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R Newton

Publications and source records attributed to R Newton.

At least 37 records · Page 2Linked to original sources
PubMed2003

Review of the distribution of Kaposi's sarcoma-associated herpesvirus (KSHV) in Africa in relation to the incidence of Kaposi's sarcoma.

In the years before human immunodeficiency virus (HIV) infection, the incidence of Kaposi's sarcoma varied markedly across the African continent, and it was a disease primarily affecting men. In contrast, the evidence reviewed here shows that the causal virus-Kaposi's sarcoma associated herpesvirus (KSHV)-is prevalent in many African countries, including places where Kaposi's sarcoma was almost unknown before HIV, and that it is as common in women as in men. Therefore, the geographical distribution of Kaposi's sarcoma in Africa before the spread of HIV and its predominance as a disease affecting men are not a simple reflection of the distribution of KSHV. Since the epidemic of HIV in Africa, Kaposi's sarcoma has become relatively more frequent in women, and the incidence has increased in countries where it was previously rare, but where KSHV is prevalent, as well as in countries where it was already common. These changes point to a role for other (as yet unknown) factors in the aetiology of Kaposi's sarcoma that may have the most effect in the absence of concurrent HIV infection.

Africa↗
PubMed2003

Treatment of Kaposi's sarcoma in HIV-1 infected individuals with emphasis on resource poor settings.

BACKGROUND: In many countries, Kaposi's sarcoma (KS) is the commonest malignancy among individuals infected with the human immunodeficiency virus-1 (HIV) and is a cause of substantial morbidity and mortality. OBJECTIVES: The aim of this review was to assess the effectiveness of current therapeutic regimens for the treatment of HIV associated KS, with a focus on options that may be available in resource poor settings. SEARCH STRATEGY: We searched Cochrane HIV/AIDS Group trials register, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2002), MEDLINE, EMBASE, AIDSLINE, CINAHL, CANCER LIT, AIDSDRUGS, AIDSTRIALS, African index medicus, physicians data query protocols, United Kingdom Co-ordinating committee on Cancer Research Register of Cancer trials, proceedings and abstracts from AIDS and cancer conferences. The search was conducted between 1st October 2001 and completed 14th December 2002. We also contacted experts in the field of cancer. SELECTION CRITERIA: Randomised trials of therapy for KS in HIV infected adults. DATA COLLECTION AND ANALYSIS: All reviewers assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Five trials involving 915 people were included. Two trials involving 499 people compared pegylated liposomal doxorubicin (PLD) to a standard regimen among patients with advanced KS were analysed together. There was no difference in mortality between the two regimens RR1.26 (95% confidence interval (CI) 0.83 to 1.91). The response to PLD was superior to that of the control regimen RR 2.16, (95% CI 1.68 to 2.78). Two other trials involving 402 people demonstrated that topical alitretinoin was effective treatment compared to placebo among patients with cutaneous Kaposi's sarcoma. The results were analysed separately due to heterogeneity; (1) the relative risk (RR) was 5.34 (95%CI 2.16 to 13.21) and (2) RR 1.96, 95% CI 1.27 to 3.01). The final trial compared different radiotherapy regimens for treatment of cutaneous KS. The initial complete response of lesions to 20Gy given in 10 fractions or 40Gy in 20 fractions was similar and slightly superior to that of lesions treated with 8Gy as a single fraction, RR 1.58, (95% CI 1.01 to 2.48) and RR 1.65, (95% CI 1.06 to 2.57) respectively. REVIEWER'S CONCLUSIONS: Alitretinoin gel is effective in treating cutaneous KS, PLD is effective treatment for advanced KS and radiotherapy appears effective in treating cutaneous lesions. Apart from the trial of radiotherapy no trials applicable to developing settings were identified.

Alitretinoin↗
PubMed2003

Childhood medulloblastoma in northwest England 1954 to 1997: incidence and survival.

