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Biomedical subjects

C A McKenzie

Publications and source records attributed to C A McKenzie.

At least 19 recordsLinked to original sources

Predicted declines in sickle allele frequency in Jamaica using empirical data.

The high frequency of the sickle allele in some parts of Africa is understood to be a consequence of high malarial endemicity. One corollary of this is that the sickle allele frequency should be declining in populations of African ancestry that are no longer exposed to malaria. We have previously shown that there has been no change in sickle allele frequency in malaria-free Jamaica between two large-scale neonatal screening exercises conducted in 1973-1981 and 1995-2003. To evaluate the determinants of, and derive expected values for, sickle allele frequency in Jamaica, local empirical data were used to estimate the parameters of deterministic models of allele frequency decline. We found that although model predictions were broadly consistent with observed values in the 1973-1981 cohort, the predicted change in allele frequency between the two cohorts was larger than the observed, nonsignificant, reduction. Close agreement between predicted and observed values was only achieved by simulating a recent, marked increase in HbSS fitness. Thus, the "unexpected" persistence of the sickle allele in Jamaica may reflect the fact that the actual fitness among SS individuals is higher than that previously realized. If true, our models suggest that without substantial changes in current screening and counseling practice, there will be little "natural" reduction in sickle allele frequency for several hundred years. Better estimates of relative fitness will be helpful in refining these predictions and may aid in assigning health care priorities in Jamaica and the African Diaspora.

Alleles↗

SNP haplotypes in the angiotensin I-converting enzyme (ACE) gene: analysis of Nigerian family data using gamete competition models.

Gamete competition models were used to explore the relationships between 13 ACE gene polymorphisms and plasma ACE concentration in a set of Nigerian families. Several markers in the 5' and 3' regions of the gene were significantly associated with ACE concentration (P < 10(-4)). Multi-locus genotypes comprising different combinations of markers from the 5' UTR and the 3' region of the gene were also analysed; in addition to G2350A, in the 3' region, two markers from the 5' UTR (A-5466C and A-240T) were found to be associated with ACE concentration. These results are consistent with reports that have suggested the presence of at least two ACE-linked QTLs, and demonstrate the utility of gamete competition models in the exploratory investigation of the relationship between a quantitative trait and multiple variants in a small genomic region.

Adult↗

The frequency of the sickle allele in Jamaica has not declined over the last 22 years.

The 'malaria hypothesis' predicts that the frequency of the sickle allele, which is high in malaria-endemic African populations, should decline with each generation in populations of African descent living in areas where malaria is no longer endemic. In order to determine whether this has been the case in Jamaica, we compared haemoglobin electrophoresis results from two hospital-based screening programmes separated by more than 20 years (i.e. approximately one generation). The first comprised 100,000 neonates screened between 1973 and 1981, the second, 104,183 neonates screened between 1995 and 2003. The difference in frequency of the sickle allele was small (5.47% in the first cohort and 5.38% in the second screening cohort) and not significant (Z = 1.23, P = 0.22). The same was true of the sickle trait frequency (10.05% in the first cohort and 9.85% in the second, Z = 1.45, P = 0.15). These differences were smaller than predicted under simple deterministic models based on the malaria hypothesis, and suggest that these models may not capture important determinants of allele and trait frequency decline (or persistence) in contemporary populations. Refining the expectations for allele and trait frequency change for Jamaica and other similar populations is an area for future study.

Anemia, Sickle Cell↗

HIV serostatus and recovery from severe childhood malnutrition. A retrospective matched case-control study.

