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Biomedical subjects

R Wood

Publications and source records attributed to R Wood.

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

Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland.

The mortality from intrahepatic cholangiocarcinoma has increased recently in England and Wales and elsewhere. This study aims to examine recent trends in the incidence of intrahepatic cholangiocarcinoma in Scotland, to assess the extent to which changes in diagnostic practice may be influencing the observed trends, and to consider whether the results are compatible with a genuine increase in the risk of this cancer. Cancer registration (intrahepatic cholangiocarcinoma and anatomically adjacent cancers) data from Scotland 1968-1997 were analysed, including examination of trends in the percentage of cases recorded as being microscopically-verified. Since the late 1960s, the incidence of intrahepatic cholangiocarcinoma has increased approximately eight-fold in both sexes in Scotland. However, the proportion of cases verified microscopically has decreased substantially since the late 1970s, presumably due to an increasing reliance on radiological imaging for diagnosis. Despite this change in diagnostic practice, the incidence of microscopically-verified intrahepatic cholangiocarcinoma has also increased. While changes in diagnostic practice and misclassification could explain, at least part of, the observed increase in incidence of intrahepatic cholangiocarcinoma, a genuine increase in the risk of this cancer in the Scottish population seems probable. Further work is indicated to examine international trends in incidence, and to assess whether incidence differs within countries according to characteristics such as area of residence, socio-economic status, ethnic origin or occupation.

Adult↗
PubMed2002

Effect of intravenous infusion of recombinant ovine leptin on feed intake and serum concentrations of GH, LH, insulin, IGF-1, cortisol, and thyroxine in growing prepubertal ewe lambs.

In sheep, serum concentrations of leptin change congruently with increases or decreases in nutritional status, while intracerebroventricular infusions of leptin dramatically suppress feed intake in well-fed lambs, and may also increase growth hormone (GH), and/or luteinizing hormone (LH) in undernourished lambs. The objective of the present study was to determine the effects of peripherally delivered ovine leptin, via intravenous infusions, on feed intake and serum concentrations of GH, LH, insulin, IGF-1, cortisol, and thyroxine. Twelve ewe lambs weighing 29.4 +/- 0.7 kg were infused intravenously with a linearly increasing dose of leptin or saline (n = 6 per group) for 10 days, reaching a maximum dose delivered of 0.5mg/h on day 10. Feed intake was assessed twice daily, and blood samples were collected every 10 min for 6 h on days 0, 2, 5, 8, and 10. Serum concentrations of leptin increased in leptin-treated lambs by day 2 (P = 0.05), and continued to increase to concentrations 9-fold greater than saline-infused lambs by day 10 (P < 0.001). Despite the substantial increase in serum leptin, feed intake did not differ between leptin and saline-infused lambs except on day 3.5 (P = 0.01). Furthermore, intravenous infusions of leptin did not significantly influence serum concentrations of insulin, cortisol, IGF-1, thyroxine, LH, or GH. Collectively, these observations contrast with the potent hypophagic effects of leptin when delivered intracerebroventricularly into well-fed lambs. The reasons for the disparate response of lambs treated intravenously with leptin, versus that reported for lambs treated intracerebroventricularly with leptin are not known, but may provide insight into the mechanism(s) of leptin resistance.

Animals↗
PubMed2002

Management of HIV and AIDS in the African context.

The initial response to the African HIV epidemic was to concentrate on the prevention of new infections. There is now an urgent need to address the health care requirements of large numbers of already infected individuals. The spectrum of disease in the African setting is dominated by tuberculosis, bacterial and protozoan infections. In much of Africa, health services are overwhelmed by the care of terminally ill AIDS patients. In the absence of specific HIV therapy, health care resources are being increasingly utilised, but with little survival benefit for the individual. Resources available for treating patients vary considerably between the richer and poorer countries of the continent. Primary prevention of opportunistic infections and maternal child transmission are at present affordable and cost-effective interventions. Whilst antiretroviral therapies may presently be unaffordable in much of Africa, they represent a modality that can have a major effect on HIV survival. The challenge is to improve the health and longevity of HIV-infected individuals with the rational use of the limited health resources available in Africa today.

AIDS-Related Opportunistic Infections↗
PubMed2002

Tuberculosis should not be considered an AIDS-defining illness in areas with a high tuberculosis prevalence.

