clusters were defined as groups of patients with pulmonary tuberculosis whose isolates had identical DNA fingerprints. Source cases were assigned by using two models. The first-case model assumed that the first diagnosed case was the source case. The incidence rate model estimated source case probabilities from the incidence rates of potential source cases and the time of diagnosis. DNA fingerprints of 6,102 isolates were matched to patient information on 5,080 (83%) cases, 3,479 of whom had pulmonary disease. According to both models, the number of infectious cases generated per source case was lower for female than for male source cases and decreased with increasing age of the source case. The authors concluded that transmission of tuberculosis is associated with the age and sex of source cases as well as the age of secondary cases. Increased transmission among immigrant groups in the Netherlands is largely attributable to the relatively young age of immigrant source cases.

Adult↗
PubMed2001

Macrofilaricides and onchocerciasis control, mathematical modelling of the prospects for elimination.

BACKGROUND: In most endemic parts of the world, onchocerciasis (river blindness) control relies, or will soon rely, exclusively on mass treatment with the microfilaricide ivermectin. Worldwide eradication of the parasite by means of this drug is unlikely. Macrofilaricidal drugs are currently being developed for human use. METHODS: We used ONCHOSIM, a microsimulation mathematical model of the dynamics of onchocerciasis transmission, to explore the potentials of a hypothetical macrofilaricidal drug for the elimination of onchocerciasis under different epidemiological conditions, as characterized by previous intervention strategies, vectorial capacity and levels of coverage. RESULTS: With a high vector biting rate and poor coverage, a very effective macrofilaricide would appear to have a substantially higher potential for achieving elimination of the parasite than does ivermectin. CONCLUSIONS: Macrofilaricides have a substantially higher potential for achieving onchocerciasis elimination than ivermectin, but high coverage levels are still key. When these drugs become available, onchocerciasis elimination strategies should be reconsidered. In view of the impact of control efforts preceding the introduction of macrofilaricides on the success of elimination, it is important to sustain current control efforts.

Animals↗
PubMed2001

Human leucocyte antigen supertypes and immune susceptibility to HIV-1, implications for vaccine design.

T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22-0.81, P=0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03-0.54, P=0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed 'supertopes'), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

AIDS Vaccines↗
PubMed2001

Logistic discrimination of mixtures of M. tuberculosis and non-specific tuberculin reactions.

Interpretation of the Mantoux test for tuberculous infection can be complicated by cross-reactions caused by infection with non-specific mycobacteria. Thus, the distribution of positive indurations is a mixture of two distributions. To estimate tuberculous infection prevalence, the marginal distribution of indurations needs to be separated into its component distributions. Observations from several populations with different mixes of the two types of infection are required. Homogeneity across populations of distributions of indurations for each type of infection is assumed. A logistic model is specified for the probability of having tuberculous infection conditional on the observed induration size. No other assumptions about the two distributions are made. Maximum likelihood is used to estimate the logistic function. Goodness-of-fit criteria are discussed. The method is applied to a series of tuberculin surveys carried out in (South) Korea. Estimated infection prevalence agrees reasonably well with several ad hoc criteria. The goodness-of-fit test rejects underlying assumptions of homogeneity. One reason appears to be a decline over time in induration sizes caused by tuberculous infection. However, not all reasons for this rejection are obvious. The proposed method of mixture analysis provides an additional tool for the interpretation of prevalence survey data where the diagnostic test lacks specificity as a result of cross-reactions.

Adolescent↗
PubMed2001

Vitamin A and risk of HIV-1 seroconversion among Kenyan men with genital ulcers.

BACKGROUND: Vitamin A is involved in normal immune function and the maintenance of mucosal integrity through complex effects on cellular differentiation. OBJECTIVE: We sought to determine whether serum vitamin A levels were associated with altered susceptibility to primary infection with HIV-1 in men with high-risk sexual behaviour and genital ulcers who presented for treatment at an STD clinic in Nairobi, Kenya. METHODS: HIV-1 seronegative men were prospectively followed. Vitamin A levels at study entry were compared among 38 men who HIV-1 seroconverted versus 94 controls who remained HIV seronegative. RESULTS: Vitamin A deficiency (retinol less than 20 microg/dl) was very common and was present in 50% of HIV-1 seroconverters versus 76% of persistent seronegatives. Seroconversion was independently associated with a retinol level greater than 20 microg/dl (HR 2.43, 95% CI 1.25-4.70, P = 0.009), and a genital ulcer aetiology caused by Haemophilus ducreyi (HR 3.49, 95% CI 1.03-11.67, P = 0.04). Circumcision was independently associated with protection (HR 0.46, 95% CI 0.23-0.93, P = 0.03). CONCLUSION: Vitamin A deficiency was not associated with an increased risk of HIV-1 infection among men with concurrent STD. A decreased risk of HIV-1 seroconversion was independently associated with lower retinol levels. The effects of vitamin A on macrophage and lymphoid cell differentiation may paradoxically increase mucosal susceptibility to HIV-1 in some vulnerable individuals, such as men with genital ulcers. Lack of circumcision and chancroid are confirmed as important co-factors for heterosexual HIV-1 transmission. The role of vitamin A in heterosexual HIV-1 transmission requires further study.

