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Biomedical subjects

M Kennedy

Publications and source records attributed to M Kennedy.

At least 19 recordsLinked to original sources
PubMed1999

Hematopoietic commitment during embryogenesis.

Hematopoiesis develops initially as discrete blood islands in the extraembryonic yolk sac of the embryo. These blood islands consist of clusters of primitive erythrocytes surrounded by developing angioblasts that ultimately form the yolk sac vasculature. The close developmental association of these early hematopoietic and endothelial cells has led to the hypothesis that they develop from a common precursor, a cell known as the hemangioblast. Using a developmental model system based on the in vitro differentiation capacity of embyronic stem (ES) cells, we have identified a precursor with the capacity to generate endothelial as well as primitive and definitive hematopoietic progeny. The developmental potential of this precursor population suggests that it represents the in vitro equivalent of the hemangioblast.

Animals↗
PubMed1999

Structure, G protein activation, and functional relevance of the cardiac G protein-gated K+ channel, IKACh.

The muscarinic-gated atrial potassium channel IKACh has been well characterized functionally, and has been an excellent model system for studying G protein/effector interactions. Complementary DNAs encoding the composite subunits of IKACh have been identified, allowing direct probing of structural and functional features of the channel. Here, we highlight recent approaches taken in our laboratory to determine the oligomeric structure of native cardiac IKACh, the mechanism of activation of IKACh by G proteins, and the relevance of IKACh to cardiac physiology.

Amino Acid Sequence↗
PubMed1999

The cost of elective and emergency repair of AAA in patients under and over the age of 80.

BACKGROUND: As Australia's population ages, the number of elderly patients presenting for surgery of abdominal aortic aneurysms (AAA), both elective and ruptured, will increase. The aim of the present study was to compare the costs of treatment of patients with AAA, under and over the age of 80, in the elective and emergency settings in a hospital with a divisional structure in which the true costs can be accurately obtained. METHODS: A total of 40 patients were selected at random from a series of 267 patients treated with open surgery for AAA between January 1987 and December 1994, 10 in each of four groups: group A, elective repair in patients aged < 80 (171/267); group B, elective AAA repair in patients aged > 80 (25/267); group C, emergency AAA repair in patients aged < 80 (50/267); and group D, emergency AAA repair in patients aged > 80 (11/267). A retrospective analysis of the hospital costs of treatment of these patients at St George Hospital was conducted. These true costs were then compared to Australian National Diagnostic Related Group (AN-DRG) costs. RESULTS: Group A and B had no mortality. In Group C and D the mortality was 20 and 60%, respectively. The emergency treatment groups also had longer lengths of stay. A statistically significant difference in cost of AAA repair between elective and emergency groups in both age groups was seen; that is, group A cost less than group C and group B cost less than group D. Costs per survivor, however, showed a dramatic difference between the cost of group C patients ($30000) and group D patients ($60000). In comparison with AN-DRG calculated costs, the true costs of groups A and B were equivalent to AN-DRG costs. In the emergency groups, however, there were marked discrepancies between the true cost ($61000) and that calculated by the DRG ($25000) in group D, with similar differences seen in group C to a lesser extent. CONCLUSION: Emergency repair of AAA is significantly more expensive and has a high mortality in the over-80 age group. Also, there is a substantial shortfall between the true costs of treating these patients and the funds allocated for treatment in this group.

Aged↗
PubMed1999

5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells.

The mechanism by which 5-aminosalicylic acid (5-ASA) reduces mucosal injury in colitis is undefined. In murine cells, 5-ASA modulates the expression of the inducible nitric oxide (NO) synthase, a potential mediator of colitic injury, but its effect on the human isoform is unknown. Given the lack of conserved regulation of iNOS expression in rodent and human systems, we sought to test the effect of 5-ASA on the expression of human iNOS in cultured enterocytes. Transformed human intestinal epithelial cells, DLD-1 and Caco-2BBe, were stimulated by IL-1beta and IFN-gamma and analyzed for iNOS upregulation and NO production in the presence of various aminosalicylates. 5-ASA, but not 4-ASA, dose-dependently inhibited NO production by both cell lines [IC50 (mM) DLD-1 =4.5, Caco-2BBe =2. 5]. 5-ASA also inhibited the expression of iNOS protein and mRNA and blocked cytokine-induced transcriptional upregulation of the iNOS gene. 5-ASA (1-5 mM) had no effect on cytokine-induced nuclear translocation of NF-kappaB or expression of IRF-1, transactivating factors which regulates the human iNOS enhancer. We conclude that 5-ASA inhibits iNOS expression and NO production at therapeutically relevant concentrations. The inhibition occurs at the level of transcriptional activation and is independent of IRF-1 and NF-kappaB. Since NO is an important final effector of mucosal injury in inflammatory bowel disease, these findings may have implications for the clinical efficacy of 5-ASA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

LeIF: a recombinant Leishmania protein that induces an IL-12-mediated Th1 cytokine profile.