The world-wide epidemic of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) has led to an increase in the number of HIV positive children, mainly through perinatal transmission. HIV/AIDS can lead to severe childhood malnutrition (SCM) and has been noted as an increasingly common cause of secondary SCM. In this context, it is important to make assessments of the appropriateness of current approaches to treatment of severe malnutrition in HIV positive children. A retrospective matched case-control study of ten HIV positive children admitted to the Tropical Metabolism Research Unit (TMRU) was conducted. There were few differences between cases and matched controls on admission to the ward. Oral candidiasis and lower respiratory tract infections appeared to occur more frequently, and serum globulin concentrations were significantly higher among HIV positive cases when compared to their controls. Despite the fact that the differences between cases and controls appeared to be small, four cases died; there were no deaths among the controls. The duration of the maintenance phase was approximately five days longer (p = 0.024) among cases than controls but the time between the end of the maintenance phase and discharge from the ward was not significantly longer for the cases. The results of this matched case-control study suggest that there are likely to be important differences between HIV positive and negative patients with SCM that influence risk of mortality and morbidity, particularly in the maintenance phase of treatment. Prospective studies will be required in order to explore these differences and to develop better approaches to the care of HIV positive children with SCM.

AIDS-Related Opportunistic Infections↗

The "Nostocoida limicola" story: resolving the phylogeny of this morphotype responsible for bulking in activated sludge.

On the basis of 16S rRNA sequence analyses of several isolates of "Nostocoida limicola" from activated sludge plants in Australia and other countries, it is clear that "N. limicola" I, II and III are not three morphological variants of a single bacterium but at least three phylogenetically different bacteria. Data show that "N. limicola" I are members of at least two genera in the low mol% G+C gram-positive bacteria, while some isolates of "N. limicola" II belong to the high mol% G+C gram positive bacteria, and "N. limicola" III is a member of the Planctomycetales. Design and application of 16S rRNA targeted probes for each to biomass samples suggests that their phylogeny is more diverse than pure culture studies would suggest.

Biomass↗

Paediatric HIV/AIDS in Jamaica. A hospital-based description.

The continuing worldwide epidemic of adult HIV/AIDS has led to an increase in the number of HIV-positive children mainly through perinatal transmission. Although national data are available, there is no published report of the epidemiology of HIV/AIDS in children in Jamaica. A multicentre retrospective analysis of 183 HIV seropositive children admitted to hospitals in Jamaica between 1990 and 1996 was conducted. Ages at diagnosis were available for 172 patients with 61% diagnosed in the first year of life. Clinical histories were available for 129 patients with the primary presenting symptoms of infected children being failure to thrive, pneumonia, diarrhoea, dermatitis and lymphadenopathy. Classification was possible in 128 patients: 49 were exposed, 76 were infected and three were seroreverters. Infected children had a longer hospital stay than those classified as exposed or seroreverters. As of December 31, 1997, 125 patients had defaulted, nine patients were alive and 51 were reported dead with a median age of death of 12 months. From these data, it is estimated that the hospital-based HIV incidence among children in Jamaica increased from 0.149 per 10,000 person years in 1990 to 1.331 per 10,000 person years in 1996. This study demonstrates a rise in the estimated incidence of HIV/AIDS but we were unable to estimate survival reliably since the data required were not available for 75% of children identified. These data highlight the urgent need for targeted interventions to reduce vertical transmission of HIV as well as a need for prospective studies to establish reliable data on incidence and long-term outcome for HIV-infected children.

Acquired Immunodeficiency Syndrome↗

Primary malnutrition. Can we always tell?

Patterns of disease in the English-speaking Caribbean have changed considerably over the past two decades. There has been a decrease in the incidence of common infectious diseases, an increase in the prevalence of chronic non-communicable disorders and an increase in the incidence and prevalence of HIV/AIDS. However, published estimates suggest that malnutrition continues to be a serious public health problem. It is possible that changing patterns of disease within the epidemiological transition may affect patterns of presentation of severe forms of childhood malnutrition. We have examined records of 435 children admitted to the clinical research ward of the Tropical Metabolism Research Unit (TMRU) from January 1, 1990, to December 31, 1999; among these were 25 children who were subsequently found to have severe childhood malnutrition (SCM) due to a defined medical or surgical disorder (i.e. secondary SCM). Among children with secondary SCM, the HIV/AIDS group was the largest and comprised 60% of these admissions. Regression analyses show that, over the ten-year period, there was a small, non-significant decline in the number of cases of primary SCM (incidence rate ratio, IRR = 0.99, 95% confidence interval = 0.96, 1.02, p = 0.98), while the number of cases of secondary SCM increased (IRR = 1.18, 95% CI = 1.03, 1.35, p = 0.02). These data are indicative of the need for continued vigilance in the evaluation of children who have clinical features of the syndromes of severe malnutrition and draw attention to the potential impact of HIV/AIDS in yet another area of healthcare delivery.

