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Biomedical subjects

J Marshall

Publications and source records attributed to J Marshall.

At least 37 records · Page 2Linked to original sources
PubMed2004

A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors.

PURPOSE: Expression of the Bcl-2 protein confers resistance to various apoptotic signals. G3139 [oblimersen sodium (Genasense)] is a phosphorothioate antisense oligodeoxynucleotide that targets Bcl-2 mRNA, downregulates Bcl-2 protein translation, and enhances the antitumor effects of subtherapeutic doses of docetaxel (Taxotere). PATIENTS AND METHODS: We performed a phase I trial to determine the maximum tolerated dose (MTD) and safety profile of combined therapy with G3139 and weekly docetaxel in patients with advanced Bcl-2-positive solid tumors. Cohorts of three to six patients were enrolled to escalating doses of G3139 and a fixed dose of weekly docetaxel using either of two schedules. In part I, G3139 was administered by continuous infusion for 21 days (D1-22), and docetaxel (35 mg/m2) was given weekly on days 8, 15 and 22. In part II, G3139 was given by continuous infusion for 5 days before the first weekly dose of docetaxel, and for 48 h before the second and third weekly docetaxel doses. For both schedules, cycles were repeated every 4 weeks. RESULTS: Twenty-two patients were enrolled. Thirteen patients were treated on the part I schedule with doses of G3139 escalated from 1 to 4 mg/kg/day. Nine patients were on the part II schedule of shorter G3139 infusion at G3139 doses of 5-9 mg/kg/day. Hematologic toxicities were mild, except for one case of persistent grade 3 thrombocytopenia in part I. The most common adverse events were cumulative fatigue and transaminase elevation, which prevented further dose escalation beyond 4 mg/kg/day for 21 days with the part I schedule. In part II of the study, using the abbreviated G3139 schedule, even the highest daily doses were tolerated without dose-limiting toxicity or the need for dose modification. Objective tumor response was observed in two patients with breast cancer, including one whose cancer previously progressed on trastuzumab plus paclitaxel. Four patients had stable disease. Pharmacokinetic results for G3139 were similar to those of other trials. CONCLUSIONS: G3139 in combination with standard-dose weekly docetaxel was well tolerated. The shortened and intermittent G3139 infusion had less cumulative toxicities and still allowed similar total G3139 delivery as the longer infusion. Further studies should examine the molecular effect of the regimen, as well as clinical activities in malignancies for which taxanes are indicated.

Adult↗
PubMed2004

Hypertriglyceridaemia in Alström's syndrome: causes and associations in 37 cases.

OBJECTIVE: To document frequency of severe hypertriglyceridaemia in Alström's syndrome (AS) and its relationship to hepatic and renal function, glycaemia and insulin resistance. PATIENTS AND METHODS: Thirty-seven subjects with AS aged 5-35 years, 51% male, were assessed at multidisciplinary clinics in Canada, UK and Italy. Diagnostic criteria were: severe cone/rod dystrophy leading to severe visual impairment in early childhood, sensorineural deafness, moderate overall obesity and normal intelligence. Three patients were treated with thyroxine for primary hypothyroidism and one female patient for secondary amenorrhoea with 20 micro g ethinyloestradial combined oral contraceptive. Two male patients were receiving monthly intramuscular testosterone enanthate for secondary hypogonadism. Fasting bloods were taken for serum insulin, serum glucose, serum triglycerides, hepatic and renal function and glycosylated Hb. Triglyceride levels > 8 mmol/l and fasting serum insulin levels > 16 microunits/ml were considered to represent severe hypertriglyceridaemia and severe insulin resistance, respectively. All subjects with (23) hypertriglyceridaemia also had high insulin resistance, as measured by HOMA modelling. However, there was no significant correlation between log tyriglyceride and log serum insulin or HOMA in the whole group (P = 0.2 and 0.14, respectively). There was no clear relationship between serum triglyceride levels and age, body mass index (BMI), hepatic or renal impairment or glycaemia. CONCLUSION: The first overview of serum triglyceride levels in a significant number of reported cases of Alström Syndrome shows an overlap between severe hypertriglyceridaemia and severe hyperinsulinism, but not a direct correlation between the two nor with insulin resistance measured by HOMA. Triglyceride levels were not related to glycaemia, hepatic or renal dysfunction.