We have evaluated the ability of the Leishmania protein LeIF to influence the Th1/Th2 cytokine responses and the generation of LeIF-specific T cell clones in the absence of adjuvant. We characterized LeIF-specific T cell responses in Leishmania major-infected and uninfected BALB/c mice. These mice develop a strong Th2 response during infection with L. major. When lymph node cells from infected BALB/c mice were stimulated in vitro with LeIF, only IFN-gamma (and no detectable IL-4) was found in the culture supernatant. In addition, LeIF down-regulated Leishmania Ag-specific IL-4 production by lymph node cells from infected BALB/c mice. Subsequently, Th responses were evaluated in naive BALB/c mice following immunization with LeIF. T cell clones derived from mice immunized with LeIF preferentially secreted IFN-gamma. Finally, to understand the basis for the preferential Th1 cytokine bias observed with LeIF, the ability of LeIF to influence the early cytokine profile was evaluated in splenocytes of SCID mice. We found that LeIF stimulated fresh spleen cells from naive SCID mice to secrete IFN-gamma by IL-12/IL-18-dependent mechanisms. The N-terminal half of the molecule (amino acid residues 1-226) maintained the ability to stimulate IFN-gamma from splenocytes of SCID mice. Finally, we also demonstrated that LeIF was able to provide partial protection of BALB/c mice against L. major. Thus, our results suggest the potential of LeIF as a Th1-type adjuvant and as a therapeutic and prophylactic vaccine Ag for leishmaniasis when used with other leishmanial Ags.

Adjuvants, Immunologic↗
PubMed1998

Does the ultrasonically activated scalpel release viable airborne cancer cells?

BACKGROUND: Viable cancer cells may implant at distant sites and cause tumor recurrence. One possible mechanism is the inadvertent exfoliation of viable tumor cells during dissection. The ultrasonically activated scalpel (UAS) uses ultrasonic energy to disrupt tissues by cavitation and produces a dense cloud of cellular debris that may contain viable cells. This study aimed to investigate the viability of airborne cells released during cancer dissection using the UAS and electrosurgery. METHODS: Flank tumors (n = 8) measuring 1 cm3 were induced in male WAG rats by subcutaneous injection of 2 x 10(6) CC531s colon cancer cells. Dissection was performed in cutting mode using the maximum power output of the respective devices. Electrosurgery was performed using a standard monopolar electrosurgical unit and a needle probe, and ultrasonic dissection was performed with the Harmonic Scalpel utilising the open surgical handset and the hooked spatula tip. The smoke plume was aspirated by a vacuum pump and bubbled under Hank's balanced salt solution to trap particulate matter. The viability of the cellular material was blindly assessed with the trypan blue test and by in vitro culture. The morphology of the cellular debris was studied by examination of cytospin preparations. RESULTS: Large quantities of cellular debris was trapped in the plume from both devices. However, no viable cells were isolated, nor did in vitro cell growth occur with either device. Examination of the debris from the UAS demonstrated a characteristic mixture of amorphous forms and very few morphologically intact cells. The cauterized tumor produced charred cells and tissue fragments. CONCLUSIONS: In conclusion, this study demonstrates that viable airborne cancer cells are not released after tumor ablation with the UAS or electrosurgery.

Animals↗
PubMed1998

Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells.

BACKGROUND & AIMS: Peroxynitrite induces cytotoxicity by generating DNA single-strand breaks and activating poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that consumes oxidized nicotinamide adenine dinucleotide (NAD+) and depletes cellular adenosine triphosphate (ATP). The aim of this study was to examine this mechanism of injury in an intestinal epithelial cell model after exposure to exogenous peroxynitrite (ONOO-) and nitric oxide (NO). METHODS: Caco-2BBe cell monolayers exposed to donors of peroxynitrite (3-morpholino-sydnonimine [SIN-1], 3 mmol/L) or NO (S-nitroso-N-acetyl penicillamine [SNAP]; 3 mmol/L) were analyzed for DNA strand breaks, [NAD+], [ATP], and transepithelial flux of fluorescein sulfonic acid. RESULTS: SIN-1 but not SNAP induced DNA single-strand breakage. Both SIN-1 and SNAP reduced [ATP], but only SIN-1 reduced [NAD+]. Inhibition of PARS activity by the PARS inhibitors 5-iodo-6-amino 1,2-benzopyrone or 3-aminobenzamide prevented the SIN-1-induced reduction in [NAD+] and [ATP] but had no effect on the SNAP-induced reduction in [ATP]. PARS inhibition reduced SIN-1-but not SNAP-induced hyperpermeability. CONCLUSIONS: Peroxynitrite but not NO increases transepithelial permeability by inducing DNA strand breaks that activate the PARS pathway and cause the depletion of intracellular energy stores. Inhibition of PARS activity may represent a novel strategy in ameliorating peroxynitrite-mediated epithelial injury during intestinal inflammation.

Adenosine Triphosphate↗
PubMed1998

Serum prolactin and dehydroepiandrosterone concentrations during the summer and winter hair growth cycles of mink (Mustela vison).