Child↗

Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE).

Circulating angiotensin I-converting enzyme (ACE) levels are influenced by a major quantitative trait locus (QTL) that maps to the ACE gene. Phylogenetic and measured haplotype analyses have suggested that the ACE-linked QTL lies downstream of a putative ancestral breakpoint located near to position 6435. However, strong linkage disequilibrium between markers in the 3' portion of the gene has prevented further resolution of the QTL in Caucasian subjects. We have examined 10 ACE gene polymorphisms in Afro-Caribbean families recruited in JAMAICA: Variance components analyses showed strong evidence of linkage and association to circulating ACE levels. When the linkage results were contrasted with those from a set of British Caucasian families, there was no evidence for heterogeneity between the samples. However, patterns of allelic association between the markers and circulating ACE levels differed significantly in the two data sets. In the British families, three markers [G2215A, Alu insertion/deletion and G2350A] were in complete disequilibrium with the ACE-linked QTL. In the Jamaican families, only marker G2350A showed strong but incomplete disequilibrium with the ACE-linked QTL. These results suggest that additional unobserved polymorphisms have an effect on circulating ACE levels in Jamaican families. Furthermore, our results show that a variance components approach combined with structured, quantitative comparisons between families from different ethnic groups may be a useful strategy for helping to determine which, if any, variants in a small genomic region directly influence a quantitative trait.

Black People↗

Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure.

Considerable effort has been expended to determine whether the gene for angiotensin I-converting enzyme (ACE) confers susceptibility to cardiovascular disease. In this study, we genotyped 13 polymorphisms in the ACE gene in 1,343 Nigerians from 332 families. To localize the genetic effect, we first performed linkage and association analysis of all the markers with ACE concentration. In multipoint variance-component analysis, this region was strongly linked to ACE concentration (maximum LOD score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE (P<.0013). The two most highly associated polymorphisms, ACE4 and ACE8, accounted for 6% and 19% of the variance in ACE, respectively. A two-locus additive model with an additive x additive interaction of these polymorphisms explained most of the ACE variation associated with this region. We next analyzed the relationship between these two polymorphisms (ACE4 and ACE8) and blood pressure (BP). Although no evidence of linkage was detected, significant association was found for both systolic and diastolic BP when a two-locus additive model developed for ACE concentration was used. Further analyses demonstrated that an epistasis model provided the best fit to the BP variation. In conclusion, we found that the two polymorphisms explaining the greatest variation in ACE concentration are significantly associated with BP, through interaction, in this African population sample. Our study also demonstrates that greater statistical power can be anticipated with association analysis versus linkage, when markers in strong linkage disequilibrium with a trait locus have been identified. Furthermore, allelic interaction may play an important role in the dissection of complex traits such as BP.

Adult↗

Gd-DTPA bolus tracking in the myocardium using T1 fast acquisition relaxation mapping (T1 FARM).

