Biomedical subjects
Publications and source records attributed to C Williams.
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BACKGROUND/AIMS: Preschool screening for amblyopia has controversially been abandoned in some localities within the United Kingdom, on the basis that there is no clear evidence of benefit to support its continuation. Data collected within a birth cohort study were used to examine visual outcomes at 7(1/2) years in children who did or did not receive preschool vision screening. METHODS: Monocular logMAR visual acuity with and without a pinhole was assessed by orthoptists. Contemporary records were used to identify children who had been offered and/or received preschool screening. RESULTS: Of 6081 children, 24.9% had been offered preschool screening and 16.7% had attended. The prevalence of amblyopia was approximately 45% lower in the children who received preschool screening than in those who did not (1.1% v 2.0%, p = 0.05). The mean acuity in the worse seeing eyes after patching treatment was better for amblyopic children who received preschool screening than for those who did not; 0.14 v 0.20 logMAR (p <0.001). These effects did not persist in an intention to screen analysis. CONCLUSIONS: Preschool screening at 37 months was associated with an improved treatment outcome for individuals with amblyopia. However, the improvement was clinically small and disappeared when considering all children offered screening rather than only those who received it. Further research is needed into improving the effectiveness of vision screening for preschool children, while in the interim these data do not conflict with current recommendations for school entry screening by orthoptists.
This review will discuss the investigation of infertility, with emphasis on laboratory testing and reference to the value of other investigations, including clinical and radiological. The role of laboratory investigations is viewed within an appropriate clinically directed pathway that includes medical, surgical, and social history together with environmental factors. Because embryology and assisted reproduction techniques are developing rapidly and produce continuous changes in everyday practice, this article gives a critical review of the plethora of tests that are currently used.
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Carbohydrate (CHO) ingestion during short-term recovery from prolonged running has been shown to increase the capacity for subsequent exercise in a warm environment. The aim of this study was to examine the effects of the amount of glucose given during recovery on substrate storage and utilisation during recovery and subsequent exercise in a warm environment. A group of 11 healthy male volunteers took part in two experiments in a controlled warm environment (35 degrees C, 40% relative humidity), 1 week apart. On each occasion the subjects completed two treadmill runs (T1 and T2) at a speed equivalent to 60% of maximal oxygen uptake, for 90 min, until they were fatigued, or until aural temperature (T(aur)) reached 39 degrees C. The two runs were separated by a 4 h recovery period (REC), during which subjects consumed 55 g of naturally enriched [U-(13)C]-glucose in the form of a 7.5% carbohydrate-electrolyte solution (CES, mass of solution 667 g) immediately after T1. The subjects then consumed either: the same quantity of CES, or an equivalent volume of an electrolyte placebo, at 60, 120 and 180 min during REC, providing a total of 220 g (C220) or 55 g (C55) of [U-(13)C]-glucose, respectively. Expired gases were collected at 15 min intervals during exercise and 60 min intervals during REC, for determination of total CHO and fat oxidation by indirect respiratory calorimetry, and orally ingested [U-(13)C]-glucose oxidation, estimated from the (13)C:(12)C ratio of expired CO(2). Substrate metabolism did not differ between conditions during T1. Despite the fact that total CHO (P < 0.05) and ingested glucose oxidation (P < 0.01) were greater during REC of the C220 condition, glycogen synthesis was estimated to be approximately fivefold greater (P < 0.01) than in the C55 condition. During T2 the rate of total CHO oxidation was higher (P < 0.01) and total fat oxidation lower (P < 0.01) at all times during the C220 compared to the C55 condition. The greater CHO oxidation during C220 appeared to be met from ingested sources, as the rate of [U-(13)C]-glucose oxidation was greater (P < 0.01) at all times during T2, compared to C55. Whilst more of the ingested substrate remained unoxidised on completion of T2 during C220, exercise duration was similar in the two experimental conditions, and was limited by thermoregulatory incapacity (T(aur) > 39 degrees C) rather than substrate availability per se.
OBJECTIVE: To assess the effectiveness of early treatment for amblyopia in children. DESIGN: Follow up of outcomes of treatment for amblyopia in a randomised controlled trial comparing intensive orthoptic screening at 8, 12, 18, 25, 31, and 37 months (intensive group) with orthoptic screening at 37 months only (control group). SETTING: Avon, southwest England. PARTICIPANTS: 3490 children who were part of a birth cohort study. MAIN OUTCOME MEASURES: Prevalence of amblyopia and visual acuity of the worse seeing eye at 7.5 years of age. RESULTS: Amblyopia at 7.5 years was less prevalent in the intensive group than in the control group (0.6% v 1.8%; P=0.02). Mean visual acuities in the worse seeing eye were better for children who had been treated for amblyopia in the intensive group than for similar children in the control group (0.15 v 0.26 LogMAR units; P<0.001). A higher proportion of the children who were treated for amblyopia had been seen in a hospital eye clinic before 3 years of age in the intensive group than in the control group (48% v 13%; P=0.0002). CONCLUSIONS: The intensive screening protocol was associated with better acuity in the amblyopic eye and a lower prevalence of amblyopia at 7.5 years of age, in comparison with screening at 37 months only. These data support the hypothesis that early treatment for amblyopia leads to a better outcome than later treatment and may act as a stimulus for research into feasible screening programmes.
