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Biomedical subjects

R Ward

Publications and source records attributed to R Ward.

At least 37 records · Page 2Linked to original sources
PubMed2004

Phase I clinical trial of a human idiotypic p53 vaccine in patients with advanced malignancy.

BACKGROUND: The purpose of this study was to induce immunity to p53 by using an idiotypic vaccine, composed of a pool of eight peptides derived from the complimentarity determining regions (CDRs) of human anti-p53 antibodies. PATIENTS AND METHODS: Subjects with advanced malignancy received up to four, monthly intradermal injections of pooled peptides (500 microg of each) admixed with granulocyte-macrophage colony-stimulating factor (GM-CSF; 100 microg). In addition, two sheep and two rabbits were also vaccinated with the pooled peptides. RESULTS: Fourteen subjects were enrolled into the study and six of these completed the vaccination schedule. The vaccine was well tolerated by all subjects and no major adverse events were attributable to the vaccine. All subjects mounted in vivo delayed type hypersensitivity (DTH) responses to two or more of the individual vaccine peptides. Vaccine-induced antibodies specific for peptides 2, 5 or 8 were detected in four of six subjects, and two of these had vaccine-specific, cell-mediated responses. Increasing titers of p53-specific antibodies were found in one patient. No T-cell response to p53 was observed in any of the subjects. All animals developed humoral immunity to the peptides and one of the sheep developed rising serum titers of anti-p53 antibodies. CONCLUSIONS: Vaccination with human antibody CDR regions represents a novel method for inducing human antibodies, which may in turn serve as immunological mimics of p53.

Adult↗
PubMed2003

Gamma-aminobutyric acid-synthesizing cells in the retina of the chameleon Chamaeleo chameleon.

Antibodies directed against gamma-aminobutyric acid (GABA) and L-glutamic acid decarboxylases 65 and 67 kDa (GAD65 and -67) were used to study the GABAergic cell populations of the chameleon retina. GABA immunoreactivity was found in the two main types of retinal interneurons, amacrine and horizontal cells. Amacrine, displaced amacrine, and intra- and interplexiform cells displayed the strongest GABA immunoreactivity of all the retinal cell types. Horizontal cells formed a continuous GABA-immunoreactive cell layer lying against the outermost portion of the inner nuclear layer. In contrast to previous studies (Quesada et al. [1996] Cell Biol. Int. 20:395-400; [1999] Eur. J. Anat. 3:13-25), the present results demonstrate that the horizontal cells of the chameleon retina are GABA immunoreactive and that a subpopulation of these is immunolabelled by an antibody against GAD65. These results indicate that GABAergic synaptic transmission plays a key role in the outer plexiform layer of the vertebrate retina.

Amacrine Cells↗
PubMed2003

CD103+ intraepithelial lymphocytes--a unique population in microsatellite unstable sporadic colorectal cancer.

Colorectal cancers with microsatellite instability (MSI) typically show increased numbers of intraepithelial lymphocytes (IEL) in comparison to microsatellite stable (MSS) cancers. The aim of this study was to determine the phenotype of this unique lymphocyte population in MSI and MSS colorectal cancers. Twenty-four individuals with sporadic colorectal cancer (17 MSI, 7 MSS) were included in this study. Intraepithelial and stromal lymphocytes were detected using immunohistochemistry with anti-CD8 and anti-CD103 antibodies, and two observers independently quantified the numbers of lymphocytes. CD103+ (alpha E beta 7+) IELs detected within tumour tissue co-expressed CD8+ while the stromal lymphocytes were phenotypically heterogeneous, with respect to CD8+ and CD103+ expression. MSI colorectal cancers harboured increased numbers of CD8+ CD103+ IELs, as well as CD8+ CD103- and CD8+ CD103+ stromal lymphocytes, when compared with MSS colorectal cancers. CD103+ IELs were found at 27-fold greater numbers in the tumour epithelium than in normal epithelium from the same patient (P = 0.001, Wilcoxon matched pairs test). From our findings, we have proposed a mechanism for the homing of these alpha E beta 7+ lymphocytes to tumour tissue in MSI and MSS colorectal cancers.

Aged↗
PubMed2003

People with dementia and their relatives: personal experiences of Alzheimer's and of the provision of care.

Little is known about the experiences of people with dementia, as there has been relatively little research carried out that includes their perspectives. In the past, user perspectives on experiences of dementia and on services have mostly been solicited from family carers, rather than from people with dementia themselves. It has been suggested that these studies may lack information and insight into the experiences of people with dementia. This study aimed at eliciting the views and feelings of people in all stages of dementia, as well as those of their relatives, on care services and on experiences of dementia. Twenty-seven people with dementia from residential and day care settings were interviewed and their daily lives videotaped. Interviews were also conducted with next of kin. This article reports on findings and issues arising from the study.

