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1.  Are anaesthetics toxic to the brain? 
It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer's disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients.
PMCID: PMC3159425  PMID: 21616941
anaesthesia, general; Alzheimer's disease; neurobehavioural manifestations; postoperative complications
2.  Quality of life and relative importance: a comparison of time trade‐off and conjoint analysis methods in patients with age‐related macular degeneration 
To investigate the relative priorities in quality of life (QoL) in patients with age‐related macular degeneration (AMD).
Measures of visual function, QoL and utility associated with visual loss were obtained from 122 patients with AMD classified according to macular morphology. The two methods of utility assessment were time trade‐off (TTO) and conjoint analysis (CA), which have been recommended by the UK's National Institute of Clinical Excellence as techniques for the assessment of healthcare priorities.
Results show that the two methods for assessing utility are poorly related: TTO relates moderately to visual function and disease severity but CA does not. CA identified two different subgroups of patients: one with outdoor mobility and the other with reading as their main priority.
Further work is needed and caution required in interpreting data obtained using these methodologies for determining their relative importance in vision‐related QoL studies.
PMCID: PMC1955576  PMID: 17229802
3.  Small cell oesophageal carcinoma: an institutional experience and review of the literature 
British Journal of Cancer  2007;96(5):708-711.
Primary small cell oesophageal carcinoma (SCOC) is rare, prognosis is poor and there is no established optimum treatment strategy. It shares many clinicopathologic features with small cell carcinoma of the lung; therefore, a similar staging and treatment strategy was adopted. Sixteen cases referred to Velindre hospital between 1998 and 2005 were identified. Patients received platinum-based combination chemotherapy if appropriate. Those with limited disease (LD) received radical radiotherapy (RT) to all sites of disease on completion of chemotherapy. Median survival of all patients was 13.2 months. Median survival of patients with LD was significantly longer than those with extensive disease (24.4 vs 9.1 months, P=0.034). This is one of the largest single institution series in the world literature. Combined modality therapy using platinum-based combination chemotherapy and radical RT may allow a nonsurgical approach to management, avoiding the morbidity of oesophagectomy. Prophylactic cranial irradiation is controversial, and should be discussed on an individual basis.
PMCID: PMC2360086  PMID: 17299393
small cell; oesophagus; chemotherapy; radiotherapy
4.  Growth-inhibitory and cell cycle-arresting properties of the rice bran constituent tricin in human-derived breast cancer cells in vitro and in nude mice in vivo 
British Journal of Cancer  2004;91(7):1364-1371.
PMCID: PMC2410014  PMID: 15316567
chemoprevention; cell cycle arrest; flavonoids; nude mice; rice bran
5.  Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line 
BMC Cancer  2003;3:2.
Many tumours undergo disregulation of polyamine homeostasis and upregulation of ornithine decarboxylase (ODC) activity, which can promote carcinogenesis. In animal models of colon carcinogenesis, inhibition of ODC activity by difluoromethylornithine (DFMO) has been shown to reduce the number and size of colon adenomas and carcinomas. Indole-3-carbinol (I3C) has shown promising chemopreventive activity against a range of human tumour cell types, but little is known about the effect of this agent on colon cell lines. Here, we investigated whether inhibition of ODC by I3C could contribute to a chemopreventive effect in colon cell lines.
Cell cycle progression and induction of apoptosis were assessed by flow cytometry. Ornithine decarboxylase activity was determined by liberation of CO2 from 14C-labelled substrate, and polyamine levels were measured by HPLC.
I3C inhibited proliferation of the human colon tumour cell lines HT29 and SW480, and of the normal tissue-derived HCEC line, and at higher concentrations induced apoptosis in SW480 cells. The agent also caused a decrease in ODC activity in a dose-dependent manner. While administration of exogenous putrescine reversed the growth-inhibitory effect of DFMO, it did not reverse the growth-inhibition following an I3C treatment, and in the case of the SW480 cell line, the effect was actually enhanced. In this cell line, combination treatment caused a slight increase in the proportion of cells in the G2/M phase of the cell cycle, and increased the proportion of cells undergoing necrosis, but did not predispose cells to apoptosis. Indole-3-carbinol also caused an increase in intracellular spermine levels, which was not modulated by putrescine co-administration.