Adolescent↗
PubMed2004

Five-year follow-up of women with borderline and mildly dyskaryotic cervical smears.

This study investigated the 5-year follow-up status of women with cervical smears showing borderline nuclear changes (BNC) or mild dyskaryosis and the effect of koilocytosis on the outcome. Thirteen per cent of women with cervical smears showing BNC had high-grade cervical intraepithelial neoplasia (CIN). In contrast, 28% of women with cervical smears showing mild dyskaryosis had high-grade CIN. The presence of koilocytosis (24% for borderline smears and 34% for mild dyskaryotic smears) did not appear to influence the risk of developing high-grade CIN. Our results suggest that the simultaneous implementation of the British Society for Clinical Cytology proposed terminology and the colposcopy guidelines from the British Society for Colposcopy and Cervical Pathology could have an impact on colposcopy services.

Cell Nucleus↗
PubMed2004

A mathematical model of factors that influence the performance of accommodative intraocular lenses.

In this work a mathematical model of capsule movement during pseudophakic accommodation is described to allow identification and evaluation of factors that may explain the variation in effect of accommodative intraocular lenses (IOLs) between patients. The model assumes that increasing vitreous pressure pushes the lens capsule forward as a circular diaphragm and that this movement is from a fixed fulcrum. With an IOL in situ, the capsule is taken to have a non-uniform thickness due to the presence of the anterior capsulorhexis. The model assumes a uniform capsular elasticity and ignores contributions from cellular elements such as posterior capsule opacification. Using our model and a regression formula to calculate capsular bag size, taking into account axial length and keratometry values, we are able to predict accommodative effect in individual patients. By simple geometry we have developed a mathematical model to identify variables that are important in pseudophakic accommodation. It provides the basis for the development of a more complex model that would address the movement of a lens taking into account the influence of the zonular system during accommodation.

Accommodation, Ocular↗
PubMed2003

Histopathological observations on the activity of diclazuril (Vecoxan) against the endogenous stages of Eimeria crandallis in sheep.

Doses of sporulated oocysts of Eimeria crandallis were administered to 60 housed lambs aged 3-4 weeks that had been raised coccidia-free. Thirty of the lambs were medicated with diclazuril at intervals over a 20-day period post-infection with the remaining lambs serving as untreated controls. Lambs were euthanased between 5 and 22 days post-infection (dpi) and sections of the small intestine and caecum examined histologically. Untreated lambs showed loss of surface epithelial cells and villous atrophy associated with first-generation meronts, crypt destruction and crypt hyperplasia associated with pro-gamont stages. Diclazuril appeared to have a direct effect on several stages of the parasite life cycle, in particular, the large first-generation meront. Indications were that the drug also had an effect on second-generation meronts and gamont stages. Therapeutic benefits of diclazuril treatment appeared greatest when given early in the infection before damage to the intestine occurs although removal of coccidial stages did appear to reduce the pathology of the disease.

Animals↗
PubMed2003

Screening for problem drinking in older people referred to a mental health service: a comparison of CAGE and AUDIT.

The aim of the study was to evaluate the validity of the Alcohol Use Disorders Identification Test (AUDIT), the five-item version (AUDIT-5) and the CAGE as screening tests for problem drinking in mentally ill older people. The study was of prospective cross-sectional design with questionnaire survey and interview and included all consecutive referrals to an old age psychiatry service fulfilling inclusion criteria. Sensitivity, specificity and positive predictive values and areas under the receiver operating characteristic curves (AUROC) for the AUDIT, AUDIT-5, and CAGE were the primary outcome measures. Using clinical criteria as the gold standard, the AUDIT, AUDIT-5 and CAGE had AUROCs of 0.961, 0.964, and 0.780 respectively. The AUDIT-5 performed best of the three scales with a sensitivity of 75.0%, specificity of 97.2% and positive predictive value of 83.3% when using a 4/5 cut-point. The AUDIT-5 performed as well as the AUDIT and better than the CAGE in identifying problem drinking in this sample. The AUDIT-5 may be a useful addition to the specialist mental health assessment of older people.

