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M McCormack

Publications and source records attributed to M McCormack.

At least 19 recordsLinked to original sources
PubMed2006

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis.

AIMS/HYPOTHESIS: ATP-sensitive K(+) (K(ATP)) channels located on the beta cell plasma membrane play a critical role in regulating insulin secretion and are targets for the sulfonylurea class of antihyperglycaemic drugs. Recent reports suggest that these channels may also reside on insulin-containing dense-core vesicles and mitochondria. The aim of this study was to explore these possibilities and to test the hypothesis that vesicle-resident channels play a role in the control of organellar Ca(2+) concentration or pH. METHODS: To quantify the subcellular distribution of the pore-forming subunit Kir6.2 and the sulfonylurea binding subunit SUR1 in isolated mouse islets and clonal pancreatic MIN6 beta cells, we used four complementary techniques: immunoelectron microscopy, density gradient fractionation, vesicle immunopurification and fluorescence-activated vesicle isolation. Intravesicular and mitochondrial concentrations of free Ca(2+) were measured in intact or digitonin-permeabilised MIN6 cells using recombinant, targeted aequorins, and intravesicular pH was measured with the recombinant fluorescent probe pHluorin. RESULTS: SUR1 and Kir6.2 immunoreactivity were concentrated on dense-core vesicles and on vesicles plus the endoplasmic reticulum/Golgi network, respectively, in both islets and MIN6 cells. Reactivity to neither subunit was detected on mitochondria. Glibenclamide, tolbutamide and diazoxide all failed to affect Ca(2+) uptake into mitochondria, and K(ATP) channel regulators had no significant effect on intravesicular free Ca(2+) concentrations or vesicular pH. CONCLUSIONS/INTERPRETATION: A significant proportion of Kir6.2 and SUR1 subunits reside on insulin-secretory vesicles and the distal secretory pathway in mouse beta cells but do not influence intravesicular ion homeostasis. We propose that dense-core vesicles may serve instead as sorting stations for the delivery of channels to the plasma membrane.

ATP-Binding Cassette Transporters↗
PubMed2006

In silico evolution of functional modules in biochemical networks.

Understanding the large reaction networks found in biological systems is a daunting task. One approach is to divide a network into more manageable smaller modules, thus simplifying the problem. This is a common strategy used in engineering. However, the process of identifying biological modules is still in its infancy and very little is understood about the range and capabilities of motif structures found in biological modules. In order to delineate these modules, a library of functional motifs has been generated via in silico evolution techniques. On the basis of their functional forms, networks were evolved from four broad areas: oscillators, bistable switches, homeostatic systems and frequency filters. Some of these motifs were constructed from simple mass action kinetics, others were based on Michaelis-Menten kinetics as found in protein/protein networks and the remainder were based on Hill equations as found in gene/protein interaction networks. The purpose of the study is to explore the capabilities of different network architectures and the rich variety of functional forms that can be generated. Ultimately, the library may be used to delineate functional motifs in real biological networks.

Algorithms↗
PubMed2005

Delayed diagnosis of cervical cancer in young women.

This study aims to determine whether women under 35 years presenting with cervical cancer experience delays between presentation and diagnosis. All women referred with cervical cancer to the gynaecological cancer centre for the North London Cancer Network from January 2002 to December 2004 were identified retrospectively. Clinical presentation and time interval from symptoms to diagnosis were compared between women under and women over 35 years. A total of 105 women were included. Median age at diagnosis was 45 years (range 23--88). Twenty-two women (19%) were under 35 years at presentation and 17 had persistent symptoms prior to diagnosis. Median time from initial presentation to diagnosis in this group was 9 months (range 3--24 months); significantly longer than in the older group (9 vs 2 months; p=0.0009). Although cervical cancer is relatively rare in young women, diagnosis should be considered in symptomatic women as delay can limit treatment options.

Adult↗
PubMed2005

French-Canadian linguistic validation of the NIH Chronic Prostatitis Symptom Index.