BACKGROUND: Paclitaxel has become a standard drug used in a number of common cancers. At first long infusions were used to reduce the rate of inflow of the drug and as a result reduce the occurrence of hypersensitivity types of allergic reactions. Trials with shorter durations of infusion, and using a cocktail of anti-allergic drugs to prevent hypersensitivity reactions, some randomised, were begun. These were interpreted as showing that effectiveness of treatment was not lessened by a short infusion time. These studies also appeared to show that some important toxicities were less common with short infusions and that they were more convenient for the patient and the hospital. OBJECTIVES: To assess the effect of varying the duration of infusion of paclitaxel on its anti-cancer effectiveness and side-effects. SEARCH STRATEGY: Electronic searches of the Cochrane Gynaecological Cancer CRG, the Cochrane Register of Controlled Trials, MEDLINE, EmBase, CANCERLIT, PDQ, Meta-register (mRCT) and the M.D. Anderson Cancer Centre, GOG were carried out. Information from the manufacturer and authors of reports of studies was also acquired. SELECTION CRITERIA: The review was restricted to randomised controlled trials of single agent paclitaxel or paclitaxel with other drugs, where the only variable was the duration of paclitaxel infusion. The review only included patients with advanced adenocarcinoma. DATA COLLECTION AND ANALYSIS: Data was extracted by two independent reviewers and where there was disagreement this was resolved by discussion. Where possible the data was synthesised in a meta-analysis. MAIN RESULTS: Three hour paclitaxel infusions appear to result in a smaller fall in white blood cell count, less fever, infection and sore mouth than 24 hour infusions. In contrast, 24 hour infusions cause less nerve toxicity. Other side-effects are not dependent on the duration of infusion. Evidence from individual trials suggesting efficacy may be slightly greater with 24 hour infusions is inconclusive. Combination of data from trials of different cancer sites in a meta-analysis must be considered speculative, but the combined data also suggest that 24 hour infusions of paclitaxel may be slightly more effective. REVIEWER'S CONCLUSIONS: This review confirms that, apart from neurological effects, three hour infusion of paclitaxel causes significantly less side effects than 24 hour infusion. Insufficient data exists to state whether varying the duration of infusion has a significant effect on its anti-cancer effectiveness. Further study would be required to establish whether there genuinely is a significant difference in efficacy according to the duration of infusion of paclitaxel.
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This study investigated whether the ingestion of a carbohydrate-electrolyte solution during running would influence muscle glycogen utilisation in subjects who had consumed a carbohydrate meal 3 hours before exercise. Eight men completed two 60-min treadmill runs at 70% VO(2)max. Before each run they consumed a carbohydrate meal (183 +/- 7 g) 3 hours before exercise and either 1) a carbohydrate-electrolyte solution during the run (46 +/- 1 g) (M+C), or 2) water during the run (M + W). Biopsy samples were obtained from the vastus lateralis muscle at rest and after 60 min of running. Serum insulin concentrations were higher (p < 0.01) in both trials at the start of exercise compared with fasting values, whereas blood glucose concentrations were higher (p < 0.01) after 60 min of running in the M+C trial. Pre-exercise muscle glycogen concentrations were similar in both trials (M+C: 321.9 +/- 27.2 vs M+W: 338.8 +/- 32.8 mmol x kg x dry weight (-1) [dw]; NS). There was no difference in the amount of glycogen used during exercise (M+C: 96.1 +/- 22.1 vs M+W: 77.9 +/- 11.7 mmol x kg x dw (-1); NS). In conclusion, a carbohydrate-electrolyte solution ingested during treadmill running at 70 % VO(2)max does not influence muscle glycogen use during the first hour of exercise when a carbohydrate meal is consumed 3 hours before exercise.
BACKGROUND: Dietary nitrate increases saliva nitrite levels and swallowed saliva is the main source of nitrite entering the acidic stomach. In acidic gastric juice, this nitrite can generate potentially carcinogenic N-nitrosocompounds. However, ascorbic acid secreted by the gastric mucosa can prevent nitrosation by converting the nitrite to nitric oxide. METHODS: To study the potential for N-nitrosocompound formation in a model simulating salivary nitrite entering the acidic stomach and the ability of ascorbic acid to inhibit the process. Concentrations of ascorbic acid, total vitamin C, nitrite, nitrosomorpholine, oxygen and nitric oxide were monitored during the experiments. RESULTS: The delivery of nitrite into HCl containing thiocyanate resulted in nitrosation of morpholine, with the rate of nitrosation being greatest at pH 2.5. Under anaerobic conditions, ascorbic acid converted the nitrite to nitric oxide and prevented nitrosation. However, in the presence of dissolved air, the ascorbic acid was ineffective at preventing nitrosation. This was due to the nitric oxide combining with oxygen to reform nitrite and this recycling of nitrite depleting the available ascorbic acid. Further studies indicated that the rate of consumption of ascorbic acid by nitrite added to natural human gastric juice (pH 1.5) was extremely rapid with 200 micromol/l nitrite consumed 500 micromol/l ascorbic acid within 10 s. CONCLUSIONS: The rapid consumption of ascorbic acid in acidic gastric juice by nitrite in swallowed saliva indicates that the potential for acid nitrosation will be maximal at the GO junction and cardia where nitrite first encounters acidic gastric juice. The high incidence of mutagenesis and neoplasia at this anatomical location may be due to acid nitrosation arising from dietary nitrate.
