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Biomedical subjects

K J Sweeney

Publications and source records attributed to K J Sweeney.

At least 19 recordsLinked to original sources
PubMed2005

Major upper gastrointestinal surgery is associated with an antigen-dependent proinflammatory T cell response.

BACKGROUND: T cells play a central role in the immune response to injury. Oesophageal and pancreatic resections are associated with significant risk of systemic inflammatory response syndrome and sepsis. This study involved a detailed analysis of T cell function in a consecutive cohort of patients undergoing such surgery. METHODS: Twenty-five patients undergoing major oncological upper gastrointestinal surgery were investigated for T cell expression of Fas and the activation markers CD69 and CD25, as well as interleukin (IL) 2, IL-10 and interferon (IFN) gamma responses to stimulation with staphylococcal enterotoxin B (SEB). T cell activation in healthy volunteer peripheral blood mononuclear cells was studied in co-culture with patients' serum, either alone or with cytotoxic T lymphocyte-associated antigen (CTLA) 4, an inhibitor of antigen presentation. RESULTS: T cells expressed significantly raised levels of CD69 and CD25 after surgery, but no change in Fas expression was evident. There was a significant increase in the production of IL-2 after surgery without a concomitant increase in IFN-gamma or IL-10 in response to SEB. Postoperative serum activated healthy volunteer T cells, a response that was inhibited (P = 0.053) by co-incubation with CTLA-4. CONCLUSION: Major surgery results in pan-T cell activation via a serum-mediated antigenic mechanism that is independent of Fas expression. Postoperative T cells are primed for an augmented proinflammatory response to superantigen, sustained for at least 1 week, implicating the adaptive immune system in the development of the postoperative systemic immunoinflammatory state.

Adult↗
PubMed2004

Minimally invasive parathyroidectomy with operative ultrasound localization of the adenoma.

BACKGROUND: Minimally invasive parathyroidectomy is the procedure of choice for primary hyperparathyroidism due to parathyroid adenoma. Adequate perioperative adenoma localization is essential for this operation. We describe a technique using ultrasound to perform minimally invasive parathyroidectomy. METHODS: 99mTc sestamibi scanning was performed on patients with primary hyperparathyroidism to localize parathyroid adenomas; no intraoperative gamma probe was used. We also performed pre- and intraoperative ultrasound scanning to localize these adenomas. RESULTS: All patients underwent successful localization and removal of their parathyroid adenomas. At follow-up, all patients were well, with calcium within normal limits. CONCLUSION: The use of intraoperative ultrasound facilitates minimally invasive parathyroidectomy and may obviate the need for intraoperative 99mTc sestamibi scanning.

Adenoma↗
PubMed2003

Changing trends in the management of gallstone disease.

BACKGROUND: Day case cholecystectomy is increasingly becoming a management option for elective cases while "same admission" cholecystectomy is now considered a favorable option in the treatment of acute cholecystitis. To assess the advent of these changes in our surgical practice, a retrospective analysis of our experience is presented. METHODS: All patients undergoing cholecystectomy between January 2000 and January 2001 were analyzed according to admission status, operation type, conversion rate, complications, and nonsurgical intervention. RESULTS: 156 patients underwent cholecystectomy and 152 charts were retrieved. Laparoscopic cholecystectomy was performed on 95% of patients with a conversion rate of 9%. Morbidity for the series was 12.5%, including one common bile duct injury (0.6%). Day case and acute cholecystectomy comprised 67% of our cholecystectomy practice. CONCLUSIONS: Our findings suggest that there is an increasing trend toward shortening the hospital stay of patients undergoing laparoscopic cholecystectomy. This does not appear to have had a deleterious effect on outcome.

Adult↗
PubMed2003

Serum antigen(s) drive the proinflammatory T cell response in acute pancreatitis.