INTRODUCTION: The NIH Chronic Prostatitis Symptom Index (CPSI) is recommended in the clinical evaluation of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, its use is not possible in French speakers, as it has not been validated in this population. We performed a linguistic validation of the CPSI. METHODS: Linguistic translation followed the forward-backward-forward technique and relied on professional medical translators, bilingual health professionals, and patient input. Along with the SF-12, the translated version was administered to a convenience sample of men presenting for pre-vasectomy visits (controls) and to consecutive patients with established CP/CPPS (cases). Men with CP/CPPS were subsequently asked to complete a 14-day retest questionnaire. Psychometric testing addressed standard reliability and validity characteristics. RESULTS: Thirty-six cases and 38 controls with respective mean ages of 46.5 and 44.0 years participated and 33 (91.2%) cases completed the retest questionnaire. Pain (p<0.001), urinary (p<0.001) and quality-of-life (QOL) scale (p<0.001) score means differed between cases and controls. For the same scales, Cronbach's alphas for cases were respectively 0.70, 0.72 and 0.79 versus 0.80, 0.57, and 0.88 for controls. The retest product-moments were 0.83 for pain, 0.55 for urinary, and 0.83 for QOL scales. In cases, strong correlation was noted between QOL and pain scales (r=0.7), and between urinary and pain scales (r=0.6), versus moderate correlation between QOL and urinary scales (r=0.4). Negative correlation was recorded between CPSI scales and SF-12 scales, which ranged from -0.2 to -0.4. CONCLUSIONS: When applied to CPPS and control subjects, the French Canadian CPSI translation demonstrates excellent discriminant properties. Moreover, its reliability and validity characteristics confirm the qualities of the CPSI as a standard evaluative tool for men with CPPS.

Adult↗
PubMed2002

Radiotherapy for perianal Paget's disease.

The role of radiotherapy in the management of perianal Paget's disease (PPD) is not well defined in clinical practice or within the medical literature. We present 6 cases, document the radiotherapy details and review our results. A comprehensive literature search has been undertaken attempting to identify all published cases of PPD and survey the number receiving radiotherapy. To further define the role for radiotherapy in PPD these cases have been reviewed. Published results are sporadic and often poorly documented with respect to technical radiotherapy details. Two main roles for radiotherapy in PPD were found. One is as primary treatment for in situ or invasive disease and the other is following surgical relapse of in-situ or invasive disease. Other possible uses of radiotherapy in PPD such as neoadjuvant or adjuvant treatment or chemo-radiotherapy are discussed. Results of radiotherapy treatment for case of in situ and invasive disease are presented. We disagree with the view in some areas of the surgical literature that radiotherapy has no place in the management of the disease. Despite a thorough surveying of the literature however, precise recommendations on several areas of the technical radiotherapy treatment such as dose-fractionation schedules and field margins are difficult because of the small number of cases and poor general documentation. Our practice recommendations are presented. Radiotherapists should be encouraged to publish their experience in this disease to help define further a role for this treatment.

Aged↗
PubMed2001

Current trends in colorectal cancer: site, incidence, mortality and survival in England and Wales.

The objective was to examine trends in colorectal cancer (CRC) incidence and mortality in England and Wales over the last 30 years. Age-standardized incidence, mortality and survival rates for CRC, based on data from the National Cancer Intelligence Centre at the Office for National Statistics, were calculated and trends assessed. Between 1971 and 1997 the total number of cases of CRC increased by 42%, from 20,400 to 28,900. The site distribution of CRC between 1971 and 1994 was: rectum 38%, sigmoid 29%, caecum 15%, transverse colon and flexures 10%, ascending colon 5%, and descending colon 3%. Between 1971 and 1997 the direct age-standardized incidence increased by 20% in males and by 5% in females. The direct age-standardized mortality fell by 24% in males and by 37% in females. Age-standardized relative 5-year survival in adults improved from 22%-27% for patients diagnosed during 1971-1975 to over 40% for those diagnosed during the period 1991-1993. In conclusion, the incidence of CRC in England and Wales has been steadily rising. It is more common in males and has increased more rapidly in males than in females. The reasons for these trends remain unclear. Five-year survival has improved substantially, but rates are still below those in comparable countries elsewhere in Europe and in the USA.

Adolescent↗
PubMed2000

The effect of superpulsed carbon dioxide laser energy on keloid and normal dermal fibroblast secretion of growth factors: a serum-free study.