Aged↗
PubMed2003

A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863.

BACKGROUND: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. PATIENTS AND METHODS: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. RESULTS: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. CONCLUSIONS: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Adult↗
PubMed2003

Outcome of women with inadequate cervical smears followed up for five years.

BACKGROUND: The clinical and prognostic significance of "inadequate" cervical smear is unknown, even though women with repeated inadequate smears are referred for colposcopy in the National Health Service (NHS) Cervical Screening Programme. AIM: To follow up a cohort of women with inadequate cervical smears over the following five years to examine outcomes, including detection of high grade cervical intraepithelial neoplasia (CIN). METHODS: The study comprised 1972 women with an inadequate cervical smear reported at Walsall Hospitals NHS Trust between 1 April 1995 and 31 March 1996. Results of cervical smears and biopsies taken over the following five years were reviewed to confirm the outcome. FINDINGS: Within five years, 2.2% of women with an inadequate cervical smear developed histologically confirmed high grade CIN, which was higher than the 1.3% seen among all women with cervical smear tests reported at the same laboratory over the same period, although the difference was not significant at the 95% level of confidence. Where inadequacy resulted from or was contributed to by "polymorphs obscuring", the risk of subsequent development/detection of high grade CIN was 2.6%. CONCLUSIONS: Women with inadequate cervical smears had an increased risk of detection of high grade CIN in the following five years compared with "all women". This increased risk was not significant, although if a larger number of women had been studied significance may have been reached, so that further studies are needed. The increased risk appeared to be at least partially dependent on the reason for inadequacy.

Adult↗
PubMed2003

Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms.

METHODS: The 22q13 deletion syndrome (MIM 606232) is characterised by moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features. We have determined the deletion size and parent of origin in 56 patients with this syndrome. RESULTS: Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions vary widely in size, from 130 kb to over 9 Mb; however all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene. The molecular structure of SHANK3 was further characterised. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate to deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. CONCLUSION: Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome.

Base Sequence↗
PubMed2002

Immunocytochemical evidence of calreticulin-like protein in pollen tubes and styles of Petunia hybrida Hort.

With a polyclonal antibody raised against calreticulin (CRT) the locations where the protein occurs in unpollinated and pollinated styles of Petunia hybrida were localized. The epitopes binding the CRT antibody were immunolocalized preferentially in pollen tubes. In transmitting tract cells, both before and after pollination, the level of CRT was low. The protein was mainly localized in the cytosol and around dictyosomes of transmitting-tract cells. In pollen tubes, a high level of CRT was found at their tips rich in endoplasmatic reticulum, cisternae piles of reticular and/or dictyosomal origin, and vesicles. Binding sites of the CRT antibody were also found in the internal callosic cell wall of the pollen tube. These results indicate a role of CRT in cells directly participating in pollen-pistil interaction.

Antibodies↗
PubMed2002

Aspect differences in above- and belowground carbon allocation: a Montana case-study.

Aboveground net primary production (ANPP) and belowground gross primary production (BGPP) of all vegetation were measured in eight young, paired plots on a north and south aspect in western Montana. Stands of high and low overstory tree leaf area index (LAI) were compared. BGPP increased with ANPP, though they were not directly proportional. ANPP ranged from 1550 to 4400 kg C ha(-1) year(-1) and BGPP ranged from 1360 to 3500 kg C ha(-1) year(-1). ANPP and BGPP were both significantly related to LAI and aspect, where both were greater on the north aspect at any given LAI. Litterfall represented the largest share of ANPP; increases in overstory biomass represented the next largest share. Soil CO2 flux was higher on the north aspect. We conclude that growth differences were not simply a matter of re-allocating carbon between root production and ANPP. Rather, both production and allocation were different among the sites.

