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1.  Expression of Six1 homeobox gene during development of the mouse submandibular salivary gland 
Oral diseases  2009;15(6):407-413.
BACKGROUND
Members of the Six family of homeoproteins are expressed in numerous tissues during vertebrate embryogenesis, and are critical regulators of both cell proliferation and survival. Here we report the temporal and spatial expression of Six1 during maturation of the mouse submandibular salivary gland (SSG) from embryonic day 18.5 (E18.5) to postnatal day 28. Additionally, we examine the role of Six1 during SSG development using Six1-deficient mice.
METHODS
Six1 expression was assessed by RT-PCR, western blot, and immunofluorescence. Proliferation was measured by bromodeoxyuride (BrdU) incorporation index, and apoptosis was evaluated by TUNEL assay.
RESULTS
Six1 mRNA and protein levels are high in the epithelial SSG cells at E18.5 and decrease progressively in the postnatal maturing SSG. Although SSGs from Six1-/- embryos are significantly smaller than wild type SSGs, the histological structures of the SSG acini and ducts are similar. Six1-/- salivary epithelial cells exhibit an intrinsic defect in cell proliferation accompanied by a significant reduction in the Six1 target gene cyclin A1, previously shown to be a critical mediator of Six1-induced proliferation.
CONCLUSION
Our results suggest that the reduction in size of Six1-/- SSGs is result of a decrease in cell proliferation during development/maturation.
doi:10.1111/j.1601-0825.2009.01560.x
PMCID: PMC2756531  PMID: 19371398
submandibular salivary gland; Six1; development; maturation; proliferation; cyclin A1
2.  The MS Symptom and Impact Diary (MSSID): psychometric evaluation of a new instrument to measure the day to day impact of multiple sclerosis 
Objectives: This study aimed to develop further a diary originally devised to measure the impact of multiple sclerosis (MS) as part of a cost utility study of beta interferon, and to evaluate its reliability, validity, and responsiveness in an outpatient sample of people with MS.
Methods: The original diary was further developed using qualitative and quantitative methods to ensure that it addressed the views of people with MS. The psychometric properties of the MS Symptom and Impact Diary (MSSID) were evaluated in a sample of 77 people who completed the MSSID daily for 12 weeks. Internal and test–retest reliability, discriminant and convergent validity, and responsiveness were assessed using traditional psychometric methods.
Results: The MSSID formed three, internally consistent scales that measured mobility, fatigue, and the overall impact of MS. The test–retest reliability of the mobility scale was adequate for individual comparisons (ICC>0.90) and the fatigue and overall impact scales were adequate for group comparisons (ICC>0.70). The MSSID was able to distinguish between clinical groups depending on clinical course, indoor ambulation status, and relapse status. It demonstrated associations with other single point instruments in the expected direction. Compared with single point instruments, its responsiveness was similar or better, especially in detecting short term improvements in functioning.
Conclusions: The MSSID may provide a useful complement to currently available instruments to measure the outcomes of MS within clinical trials. Further research is needed to explore its feasibility in the context of a randomised controlled trial and its utility for clinicians.
doi:10.1136/jnnp.2003.020529
PMCID: PMC1739024  PMID: 15026500
3.  Multiple sclerosis and pregnancy 
Postgraduate Medical Journal  2002;78(922):460-464.
Multiple sclerosis causes disability in young adults and, like most autoimmune diseases, affects women more commonly than men. The disease can therefore present at a time when many have, or are considering, starting a family. The effect of pregnancy on the outcome of multiple sclerosis is reviewed and the management of pregnant women who have multiple sclerosis is discussed.
doi:10.1136/pmj.78.922.460
PMCID: PMC1742473  PMID: 12185217
4.  Phase I study of irinotecan and raltitrexed in patients with advanced astrointestinal tract adenocarcinoma 
British Journal of Cancer  2000;83(2):146-152.
To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175–350 mg m–2followed by raltitrexed 2.6 mg m–2. Level VI was irinotecan 350 mg m–2plus raltitrexed 3.0 mg m–2, level VII was irinotecan 400 mg m–2plus raltitrexed 2.6 mg m–2; 261 courses were administered. Only one patient at dose levels I–V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m–2and raltitrexed 3.0 mg m–2. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.2000.1192
PMCID: PMC2363476  PMID: 10901362
irinotecan; raltitrexed; drug combination; phase I; pharmacokinetics
5.  The prevalence of multiple sclerosis in the Leeds Health Authority 
OBJECTIVES—To determine the prevalence of multiple sclerosis in the Leeds Health District.