We investigated the relationship between serum concentrations of prolactin (PRL) and dehydroepiandrosterone (DHEA) during initiation and development of summer and winter hair growth (anagen) cycles in mink. In the spring, haloperidol (HAL) increased PRL concentrations and induced summer anagen earlier than controls, whereas melatonin (MEL) inhibited PRL secretion and completely blocked summer anagen. In the fall, HAL increased PRL concentrations, inducing anagen at an earlier time than controls, although the resulting fur was abnormal being almost devoid of underhair fibers. Exogenous MEL during the fall reduced PRL concentrations, initiating winter anagen 4 weeks earlier than controls. Adrenalectomy (ADX) induced earlier onset of summer and winter anagen and neutralized the inhibitory effects of HAL in the fall and MEL in the spring. No change in serum DHEA concentrations was observed during the onset of summer or winter anagen in any group although MEL increased DHEA levels from 27 March through 5 June relative to HAL-treated mink. We conclude that changes in serum levels of DHEA and PRL are not requisite to onset of summer or winter anagen in mink. It is possible that metabolites of DHEA and/or PRL may still affect other aspects of the hair growth cycle.

Adrenal Glands↗
PubMed1998

The beta-globin LCR is not necessary for an open chromatin structure or developmentally regulated transcription of the native mouse beta-globin locus.

The murine beta-globin locus control region (LCR) was deleted from its native chromosomal location. The approximately 25 kb deletion eliminates all sequences and structures homologous to those defined as the human LCR. In differentiated ES cells and erythroleukemia cells containing the LCR-deleted chromosome, DNasel sensitivity of the beta-globin domain is established and maintained, developmental regulation of the locus is intact, and beta-like globin RNA levels are reduced 5%-25% of normal. Thus, in the native murine beta-globin locus, the LCR is necessary for normal levels of transcription, but other elements are sufficient to establish the open chromatin structure, transcription, and developmental specificity of the locus. These findings suggest a contributory rather than dominant function for the LCR in its native location.

Animals↗
PubMed1998

Close relationships and safer sex among HIV-infected men with haemophilia.

The present study sought to inform future behavioural intervention efforts by obtaining information from HIV-positive heterosexual men with haemophilia about their attitudes towards close relationships, attitudes towards risk reduction practices, and actual risk reduction practices. HIV-infected males with haemophilia (n = 358) responded to a self-administered questionnaire. Men who reported being involved in a close relationship (n = 237) were compared to men who said that they were not involved at the time of data collection (n = 121). Involved men were more likely than uninvolved men to agree that close relationships provide benefits such as physical intimacy and communication, and that these benefits are important. Men who were not involved perceived more negative consequences of discussing HIV risk reduction with partners (including partner rejection and negative emotional reactions) than did involved men and were much more concerned about the potential negative consequences of risk reduction discussions. Involvement was associated with having disclosed HIV-seropositivity and having discussed HIV risk reduction. Risk reduction interventions for men with haemophilia who are not involved in close, sexual relationships should address positive and negative attitudes towards close relationships and towards discussing risk reduction. Interventions should emphasize communication skills and rehearsal of serostatus disclosure as well as of risk reduction discussions.

Adult↗
PubMed1998

Liver biopsy pathology in human immunodeficiency virus infection.

OBJECTIVES: To determine the hepatic changes in patients with human immunodeficiency virus (HIV) infection in Dublin and to assess the usefulness of liver biopsy in this condition. DESIGN: A consecutive series of liver biopsies was examined retrospectively and correlated with clinical findings. METHODS: A histological review was conducted of specimens from all patients who had undergone liver biopsy in a tertiary referral centre for HIV-infected patients in Dublin. RESULTS: Thirty-nine liver biopsies were studied from 36 patients. Thirty-one (86%) showed pathological changes. Non-specific changes were most frequent, followed by viral-induced chronic hepatitis (15 cases). Acute hepatitis was documented in five and cirrhosis in four cases. Five biopsies performed for pyrexia of unknown origin (PUO) or suspected tuberculosis showed granulomas. Organisms were rarely identified (2) and bile duct changes were uncommon. CONCLUSIONS: Liver biopsy was useful in detecting primary hepatic pathology and, in some cases, the cause of PUO, but not useful in detecting opportunistic infections despite their known presence in other organs.

Acute Disease↗
PubMed1998

A common precursor for hematopoietic and endothelial cells.

Embryonic stem cell-derived embryoid bodies contain a unique precursor population which, in response to vascular endothelial growth factor, gives rise to blast colonies in semi-solid medium. Upon transfer to liquid culture with appropriate cytokines, these blast colonies generate both hematopoietic and adherent, stromal-type cells. Cells within the adherent population display characteristics of endothelial lineage including the expression of CD31, flk-1, flt-1, tie-2, the capacity to take up acetylated LDL and the presence of cytoplasmic Weibel-Palade bodies. Mixing studies demonstrated that the hematopoietic and endothelial precursors within the blast colonies develop from the same cell, the blast colony-forming cell. Kinetic analysis showed that the blast colony-forming cell represents a transient cell population that develops early and is lost quickly during embryoid body development. These findings provide strong evidence that the blast colony-forming cell represents the long-hypothesized hemangioblast, the common precursor of the hematopoietic and endothelial lineages.

Animals↗