OBJECTIVE: To assess the prognosis of human immunodeficiency virus (HIV) associated tuberculosis in a high tuberculosis prevalence setting. METHODS: Survival and subsequent AIDS-defining illnesses (ADI) of patients with tuberculosis were compared with patients remaining tuberculosis-free in a prospective cohort study in two university-affiliated adult HIV clinics in Cape Town. RESULTS: Tuberculosis without prior or simultaneous ADI was diagnosed in 141 patients. CD4+ T-lymphocyte count was >200 cells/microl in 67% of the incident tuberculosis cases. Survival in tuberculosis patients was comparable to that of patients with oral hairy leukoplakia and/or oral candidiasis (median = 23.6 vs. 27.8 months respectively; P = 0.59, adjusted hazard ratio [AHR] = 0.87; 95%CI 0.63-1.58), and better than in patients with AIDS (median = 11.5 months; P < 0.001, AHR = 2.37; 95% CI 1.93-4.66). Subsequent ADI were less frequent in tuberculosis than in AIDS patients (AHR = 0.36; 95%CI 0.23-0.58). Survival of patients with pulmonary or extra-pulmonary tuberculosis was similar (P = 0.32). CONCLUSION: Tuberculosis in HIV-infected patients from areas endemic with tuberculosis occurs across a wide spectrum of immune suppression and has a considerably better prognosis than other ADI. Inclusion of tuberculosis in the clinical case definition of AIDS in such areas should be reconsidered.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine.

OBJECTIVES: To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR). METHODS: Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR. RESULTS: Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51). CONCLUSIONS: The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

Adult↗
PubMed2001

World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing.

OBJECTIVES: To examine the natural phenotypic variability in drug susceptibility among recombinant HIV-1 isolates from a large number of untreated HIV-positive individuals from wide-ranging geographic locations, and to use this information to establish biologically relevant cut-off values for phenotypic antiretroviral susceptibility testing. METHODS: Phenotypic susceptibility to 14 antiretroviral agents was determined for HIV-1 samples from > 1000 treatment-naive individuals in seven clinical trials. Samples were from the USA (n = 351), Germany (n = 306), Canada (n = 265), and South Africa (n = 358). Geometric mean fold-resistance and confidence intervals were determined relative to a standard laboratory wild-type virus. RESULTS: Baseline fold-resistance was approximately log-normally distributed for all antiretroviral agents examined. There was no evidence of large geographical differences in average antiviral susceptibility. Geometric mean fold-resistance for each of 14 antiviral agents was similar (+/- 0.5-fold) for samples derived from the USA, Canada, Germany, or South Africa. The non-nucleoside reverse transcriptase inhibitors (NNRTI) exhibited the broadest distribution of susceptibility; approximately 97.5% of all isolates had < 2.5-4.0, < 3.0-4.5, and < 5-10 fold-decrease in susceptibility to five protease inhibitors, six nucleoside analogues, and three NNRTI, respectively. No consistent geographic pattern or clade effect (B versus C) in either the mean or the distribution of baseline antiretroviral susceptibility was observed. CONCLUSIONS: Phenotypic drug susceptibility of HIV-1 in untreated individuals varies markedly from drug to drug, with broadly similar patterns world-wide. These results have important implications in defining the 'normal range' of phenotypic susceptibility to antiretroviral agents and establish biologically relevant cut-off values for this phenotypic drug susceptibility test.

Anti-HIV Agents↗
PubMed2001

Initiating co-trimoxazole prophylaxis in HIV-infected patients in Africa: an evaluation of the provisional WHO/UNAIDS recommendations.

OBJECTIVE: To evaluate the proposed WHO/UNAIDS criteria for initiating co-trimoxazole prophylaxis in adult HIV-infected patients in Africa [WHO clinical stages 2--4 or CD4 count < 500 x 10(6) /l or total lymphocyte count (TLC) equivalent]. DESIGN: Observational cohort study of 5-year follow-up. SETTING: Adult HIV clinics, University of Cape Town, South Africa. METHODS: Effect of prophylactic low dose co-trimoxazole (480 mg per day or 960 mg three times per week) on survival and morbidity was assessed in patients stratified by WHO clinical stage, CD4 T-lymphocyte count or TLC. Patients receiving antiretroviral therapy were excluded. RESULTS: Co-trimoxazole reduced mortality [adjusted hazard ratio (AHR), 0.56; 95% confidence interval (CI), 0.33--0.85; P > 0.001] and the incidence of severe HIV-related illnesses (AHR, 0.52; 95% CI, 0.38--0.68; P < 0.001) in patients with evidence of advanced immune suppression on clinical (WHO stages 3 and 4) or laboratory assessment (TLC < 1250 x 10(6)/l or CD4 count < 200 x 10(6)/l). No significant evidence of efficacy was found in patients with WHO stage 2 or CD4 count 200--500 x 10(6)/l/TLC 1250--2000 x 10(6)/l. If we had applied the WHO/UNAIDS recommendations 88.3% of our patients would have received co-trimoxazole prophylaxis at their initial clinic visit. CONCLUSION: Co-trimoxazole in HIV-infected adults from an area in which Pneumocystis carinii pneumonia is uncommon demonstrated a survival benefit consistent with previous randomized trials. Further studies are needed to assess the optimal time of commencement of prophylaxis, as widespread co-trimoxazole use will lead to increasing antimicrobial resistance to other major pathogens in Africa.