BACKGROUND: Immune cells and cytokines are central to the systemic inflammatory response syndrome and multiple organ failure associated with acute pancreatitis. The specific role of T cells in this response is unclear, and this study focused on evaluating T cell activation and its regulation in patients with acute pancreatitis. METHODS: Peripheral blood samples of 14 patients with acute pancreatitis were obtained within 24 h of the onset of pain, within 48 h and at 1 week. T cell expression of surface markers CD69, CD62L and CD25 was measured. The production of interleukin (IL) 10 and IL-2 in vitro in response to the superantigen Staphylococcus enterotoxin B (SEB) was assessed. Serum samples from these patients were co-cultured with peripheral blood mononuclear cells from volunteers in the presence or absence of cytotoxic T lymphocyte-associated antigen (CTLA) 4 immunoglobulin, a specific inhibitor of antigen-dependent T cell activation. RESULTS: Expression of CD69 was significantly increased in CD3(+) and CD4(+) populations at 48 h and 1 week, and on CD8(+) cells at 1 week. There was a significant increase in the production of SEB-induced IL-2 compared with findings in controls, but no significant IL-10 response. Serum from patients with pancreatitis activated normal T cells. This response was abolished completely by CTLA-4. CONCLUSION: Acute pancreatitis results in the systemic activation of T cells. These cells are primed for a proinflammatory response to antigen stimulation and can be inhibited by antigen-specific T cell blockade. These data indicate that the immunoinflammatory response in acute pancreatitis is fueled by one or more serum antigens and offer prospects for further understanding of the aetiogenesis of pancreatitis.

Acute Disease↗
PubMed2003

Surgical informatics on the Internet: any improvement?

PURPOSE: The Internet is a popular, but ungoverned, source of medical information. This study tracked the change in performance of commonly available search engines and the quality of medical data therein over a four-year period. METHODS: We compared the accuracy of information on a commonly performed surgical procedure (vasectomy) using six standard search engines in a four-year period and with two recently developed search engines. The top 25 ranked sites cited by each search engine were scored for description of the procedure, post-operative instructions, complications and unproven associations. RESULTS: There was no improvement in quality of individual sites over the study period. Additionally, the hit rate of search engines remained poor with 27 sites cited (40%) in 2002 either irrelevant or unavailable. DISCUSSION: Few useful sites with accurate information on surgical procedures are available on the Internet and simple search strategies fail to identify site quality or relevancy. CONCLUSION: At present, the Internet cannot be recommended as a reliable resource for many aspects of health information for patients. The onus is on health-care providers to provide high quality sites and direct patients to these sources of reliable information

Humans↗
PubMed2002

Endovascular approach to abdominal aortic aneurysms limits the postoperative systemic immune response.

OBJECTIVES: endovascular repair of abdominal aortic aneurysms (E-AAA) has in recent years developed as an alternative to the conventional open repair (C-AAA). Adverse outcomes following the open approach may relate to immune cell activation and the systemic inflammatory response syndrome (SIRS) and organ failure but the benefits in this respect of the endovascular approach are unclear. This study evaluated this question and focused on T-cell activation and function. DESIGN: prospective clinical study. MATERIALS: twenty patients undergoing abdominal aortic aneurysm repair (12 C-AAA and 8 E-AAA). METHODS: peripheral T-cell expression of surface markers CD69, CD62L and CD25 in vivo and Interleukin 2 (IL-2) and Interleukin-10 (IL-10) responses to the superantigen staphylococcal enterotoxin B (SEB) in vitro were measured preoperatively, 24 h and 1 week postoperatively. RESULTS: there was no significant increase (p=0.23) in the incidence of SIRS in the open compared with the endovascular group. Enhanced T cell activation occurred following C-AAA and this was associated with significantly greater IL-2 production in response to SEB, with no change in IL-10 production. CONCLUSIONS: E-AAA attenuates proinflammatory T-cell changes compared with C-AAA repair. A reduction in T-cell activation and impaired responsiveness to superantigen suggests that the immunological sequelae of the endovascular approach to aneurysm repair is more favourable than after the open approach with potentially less risk of adverse outcomes. Proof of this thesis will require a larger prospective study.