An in vitro model was used to determine the effect of superpulsed CO2 laser energy on normal dermal and keloid-producing fibroblast proliferation and release of growth factors. Growth factors assayed included basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF-beta1). bFGF is mitogenic, inhibits collagen production, and stabilizes cellular phenotype. TGF-beta1 stimulates growth and collagen secretion and is thought to be integral to keloid formation. Growth in a serum-free medium allowed measurement of these growth factors without confounding variables. Keloid and normal dermal fibroblasts cell lines were established from facial skin samples using standard explant techniques. Samples consisted of three separate keloid and three separate normal dermal fibroblast cell lines. Cells were used at passage 4 to seed 24-well trays at a concentration of 6 x 10(4) cells per milliliter in serum-free medium. At 48 hours, 18.8 percent of each cell well was exposed to a fluence of 2.4, 4.7, and 7.3 J/cm2 using the superpulsed CO2 laser. Cell viability and counts were established at four time points: 0 (time of superpulsed CO2 laser treatment), 24, 72, and 120 hours. Supernatants were collected and assessed for bFGF and TGF-beta1 using a sandwich enzyme immunoassay. All cell lines demonstrated logarithmic growth through 120 hours (conclusion of experiment), with a statistically significant shorter population doubling time for keloid fibroblasts (p < 0.05). Use of the superpulsed CO2 laser shortened population doubling times relative to that of controls; the differences were statistically significant in keloid dermal fibroblasts when fluences of 2.4 and 4.7 J/cm2 were used (p < 0.05 and 0.01, respectively). bFGF was present in greater levels in normal dermal fibroblasts than in keloid dermal fibroblasts. Application of superpulsed CO2 demonstrated a trend toward increased bFGF secretion in both fibroblast types; the increase was significant in the keloid group at 4.7J/cm2. A consistent trend in suppression of TGF-beta1 was seen in both groups exposed to superpulsed CO2, with the maximal effect occurring at 4.7 J/cm2. Serum-free culture sustains logarithmic cell growth and allows growth factor measurement without confounding variables from serum-containing media. Superpulsed CO2 enhances fibroblast replication and seems to stimulate bFGF secretion and to inhibit TGF-beta1 secretion. Given the function of these growth factors, the application of superpulsed CO2 may support normalized wound healing. These findings may explain the beneficial effects of laser resurfacing on a cellular level and support the use of superpulsed CO2 in the management of keloid scar tissue.

Cell Division↗
PubMed1998

Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice.

Previously we described activating mutations of hbetac, the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, hbetacFIDelta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the hbetacFIDelta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in hbetac may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic hbetac activation has the potential to contribute to pathological events in the central nervous system.

Animals↗
PubMed1997

Cancer-related thromboembolic disease in patients with solid tumours: a retrospective analysis.

BACKGROUND: Cancer patients frequently suffer thromboembolic events. This study assessed the incidence and resource implications of cancer-related thromboembolic disease (CTD) in a single, large cancer centre. PATIENTS AND METHODS: A retrospective analysis of patients admitted with CTD and/or the complications of treatment of CTD over a two-year period has been conducted. Forty-eight patients (23 male, 25 female, median age 60 years) with a variety of solid tumours were identified. RESULTS: The initial presentations were venous thromboses (28 patients) and pulmonary embolism (20 patients). The median interval from cancer diagnosis to the initial episode of CTD was eight (range 0-112) months. Twenty-two patients suffered additional thromboses, despite maintenance warfarin anticoagulation in 18 patients. Six patients experienced anticoagulation-induced haemorrhage. Forty-one (85.4%) patients have died. The median survival from the first thromboembolic event was 8.5 months. The median inpatient stay for management of the first event was 10 (range 4-75) days, accounting for 729 inpatient days during the study period. Recurrent episodes of CTD or complications of anticoagulation resulted in 28 readmissions, accounting for 295 inpatient days. During the two-year period 1024 inpatient days were directly caused by CTD and its complications, representing 6.1% bed occupancy on our unit. CONCLUSION: This study demonstrates that CTD represents a significant cause of morbidity in cancer patients with considerable resource implications for cancer centres. Improvements in prevention and management of CTD would reduce morbidity and lead to considerable cost savings.

Adult↗