AIDS-Related Opportunistic Infections↗
PubMed2001

Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells.

This study was designed to analyze whether ceramide, a bioeffector of growth suppression, plays a role in the regulation of telomerase activity in A549 cells. Telomerase activity was inhibited significantly by exogenous C(6)-ceramide, but not by the biologically inactive analog dihydro-C(6)-ceramide, in a time- and dose-dependent manner, with 85% inhibition produced by 20 microm C(6)-ceramide at 24 h. Moreover, analysis of phosphatidylserine translocation from the inner to the outer plasma membrane by flow cytometry and of poly(ADP-ribose) polymerase degradation by Western blotting showed that ceramide treatment (20 microm for 24 h) had no apoptotic effects. Trypan blue exclusion, [(3)H]thymidine incorporation, and cell cycle analyses, coupled with clonogenic cell survival assay on soft agar, showed that ceramide treatment with a 20 microm concentration at 24 h resulted in the cell cycle arrest of the majority of the cell population at G(0)/G(1) with no detectable cell death. These results suggest that the inhibition of telomerase by ceramide is not a consequence of cell death but is correlated with growth arrest. Next, to determine the role of endogenous ceramide in telomerase modulation, A549 cells were transiently transfected with an expression vector containing the full-length bacterial sphingomyelinase cDNA (b-SMase). The overexpression of b-SMase, but not exogenously applied purified b-SMase enzyme, resulted in significantly decreased telomerase activity compared with controls, showing that the increased endogenous ceramide is sufficient for telomerase inhibition. Moreover, treatment of A549 cells with daunorubicin at 1 microm for 6 h resulted in the inhibition of telomerase, which correlated with the elevation of endogenous ceramide levels and growth arrest. Finally, stable overexpression of human glucosylceramide synthase, which attenuates ceramide levels by converting ceramide to glucosylceramide, prevented the inhibitory effects of C(6)-ceramide and daunorubicin on telomerase. Therefore, these results provide novel data showing for the first time that ceramide is a candidate upstream regulator of telomerase.

Adenocarcinoma↗
PubMed2001

When is now? Perception of simultaneity.

We address the following question: Is there a difference (D) between the amount of time for auditory and visual stimuli to be perceived? On each of 1000 trials, observers were presented with a light-sound pair, separated by a stimulus onset asynchrony (SOA) between -250 ms (sound first) and +250 ms. Observers indicated if the light-sound pair came on simultaneously by pressing one of two (yes or no) keys. The SOA most likely to yield affirmative responses was defined as the point of subjective simultaneity (PSS). PSS values were between -21 ms (i.e. sound 21 ms before light) and +150 ms. Evidence is presented that each PSS is observer specific. In a second experiment, each observer was tested using two observer-stimulus distances. The resultant PSS values are highly correlated (r = 0.954, p = 0.003), suggesting that each observer's PSS is stable. PSS values were significantly affected by observer-stimulus distance, suggesting that observers do not take account of changes in distance on the resultant difference in arrival times of light and sound. The difference RTd in simple reaction time to single visual and auditory stimuli was also estimated; no evidence that RTd is observer specific or stable was found. The implications of these findings for the perception of multisensory stimuli are discussed.

Acoustic Stimulation↗
PubMed2001

Assessment of murine bladder permeability with fluorescein: validation with cyclophosphamide and protamine.

OBJECTIVES: Bladder hyperpermeability should result in elevated blood levels of intravesically administered agents. Reabsorption from a hyperpermeable bladder should result in prolonged urinary excretion of an agent after parenteral administration. To test these hypotheses, urinary clearance and plasma levels of sodium fluorescein (NaF) were measured in mice before and during cyclophosphamide (CYP) and protamine-induced hemorrhagic cystitis. METHODS: To measure the plasma uptake of NaF from the bladder, 10 mg/mL NaF was instilled, either by catheter or retrograde urethral infusion, 15 minutes before retro-orbital or ventricular sampling. The plasma levels were measured 24 hours and 14 days after exposure to CYP 300 mg/kg or 15 minutes after instillation of protamine 10 mg/mL. Hourly urine concentrations were measured immediately after intraperitoneal administration of 10 mg/kg NaF. Pretreatment samples were compared with those obtained 24 hours after intraperitoneal administration of 300 mg/kg CYP. RESULTS: Urinary NaF excretion was delayed in CYP-exposed mice. A bi-exponential model provided an appropriate fit of the data, both before and after CYP administration. The plasma levels of NaF were significantly elevated at 24 hours and 14 days after CYP exposure when sampled by ventricular nick or retro-orbitally. The median concentration of fluorescein in the protamine-treated mice was significantly higher than in the control mice. CONCLUSIONS: Fluorescein can be used to measure alterations in bladder permeability after bladder mucosal injury in mice. Urinary excretion of NaF is a bi-exponential process that is delayed after bladder mucosal injury, presumably because of increased mucosal permeability and resorption from the urine into the bloodstream.