Aged↗
PubMed2001

NudE-L, a novel Lis1-interacting protein, belongs to a family of vertebrate coiled-coil proteins.

The LIS1-encoded protein (Lis1) plays a role in brain development because a hemizygous deletion or mutation of the human gene causes neuronal migration disorders, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS). Using a yeast two-hybrid screen, we have isolated a novel protein that interacts with mouse Lis1 (mLis1) which is termed mouse NudE-like protein (mNudE-L) because of its 49% amino acid conservation with NudE, a protein involved in nuclear migration in Aspergillus nidulans. GST pull-down assays and co-immunoprecipitation of fusion proteins expressed in mammalian cells confirmed the interaction of mLis1 and mNudE-L. mNudE-L gives rise to a approximately 2.3 kb mRNA and encodes an ORF corresponding to approximately 38 kDa protein. The overall amino acid sequence of mNudE-L is 49-95% identical to proteins found in a variety of organisms, thus establishing mNudE-L as a new member of a protein family. The hallmark of this family is an N-terminal region predicted to form a coiled-coil domain. We show that mNudE-L and mLis1 are coexpressed in the postnatal and adult cerebral cortices and in the Purkinje neurons of the cerebellum. In contrast to mLis1, mNudE-L transcripts are absent in the mitral cell layer of the olfactory bulb and in the inward migrating granular neurons of the developing cerebellum. Mutant mLis1 proteins modelling mutations found in human lissencephaly patients fail to interact with mNudE-L, raising the possibility that phenotypic changes result, in part, from the inability of mutant Lis1 proteins to interact with the human NudE-L polypeptide.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development.

Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

The isolated hypertensive lower oesophageal sphincter: audit in a specialist unit.

The hypertensive lower oesophageal sphincter (HLOS) is a distinct clinical entity defined by a lower oesophageal sphincter (LOS) pressure > or = 30mmHg and normal LOS relaxation and oesophageal peristalsis. The clinical, physiological, and radiological details of 27 patients with HLOS diagnosed in a 3-year period were reviewed. The reasons for referral included: gastro-oesophageal reflux disease (GORD) (33%), dysphagia (18.5%), epigastric discomfort (11%), non-cardiac chest pain (15%), globus (7.5%) and other (15%). All patients had manometric evidence of HLOS (Median LOS pressure 30 mmHg, range 25-50 mmHg) and 6 patients (20.7%) had abnormal pH studies. Less than 22% of contrast studies demonstrated an abnormality. There was no change in manometric findings following pharmacological treatment. Two patients underwent oesophagomyotomy and had normal manometry on follow up. We conclude that HLOS mimics a variety of upper gastrointestinal disorders and oesophageal manometry is the gold standard of diagnosis. There was an unexpectedly high incidence of GORD (22%) in this group. The significance and treatment of HLOS is discussed.

Adult↗
PubMed1998

Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells.

The G1 cyclins, cyclin D1 and E, are rate limiting for progression through G1 phase of the cell cycle in breast epithelial cells and are oncogenic when expressed in the mammary epithelium of transgenic mice. These genes are frequently overexpressed in clinical breast cancer where overexpression appears to be associated with specific disease phenotypes, altered responsiveness to therapeutic intervention and patient survival. In order to investigate the functional correlates of cyclin D1 and cyclin E overexpression we employed a panel of normal, immortalized and neoplastic breast epithelial cell lines to examine the relationships between cyclin gene expression, cyclin-CDK complex formation and CDK activity. In agreement with earlier studies cyclin D1 and E expression varied over an approximately tenfold range among the 18 cell lines studied. There was no apparent relationship, however, between cyclin D1 expression and the in vitro activity of its major kinase partner, Cdk4, although MDA-MB-134 cells displayed the highest level of both cyclin D1 expression and Cdk4 activity. Similarly, there was no significant relationship between cyclin E expression and cyclin E-Cdk2 activity. Fractionation of whole cell lysates by gel filtration chromatography revealed that approximately 90% of the cyclin E protein was present in inactive complexes containing the CDK inhibitors p21 and p27. Much of the small fraction of active cyclin E protein was of very high apparent molecular mass, >400 kDa, suggesting that formation of these complexes is a more important determinant of cyclin E-Cdk2 activity than cyclin E abundance. These data suggest that properties of cyclins D1 and E in addition to their ability to activate Cdk4 and Cdk2 may contribute to the effects of overexpression on the breast cancer phenotype.