Biomass↗
PubMed2002

The co-application of sprayed cultured autologous keratinocytes and autologous fibrin sealant in a porcine wound model.

We have explored the potential for cultured autologous keratinocytes to form an epidermis when delivered as a spray intermixed with autologous fibrin sealant. Twelve full-thickness wounds in Large White pigs (six wounds in each of two pigs) were isolated from the surrounding skin by 4 cm diameter polytetrafluoroethylene chambers, and grafted with Integra artificial skin (Ethicon). Autologous fibrin sealant was produced 10 days later, using an automated processor unit (Vivostat System, ConvaTec, Bristol Myers Squibb), from 120 ml of autologous citrated blood taken 30 min before keratinocyte application. Nine wounds were sprayed, using a Vivostat System automated applicator unit, with a mixture of the sealant preparation and freshly trypsinised cultured autologous keratinocytes in growth medium, at a density of 1-3 x 10(5) cm(-2). Three control wounds were sprayed with the same mixture without cells. The sealant-cell mixture polymerised and adhered to the wound surface immediately. Histological analysis of biopsies taken following sealant-cell application showed that isolated spherical keratinocytes were distributed throughout the sealant at between 3.1 x 10(4) cm(-2) and 7.6 x 10(4) cm(-2). After 4 days discreet colonies of keratinocytes were observed on the wound bed. At 14 days a multi-layered undulating epidermis was formed, punctuated by sporadic epidermal cysts; the mean area of epithelium was 50.1% (s.d. = 19.7%, n = 9). There was no epithelium in the controls (s.d. = 0, n = 3). The difference was statistically significant (P=0.016). This study suggests that co-sprayed cultured keratinocytes and autologous fibrin sealant may be an effective means of delivering epithelial cells to assist wound healing.

Aerosols↗
PubMed2002

A portable instrument for measuring macular pigment with central fixation.

PURPOSE: To evaluate the reliability and validity of a portable instrument for measuring macular pigment optical density. METHODS: The instrument is small, uses light emitting diodes as light sources and the principles of heterochromatic flicker photometry of comparing foveal and extra-foveal minimum flicker matches. It uses central fixation for the extra-foveal matches, which subjects found easier than eccentric fixation. Subjects with healthy eyes used the instrument to measure their pigment density in a number of eye clinics. RESULTS: The mean pigment density in 124 eyes in 124 individuals was 0.41 +/- 0.16 (mean +/- SD), there was no significant change with age but the density was less in females, those with light irides, smokers, subjects on diets low in precursor carotenoids and in those exposed to several hours of daylight every day or who used sun beds. CONCLUSIONS: The portable instrument gave valid and reliable data that confirmed published values for macular pigment. It was convenient to use in the clinic and has potential as a screening tool.

Adolescent↗
PubMed2002

Transfection of HEK cells via DNA-loaded PLGA and P(FASA) nanospheres.

HEK cells were transfected with the GFP gene using various vectors: naked DNA, lipofectamine, and both PLGA and P(FASA) plasmid-loaded nanospheres. All methods were assessed alone and with the use of chloroquine, a lysosomal enzyme inhibitor. Transfection efficiencies were determined and compared at various times post-incubation using a fluorescence standard curve. Neither naked DNA alone nor naked DNA and chloroquine were capable of transfecting cells. No differences were evident between lipofectamine with chloroquine and lipofectamine alone which transfected cells with a constant increase in efficiency up to 2 weeks. While transfection was not feasible with polymeric nanospheres alone, the addition of chloroquine allowed DNA released from nanospheres within cells to escape endosomal degradation and transfect the cells. The increase in transfection efficiency via nanospheres over time was exponential up to 1 week, as compared to the constant rate seen for the bolus-type administration of lipofectamine, indicating that nanospheres delivered DNA to the cells by a controlled release mechanism. Additionally, the effective dose delivered to cells via nanospheres was approximately 25% that of lipofectamine, indicating that transfection via PLGA and P(FASA) nanospheres might actually be more efficient.