MRI methods currently used for bolus tracking in the myocardium, such as saturation recovery turbo-fast low-angle shot (FLASH) (srTFL), are limited by signal intensity (SI) saturation at high contrast agent (CA) concentrations. By using T1 fast acquisition relaxation mapping (T1 FARM), a Gd-DTPA bolus (0.075 vs. 0.025 mmol/kg) may be injected without causing saturation. This study tested the feasibility of in vivo T1 FARM bolus tracking under rest/stress conditions in seven beagles with multiple permanently occluded branches of the left anterior descending (LAD) coronary artery. Although it underestimated the myocardial perfusion reserve (MPR) measured ex vivo using radioactive microspheres (mean +/- SEM; 3.60 +/- 0.26), the MPR determined upon application of the modified Kety model (1.86 +/- 0.10) enabled distinction between normal and infarcted tissue. The partition coefficient (lambda) estimated at rest and stress using the modified Kety model underestimated ex vivo radioactive measurements in infarcted tissue (0.25 +/- 0.01 vs. 0.26 +/- 0.01 vs. 0.79 +/- 0.08 ml/g, P < 0.0001) yet was accurate in normal tissue (0.28 +/- 0.01 vs. 0.30 +/- 0.01 vs. 0.33 +/- 0.01 ml/g, P = NS). Thus, although unsuitable for myocardial viability assessment, T1 FARM bolus tracking shows potential for assessment of myocardial perfusion.

Animals↗

Coil-by-coil image reconstruction with SMASH.

The SiMultaneous Acquisition of Spatial Harmonics (SMASH) technique uses linear combinations of undersampled datasets from the component coils of an RF coil array to reconstruct fully sampled composite datasets in reduced imaging times. In previously reported implementations, SMASH reconstructions were designed to reproduce the images that would otherwise be obtained by simple sums of fully gradient encoded component coil images. This strategy has left SMASH images vulnerable to phase cancellation artifacts when the sensitivities of RF coil array elements are not suitably phase-aligned. In fully gradient encoded imaging schemes these artifacts can be eliminated using a variety of methods for combining the individual coil images, including matched filter combinations as well as sum of squares combinations. Until now, these reconstruction schemes have been unavailable to SMASH reconstructions as SMASH produced a final composite image directly from the raw component coil k-space datasets. This article demonstrates a modification to SMASH that allows reconstruction of a full set of accelerated individual component coil images by fitting component coil sensitivity functions to a complete set of spatial harmonics tailored for each coil in the array. Standard component coil combinations applied to the individual reconstructed images produce final composite images free of phase cancellation artifacts.

Abdomen↗

Improved spatial harmonic selection for SMASH image reconstructions.

The fitting of coil sensitivity functions to spatial harmonics is central to image reconstructions using the simultaneous acquisition of spatial harmonics (SMASH) technique. It has previously been shown that the selection of the set of spatial harmonics used in a SMASH reconstruction can have a noticeable effect on the quality of the reconstructed image. However, a mechanism for automatic selection of the best set of harmonics in any particular situation has not been provided. In this work, a modification to the SMASH reconstruction procedure is introduced that allows the use of a weighted average of all possible harmonics in a reconstruction. The new reconstruction procedure is shown to allow automatic selection of the spatial harmonics and substantially improve SNR for both phantom and in vivo images.

Humans↗

MR angiography using spin-lock flow tagging.

A method for MR angiography using an RF labeling technique is suggested. The method utilizes a slice-selective spin-lock pulse sequence for tagging the spins of inflowing blood. The pulse sequence begins with a spatially selective 90 degrees (x) RF pulse, followed by a nonselective composite locking pulse of 135 degrees (y) - n[360 degrees (y)]-135 degrees (y) and by a 90 degrees (-x) pulse. A spoiler gradient is then applied. A rapid imaging stage, which yields a T(1)rho-weighted signal from the tagged spins, completes the sequence. Untagged spins are thoroughly dephased and consequently suppressed in the image. Thus, contrast is obtained without an injection of a contrast material or image subtraction. Furthermore, the flow of the tagged bolus can be visualized. The sequence was implemented on phantoms and on human volunteers using a 1.5T scanner. The results indicate the feasibility of the suggested sequence.

Coronary Circulation↗

SNPs and snails and puppy dogs' tails: analysis of SNP haplotype data using the gamete competition model.