Breast Neoplasms↗
PubMed1997

Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells.

To investigate the possibility of differing roles for cyclins D1 and D2 in breast epithelial cells, we examined the expression, cell cycle regulation and activity of these two G1 cyclins in both 184 normal breast epithelial cells and T-47D breast cancer cells. Synchronisation studies in 184 cells demonstrated that cyclin D1 and cyclin D2 were differentially regulated during G1, with cyclin D2 abundance increasing by 3.7-fold but only small changes in cyclin D1 abundance observed. The functional consequences of increased cyclin D2 expression were examined in T-47D cells, which express no detectable cyclin D2. Induced expression of cyclin D2 resulted in increases in cyclin E expression, pRB phosphorylation and the percentage of cells in S-phase, while constitutive expression resulted in a consistent trend toward reduced dependence on serum for continued proliferation. Thus, cyclin D2 is a positive regulator of G1 progression in breast cells analogous to the well-documented effects of cyclin D1. Indeed, equimolar concentrations of inducible cyclin D1 and D2 resulted in quantitatively similar cell cycle effects. Marked divergence was found, however, in the CDKs activated by the two cyclins in breast epithelial cells. Cyclin D2 complexes contained a higher Cdk2/Cdk4 ratio than cyclin D1 complexes. The cyclin D2-associated kinase activity was largely inhibited by Cdk2-specific inhibitors and could phosphorylate histone H1, a substrate for Cdk2 but not for Cdk4 and Cdk6. Therefore, cyclin D2 preferentially activated Cdk2 in breast epithelial cells. In contrast, Cdk4 and Cdk6 were predominantly responsible for cyclin D1-associated kinase activity as previously reported. Thus, although cyclins D1 and D2 elicited similar effects on breast epithelial cell cycle progression they appeared to achieve this end via activation of different CDKs. This is the first evidence of cyclin D2 activating Cdk2 in mammalian cells thus providing further evidence that D-type cyclins are not necessarily redundant.

Breast↗
PubMed1996

Cyclins and breast cancer.

Recent advances in the understanding of cell cycle control by cyclins and cyclin-dependent kinases provide a basis for delineating the molecular mechanisms of proliferation control by steroids and the development and progression of hormone-dependent cancers. Cyclin D1 is necessary, rate-limiting and sufficient for G1 progression in breast cancer cells and regulation of cyclin D1 expression or function is an early response to steroid and steroid antagonist regulation of proliferation. The cyclin D1 gene is amplified in approximately 15%, and its product overexpressed in 40-50%, of primary breast carcinomas. The strong evidence that cyclin D1 plays a major role in cell cycle control in breast epithelial cells suggests that its deregulated expression may have effects on disease progression and phenotype including sensitivity to endocrine therapies.

Breast Neoplasms↗
PubMed1995

Steroidal regulation of cell cycle progression.

Sex steroid hormones and their antagonists have well-defined mitogenic and growth-inhibitory effects on target cells including cancer cells. These effects are mediated by cell cycle phase-specific actions, implying that steroids control rates of cell cycle progression by regulating the expression of key cell cycle regulatory genes. An emerging model of cell cycle control involves transcriptional induction of cyclin genes and consequent activation of cyclin-dependent kinases, which initiate cellular events necessary to complete checkpoints within the cell cycle. Our recent studies have focused on the roles of G1 cyclins, particularly cyclin D1, in the control of cell cycle progression in human breast cancer cells. These studies show that cyclin D1 induction is an early response to mitogenic stimulation by oestrogens and progestins, is rate-limiting for G1 progression and is sufficient for completion of the cell cycle in cells arrested in early G1 phase by serum deprivation. Furthermore, inhibition of cyclin D1 expression is an early response to growth-inhibitory anti-oestrogens. These results suggest that cyclin D1 is a target for regulation of cell cycle progression by sex steroids and their antagonists.