Adaptation, Psychological↗
PubMed2003

Concentration of polar MFGM lipids from buttermilk by microfiltration and supercritical fluid extraction.

Buttermilk contains the milk fat globule membrane (MFGM), a material that possesses many complex lipids that function as nutritionally valuable molecules. Milk-derived sphingolipids and phospholipids affect numerous cell functions, including regulating growth and development, molecular transport systems, stress responses, cross membrane trafficking, and absorption processes. We developed a two-step method to produce buttermilk derivative ingredients containing increased concentrations of the polar MFGM lipids by microfiltration and supercritical fluid extraction (SFE). These processes offer environmentally benign alternatives to conventional lipid fractionation methods that rely on toxic solvents. Firstly, using a ceramic tubular membrane with 0.8-micron pore size, we evaluated the cross flow microfiltration system that maximally concentrated the polar MFGM lipids using a 2n factorial design; the experimental factors were buttermilk source (fresh, or reconstituted from powder) and temperature (50 degrees C, and 4 degrees C). Secondly, a SFE process using supercritical carbon dioxide removed exclusively nonpolar lipid material from the microfiltered buttermilk product. Lipid analysis showed that after SFE, the product contained a significantly reduced concentration of nonpolar lipids, and a significantly increased concentration of polar lipids derived from the MFGM. Particle size analysis revealed an impact of SFE on the product structure. The efficiency of the SFE system using the microfiltration-processed powder was compared much more favorably to using buttermilk powder.

Animals↗
PubMed2002

Evolutionary significance of different neurochemical organisation of the internal and external regions of auditory centres in the reptilian brain: an immunocytochemical and reduced NADPH-diaphorase histochemical study in turtles.

An immunocytochemical and histochemical study was undertaken of the torus semicircularis and nucleus reuniens, the mesencephalic and diencephalic auditory centres, in two chelonian species, Testudo horsfieldi and Emys orbicularis. The nucleus centralis of the torus semicircularis receives few 5-HT-, TH-, substance P-, and menkephalin-immunoreactive fibres and terminals, in marked contrast to the external nucleus laminaris of the torus semicircularis, in which 5-HT-, TH-, substance P-, and menkephalin-immunoreactive elements and cell bodies show a laminar distribution. Dense NPY-positive terminal-like profiles and cell bodies were observed in both the nuclei centralis and laminaris, and many NADPH-d-positive cell bodies were observed in the cell layers of the latter. In the nucleus reuniens, the distribution of 5-HT-, TH-, substance P-, and menkephalin-immunolabelling resembles that seen in the torus semicircularis, but at a lower density. The dorsorostral regions of the nucleus reuniens, as in the nucleus centralis, is insignificantly labelled, in contrast to the ventrocaudal regions in which labelled elements abound. NPY-positive elements are uniformly distributed throughout the nucleus, but no labelled cell bodies were observed. NADPH-d-positive fibres and terminals were observed in both dorsal and ventral regions of the nucleus reuniens, but the few labelled cell bodies to be observed were located in the peripheral regions of the nucleus. These findings are discussed in terms of the evolution of the core-and-belt organisation of sensory nuclei observed in other vertebrate species.

Animals↗
PubMed2002

CD40L association with protection from severe malaria.

CD40 ligand (CD40L), a glycoprotein involved in B cell proliferation, antigen presenting cell activation, and Ig class switching, is important in the immune response to infection. Rare coding mutations in CD40L can lead to life-threatening immunodeficiency but the potential for common variants to alter disease susceptibility remains to be explored. To identify polymorphisms in CD40L, we sequenced 2.3 kb of the 5' flanking region and the first exon of the gene in DNA samples from 36 Gambian females and one chimpanzee. Diversity was lower than the average reported for other areas of the X chromosome, and only two polymorphisms were identified. The polymorphisms were genotyped in DNA samples from 957 Gambian individuals, cases and controls from a study of severe malaria. A significant reduction in risk for severe malaria (OR = 0.52, P = 0.002) was associated with males hemizygous for the CD40L-726C. Analysis by transmission disequilibrium test of 371 cases, for whom DNA from both parents was also available, confirmed the result was not due to stratification (P = 0.04). A similar but non-significant trend was found in females. This preliminary association of a common variant in CD40L with a malaria resistance phenotype encourages further genetic characterization of the role of CD40L in infectious disease.