Cell Line↗
PubMed2002

First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.

PURPOSE: To evaluate the safety profile of capecitabine using data from a large, well-characterized population of patients with metastatic colorectal cancer treated in two phase II studies. In these trials, capecitabine achieved significantly superior response rates, equivalent time to disease progression and equivalent survival compared with 5-fluorouracil (5-FU)/leucovorin. PATIENTS AND METHODS: Patients (n = 1207) were randomized to either oral capecitabine (1250 mg/m2 twice daily, on days 1-14 every 21 days) or intravenous (i.v.) bolus 5-FU/leucovorin (Mayo Clinic regimen). RESULTS: Capecitabine demonstrated a safety profile superior to that of 5-FU/leucovorin, with a significantly lower incidence of diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia leading to significantly fewer neutropenic fever/sepsis cases and fewer hospitalizations. All patients in the capecitabine group received a starting dose of 1250 mg/m2 twice daily and the majority (66%) did not require dose modification for adverse events. In the 5-FU/leucovorin group, 58% of patients did not require dose reduction for toxicities. The capecitabine dose-modification scheme reduced the recurrence of key toxicities without compromising efficacy. In both treatment arms, patients with moderate renal impairment at baseline (estimated creatinine clearance 30-50 ml/min) experienced a higher incidence of grade 3 or 4 toxicities. This increase was more pronounced with 5-FU/leucovorin. CONCLUSIONS: Capecitabine is at least as effective, better tolerated and more convenient than i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer. Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events. The phase III data and an additional pharmacokinetic study support a lower starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30-50 ml/min) and a contra-indication in patients with severely impaired creatinine clearance at baseline (<30 ml/min). For patients with normal or mildly impaired renal function at baseline, the standard starting dose is well tolerated. The incidence and severity of adverse events in patients with moderate renal impairment at baseline who were treated with 5-FU/leucovorin was more pronounced, indicating that capecitabine provides a better-tolerated alternative.

Administration, Oral↗
PubMed2001

Cardiopulmonary resuscitation directives on admission to intensive-care unit: an international observational study.

BACKGROUND: Resuscitation directives should be a sign of patient's preference. Our objective was to ascertain prevalence, predictors, and procurement pattern of cardiopulmonary resuscitation directives within 24 h of admission to the intensive-care unit (ICU). METHODS: We enrolled 2916 patients aged 18 years and older from 15 ICUs in four countries, and recorded whether, when, and by whom their cardiopulmonary resuscitation directives were established. By polychotomous logistic regression we identified factors associated with a resuscitate or do-not-resuscitate directive. FINDINGS: Of 2916 patients, 318 (11%; 95% CI 9.8-12.1) had an explicit resuscitation directive. In 159 (50%; 44.4-55.6) patients, the directive was do-not-resuscitate. Directives were established by residents for 145 (46%; 40.0-51.3) patients. Age strongly predicted do-not-resuscitate directives: for 50-64, 65-74, and 75 years and older, odds ratios were 3.4 (95% CI 1.6-7.3), 4.4 (2.2-9.2), and 8.8 (4.4-17.8), respectively. APACHE II scores greater than 20 predicted resuscitate and do-not-resuscitate directives in a similar way. An explicit directive was likely for patients admitted at night (odds ratio 1.4 [1.0-1.9] and 1.6 [1.2-2.3] for resuscitate and do-not-resuscitate, respectively) and during weekends (1.9 [1.3-2.7] and 2.2 [1.5-3.2], respectively). Inability to make a decision raised the likelihood of a do-not-resuscitate (3.7 [2.6-5.4]) than a resuscitate (1.7 [1.2-2.3]) directive (p=0.0005). Within Canada and the USA, cities differed strikingly, as did centres within cities. INTERPRETATION: Cardiopulmonary resuscitation directives established within 24 h of admission to ICU are uncommon. As well as clinical factors, timing and location of admission might determine rate and nature of resuscitation directives.

APACHE↗