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Biomedical subjects

J McCue

Publications and source records attributed to J McCue.

At least 19 recordsLinked to original sources
PubMed2005

Cell-based cardiovascular repair--the hurdles and the opportunities.

Cardiovascular cell therapy offers the first real potential to treat the underlying injuries associated with cardiac and vascular disease. By delivering appropriate exogenous cells to an injury site, the potential exists to mitigate injury or even to begin to reverse damage. Based on their inordinate pre-clinical promise as myogenic or angiogenic precursors, skeletal myoblasts and bone marrow or blood-derived mesenchymal and hematopoietic progenitor cells have all rapidly moved from bench to early clinical studies. From these parallel paths we are learning a number of useful lessons and have begun to visualize the hurdles to be overcome as we move these therapies forward. It is now obvious that cell-based cardiac and vascular repair are feasible-both early and later in the disease process. In fact, cell therapy may offer an unparalleled opportunity for improvement to millions of individuals living with cardiovascular disease. However, many questions about the technology remain. The mechanisms associated with cardiovascular repair remain unclear. Whether a best cell type, delivery method, or route of administration exists is unknown. And, whether cellbased disease prevention is feasible is still unanswerable. Now is the time to delve deeply into the questions of cell-based myocardial and vascular repair-even as we cautiously proceed clinically. Only by understanding these issues will we be able to decrease unanticipated clinical effects and to fulfill the potential promise of the most exciting opportunity yet to treat CVD. As we do so, we must prevent uncontrolled, poorly planned studies and until we understand cell therapy's potential, we must limit "too good to be true" promises. Only by addressing unanswered questions, carefully limiting our promises, and rigorously performing pre-clinical and clinical studies can we provide the surest opportunity for safely moving the field forward.

Animals↗
PubMed2005

The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy.

AIMS: To determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer. MATERIALS AND METHODS: One hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6-12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m2 via a 60-min infusion on days 1-5 and 29-33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (< or = 1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40). RESULTS: After SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0-21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36-1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26-0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55-5.97). CONCLUSIONS: The number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.

Adenocarcinoma↗
PubMed2000

Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.

This study characterizes a transgenic animal model for the troponin T (TnT) mutation (I79N) associated with familial hypertrophic cardiomyopathy. To study the functional consequences of this mutation, we examined a wild type and two I79N-transgenic mouse lines of human cardiac TnT driven by a murine alpha-myosin heavy chain promoter. Extensive characterization of the transgenic I79N lines compared with wild type and/or nontransgenic mice demonstrated: 1) normal survival and no cardiac hypertrophy even with chronic exercise; 2) large increases in Ca(2+) sensitivity of ATPase activity and force in skinned fibers; 3) a substantial increase in the rate of force activation and an increase in the rate of force relaxation; 4) lower maximal force/cross-sectional area and ATPase activity; 5) loss of sensitivity to pH-induced shifts in the Ca(2+) dependence of force; and 6) computer simulations that reproduced experimental observations and suggested that the I79N mutation decreases the apparent off rate of Ca(2+) from troponin C and increases cross-bridge detachment rate g. Simulations for intact living fibers predict a higher basal contractility, a faster rate of force development, slower relaxation, and increased resting tension in transgenic I79N myocardium compared with transgenic wild type. These mechanisms may contribute to mortality in humans, especially in stimulated contractile states.

Animals↗
PubMed1999

Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1.