Alleles↗
PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗
PubMed2001

Rotavirus and central nervous system symptoms: cause or contaminant? Case reports and review.

Rotavirus is a common cause of severe gastroenteritis in children. In 2 patients with rotavirus gastroenteritis who developed encephalopathy, rotavirus RNA was detected in the cerebrospinal fluid (CSF) by reverse transcription-polymerase chain reaction; in 1 patient, rotavirus RNA was detected on 2 occasions 3 weeks apart. There are increasing reports of cases in which patients who have seizures after an episode of rotavirus diarrhea have evidence of rotavirus in their CSF. A search of 2 large hospital discharge databases suggested that seizures are noted as part of the discharge diagnosis in the records of, at most, <4% of patients with rotavirus diarrhea versus 7% of patients with bacterial diarrhea. Although evidence suggesting that rotavirus is a cause of central nervous system sequelae remains inconclusive, the 2 case reports presented in this study further illustrate a possible association. Further study is required to determine whether detection of rotavirus in CSF represents a true pathogen, CSF contamination that occurs at the time of lumbar puncture or in the laboratory, or carriage of rotavirus RNA in trafficking lymphocytes.

Central Nervous System Diseases↗
PubMed2001

Linkage disequilibrium in the human genome.

With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs), a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting 'haplotypes' descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations and empirical data have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1-3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000-53,000 years ago.

Alleles↗
PubMed2001

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↗
PubMed2001

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Alleles↗
PubMed2001

Complete mitochondrial genome sequences of two extinct moas clarify ratite evolution.

The origin of the ratites, large flightless birds from the Southern Hemisphere, along with their flighted sister taxa, the South American tinamous, is central to understanding the role of plate tectonics in the distributions of modern birds and mammals. Defining the dates of ratite divergences is also critical for determining the age of modern avian orders. To resolve the ratite phylogeny and provide biogeographical data to examine these issues, we have here determined the first complete mitochondrial genome sequences of any extinct taxa--two New Zealand moa genera--along with a 1,000-base-pair sequence from an extinct Madagascan elephant-bird. For comparative data, we also generated 12 kilobases of contiguous sequence from the kiwi, cassowary, emu and two tinamou genera. This large dataset allows statistically precise estimates of molecular divergence dates and these support a Late Cretaceous vicariant speciation of ratite taxa, followed by the subsequent dispersal of the kiwi to New Zealand. This first molecular view of the break-up of Gondwana provides a new temporal framework for speciation events within other Gondwanan biota and can be used to evaluate competing biogeographical hypotheses.

Animals↗
PubMed2001

mtDna and the islands of the North Atlantic: estimating the proportions of Norse and Gaelic ancestry.

A total of 1,664 new mtDNA control-region sequences were analyzed in order to estimate Gaelic and Scandinavian matrilineal ancestry in the populations of Iceland, Orkney, the Western Isles, and the Isle of Skye and to investigate other aspects of their genetic history. A relative excess of private lineages in the Icelanders is indicative of isolation, whereas the scarcity of private lineages in Scottish island populations may be explained by recent gene flow and population decline. Differences in the frequencies of lineage clusters are observed between the Scandinavian and the Gaelic source mtDNA pools, and, on a continent-wide basis, such differences between populations seem to be associated with geography. A multidimensional scaling analysis of genetic distances, based on mtDNA lineage-cluster frequencies, groups the North Atlantic islanders with the Gaelic and the Scandinavian populations, whereas populations from the central, southern, and Baltic regions of Europe are arranged in clusters in broad agreement with their geographic locations. This pattern is highly significant, according to a Mantel correlation between genetic and geographic distances (r=.716). Admixture analyses indicate that the ancestral contributions of mtDNA lineages from Scandinavia to the populations of Iceland, Orkney, the Western Isles, and the Isle of Skye are 37.5%, 35.5%, 11.5%, and 12.5%, respectively.

Atlantic Islands↗
PubMed2001

Sources of variation in the nesting behavior of chimpanzees (Pan troglodytes schweinfurthii) in the Budongo forest, Uganda.

Data on nesting behavior and nests of the Sonso community of chimpanzees (Pan troglodytes schweinfurthii) living in the Budongo Forest, Uganda, were collected between October 1995 and December 1996. Analysis of the selection of nests shows a preference for particular tree species, especially Cynometra alexandri. Male chimpanzees nested lower than females. Day nests were found to be structurally simpler than night nests and were built in tree species used for feeding, at the same height as feeding activity. Day and night nests serve different functions, and should be clearly distinguished in studies of nesting behavior.

Animals↗