The incidence, survival patterns, and presenting symptoms of children with medulloblastoma were studied. Data were ascertained from the Manchester Tumour Registry which is population-based and has collected data on all childhood malignancies in northwest England since 1954. Incidence rates standardized to the European standard population were calculated and Poisson regression models were used to examine temporal changes in the incidence rates during the period 1954 to 1997. Kaplan-Meier survival curves were derived and used to study changes in survival patterns. World-standardized incidence rates were 5.5 per million child years in males and 3.4 per million child years in females. Incidence rates increased from the 1950s to the 1980s but have declined recently. The 5-year survival rate has improved from 29 to 58% with similar rates for males and females. The 1-year survival rate has also improved, but females had worse survival at this point (58%) than males (75%). The type of symptom or sign at presentation is strongly affected by age, with 10 of the 22 recorded symptoms or signs showing significant age differences. The older the child is, the more likely is the presentation to show pressure features of headache, vomiting, and ophthalmic signs. Younger children present with non-specific features such as lethargy, behavioural disturbance, or increasing head size. Ataxia is seen in about 75% of children across the age range.

Adolescent↗
PubMed2002

The epidemiology of conjunctival squamous cell carcinoma in Uganda.

As part of a larger investigation of cancer in Uganda, we conducted a case-control study of conjunctival squamous cell carcinoma in adults presenting at hospitals in Kampala. Participants were interviewed about social and lifestyle factors and had blood tested for antibodies to HIV, KSHV and HPV-16, -18 and -45. The odds of each factor among 60 people with conjunctival cancer was compared to that among 1214 controls with other cancer sites or types, using odds ratios, estimated with unconditional logistic regression. Conjunctival cancer was associated with HIV infection (OR 10.1, 95% confidence intervals [CI] 5.2-19.4; P<0.001), and was less common in those with a higher personal income (OR=0.4, 95% CI 0.3-0.7; P<0.001)[corrected]. The risk of conjunctival cancer increased with increasing time spent in cultivation and therefore in direct sunlight (chi2 trend=3.9, P=0.05), but decreased with decreasing age at leaving home (chi2 trend=3.9, P=0.05), perhaps reflecting less exposure to sunlight consequent to working in towns, although both results were of borderline statistical significance. To reduce confounding, sexual and reproductive variables were examined among HIV seropositive individuals only. Cases were more likely than controls to report that they had given or received gifts for sex (OR 3.5, 95% CI 1.2-10.4; P=0.03), but this may have been a chance finding as no other sexual or reproductive variable was associated with conjunctival cancer, including the number of self-reported lifetime sexual partners (P=0.4). The seroprevalence of antibodies against HPV-18 and -45 was too low to make reliable conclusions. The presence of anti-HPV-16 antibodies was not significantly associated with squamous cell carcinoma of the conjunctiva (OR 1.5, 95% CI 0.5-4.3; P=0.5) and nor were anti-KSHV antibodies (OR 0.9, 95% CI 0.4-2.1; P=0.8). The 10-fold increased risk of conjunctival cancer in HIV infected individuals is similar to results from other studies. The role of other oncogenic viral infections is unclear.

Adolescent↗
PubMed2002

Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans.

The authors used data collected from 1995 to 1999, from an on-going cancer case-control study in greater Johannesburg, to estimate the importance of tobacco and alcohol consumption and other suspected risk factors with respect to cancer of the oesophagus (267 men and 138 women), lung (105 men and 41 women), oral cavity (87 men and 37 women), and larynx (51 men). Cancers not associated with tobacco or alcohol consumption were used as controls (804 men and 1370 women). Tobacco smoking was found to be the major risk factor for all of these cancers with odds ratios ranging from 2.6 (95% CI 1.5-4.5) for oesophageal cancer in female ex-smokers to 50.9 (95% CI 12.6-204.6) for lung cancer in women, and 23.9 (95% CI 9.5-60.3) for lung cancer and 23.6 (95% CI 4.6-121.2) for laryngeal cancer in men who smoked 15 or more grams of tobacco a day. This is the first time an association between smoking and oral and laryngeal cancers has been shown in sub-Saharan Africa. Long-term residence in the Transkei region in the southeast of the country continues to be a risk factor for oesophageal cancer, especially in women (odds ratio=14.7, 95% CI 4.7-46.0), possibly due to nutritional factors. There was a slight increase in lung cancer (odds ratio=2.9, 95% CI 1.1-7.5) in men working in 'potentially noxious' industries. 'Frequent' alcohol consumption, on its own, caused a marginally elevated risk for oesophageal cancer (odds ratio=1.7, 95% CI 1.0-2.9, for women and odds ratio=1.8, 95% CI 1.2-2.8, for men). The risks for oesophageal cancer in relation to alcohol consumption increased significantly in male and female smokers (odds ratio=4.7, 95% CI=2.8-7.9 in males and odds ratio=4.8, 95% CI 3.2-6.1 in females). The above results are broadly in line with international findings.