Metallothioneins (MTs) are a family of stress-induced proteins with diverse physiological functions, including protection against metal toxicity and oxidants. They may also contribute to the regulation of cellular proliferation, apoptosis, and malignant progression. We reported previously that the human (h)MT-IIA isoform is induced in carcinoma cells (A431, SiHa, and HT29) exposed to low oxygen, conditions commonly found in solid tumors. The present study demonstrates that the genes for hMT-IIA and mouse (m)MT-I are transcriptionally activated by hypoxia through metal response elements (MREs) in their proximal promoter regions. These elements bind metal transcription factor-1 (MTF-1). Deletion and mutational analyses of the hMT-IIA promoter indicated that the hMRE-a element is essential for basal promoter activity and for induction by hypoxia, but that other elements contribute to the full transcriptional response. Functional studies of the mMT-I promoter demonstrated that at least two other MREs (mMRE-d and mMRE-c) are responsive to hypoxia. Multiple copies of either hMRE-a or mMRE-d conferred hypoxia responsiveness to a minimal MT promoter. Mouse MT-I gene transcripts in fibroblasts with targeted deletions of both MTF-1 alleles (MTF-1(-/-); dko7 cells) were not induced by zinc and showed low responsiveness to hypoxia. A transiently transfected MT promoter was unresponsive to hypoxia or zinc in dko7 cells, but inductions were restored by cotransfecting a mouse MTF-1 expression vector. Electrophoretic mobility shift assays detected a specific protein-DNA complex containing MTF-1 in nuclear extracts from hypoxic cells. Together, these results demonstrate that hypoxia activates MT gene expression through MREs and that this activation involves MTF-1.

3T3 Cells↗
PubMed1997

A proposal for minimum detectable compartment in MIRD dosimetry modelling.

The accuracy of radiation dose estimates from radiopharmaceutical administrations has recently become more important for three main reasons: (i) clinical providers are demanding more information on diagnostic procedures; (ii) regulatory groups are scrutinizing dosimetry for research subjects; and (iii) accurate organ doses are crucial in therapeutic administrations. These dose estimates are a sensitive function of the residence times. Because most clinical data acquisition protocols are limited to the first 24 h after dose administration, the area under the remainder of the time-activity curve (TAC) must be estimated. Estimation methods range from assuming physical decay only (overly conservative) to extrapolating end point physiological kinetics (overly liberal). This study demonstrates how much the results from these two methods vary and develops an alternative method which more accurately estimates this remainder term. A method, called the minimum detectable compartment (MDC), is constructed so that an accurate dose estimate can be made with a realistic measure of the remainder term. The method for determining MDC uses standard hypothesis testing. Using an analogue of the traditional minimal detectable activity calculation, a model with and without constant compartments is fitted to the TAC. The size of the constant compartment is varied until the relative likelihood of the two models meets the desired measure of power and sensitivity. Computer simulations of a simple mono-exponential are used to demonstrate the MDC as a function of the model, the number of data points, the range of the data and the noise in the data. The MDC is a very sensitive function of the data range. It falls by more than 50% when the data range is increased from two to three half-lives. In addition, the MDC is moderately sensitive to the noise in the data and relatively insensitive to the number of data points. These findings suggest that the MDC method can also be uses a priori to indicate what type of data collection regimen is necessary to achieve a certain accuracy.

Humans↗
PubMed1996

Ambivalence and dialysis discontinuation.

Although dialysis discontinuation is the second leading "cause" of death among individuals who are maintained with chronic dialysis, little attention is accorded in the literature to patient ambivalence with this crucial decision. Three cases are presented of clinical situations involving termination of dialysis and ambivalence. The ambivalence of the patients is mirrored by the literature's vacillation between viewing cessation of life-support as pathological, and perceiving it as rational. There is considerable variability in the presentation of these cases, and they require exquisite sensitivity and flexibility on the part of medical personnel. As patient-physician communication is encouraged, and staff attempt to honor requests for initiation and/or discontinuation of treatment, we will see increasing numbers of ambivalent patients.

Adult↗
PubMed1996

A portable survey meter method for locating and quantifying removable contamination after 131I therapies.