While indole-3-carbinol decreased ornithine decarboxylase activity in the colon cell lines, it appears unlikely that this constitutes a major mechanism by which the agent exerts its antiproliferative effect, although accumulation of spermine may cause cytotoxicity and contribute to cell death. The precise mechanism by which putrescine enhances the growth inhibitory effect of the agent remains to be elucidated, but does result in cells undergoing necrosis, possibly following accumulation in the G2/M phase of the cell cycle.
PMCID: PMC149232  PMID: 12525265
6.  Differences between human breast cell lines in susceptibility towards growth inhibition by genistein 
British Journal of Cancer  2001;85(4):618-624.
Genistein is thought to contribute to the putative breast cancer preventive activity of soya. The mechanisms by which it arrests the growth of breast cells are incompletely understood. In order to explore generic features of the modulation of human breast cell growth by genistein, its effects on cell lines MCF-7, ZR-75.1, T47-D, MDA-MB 468, MDA-MB 231 and HBL 100 were compared. Genistein at 1 μM stimulated growth only in MCF-7 cells. At 10 μM it arrested the growth of all 6 cell types, however that of T47-D and HBL 100 cells only in medium with reduced (2%) fetal calf serum. Genistein induced apoptosis in only MDA-MB 468 cells. It arrested cells in the G2 stage of the cell cycle in all cell lines except ZR-75.1. Cells differed in their susceptibility towards inhibition by genistein of phorbol ester-induced proto-oncogene c-fos levels, transcription factor activator protein-1 (AP-1) activity and extracellular signal-regulated kinase (ERK) activity. Genistein augmented anisomycin-induced levels of proto-oncogene c-jun in ZR 75.1 and MCF-7 cells. The results suggest that induction of apoptosis, G2 cell cycle arrest and inhibition of c-fos expression, AP-1 transactivation and ERK phosphorylation may contribute to the growth-inhibitory effect of genistein in some breast cell types, but none of these effects of genistein constitutes a generic mode of growth-arresting action. © 2001 Cancer Research Campaign
PMCID: PMC2364092  PMID: 11506505
breast cancer; cancer chemoprevention; genistein; soya; malignant cell growth; signal transduction
8.  Endoscopic laser therapy in malignant tracheobronchial obstruction using sequential Nd YAG laser and photodynamic therapy 
Thorax  1997;52(3):281-283.
BACKGROUND: Because the survival after treatment of advanced inoperable endo-tracheobronchial carcinoma is so poor, a pilot study was undertaken to evaluate the combined cumulative effect on survival of neodymium yttrium aluminium garnet (Nd YAG) laser followed by photodynamic treatment used endoscopically. METHODS: Seventeen patients who presented between January 1992 and March 1996 with inoperable tracheobronchial lesions causing more than 50% endoluminal obstruction were selected to enter the pilot study. Initially they had bronchoscopic Nd YAG laser treatment to debulk the tumour, and this was followed six weeks later by photodynamic therapy to treat the residual tumour. RESULTS: All patients had symptomatic relief and at least a partial response, and seven had a complete response for 3-6 months. Eight of the 17 (47%) survived for at least two years and 11 (65%) survived for a year or more. The median survival of the 10 patients who had died by the time of writing was 18.5 months (range 5-39), 95% confidence interval (CI) 9.9 to 29.5. CONCLUSIONS: Combined Nd YAG laser and endoscopic photodynamic therapy may be an effective palliative treatment for patients with inoperable endotracheobronchial cancer. 

PMCID: PMC1758524  PMID: 9093347
9.  Age-associated increase in 8-oxo-deoxyguanosine glycosylase/AP lyase activity in rat mitochondria. 
Nucleic Acids Research  1999;27(8):1935-1942.