Adolescent↗
PubMed2002

A randomized control trial of the effect of negotiated telephone support on glycaemic control in young people with Type 1 diabetes.

AIM: To evaluate changes in self-efficacy for self-management in young people with Type 1 diabetes participating in a "Negotiated Telephone Support" (NTS) intervention developed using the principles of problem solving and social learning theory. METHODS: One-year RCT with 79 young people (male 39; mean age +/- sd 16.5 +/- 3.2 years, duration 6.7 +/- 4.4 years, HbA(1c) 8.6 +/- 1.5%) randomized into: Group 1 (control group), continued routine management, n = 28; Group 2, continued routine management with NTS, n = 25; Group 3, annual clinic with NTS, n = 26. OUTCOME MEASURES: HbA(1c), self-efficacy, barriers to adherence, problem solving, and diabetes knowledge. RESULTS: There were no differences between the groups at baseline. Participants in Groups 2 and 3 received an average of 16 telephone calls/year (range 5-19), median duration 9 min (2-30), with a median interval of 3 weeks (1-24) between calls. Significant correlations were found between age and average length of call (r = 0.44, P < 0.01) and frequency of contact (r = 0.36, P < 0.05). Social and school topics were discussed frequently. After 1 year, while the participants in the two intervention groups showed significant improvements in self-efficacy (P = 0.035), there was no difference in glycaemic control in the three groups. Barriers to insulin use adherence were a significant predictor of HbA(1c) (P < 0.001) after controlling for baseline. CONCLUSIONS: NTS is an effective medium to deliver a simple theory-based psychological intervention to enhance self-efficacy for diabetes self-management. Reduced clinic attendance, combined with NTS, did not result in a deterioration of HbA(1c). Intensive personal support needs to be combined with intensive diabetes therapy to improve glycaemic control in this age group.

Adolescent↗
PubMed2002

The effect of gel burns dressings on skin temperature.

OBJECTIVES: This study was designed to investigate the effect on skin temperature of different methods of use of a hydrogel dressing. METHODS: Twelve volunteers had temperature measured under a hydrogel dressing with different combinations of air movement and bandaging. RESULTS: A large drop in skin temperature was only achieved when the dressing was left exposed with air movement over the surface of the dressing. CONCLUSIONS: A temperature that gives effective analgesia is not reached if the dressing is used in accordance with the manufacturer's instructions (covered with an insulating layer). This explains the authors' observation that paramedics and patients often leave these dressings uncovered.

Burns↗
PubMed2002

Effect of bradykinin, TGF-beta1, IL-1beta, and hypoxia on COX-2 expression in pulmonary artery smooth muscle cells.

Prostanoids are major regulators of smooth muscle function that are generated by cyclooxygenase (COX). Here we hypothesized that cytokines and mediators that regulate the pulmonary circulation would alter COX expression and prostanoid generation in pulmonary artery smooth muscle cells. Bradykinin, transforming growth factor-beta1 (TGF-beta1), and interleukin-1beta (IL-1beta) increased inducible COX-2 expression and prostaglandin E(2) (PGE(2)) release. Transfection studies using a COX-2 promoter construct demonstrated that all three agents acted transcriptionally. Constitutive COX-1 protein expression was unchanged. The COX inhibitor indomethacin, the COX-2 inhibitor NS-398, the protein synthesis inhibitor cycloheximide, and the glucocorticoid dexamethasone abrogated the increased PGE(2) levels. Dexamethasone and cycloheximide prevented COX-2 induction. Hypoxia (3% O(2)-5% CO(2)-92% N(2)) for 24 h selectively augmented TGF-beta1-stimulated PGE(2) production and COX-2 induction but had no effect alone. Prolonged hypoxic culture alone for 48 and 72 h enhanced COX-2 induction and increased PGE(2). These studies show that a number of stimuli are capable of inducing COX-2 in pulmonary artery smooth muscle cells. The interaction between hypoxia and TGF-beta1 may be particularly relevant to pulmonary hypertension.

Adult↗
PubMed2002

Cross-cultural differences in the management of children and adolescents with diabetes.