The gamete competition model is a likelihood version of the transmission disequilibrium test (TDT) that is inspired by conditional logistic regression and the Bradley-Terry ranking procedure. In family-based association studies, both the TDT and the gamete competition model apply directly to data on a single nucleotide polymorphism (SNP). Because any given SNP has limited polymorphism, it is tempting to collect several SNPs within a gene into a single super marker whose alleles are haplotypes. Unfortunately, this tactic wreaks havoc with the traditional TDT, which requires codominant markers (Spielman et al. 1993; Terwilliger & Ott, 1992). Eliminating phase ambiguities by assigning haplotypes to individuals before conducting the TDT may give misleading results because only the most probable haplotypes are then considered. Because pedigree implementations of the gamete competition model can accommodate dominant as well as codominant markers, they circumvent the phase problem by including all possible phases weighted by their estimated frequencies.

Germ Cells↗

Phylogeny of the filamentous bacterium 'Nostocoida limicola' III from activated sludge.

Five strains of the filamentous bacterium 'Nostocoida limicola' III were successfully isolated into pure culture from samples of activated sludge biomass from five plants in Australia. 16S rRNA gene sequence analyses showed that all isolates were members of the Planctomycetales, most closely related to Isosphaera pallida, but they differed phenotypically from this species in that they did not glide and were not thermotolerant. The ultrastructure of these 'N. limicola' III isolates was also consistent with them being Planctomycetales, in that they possessed complex intracellular membrane systems compartmentalizing the cells. However, the arrangements of these intracellular membranes differed between isolates. These data confirm that 'N. limicola' III is phylogenetically unrelated to both 'N. limicola' I and 'N. limicola' II, activated sludge filamentous bacteria which share morphological features in common with 'N. limicola' III and which have been presumed historically to be the same or very similar bacteria.

Bacteria↗

A generalized approach to parallel magnetic resonance imaging.

Parallel magnetic resonance (MR) imaging uses spatial encoding from multiple radiofrequency detector coils to supplement the encoding supplied by magnetic field gradients, and thereby to accelerate MR image acquisitions beyond previous limits. A generalized formulation for parallel MR imaging is derived, demonstrating the relationship between existing techniques such as SMASH and SENSE, and suggesting new algorithms with improved performance. Hybrid approaches combining features of both SMASH-like and SENSE-like image reconstructions are constructed, and numerical conditioning techniques are described which can improve the practical robustness of parallel image reconstructions. Incorporation of numerical conditioning directly into parallel reconstructions using the generalized approach also removes a cumbersome and potentially error-prone sensitivity calibration step involving division of two distinct in vivo reference images. Hybrid approaches in combination with numerical conditioning are shown to extend the range of accelerations over which high-quality parallel images may be obtained.

Algorithms↗

Continuous venovenous haemofiltration for the treatment of theophylline toxicity.

In patients with severe theophylline toxicity charcoal haemoperfusion is the recommended method for rapid reduction of serum theophylline levels. However, access to this technique is limited in most hospitals. This case report shows that continuous venovenous haemofiltration, a technique available in most hospitals, is an effective alternative to charcoal haemoperfusion.

Bronchodilator Agents↗

Localization of a small genomic region associated with elevated ACE.

Defining the relationship between multiple polymorphisms in a small genomic region and an underlying quantitative trait locus (QTL) represents a major challenge in human genetics. Pedigree analyses have shown that angiotensin I-converting enzyme (ACE) levels are influenced by a QTL located within or close to the ACE gene and most likely resides in the 3' region of this locus. We genotyped seven polymorphisms spanning 13 kb in the 3' end of ACE in 159 Afro-Caribbean subjects to evaluate the linkage disequilibrium between these sites and to narrow the genomic region associated with an elevated ACE level using a cladistic analysis. The linkage disequilibrium measurement D' and a haplotype tree revealed three distinct haplotype segments, presumably because of recombination. The value of the linkage disequilibrium parameter p(excess) was highest for site 22982, which is located in the middle segment. A series of nested, cladistic analyses confirmed that the other two regions are unlikely to be the ACE-linked QTL and that the variant resides in the middle region. Analyses of the same polymorphisms in 98 unrelated Europeans in the Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) study resulted in fewer haplotypes than were observed among the Afro-Caribbean subjects, suggesting that populations with greater genetic diversity may be especially informative for fine-scale mapping.

Black People↗