Leukocyte migration and activation play an important role in immune surveillance and the pathogenesis of a variety of neurodegenerative disorders, including human immunodeficiency virus (HIV)-1-associated dementia (HAD). A novel chemokine named fractalkine (FKN, CX3CL1), which exists in both membrane-anchored and soluble isoforms, has been proposed to participate in the generation and progression of inflammatory brain disorders. Upon binding to the CX3C receptor one (CX3CR1), FKN induces adhesion, chemoattraction, and activation of leukocytes, including brain macrophages and microglia (MP). Constitutively expressed in the central nervous system (CNS), mainly by neurons, FKN is up-regulated and released in response to proinflammatory stimuli. Importantly, FKN is up-regulated in the brain tissue and cerebrospinal fluid (CSF) of HAD patients. Together, these observations suggest that FKN and its receptor have a unique role in regulating the neuroinflammatory events underlying disease. This review will examine how FKN contributes to the recruitment and activation of CX3CR1-expressing MP, which are critical events in the neuropathogenesis of HAD.
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Recombinant gp120 of the HIV-1(IIIB) isolate (BH10 clone) has been mutated to form the PR12 protein with the first 74 C-terminal amino acids and the V1, V2 and V3 hypervariable loops deleted. A variety of studies have shown that the CD4 binding domain (CD4bd) is very well exposed in PR12 in contrast to rgp120(LAI). Using PR12 for selection of human monoclonal antibodies (MAbs) from HIV-infected individuals, five MAbs were generated with specificities to the epitopes overlapping the CD4bd (1570A,1570C,1570D,1595 and 1599). The three MAbs, 1570A, C and D, generated from one HIV-infected individual, represent one MAb as determined by sequence analysis of the V(H)3 region. Since the epitopes overlapping the CD4bd exhibit variability among HIV-1 clades, the specificity of anti-CD4bd MAbs were distinguished by differing patterns of binding to recombinant envelope proteins derived from clade A, B, C, D and E viruses. The PR12-selected MAbs were also compared with a panel of gp120-selected anti-CD4bd MAbs and showed a different range of specificities. MAb 1599 is clade B specific, MAb 1595 reacts with the A, B and D clades, while MAb 1570 recognises the most conserved epitope, as it binds to all proteins. The results show that the exposure of different epitopes in the CD4bd of the PR12 protein allows this protein to serve as an immunogen and to induce anti-CD4bd antibodies.
Arzoxifene ([6-hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene) is a selective estrogen receptor modulator (SERM) that is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.
It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer. We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors. Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.
1. The aim of this study was to examine the effect of carbohydrate (CHO) ingestion on changes in ATP and phosphocreatine (PCr) concentrations in different muscle fibre types during prolonged running and relate those changes to the degree of glycogen depletion. 2. Five male subjects performed two runs at 70 % maximum oxygen uptake (.V(O2,max)), 1 week apart. Each subject ingested 8 ml (kg body mass (BM))(-1) of either a placebo (Con trial) or a 5.5 % CHO solution (CHO trial) immediately before each run and 2 ml (kg BM)(-1) every 20 min thereafter. In the Con trial, the subjects ran to exhaustion (97.0 +/- 6.7 min). In the CHO trial, the run was terminated at the time coinciding with exhaustion in the Con trial. Muscle samples were obtained from the vastus lateralis before and after each trial. 3. Carbohydrate ingestion did not affect ATP concentrations. However, it attenuated the decline in PCr concentration by 46 % in type I fibres (CHO: 20 +/- 8 mmol (kg dry matter (DM))(-1); Con: 34 +/- 6 mmol (kg DM)(-1); P < 0.05) and by 36 % in type II fibres (CHO: 30 +/- 5 mmol (kg DM)(-1); Con: 48 +/- 6 mmol (kg DM)(-1); P < 0.05). 4. A 56 % reduction in glycogen utilisation in type I fibres was observed in CHO compared with Con (117 +/- 39 vs. 240 +/- 32 mmol glucosyl units (kg DM)(-1), respectively; P < 0.01), but no difference was observed in type II fibres. 5. It is proposed that CHO ingestion during exhaustive running attenuates the decline in oxidative ATP resynthesis in type I fibres, as indicated by sparing of both PCr and glycogen breakdown. The CHO-induced sparing of PCr, but not glycogen, in type II fibres may reflect differential recruitment and/or role of PCr between fibre types.
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