METHODS—Multiple sources of case ascertainment were used—namely, neurology departments, hospital episode statistics, general practitioners, the Leeds branch of the Multiple Sclerosis Society, the West Yorkshire Multiple Sclerosis Therapy Centre, community physiotherapists and occupational therapists, the Leeds Wheelchair Centre, and the Young Disabled Unit. Data collection was from retrospective analysis of hospital and primary care case records. A population based incidence register was established by prospectively registering all new patients with diagnoses of multiple sclerosis.
RESULTS—On prevalence day, 30 April 1996, 712 people with multiple sclerosis were identified living in Leeds (population 732 061), giving a prevalence of 97/105. The prevalence for definite and probable multiple sclerosis was 84/105, and for suspected multiple sclerosis it was 13/105. The sex ratio of prevalent people with multiple sclerosis was 2.79 to 1 women to men. The mean age of prevalent cases was 51years, the mean age at symptom onset was 34 years, and the mean duration of disease was 16 years. Forty cases were prospectively reported as incident cases from 1 November 1995 to 1 February 1996.
CONCLUSIONS—The prevalence of multiple sclerosis in Leeds was found to be similar to that in the south of the United Kingdom but lower than that in Scotland. There is no evidence of a latitudinal gradient of increasing prevalence of multiple sclerosis from the south to the north of England.


PMCID: PMC2170076  PMID: 9598675
6.  Telling your patient he/she has multiple sclerosis. 
Postgraduate Medical Journal  1995;71(838):449-452.
It is difficult to tell a person that s/he has multiple sclerosis. The diagnosis is based on clinical findings and often cannot be made on first meeting. In many cases investigations do not help. When the diagnosis is made, the patient should be fully informed in the majority of cases. Guidelines have been developed for imparting the diagnosis. Early diagnosis will become increasingly important with the development of new treatments for multiple sclerosis.
PMCID: PMC2398212  PMID: 7567749
7.  Potent activity of 2'-beta-fluoro-2',3'-dideoxyadenosine against human immunodeficiency virus type 1 infection in hu-PBL-SCID mice. 
Antimicrobial Agents and Chemotherapy  1996;40(10):2369-2374.
A new antiretroviral agent, 2'-beta-fluoro-2',3'-dideoxyadenosine (FddA), is an acid-stable compound whose triphosphate form is a potent reverse transcriptase inhibitor with in vitro anti-human immunodeficiency virus (HIV) activity and a favorable pharmacokinetic profile. Severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) provide a useful small-animal model for HIV research. In the present study we utilized this experimental system for the in vivo evaluation of the anti-HIV activity of this new compound when administered prior to infection. Initial studies revealed that, following a challenge with 50 100% tissue culture infective doses of HIV type 1 lymphadenopathy-associated virus, 39 of 42 (93%) control mice developed HIV infection, as evidenced by positive coculture or positive PCR. Administration of zidovudine decreased the infection rate to 5 of 16 (31%), while administration of FddA decreased the infection rate to 0 of 44 (0%). In follow-up controlled studies, the anti-HIV activity of FddA was confirmed, with 18 of 20 control mice showing evidence of HIV infection, compared with 4 of 20 FddA-treated mice. In addition to having direct anti-HIV effects, FddA was found to have a protective effect on human CD4+ T cells in the face of HIV infection. Mice treated with FddA were found to have a significantly higher percentage of CD4+ T cells than controls (10.3% +/- 3.4% versus 0.27% +/- 0.21%; P = 0.01). Thus, FddA, with its potent anti-HIV activity in vivo, high oral bioavailability, long intracellular half-life, and ability to preserve CD4+ cells in the presence of HIV, appears to be a promising agent for clinical investigation.
PMCID: PMC163536  PMID: 8891146
9.  Assesssment of the effect of pretreatment with neoadjuvant therapy on primary breast cancer. 
British Journal of Cancer  1996;73(6):758-762.