The mitochondrial theory of aging postulates that organisms age due to the accumulation of DNA damage and mutations in the multiple mitochondrial genomes, leading to mitochondrial dysfunction. Among the wide variety of DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) has received the most attention due to its mutagenicity and because of the possible correlation between its accumulation and pathological processes like cancer, degenerative diseases and aging. Although still controversial, many studies show that 8-oxo-dG accumulates with age in the mitochondrial (mt) DNA. However, little is known about the processing of this lesion and no study has yet examined whether mtDNA repair changes with age. Here, we report the first study on age-related changes in mtDNA repair, accomplished by assessing the cleavage activity of mitochondrial extracts towards an 8-oxo-dG-containing substrate. In this study, mitochondria obtained from rat heart and liver were used. We find that this enzymatic activity is higher in 12 and 23 month-old rats than in 6 month-old rats, in both liver and heart extracts. These mitochondrial extracts also cleave oligonucleotides containing a U:A mismatch, at the uracil position, reflecting the combined action of mitochondrial uracil DNA glycosylase (mtUDG) and mitochondrial apurinic/apyrimidinic (AP) endonucleases. The mtUDG activity did not change with age in liver mitochondria, but there was a small increase in activity from 6 to 23 months in rat heart extracts, after normalization to citrate synthase activity. Endonuclease G activity, measured by a plasmid relaxation assay, did not show any age-associated change in liver, but there was a significant decrease from 6 to 23 months in heart mitochondria. Our results suggest that the mitochondrial capacity to repair 8-oxo-dG, the main oxidative base damage suggested to accumulate with age in mtDNA, does not decrease, but rather increases with age. The specific increase in 8-oxo-dG endonuclease activity, rather than a general up-regulation of DNA repair in mitochondria, suggests an induction of the 8-oxo-dG-specific repair pathway with age.
PMCID: PMC148404  PMID: 10101204
11.  Establishing a community network for recruitment of African Americans into a clinical trial. The African-American antiplatelet stroke Prevention Study (AAASPS) experience. 
A major aspect of a clinical trial is the ability to successfully recruit patients. There is a paucity of information concerning the nuances of recruiting study patients, especially those from minority communities. As minorities generally have been underrepresented in the health-care system, they may be less likely to participate in clinical trials or other studies. Thus, a strategy is needed to overcome this potential shortfall. One of our solutions has been the development of a community network to help disseminate information about our program. We believe that a key aspect has been the involvement of community members during pre-trial planning, community awareness programs, and our Community Advisory Panel. We also believe that it may be a major error to bring a health-care initiative unannounced into a targeted community without extensive pre-program planning in cooperation with that community. As our community awareness scheme suggests (Figure), there are many possible avenues to heighten awareness about a health-care program. While the church remains an important institution for religious and cultural activities in the African-American community, we have found that the news, television, and radio media also can be a powerful source for spreading awareness. Thus, we recommend creating awareness about an initiative through a "grassroots" approach of church and community organizations, along with a global approach through news, television, and radio media. As part of the awareness promotion campaign, it must be emphasized that the study is safe and provides benefits to enrollees. The success of health programs is largely dependent on community acceptance, which must be established in the pre-program planning stages of the initiative. This concept of obtaining community approval and acceptance prior to program initiation is not a new one, nor does it exclusively apply to the African-American community. Community leaders and members need to have a vested interest in such a program and a sense of empowerment. Through this type of communication, patient enrollment and community satisfaction can be substantial. Such success can serve as a springboard for other targeted health-care studies or programs in high-risk communities.
PMCID: PMC2608181  PMID: 8961687
12.  Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. 
British Journal of Cancer  1994;69(3):605-608.