Adult↗
PubMed2001

Estimating the magnitude of STD cofactor effects on HIV transmission: how well can it be done?

BACKGROUND: If sexually transmitted disease (STD) cofactor effects are strong and STDs are highly prevalent, STD control can be a strategy for HIV prevention. OBJECTIVE: To review possibilities for estimating cofactor effects of STDs on HIV transmission based on observational studies. STUDY DESIGN: This study consisted of an analysis of factors influencing associations between HIV and STDs, which can bias STD cofactor studies, from a sexual network perspective. Study designs that reduce distortions and methods to improve estimates in the presence of confounding are discussed. RESULTS: Standard statistical adjustments of cofactor estimates are insufficient because they ignore clustering between HIV and STDs in partners of study subjects, resulting from population heterogeneity in risk factors and assortative mixing. Reverse causation due to HIV-related immunosuppression may further inflate cofactor estimates. Misclassification of STDs and clustering between STDs can bias estimates in either direction. This study demonstrates quantitatively that ignorance of sexual network effects may result in considerable overestimation of cofactor magnitudes. CONCLUSION: The limitations of observational studies complicate quantitative inferences on the role of STDs in HIV transmission.

Confounding Factors, Epidemiologic↗
PubMed2000

The HLA A2/6802 supertype is associated with reduced risk of perinatal human immunodeficiency virus type 1 transmission.

Certain HLAs may, in part, account for differences in human immunodeficiency virus type 1 (HIV-1) susceptibility by presenting conserved immunogenic epitopes for T cell recognition. The HLA supertype A2/6802 is associated with decreased susceptibility to HIV-1 among sex workers. The alleles in this supertype present the same HIV-1 peptide epitopes for T cell recognition in some cases. This study sought to determine whether the HLA A2/6802 supertype influenced HIV-1 transmission in a prospective cohort of HIV-1-infected mothers and children in Kenya. Decreased perinatal HIV-1 infection risk was strongly associated with possession of a functional cluster of related HLA alleles, called the A2/6802 supertype (odds ratio, 0.12; 95% confidence interval, 0.03-0.54; P=.006). This effect was independent of the protective effect of maternal-child HLA discordance. These data provide further evidence that HLA supertypes are associated with differential susceptibility to HIV-1 transmission.

Adult↗
PubMed2000

Risk factors for postnatal mother-child transmission of HIV-1.

OBJECTIVE: To identify factors affecting HIV-1 breastfeeding transmission. DESIGN: Longitudinal observational cohort study. METHODS: HIV-1 seropositive pregnant women and seronegative controls were enrolled at a maternity hospital in Nairobi. Women and their children were followed from birth, and data on HIV-1 transmission, breastfeeding, clinical illness, and growth were collected. Specimens for HIV-1 serology and/or polymerase chain reaction were obtained at birth, 2, 6, and 14 weeks, 6, 9, 12, and 18 months, and every 6 months thereafter. Children were classified as HIV-1 uninfected, perinatally, or postnatally infected. Potentially breastfeeding transmission related risk factors were compared between postnatally infected and uninfected children. RESULTS: Among children born to seropositive or seroconverting mothers, 317 were uninfected, 51 infected perinatally and 42 infected postnatally. Identified risk factors for postnatal transmission were maternal nipple lesions (OR = 2.3, CI 95% 1.1-5.0), mastitis (OR = 2.7, CI 95% 1.1-6.7), maternal CD4 cell count < 400 mm3 (OR = 4.4, CI 95% 1.9-9.9), maternal seroconversion while breastfeeding (OR = 6.0, CI 95% 1.8-19.8), infant oral thrush at < 6 months of age (OR = 2.8, CI 95% 1.3-6.2) and breastfeeding longer than 15 months (OR = 2.4, CI 95% 1.2-5.1). All factors, except maternal seroconversion due to its rarity, were independently associated with an increased postnatal transmission risk by multivariate logistic regression analysis. CONCLUSION: In addition perinatal antiretroviral therapies, public health strategies should address: (i) prevention of maternal nipple lesions, mastitis and infant thrush; (ii) reduction of breastfeeding duration by all HIV-1-infected mothers; (iii) absolute avoidance of breastfeeding by those at high risk, and (iv) prevention of HIV-1 transmission to breastfeeding mothers.