Analysis of Variance↗
PubMed2001

Monitoring patients in the community with suspected Escherichia coli O157 infection during a large outbreak in Scotland in 1996.

During outbreaks of Escherichia coli O157 a minority of patients with suspected infection develop haemolytic uraemic syndrome (HUS). The ability to identify this subgroup at an early stage is beneficial as mortality from HUS is high and may be influenced by intervention. During the 1996 Central Scotland E. coli O157 outbreak, of 886 patients from the community with suspected infection monitored at an outbreak clinic, nine developed HUS. We assessed factors associated with the development of HUS in this group. Children and the elderly were at increased risk of HUS. However, high white cell count was as least as good a predictor of HUS as age. High white cell counts predicted development of HUS with a sensitivity of 89%, specificity of 87%, positive predictive value of 7% and a negative predictive value of over 99%. We have used the results from this study along with other currently available evidence to propose a monitoring protocol for patients from the community with suspected E. coli O157 infection.

Adolescent↗
PubMed2001

Optimised uncertainty at minimum overall cost to achieve fitness-for-purpose in food analysis.

An optimised uncertainty (OU) methodology is described, that balances the uncertainty of measurements on food against the cost of the measurements and the other expenditure that may arise as a consequence of the possible misclassification of the food. Measurement uncertainty from the sources of primary sampling and chemical analysis is estimated using an existing technique, which is based on the taking of duplicated samples and duplicated analyses. The input information required for the OU method is the actual costs of sampling and analysis, and the expected costs that could arise from either the 'false positive' or 'false negative' classification of batches of food. A loss function is then constructed that calculates the 'expectation of loss' which will arise for a given uncertainty of measurement. This function has a minimum value of cost at an optimal value of uncertainty, which can be estimated numerically. Application of this OU method to a case study on the determination of aflatoxin levels in pistachio nuts has demonstrated this minimum value. Below the optimum value of uncertainty, the costs increased due to higher measurement costs. Above the optimum value, the costs increased due to increasing probability of expenditure on consequences such as unnecessary rejection of the batch, potential litigation or loss of corporate reputation because of undetected contamination. A second stage of the OU method optimises the division of the expenditure on the measurement between that on sampling and that on analysis. The technique is demonstrated as a useful new approach for judging the fitness-for-purpose of chemical measurements in the food industry. Several areas for further development of the technique are identified. By matching the expenditure on the measurement against that caused by the misclassification of the food, the OU method has the potential to reduce overall expenditure whilst ensuring an appropriate reliability of measurement.

Aflatoxins↗
PubMed2001

Automated noninvasive measurement of cyclophosphamide-induced changes in murine voiding frequency and volume.

PURPOSE: We developed an automated noninvasive method for studying bladder function in mice. Changes in voided volume and frequency accompanying cyclophosphamide-induced cystitis were measured using computerized digital balances. MATERIALS AND METHODS: Eight CRL CD-1 mice were given a solution of glucose and saccharin to increase urine output and studied during the dark cycle, when most voiding occurs. Urine fell directly onto electronic balance pans. The time and weight of each void was recorded. Computer programs adjusted for evaporative loss analyzed voiding data within and across sessions. After establishing stable voiding patterns 300 mg./kg. cyclophosphamide were administered intraperitoneally. The Wilcoxon signed rank test was done to compare median voided volumes, frequency and gm. per hour of urine produced before and after cyclophosphamide. RESULTS: We implemented an automated method for voiding studies in mice. After cyclophosphamide administration the number of voids per hour increased and voided volume decreased. Some mice had as much as a 70% decrease in bladder volume and a tripling of urinary frequency. Mice responded by a sustained elevation in frequency and decreased voided volume as early as 24 hours after cyclophosphamide administration or by a pattern of delayed toxicity. CONCLUSIONS: This noninvasive technique measures changes in mouse voiding patterns with great sensitivity and minimal effort. The method is applicable to murine models of interstitial cystitis, detrusor instability and other abnormal voiding states. It may be used for evaluating potential therapies for such conditions.

Animals↗