Patients with invasive cancer of the breast (T1-4, N0-2, M0) were assigned to pretreatment based on oestrogen receptor (ER) status; patients with ER-negative tumours received chemotherapy [mitozantrone, methotrexate and mitomycin C (MMM)] for 3 months, patients with ER-positive tumours underwent endocrine therapy [luteinising hormone releasing hormone (LHRH) agonist goserelin (leuprolide-premenopausal) or 4-hydroxyandrostenedione (formestane-post-menopausal)] for 3 months. Of the first 100 patients assessed at 3 months, 47 with ER-positive tumours had a 40.4% response (premenopausal 53.8%; post-menopausal 35%) and 53 with ER-negative tumours had a 60% response (premenopausal 57%; post-menopausal 63%). Patients with early breast cancer (T1/T2) had a complete clinical resolution in 41% (16/39) of cases after MMM and in 20% (7/35) of cases following endocrine therapy compared with 14% (2/14) advanced tumours (T3/T4) following MMM and (0/12) following endocrine therapy. However, in those patients achieving a complete clinical response, subsequent appropriate surgery showed that 16 of 19 patients (84%) had evidence of residual viable tumour on histological examination.
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PMCID: PMC2074387  PMID: 8611376
11.  Measurement of S-phase fraction and ploidy in sequential fine-needle aspirates from primary human breast tumours treated with tamoxifen. 
British Journal of Cancer  1994;70(6):1211-1216.
Sequential fine-needle aspirates (FNAs) for cytodiagnosis and flow cytometry were taken from 21 patients with primary breast carcinoma at intervals ranging from 1 to 3 months after the commencement of first-line tamoxifen therapy. Nine patients achieved a sustained complete or near complete response over a 3-9 month period. The tumour cells from seven out of nine of these patients were initially aneuploid, while the remaining two patients had diploid tumours. An analysis of sequential FNAs showed that, in three out of the seven aneuploid tumours, only benign epithelial cells could be detected by cytology in the post-tamoxifen sample. In the remaining six cases, including the two diploid tumours, there was no change in ploidy but a reduction in S-phase fraction (SPF) to approximately 50% of the pretreatment level. In all cases, these changes in ploidy or SPF were seen with a mean lead time of 4 months before the tumour had reached clinical complete remission. None of these patients have relapsed after a mean follow-up period of 18 months. The tumours of 12 patients achieved no more than a temporary partial response to primary tamoxifen therapy. In seven out of eight of these cases, which were all initially aneuploid, sequential FNAs during tamoxifen therapy revealed either an increase or no change in the SPF with the tumour remaining aneuploid. In the remaining four cases the tumours were all recorded as being diploid in the pretreatment sample. However, although three of these cases had a temporary partial response to tamoxifen, an aneuploid component was picked up in repeat sequential FNAs with a mean lead time of 5 months before clinical confirmation of eventual disease progression. We conclude that changes in ploidy and SPF detected by flow cytometry may predict initial response and the likelihood of relapse of breast tumours to tamoxifen before clinical changes become evident. These data justify a larger study.
PMCID: PMC2033693  PMID: 7981079
12.  Bacterial meningitis in Swaziland: an 18 month prospective study of its impact. 
STUDY OBJECTIVE--To describe the epidemiology, clinical features, and outcome of bacterial meningitis in Swaziland. DESIGN--Prospective study of patients diagnosed as having meningitis of nonviral aetiology during an 18 month period from February 1991 to July 1992. SETTING--Four regional hospitals covering the population of the four districts in Swaziland. SUBJECTS--All patients with non-viral meningitis admitted to hospital within the study period. MAIN RESULTS--Altogether 85 patients were reported to have bacterial meningitis: 48.3% were aged under 1 year. Causative organisms were identified in 60% of cases, and Streptococcus pneumoniae was found to be the commonest (49% of cases). Overall, case fatality was 38.8% for all age groups, and 62.5% (15 of 25) for adults. Neurological sequelae occurred in 22.4%. Three of the adult cases were HIV seropositive. Seizures, but not duration of symptoms before admission, were associated with a poor prognosis. There was a significant rise in incidence related to a period of drought. Fifteen patients were reported with tuberculous meningitis, of whom five were known to be HIV seropositive; the case fatality was 73.3%. CONCLUSIONS--The aetiology and age distribution of cases of meningitis differs greatly from that in developed countries. Rising HIV infection may have an important impact on the future incidence of meningitis. The high case mortality found should encourage efforts towards earlier diagnosis and treatment, and strengthens the need to develop appropriate vaccines.
PMCID: PMC1059959  PMID: 8051527
13.  In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine. 
Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.
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PMCID: PMC187769  PMID: 8494379
14.  Haemostasis in hypothyroidism. 
Postgraduate Medical Journal  1990;66(774):280-284.
Abnormalities that have been reported for platelet indices and function, coagulation factors and tests, and the fibrinolytic system in hypothyroidism are reviewed. These abnormalities, although usually of limited importance clinically, may occasionally lead to major bleeding episodes and to diagnostic confusion.