Between January 1991 and December 1992 a phase I trial of superficial photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) was undertaken to treat Bowen's disease, superficial basal cell carcinomas (BCCs) and metastatic skin secondaries from breast (adenocarcinoma) or pinna (squamous cell carcinoma). Promising results were obtained with 36 areas of Bowen's disease, with a complete response rate of 89% at a median follow-up of 18 months. The treatment of BCCs was less successful, with 50% complete responses in 16 lesions at a median follow-up of 17 months. Metastatic nodules responded poorly. The treatment was well tolerated and discomfort during light irradiation could be reduced by prior application of 'Emla' cream. Lesions wept for 1-2 weeks following treatment and healed over a period of approximately 2 months. For large areas of Bowen's disease, particularly in anatomically difficult areas and in elderly patients, PDT using ALA may constitute a single simple alternative outpatient treatment to existing therapies. Further work is required to improve the results with BCCs.
PMCID: PMC1968847  PMID: 8123497
13.  Comparison of fine needle aspiration cytology, radioisotopic and ultrasound scanning in the management of thyroid nodules. 
Postgraduate Medical Journal  1990;66(781):914-917.
In 175 patients presenting with thyroid nodules, the diagnostic value in management of fine needle aspiration and cytology (FNAC), pertechnetate (99mTc) scanning and ultrasound imaging was examined. In 82 patients, the diagnosis was confirmed at operation; in the remaining 93, there was a follow-up period of at least 2 years. Thyroid cancer was found in 13 patients. For FNAC the sensitivity, specificity and positive predictive value for thyroid cancer were 92%, 85% and 41% respectively compared with 82%, 34% and 11% for 99mTc pertechnetate scanning, 75%, 61%, 19% for ultrasound and 73%, 58% and 19% for combined pertechnetate and ultrasound scanning. In 14% of patients, the aspirates were inadequate for cytology at the first examination. FNAC is therefore the preferable initial investigation and usually gives results adequate for a decision on surgical or medical management. With medical management and follow-up, ultrasound is of value in defining the nodule and the appearance of the rest of the gland.
PMCID: PMC2429754  PMID: 2176287
14.  Cervical cytology. 
BMJ : British Medical Journal  1990;300(6736):1353-1354.
PMCID: PMC1663007  PMID: 2196945
15.  Management of women with abnormal cervical smears: supplement to terminology in gynaecological cytopathology. 
Journal of Clinical Pathology  1987;40(5):530-531.
Recommendations are made for the management of patients with abnormal cervical smears. Colposcopic examination is indicated for persistent mild and moderate dyskaryosis, as well as for severe dyskaryosis.
PMCID: PMC1141018  PMID: 3584504
16.  Morphometry of spermatozoa using semiautomatic image analysis. 
Journal of Clinical Pathology  1986;39(12):1347-1352.
Human sperm heads were detected and tracked using semiautomatic image analysis. Measurements of size and shape on two specimens from each of 26 men showed that the major component of variability both within and between subjects was the number of small elongated sperm heads. Variability of the computed features between subjects was greater than that between samples from the same subject.
PMCID: PMC1140800  PMID: 3805320
17.  Terminology in gynaecological cytopathology: report of the Working Party of The British Society for Clinical Cytology 
Journal of Clinical Pathology  1986;39(9):933-944.
The report defines and recommends terms for use in cervical cytology.
PMCID: PMC500183  PMID: 3760239
18.  Liver aspiration in the diagnosis of hepatocellular carcinoma in the Gambia. 
Journal of Clinical Pathology  1985;38(2):185-192.
Fine needle aspiration was used for the cytological diagnosis of hepatocellular carcinoma in 151 Gambian patients. Of 133 with hepatic tumours a correct positive cytological diagnosis was obtained in 116 (87.2%). This simple test was a safe and accurate diagnostic procedure. It is particularly suitable for use in countries where medical resources are limited and hepatocellular carcinoma is prevalent.
PMCID: PMC499100  PMID: 2578485
19.  Immunocytochemical reaction of Ca1 and HMFG2 monoclonal antibodies with cells from serous effusions. 
Journal of Clinical Pathology  1985;38(2):180-184.