Breast Feeding↗
PubMed2000

Acute sexually transmitted infections increase human immunodeficiency virus type 1 plasma viremia, increase plasma type 2 cytokines, and decrease CD4 cell counts.

In Kenya, the median incubation time to AIDS in seroconverting sex workers is 4 years; this incubation time is specific to female sex workers. We studied the influence of acute sexually transmitted infections (STIs) on several immunologic parameters in 32 human immunodeficiency virus type 1 (HIV-1)-positive and 10 HIV-1-negative women sex workers who were followed for 1-5 months. Plasma cytokines, soluble cytokine receptors, CD4 and CD8 T cell counts, and HIV-1 plasma viremia were quantitated before, during, and after episodes of STI. Increases in interleukin (IL)-4, IL-6, IL-10, soluble tumor necrosis factor (TNF)-alpha, and viremia and a decline in CD4(+) T cell counts occurred during gonococcal cervicitis and returned to baseline after treatment. Increases in viremia correlated with increased IL-4 and decreased IL-6 concentrations. Similar changes were seen among women with acute pelvic inflammatory disease. Acute bacterial STI resulted in increased HIV-1 viremia. This may be mediated through increased inflammatory cytokines or through modulation of immune responses that control HIV-1 viremia.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection.

Certain human leukocyte antigens, by presenting conserved immunogenic epitopes for T cell recognition, may, in part, account for the observed differences in human immunodeficiency virus type 1 (HIV-1) susceptibility. To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge. These data provide further evidence that resistance to HIV-1 infection in this cohort of sex workers is immunologically mediated.

Acquired Immunodeficiency Syndrome↗
PubMed2000

The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world. Seven Countries Study Research Group.

BACKGROUND: Elevated blood pressure is known to be a risk factor for death from coronary heart disease (CHD). However, it is unclear whether the risk of death from CHD in relation to blood pressure varies among populations. METHODS: In six populations in different parts of the world, we examined systolic and diastolic blood pressures and hypertension in relation to long-term mortality from CHD, both with and without adjustment for variability in blood pressure within individual subjects. Blood pressure was measured at base-line in 12,031 men (age range, 40 to 59 years) who were free of CHD. During 25 years of follow-up, 1291 men died from CHD. RESULTS: At systolic and diastolic blood pressures of about 140 and 85 mm Hg, respectively, 25-year rates of mortality from CHD (standardized for age) varied by a factor of more than three among the populations. Rates in the United States and northern Europe were high (approximately 70 deaths per 10,000 person-years), but rates in Japan and Mediterranean southern Europe were low (approximately 20 deaths per 10,000 person-years). However, the relative increase in 25-year mortality from CHD for a given increase in blood pressure was similar among the populations. The overall unadjusted relative risk of death due to CHD was 1.17 (95 percent confidence interval, 1.14 to 1.20) per 10 mm Hg increase in systolic pressure and 1.13 (95 percent confidence interval, 1.10 to 1.15) per 5 mm Hg increase in diastolic pressure, and it was 1.28 for each of these increments after adjustment for within-subject variability in blood pressure. CONCLUSIONS: Among the six populations we studied, the relative increase in long-term mortality due to CHD for a given increase in blood pressure is similar, whereas the absolute risk at the same level of blood pressure varies substantially. If the absolute risk of CHD is used as an indication for antihypertensive therapy, these findings will have major implications for treatment in different parts of the world.

Adult↗
PubMed2000

Estimating the prevalence of hypertension corrected for the effect of within-person variability in blood pressure.

The objective of our study was to assess the applicability of using estimates of within-person variance (WPV) from reproducibility studies for a correction of blood pressure values in another study to improve the accuracy of the prevalence estimation of hypertension. Data were collected from two cross-sectional population-based studies on cardiovascular disease risk factors conducted from 1987 to 1995 among 55,026 subjects aged 20-59 years. Correction factors were calculated from a reproducibility study among 924 subjects who were examined in 1989 and 1990. All other studies with repeated measurements of blood pressure were searched in MEDLINE from 1966 onward. Six studies satisfied the inclusion criteria. The prevalence of hypertension, uncorrected and corrected with factors from other studies, were compared with the prevalence of hypertension corrected with the factor from our study. The uncorrected prevalence of hypertension was 17.3% [95%CI:17.0-17.7]. The prevalence of hypertension after correction for WPV with the factor from our study was 13.5% [95%CI:13.2-13.8]. Correction for WPV with factors from the appropriate studies (depending on factors such as number of measurements taken per visit, and time interval between visits) resulted in prevalences ranging from 13.9% to 14.7%. The bias that occurs when no correction for WPV is performed is much larger (29% overestimation) than the bias that occurs when correction factors are derived from other studies (3.1-8.4% overestimation). When repeated measurements of blood pressure are not available in a population study for a sample of that same study, it is advisable to use data from another study to correct for WPV.