Glycaemic control deteriorates frequently in adolescents with diabetes. There is a considerable body of work on the effect of psychological aspects of management in this age group, but few randomized controlled trials of the effect of specific behavioural therapy and lifestyle modification on the improvement of glycaemic control. Of recent interest have been the observations from the Hvidøre Study Group on cross-cultural differences in glycaemic control. The average glycosylated haemoglobin in 22 centres, across 18 countries, varied in young people, with HbA1c levels ranging from 7.6 to 10.2%. No obvious differences in management were identified in this survey that could account for the disparities in glycaemic control. Data from the Scottish Study Group demonstrated similar variation in average glycaemic control in centres across a single culture. Using the qualitative methodology of anthropological research, some specific factors were identified that appear to influence young people's response to diabetes management and strategies employed by health professionals in their advice and care of the diabetes, particularly in relation to intensive insulin regimens. The main cultural factors influencing glycaemic control appear to be communication, reciprocal support between young people and professional heart carers and family structure within an individualistic, as against an egalitarian, society. Shared beliefs about teenage risk behaviour together with the medicalization of adolescence within medical culture also appears to be highly influential. The aim of this educational discussion group was to explore how a variety of health care professionals from distinctive cultures approach diabetes care delivery in this age group. The specific success and difficulties in different cultures in managing the young person with diabetes were investigated. Also discussed was how qualitative research methodology may generate further research in this area.

Adolescent↗
PubMed2001

Time course and nerve growth factor dependence of inflammation-induced alterations in electrophysiological membrane properties in nociceptive primary afferent neurons.

Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C- and Adelta-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons (Djouhri and Lawson, 1999) were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and Adelta), the increased proportions of units with ongoing activity (C and Adelta), the decreased AP duration (C and Adelta), but not the decreased afterhyperpolarization (AHP) durations (C, Adelta, and Aalpha/beta) (Djouhri and Lawson, 1999). AP variables of nociceptive units with spontaneous activity were examined. The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states.

Action Potentials↗
PubMed2001

TGFbeta1 allele association with asthma severity.

Transforming growth factor beta1 (TGFbeta1) is a multifunctional cytokine involved in pro- and anti-inflammatory pathways and is expressed in several cell types. Subepithelial fibrosis is one of the principle features of airway remodelling in asthma and is increased in severe patients. TGFbeta1 is implicated in fibrosis, including the deposition of extracellular matrix proteins. TGFbeta1 mRNA levels in eosinophils are increased in severe asthmatics relative to mild asthmatics. Therefore, TGFbeta1 is a promising candidate gene for contributing to asthma severity. Four polymorphisms located in the promoter region and signal peptide (C-509T, 72insC, T869C and G915C) were genotyped in groups of severe asthmatic, mild asthmatic or control individuals defined by steroid usage and pulmonary function. Significant differences ( P=0.016) were found between the groups for the genotype frequencies at C-509T, attributable mainly to a greater relative frequency of homozygosity for the -509T allele in the severe group compared to the mild and control groups. Individuals homozygous for -509T were also homozygous at the other variant sites for the 72C, 869C and 915G alleles (haplotype 1). The T allele creates a putative YY1 transcription factor binding site, but binding between YY1 and the DNA sequence of the T allele was not detected in vitro. In this study, we show that the -509T variant on haplotype 1 is the most informative marker of the TGFbeta1 contribution to asthma severity.

Adrenal Cortex Hormones↗
PubMed2001

Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors.

A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.

Administration, Oral↗
PubMed2001

GM-CSF expression in pulmonary epithelial cells is regulated negatively by posttranscriptional mechanisms.

Incubation of pulmonary A549 cells with D609, a phosphatidyl-choline specific phospholipase C (PC-PLC)-inhibitor, or the anti-oxidant, pyrrolidine dithiocarbamate (PTDC), markedly increased IL-1beta-induced GM-CSF elaboration. This effect was observed at the mRNA level and could be partially reproduced by the protein synthesis inhibitor, cycloheximide. Following the peak in GM-CSF mRNA, the mRNA half-life (t(1/2)) was 0.5-1 h. This was increased to around 3 h by cycloheximide, whilst following D609 or PDTC treatment there was essentially no degradation. These data suggest the existence of inhibitory pathways that posttranscriptionally regulate GM-CSF expression via new protein synthesis and D609- and PDTC-sensitive steps. These observations may have important clinical implications. First, drugs that target gene induction may also knock out these inhibitory pathways to lessen their effect. Second, defects in such pathways could lead to overexpression of cytokines or growth factors and contribute to the pathogenesis of inflammatory or proliferative diseases.