Identifying 131I surface contamination and decontaminating the removable fraction from rooms where patients have received iodine therapies is a common task at many hospitals. The current regulatory preferred method for this task is wipe testing for removable contamination. The purpose of this paper is to evaluate the suitability of a sensitive survey meter for this task. Both methods and their detection systems are evaluated in the laboratory as well as in a clinical environment. The results indicate that the portable survey meter method is better at both locating and quantifying removable contamination. An additional benefit of the survey meter method is the ability to clean rooms promptly for reoccupancy.

Humans↗
PubMed1994

Research in surgical training: the trainees' experience.

Research projects culminating in a higher surgical degree are now an almost inevitable part of training in general surgery. However, little information exists on the trainees' experience of research. Fifty-nine general surgical trainees (39 registrars and 20 senior registrars) from the North East Thames region completed a confidential questionnaire which addressed various aspects of surgical research. While the benefits of training in research were accepted by the majority of trainees, many expressed reservations about the current practice of 'research by experience' and the need for a higher surgical degree. A one-year period of structured training in research methods with the emphasis on educational content, rather than the production of a thesis, would be a popular alternative. There was a highly significant correlation between the degree of satisfaction with project supervision and the subsequent impression of the value of research (Spearman's rho = 0.54, p < 0.001) stressing the crucial role of the research supervisor. Significant variability in satisfaction with research supervision was noted between the various research centres in the region suggesting a need for closer external monitoring of research posts.

Attitude of Health Personnel↗
PubMed1990

Postoperative muscle strength.

This study investigates the role of motivation in voluntary strength measurements during the postoperative period. Thirty patients underwent surgery which was deemed minor, intermediate or major in severity. Before operation and on the 4th postoperative day measurement of grip strength, maximal voluntary and maximal tetanic (stimulated) contraction of adductor pollicis and assessment of mood were recorded. These investigations were also repeated on the 7th postoperative day in those who had major surgery. No patient had postoperative complications. Minor surgery had no influence on any of the values. Those who underwent major surgery showed significant reductions in grip strength, maximal voluntary contraction and mood; however, maximal tetanic contraction was unaffected. The results in the intermediate group were similar to the major group, although mood depression was less marked. Real strength of a hand muscle appears to be unaltered even by major surgery, but voluntary muscle force is decreased by intermediate and major surgery, and correlates with the patient's subjective state of well-being.

Adult↗
PubMed1989

Coexistent Crohn's disease and sigmoid diverticulosis.

This study reports six patients with a diagnosis of diverticular disease with associated localized Crohn's colitis who were all treated by segmental resection. Two patients died in the post-operative period from disease unrelated to their colonic pathology. The remaining four patients remain well, show no signs of recurrent disease and have required no further surgery. The behaviour and significance of the two conditions occurring in the same patient is discussed.

Aged↗
PubMed1988

Crohn's disease of the appendix.

This study reports eight patients who underwent appendicectomy between 1978 and 1986 for apparently isolated, previously undiagnosed Crohn's disease of the appendix. All patients have since remained well with no sign of disease recurrence. This may represent a less aggressive form of Crohn's disease or be a different entity, namely granulomatous appendicitis.

Adolescent↗
PubMed1984

Amrinone-induced thrombocytopenia.

The frequency and characteristics of thrombocytopenia resulting from administration of amrinone, a new inotropic and vasodilator agent, was evaluated in 43 patients. Thrombocytopenia attributable to amrinone developed in eight patients (18.6%). The thrombocytopenia was due to accelerated peripheral loss of platelets. There appeared to be a dose relationship with regard to the rapidity of onset and degree of thrombocytopenia. Although platelet-associated IgG levels were elevated when measured in patients with thrombocytopenia, the clinical features were suggestive of a direct, perhaps nonimmunologic effect of amrinone on platelets. Thrombocytopenia was mild in most cases and bleeding attributable to thrombocytopenia did not occur. Several patients continued amrinone therapy over long periods despite low platelet counts, showing that mild to moderate thrombocytopenia is not necessarily an indication that therapy should be discontinued, but that platelet counts should be observed closely.

Adult↗