Adult↗
PubMed2000

Influence of correction for within-person variability in blood pressure on the prevalence, awareness, treatment, and control of hypertension.

We assessed the influence of correction for within-person variability (WPV) on the prevalence, awareness, treatment, and control of hypertension. Data were collected from two cross-sectional population-based studies on cardiovascular disease risk factors from 1987 to 1995 among 56,026 subjects aged 20 to 59 years. Correction factors were calculated from an internal reproducibility study among 924 subjects who were examined in 1989 and 1990. The prevalence of hypertension without a correction of blood pressure values for WPV was substantially overestimated (38%), whereas the prevalence of awareness and treatment of hypertension were substantially underestimated (-13% and -28%). The prevalence of control of hypertension did not change much after this correction. It may be advisable to perform a correction for within-person variability to obtain valid prevalence estimates in surveys that only take one or two measurements of blood pressure.

Adult↗
PubMed2000

Defaulting from tuberculosis treatment in The Netherlands: rates, risk factors and trend in the period 1993-1997.

The aim of this study was to assess the rate of defaulting from treatment among tuberculosis patients diagnosed in the Netherlands in the period 1993-1997, whether risk groups for defaulting can be identified at the start of treatment and the trend of defaulting over time. The Netherlands Tuberculosis Register provided data on all patients diagnosed in the Netherlands during the period 1993-1997. Defaulting probabilities were determined using Kaplan-Meier survival analysis and risk factors were identified with Cox's proportional hazard analysis. Of 7,529 patients with reported treatment outcome, 718 (10%) defaulted or left the country within 1 yr after starting treatment. Defaulting probabilities were 9% (95% confidence interval (CI) 8-10%) among 5,256 patients in low-risk groups, 17% (95% CI 14-19%) among 1,437 asylum seekers and 29% (95% CI 24-34%) among 836 patients in other high-risk groups (other recent immigrants, illegal immigrants, the homeless, prisoners and nationals from Eastern Europe). Defaulting probabilities decreased over time from 12% in 1993 to 7% in 1997. Risk groups for defaulting can be recognized at the start of treatment. The decreasing defaulting probabilities were probably due in part to shortening treatment from 9 to 6 months and improved follow-up of asylum seekers. However, additional measures are needed to reduce defaulting among the homeless, recent immigrants, illegal immigrants and prisoners.

Adult↗
PubMed2000

HIV-1-specific cellular immune responses among HIV-1-resistant sex workers.

The goal of the present study was to determine whether there were HIV-1 specific cellular immune responses among a subgroup of women within a cohort of Nairobi prostitutes (n = 1800) who, despite their intense sexual exposure to HIV-1, are epidemiologically resistant to HIV-1 infection. Of the 80 women defined to be resistant, 24 were recruited for immunological evaluation. The HIV-1-specific T-helper responses were determined by IL-2 production following stimulation with HIV-1 envelope peptides and soluble gp120. Cytotoxic T lymphocyte responses were determined by lysis of autologous EBV-transformed B cell lines infected with control vaccinia virus or recombinant vaccinia viruses containing the HIV-1 structural genes env, gag and pol. Resistant women had significantly increased HIV-1 specific T-helper responses, as determined by in vitro IL-2 production to HIV-1 envelope peptides and soluble glycoprotein 120, compared with low-risk seronegative and HIV-1-infected controls (P < or = 0.01, Student's t-test). Seven of the 17 (41%) resistant women showed IL-2 stimulation indices > or = 2.0. HIV-1-specific CTL responses were detected among 15/22 (68.2%) resistant women compared with 0/12 low-risk controls (Chi-squared test, P < 0.001). In the two resistant individuals tested, the CTL activity was mediated by CD8+ effectors. Many HIV-1-resistant women show evidence of HIV-1-specific T-helper and cytotoxic responses. These data support the suggestion that HIV-1-specific T-cell responses contribute to protection against HIV-1 infection.

Adult↗