The Ca1 antibody was used in an alkaline phosphatase immunocytochemical method on cells obtained from 150 specimens of pleural and ascitic fluids. The results were compared with the routine cytology report based on the light microscopical appearances. The Ca1 antibody identified tumour cells in 51 of 57 specimens with malignant cells. The exceptions were four small cell carcinomas, one malignant lymphoma, and one adenocarcinoma. A further seven specimens reported as containing atypical cells but without conclusive evidence of malignancy were Ca1 positive. The Ca1 antibody did not give a positive reaction with benign mesothelial cells. Similar results were obtained with the HMFG2 antibody and malignant cells, but in eight of 18 benign effusions it reacted with mesothelial cells.
PMCID: PMC499099  PMID: 3881482
21.  Screening hospital patients for uterine cervical cancer. 
Journal of Clinical Pathology  1983;36(6):611-615.
Women patients admitted to a district general hospital with non-gynaecological conditions were offered a cervical smear test. In three years 2296 women were tested. Serious uterine pathology was detected in 13 patients (5.7 per 1000) and significant cytological abnormalities (dyskaryosis of all grades) in 46 (20.0 per 1000). Of the women screened 963 (41.9%) had never had a smear test before and 1608 (70.0%) were over 39 yr. The results show that cervical screening of non-gynaecological patients in hospital reaches many of the women at risk for cervical cancer who do not otherwise have smears taken and reveals considerable uterine pathology.
PMCID: PMC498336  PMID: 6853729
22.  Sulphasalazine and male infertility: reversibility and possible mechanism. 
Gut  1981;22(6):445-451.
Earlier observations on infertility related to sulphasalazine treatment were extended and semen samples obtained from 28 patients with inflammatory bowel disease on treatment with sulphasalazine at 2-4 g per day. Semen was examined for changes in density, motility, and morphology before, during, and after withdrawal of sulphasalazine. Gross semen abnormalities were seen in 18 patients on this drug for more than two months. Semen quality improved after sulphasalazine had been withdrawn for more than two months and 10 pregnancies are reported after sulphasalazine withdrawal. Preliminary endocrine and acetylator phenotype studies do not elucidate the mechanism of this important new side-effect of this drug. The time course of the drug's effect on semen quality is consistent with the hypothesis that sulphasalazine or a metabolite, possibly sulphapyridine, is directly toxic to developing spermatozoa. These studies confirmed the preliminary report and suggest that prolonged treatment with sulphasalazine may universally depress semen quality and cause reversible infertility.
PMCID: PMC1419267  PMID: 6114897
23.  An assessment of the Mi-Mark endoemtrial sampling technique. 
Journal of Clinical Pathology  1980;33(1):72-80.
One hundred and twenty cytological smears and 106 histological specimens were obtained from 115 patients using a new technique of endometrial sampling. It proved an atraumatic procedure and was well accepted by the patients. Some problems were encountered in the preparation of satisfactory cytological specimens and in their interpretation. The method was not completely reliable for detecting endometrial pathology and is therefore considered unsuitable for monitoring patients on hormone replacement therapy. It was found to be useful as a gynaecological outpatient technique for sampling the endometrium when formal curettage was unsuccessful, in avoiding the necessity for a preoperative curettage to confirm suspected carcinoma, and in the investigation of infertility.
PMCID: PMC1145985  PMID: 7358859
24.  Evaluation of two regimens to immobilise the knee after injections of yttrium-90. 
British Medical Journal  1979;1(6169):986-987.
Two regimens to immobilise the knee after injection were compared in patients receiving intra-articular yttrium-90 for persistent synovitis of the knee, the patients being randomly allocated to receive either complete bed rest or full mobilisation with the affected knee in a firm splint. There was no difference in the percentage of the radioisotope retained in the knee or in that taken up by other tissues between the two regimens. It is concluded that after intra-articular injections of yttrium-90 strict bed rest in hospital is unnecessary.
PMCID: PMC1598646  PMID: 435953

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