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Biomedical subjects

J Rutherford

Publications and source records attributed to J Rutherford.

At least 19 recordsLinked to original sources
PubMed2002

Investigations on a clinically and functionally unusual and novel germline p53 mutation.

This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21(WAF1), bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.

Adult↗
PubMed2001

New insights into HIV-1 specific cytotoxic T-lymphocyte responses in exposed, persistently seronegative Kenyan sex workers.

A clearer understanding of HIV-1 specific immune responses in highly-exposed, persistently seronegative (HEPS) subjects is important in developing models of HIV-1 protective immunity. HIV-1 specific cytotoxic T-lymphocytes (CTL) have been described in a cohort of HEPS Kenyan sex workers, and recent work has further elucidated these responses. CTL specific for HIV-1 Env were found in the blood of over half the sex workers meeting criteria for HIV resistance, and in some women recognized unmapped epitopes. The proportion of women with Env-specific CTL increased with the duration of uninfected HIV exposure, suggesting that these responses were acquired over time. CD8+ lymphocyte responses directed against predefined HIV-1 CTL epitopes from various HIV-1 genes were found in the blood and genital tract of >50% resistant sex workers, at a ten-fold lower frequency than in infected subjects. The epitope specificity of CD8+ responses differs between HEPS and HIV infected women, and in HEPS the maintenance of responses appears to be dependent on persistent HIV exposure. Several HIV-1 'resistant' sex workers have become HIV infected over the past 6 years, possibly related to waning of pre-existing HIV-specific CTL, and infection has often been associated with a switch in the epitope specificity of CD8+ responses. These findings suggest that vaccine-induced protective HIV immunity is a realistic goal, but that vaccine strategies of boosting or persistent antigen may be necessary for long-lived protection.

Adult↗
PubMed2001

p53 functional assays: detecting p53 mutations in both the germline and in sporadic tumours.

The tumour suppressor gene p53 is the gene most often reported to be mutated in clinical cancers with something like half of all tumours harbouring mutations. Further, many studies have suggested that p53 mutations have prognostic importance and sometimes are a significant factor in determining the response of tumours to therapy. The value of knowing the p53 status of individual tumours will increase if currently researched strategies aimed at developing p53-based treatment protocols come to fruition. There are quite a number of techniques used to detect p53 defects in both tumours and in the germline of cancer-prone families, although some of these methods are indirect and each has certain drawbacks. In this brief review we will discuss the value of two assays of p53 function as a means of detecting and partly characterizing p53 mutations. The two assays are the apoptotic assay, which measures the response of peripheral blood lymphocytes to radiation-induced DNA damage and the FASAY, a yeast based assay which assesses the ability of a given p53 protein to transactivate p53 target genes. Both of these assays are rapid, yielding results within 5 days. Further, they not only offer the possibility of detecting p53 mutations but also of characterizing a given mutation in terms of two of p53's most important functions, namely the induction of apoptosis and the transactivation of target genes.

Alleles↗
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↗
PubMed1999

Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.

BACKGROUND: The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS: To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS: Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

Aged↗
PubMed1996

A hospital-based twin register of the heritability of DSM-IV unipolar depression.

OBJECTIVES: To estimate the contribution of genes and shared family environment to the liability to DSM-IV major depression and to examine the influence of certain proband characteristics on twin concordance. METHODS: We studied 177 probands with major depressive disorder ascertained via the Maudsley Hospital Twin Register (London, England) and their same-sex co-twins. Diagnostic assessments were carried out blind to zygosity and information on the other member of the twin pair. Probandwise concordances were used to compute correlations in liability, and model fitting was performed using maximum likelihood procedures. RESULTS: The probandwise concordance was 46% in monozygotic (n = 68) and 20% in dizygotic (n = 109) twins, a statistically highly significant difference. There was no evidence of a sex difference in heritability or of shared environmental effects. Depending on the assumed population risks for DSM-IV, major depression estimates of heritability were between 48% and 75%. A duration of longest episode of less than 13 months, multiple episodes, and an endogenous rather than neurotic pattern of symptoms as established by the International Classification of Diseases, Ninth Revision, in the proband were associated with a trend toward a higher monozygotic-dizygotic concordance ratio. Using log-linear analysis, only the association between duration of episodes and monozygotic-dizygotic concordance ratio was significant. CONCLUSIONS: Liability to DSM-IV major depression has a substantial heritable component, and there is no evidence of an effect of shared family environment. Some proband characteristics, especially shorter duration of episodes, may be associated with a larger degree of genetic determination.

Adult↗
PubMed1994

Redefining the psychosomatic family: family process of 26 eating disorder families.

This paper reports part of the data from a comparative trial of two forms of family intervention for the management of eating disorders in adolescents. Measures of family process at the beginning of treatment included Expressed Emotion (EE) and the Family Adaptability and Cohesion Evaluation Scales (FACES). EE in the families of both anorexic and bulimic patients were, on the whole, at low levels. The low levels of parental Critical Comments might be taken to represent the conflict avoiding character of the families of psychosomatic patients. However, the families showed low levels of Emotional Overinvolvement, which contradicts the clinical descriptions. The FACES scores revealed patterns that were superficially contradictory to the accepted clinical descriptions in that the patients appeared to have perceived their families as not close and as highly structured. The parents experienced their family structure as more similar to the clinical descriptions, scoring their families as more flexible and cohesive than do the patients. The FACES ideals for family organization scored by patients and parents more nearly equate with the clinical descriptions of enmeshment and lack of boundary structure. The relationship between the research findings and the clinical evaluation will be discussed.