PMCID: PMC2429394  PMID: 2201013
15.  Another African disaster. 
BMJ : British Medical Journal  1992;305(6867):1479-1480.
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PMCID: PMC1884085  PMID: 1493396
16.  The haematology of hyperthyroidism: abnormalities of erythrocytes, leucocytes, thrombocytes and haemostasis. 
Postgraduate Medical Journal  1988;64(756):735-742.
The abnormalities of erythrocytes, leucocytes, thrombocytes and coagulation that have been reported, particularly in more recent years, to be associated with hyperthyroidism are surveyed. Several areas are highlighted where further investigations could lead to clinically useful insights, improved information about the haematological processes involved or to a better understanding of thyroid hormone action.
PMCID: PMC2429012  PMID: 3076660
17.  Tuberculosis and HIV infection. 
BMJ : British Medical Journal  1991;302(6792):1603.
PMCID: PMC1670353  PMID: 1855057
19.  Diagnosing breast carcinoma in young women. 
BMJ : British Medical Journal  1991;302(6777):618-620.
OBJECTIVE--To assess the individual and combined diagnostic accuracy of clinical examination, mammography, and fine needle aspiration biopsy in young women with breast cancer. DESIGN--Analysis based on case notes of patients presenting with breast cancer during 1971-89. SETTING--A combined breast clinic. PATIENTS--Consecutive series of 81 women aged less than 36 with histologically proved breast cancer presenting with a discrete mass over 19 years. MAIN OUTCOME MEASURES--Results of clinical examination, xeromammography or conventional mammography, fine needle aspiration biopsy, and examination of tissue removed by surgery. RESULTS--The clinical diagnosis was correct in 47 women and radiography in 35. Fine needle aspiration biopsy was correct in 47 of the 63 women in whom it was successfully performed. Fine needle aspiration was significantly more accurate than mammography (78% v 45%, p less than 0.01). Ten (16%) patients had negative results on clinical examination, mammography, and fine needle aspiration. CONCLUSION--Mammography alone seems inadequately sensitive to detect breast cancer in young patients. When all investigations give negative results excision biopsy is the only way of obtaining a definitive diagnosis.
PMCID: PMC1675471  PMID: 2012873
20.  Randomised trial of chemotherapy versus endocrine therapy in patients presenting with locally advanced breast cancer (a pilot study). 
British Journal of Cancer  1991;63(2):279-282.
Sixty patients with locally advanced breast cancer, but with no evidence of distant metastases were randomised to receive primary endocrine therapy or chemotherapy after assessment and 'Trucut' biopsy of the primary tumour. After 12 weeks all patients were assessed. Eight out of 30 (27%) of the patients who received chemotherapy showed complete clinical regression of the primary cancer, eight patients' tumours had regressed by more than 50%, and ten showed a 25-50% reduction in bi-dimensional diameter. Only four (13%) patients' tumours failed to reduce in size. Seven patients were judged to require mastectomy at the end of the 12 week period of treatment with chemotherapy. In contrast, only three out of 30 (10%) patients receiving endocrine therapy showed a greater than 50% reduction in tumour size, and four patients had a 25-50% reduction at 12 weeks. The remaining patients' tumours either stabilised (12 patients) or enlarged (11 patients). We conclude that primary chemotherapy in patients with primary breast cancer is more effective in rapidly reducing the size of the primary breast cancer than endocrine therapy (P = 0.001) and alters significantly the future management of these patients. However, at 65 weeks on completion of the follow-up, there is no significant difference in the number of patients' disease-free, locally or distant recurrent, or dead.
PMCID: PMC1971800  PMID: 1825469
21.  The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. 
British Journal of Cancer  1990;62(4):679-683.
The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.
PMCID: PMC1971476  PMID: 2145964
22.  Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study. 
British Journal of Cancer  1990;61(3):451-453.
We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.
PMCID: PMC1971274  PMID: 2328214
24.  Survey of treatment of primary breast cancer in Great Britain. 
A postal survey of current management of breast cancer among surgeons in Great Britain was carried out. The results showed that there is no consensus among surgeons about the treatment of primary breast cancer. Many different types of primary surgery are practised, and patterns of referral for postoperative radiotherapy vary widely. Adjuvant systemic treatment is given often by some surgeons and not at all by others. Few patients are entered into controlled randomised trials.
PMCID: PMC1415993  PMID: 3924260
25.  Anterior mediastinal mass and Graves' disease. 
Thorax  1985;40(6):469-470.
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PMCID: PMC460107  PMID: 3839604

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