Antioxidants↗
PubMed2001

Adenosine 3',5'-cyclic monophosphate (cAMP)-dependent inhibition of IL-5 from human T lymphocytes is not mediated by the cAMP-dependent protein kinase A.

IL-5 is implicated in the pathogenesis of asthma and is predominantly released from T lymphocytes of the Th2 phenotype. In anti-CD3 plus anti-CD28-stimulated PBMC, albuterol, isoproterenol, rolipram, PGE2, forskolin, cholera toxin, and the cAMP analog, 8-bromoadenosine cAMP (8-Br-cAMP) all inhibited the release of IL-5 and lymphocyte proliferation. Although all of the above compounds share the ability to increase intracellular cAMP levels and activate protein kinase (PK) A, the PKA inhibitor H-89 failed to ablate the inhibition of IL-5 production mediated by 8-Br-cAMP, rolipram, forskolin, or PGE2. Similarly, H-89 had no effect on the cAMP-mediated inhibition of lymphocyte proliferation. Significantly, these observations occurred at a concentration of H-89 (3 microM) that inhibited both PKA activity and CREB phosphorylation in intact cells. Additional studies showed that the PKA inhibitors H-8, 8-(4-chlorophenylthio) adenosine-3',5'-cyclic monophosphorothioate Rp isomer, and a myristolated PKA inhibitor peptide also failed to block the 8-Br-cAMP-mediated inhibition of IL-5 release from PBMC. Likewise, a role for PKG was considered unlikely because both activators and inhibitors of this enzyme had no effect on IL-5 release. Western blotting identified Rap1, a downstream target of the cAMP-binding proteins, exchange protein directly activated by cAMP/cAMP-guanine nucleotide exchange factors 1 and 2, in PBMC. However, Rap1 activation assays revealed that this pathway is also unlikely to be involved in the cAMP-mediated inhibition of IL-5. Taken together, these results indicate that cAMP-elevating agents inhibit IL-5 release from PBMC by a novel cAMP-dependent mechanism that does not involve the activation of PKA.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda.

Uganda offers a unique setting in which to study the effect of human immunodeficiency virus-1 (HIV-1) on cancer. HIV-1 is prevalent there, and cancers which are known to be HIV-associated, such as Kaposi's sarcoma and Burkitt's lymphoma, are endemic. Adults residing in Kampala, Uganda, presenting with cancer in city hospitals were interviewed and had an HIV test. Of the 302 adults recruited, 190 had cancers with a potentially infectious aetiology (cases). The remaining 112 adults with tumours not known to have an infectious aetiology formed the control group. In addition, 318 children who were also Kampala residents were recruited and tested for HIV: 128 with cancer (cases) and 190 with non-malignant conditions (controls). HIV seroprevalence was 24% in adult controls and 6% in childhood controls. The odds of HIV seropositivity among cases with specific cancers (other than Kaposi's sarcoma in adults) were compared with that among controls, using odds ratios (ORs), estimated with unconditional logistic regression. All ORs were adjusted for age (<5, 5-14, 15-19, 30-44, 45+) and sex and, in adults, also for the number of lifetime sexual partners (1 or 2, 3-9, 10+). In adults, HIV infection was associated with a significantly (p < 0.05) increased risk of non-Hodgkin's lymphoma [OR = 6.2, 95% confidence interval (CI) 1.9-19.9, based on 21 cases] and conjunctival squamous-cell carcinoma (OR = 10.9, 95% CI 3.1-37.7, based on 22 cases) but not with cancer at other common sites, including liver and uterine cervix. In children, HIV infection was associated with a significantly increased risk of Kaposi's sarcoma (OR = 94.9, 95% CI 28.5-315.3, based on 36 cases) and Burkitt's lymphoma (OR = 7.5, 95% CI 2.8-20.1, based on 33 cases) but not with other cancers. The pattern of HIV-associated cancers in Uganda is broadly similar to that described elsewhere, but the relative frequency of specific cancers, such as conjunctival carcinoma, in HIV-infected people differs.

Adolescent↗