Adolescent↗
PubMed1993

Genetic influences on eating attitudes in a normal female twin population.

The Eating Attitudes Test (EAT) and the Eating Disorder Inventory (EDI) were administered to a female volunteer twin population aged 18 to 45 years. Both members of 147 monozygotic (MZ) and 99 dizygotic (DZ) twin pairs completed the questionnaires. Thirty-five subjects scored over the cut-off point of the EAT-26. Interviews of these high-scoring twins and their co-twins identified three subjects with a past history of anorexia nervosa, and three others with a history of a partial syndrome. A heritability value of 41% was obtained for the overall EAT scores, while factor analysis produced a 'dieting' factor with a heritability of 42%. The 'body dissatisfaction' and 'drive for thinness' subscales of the EDI had heritability values of 52 and 44% respectively. The genetic contribution to the variance in body mass index in the twin sample was estimated at 64%. For all the above phenotypes, an environmental model of transmission with heritability constrained to be zero, could be rejected. Conversely, we were unable to reject a purely additive genetic model with shared environmental variance constrained at zero, suggesting that family environment has little or no effect on the transmission of many of these traits.

Adolescent↗
PubMed1991

The single zeta globin gene rearrangement: hematologic phenotype and its frequent occurrence in Polynesian Niueans.

The single zeta globin gene rearrangement (-zeta/) is an unusual mutation associated with the alpha globin gene cluster on chromosome 16p13.3. It has been detected regularly among West Africans (gene frequency approximately 0.05) and sporadically among other populations. DNA samples from 186 Polynesian Niueans living in Auckland, New Zealand, were studied. Eighteen (gene frequency 0.05) were shown to have the -zeta/gene arrangement, which results from loss of the psi zeta 1 gene. Hematological phenotypes in six cord blood samples and 12 affected adults were normal. The high frequency for -zeta/in Niueans may represent another example of genetic drift and a founder effect in Polynesians or may reflect a different founding population.

Chromosomes, Human, Pair 16↗
PubMed1991

Nature, nurture and depression: a twin study.

We studied a series of twins systematically ascertained through 214 probands (84 monozygotic, 130 dizygotic) who had had one or more episodes of hospital-treated major depression. A variety of definitions of depression were applied to the co-twins all of which resulted in (a) markedly higher rates of disorder than are found in the general population, (b) significantly higher monozygotic than dizygotic concordance. The results of applying a simple additive model in which depression is considered as a threshold trait suggested that both genetic factors and shared family environment make substantial and significant contributions to the familiality of depression.

Adult↗
PubMed1990

Beta-globin gene haplotypes in Polynesians are predominantly southern Chinese in type.

beta-Globin gene haplotypes obtained in Polynesian Samoans were similar to those described in Southern Chinese. An atypical HindIII restriction fragment length polymorphism detected with pRK29, a 3' beta-globin gene probe, was present at a gene frequency of 7% in Samoans. Haplotype patterns suggest that this polymorphism may have arisen by 1 or 2 mutational events. DNA haplotypes derived from the beta-globin gene cluster confirm nuclear and mitochondrial DNA data that Polynesian precursor populations were East Asian in origin.

Chromosomes, Human, Pair 11↗
PubMed1990

Anorexia nervosa and baby gazing.

The uncommon behaviour of baby gazing is described in a patient who had also suffered three episodes of anorexia nervosa. The baby gazing responded to joint therapeutic interviews leading to the patient and her husband resolving their different views about having a family and the patient becoming pregnant. Even then there was a minor recurrence of anorexic behaviour which yielded to treatment.

Adult↗
PubMed1989

British type alpha 0-thalassaemia in New Zealand.

Alpha zero-thalassaemia of the British type is described for the first time in a New Zealand family. Microcytic, hypochromic red blood cells were found in affected individuals. Exclusion of iron deficiency and beta-thalassaemia suggested alpha-thalassaemia as a possible cause. This was confirmed by the detection of haemoglobin (Hb) H inclusion bodies. Definitive characterisation of the alpha-thalassaemia defect required DNA mapping which demonstrated the British alpha zero-thalassaemia deletion involving both alpha globin genes. alpha zero-thalassaemia should no longer be considered a disorder affecting individuals of Mediterranean or Asian backgrounds. Anglo-Saxons are also an at risk group. Co-inheritance of this abnormality with a second alpha-thalassaemia defect can lead to Hb H disease or Hb Bart's hydrops fetalis.

Adolescent↗
PubMed1985

Influence of alpha thalassaemia on haematological parameters in Polynesian patients.

DNA mapping of the alpha globin gene cluster in cord blood from Polynesians has shown an increased frequency of alpha thalassaemia and triplicated alpha genes. Reduced levels of haemoglobin, mean corpuscular haemoglobin or mean corpuscular volume in these neonates may indicate alpha thalassaemia. Recognition of this will avoid unnecessary haematological investigations and iron supplementation.

Chromosome Mapping↗