Breast Neoplasms↗
PubMed1995

Expression and regulation of cyclin genes in breast cancer.

Cyclins, the regulatory subunits of cyclin-dependent kinases, control passage through key check-points within the cell cycle. Since dysregulated expression and function of cyclins can lead to loss of normal growth control some of these genes are oncogenes. We have studied cyclin gene expression, regulation and function in breast cancers. Induction of cyclin D1 is an early event in mitogenic stimulation of breast cancer cells by growth factors and steroids. Furthermore, inhibition of cyclin D1 expression is an early response to growth inhibition by antioestrogens. Ectopic expression of cyclin D1 in T-47D breast cancer cells demonstrated that cyclin D1 is rate-limiting for progression through G1 phase and is sufficient for growth arrested cells to complete the cell cycle. Since this gene is frequently overexpressed in human breast cancers it may contribute to the development and progression of some breast carcinomas.

Breast Neoplasms↗
PubMed1994

Antiestrogen regulation of cell cycle progression and cyclin D1 gene expression in MCF-7 human breast cancer cells.

The molecular mechanisms by which antiestrogens inhibit breast cancer cell proliferation are not well understood. Using cultured breast cancer cell lines, we studied the effects of antiestrogens on proliferation and cell cycle progression and used this information to select candidate cell cycle regulatory genes that are potential targets for antiestrogens. Under estrogen- and serum-free conditions antiestrogens inhibited proliferation of MCF-7 cells stimulated with insulin. Cells were blocked at a point in G1 phase. These effects are comparable with those in serum- and estrogen-containing medium and were also seen to a lesser degree in nude mice bearing MCF-7 tumors. Similar observations with other peptide mitogens suggest that the process inhibited by antiestrogens is common to estrogen and growth factor activated pathways. Other studies have identified G1 cyclins as potential targets for growth factor and steroid hormone/steroid antagonist regulation of breast epithelial cell proliferation. In MCF-7 cells growing in the presence of fetal calf serum, cyclin D1 mRNA was rapidly down-regulated by steroidal and nonsteroidal antiestrogens by an apparently estrogen receptor mediated mechanism. Cyclin D1 gene expression was maximally inhibited before effects on entry into S phase and inhibition was therefore not merely a consequence of changes in cell cycle progression. Together with data on the effects of antiestrogens in serum-free conditions [1], these results suggest down-regulation of cyclin D1 by antiestrogens may be a general phenomenon in estrogen receptor-positive breast cancer cells, independent of culture conditions and class of antiestrogen. These observations are compatible with the hypothesis that reductions in cyclin D1 levels may mediate in part the action of antiestrogens in blocking entry of cells into S phase.

Animals↗
PubMed1993

Stability and nonreactivity of ergothioneine in human erythrocytes studied by 1H NMR.

The N(CH3)3 resonance of ergothioneine in 1H spin-echo Fourier transform (SEFT) NMR spectra of red blood cells is usually a large singlet and it has been common practice to use this apparently unchanging resonance as an intensity reference. Recently, Reglinski et al. (Magn. Reson. Med. 6, 217-223 (1988)) have questioned this practice, reporting changes seen in the resonance in response to oxidative stress induced by arsenicals. We propose that the changes in the ergothioneine resonance that were reported are artifacts due to alterations in osmolality and magnetic susceptibility induced by the addition of nonisotonic solutions to red blood cell suspensions. These factors change the specific intensity of the intracellular resonances of all compounds. Ergothioneine was observed not to take part in any chemical reactions with arsenicals in free solution or in intact erythrocytes, and we conclude that ergothioneine may still be used as an internal intensity reference in 1H SEFT NMR spectra, bearing in mind the above physical factors.

Artifacts↗