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Biomedical subjects

P McKeown

Publications and source records attributed to P McKeown.

At least 19 recordsLinked to original sources
PubMed2005

In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients.

CONTEXT: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood. METHODS AND RESULTS: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern. CONCLUSION: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.

Animals↗
PubMed2004

Antimicrobial resistance and phage types of human and non-human Salmonella enterica isolates in Ireland, 1998-2003.

Between 1998 and 2003, 5,161 isolates (3,182 human) of Salmonella enterica were received by the National Salmonella Reference Laboratory of Ireland. Serotyping, antimicrobial susceptibility testing and phage typing were performed by standard methods. The number of isolates of S. enterica serovar Typhimurium decreased from 579 (80%) in 1998 to 208 (19%) in 2003, while S. enterica serovar Enteritidis increased from 59 (8%) in 1998 to 219 (20%) in 2003. Definitive (DT) phage types 104 and DT104b accounted for a declining proportion of all Salmonella Typhimurium isolates (from n = 523 [90%] in 1998 to 126 [60%] in 2003). Numbers of Salmonella Enteritidis phage type 4 declined from 50 (85%) in 1998 to 59 (27%) in 2003. Twenty-eight isolates of typhoidal Salmonella were received with a history of recent travel in 17 cases. Resistance to multiple (four or more) antimicrobial agents was related to serotype and, where applicable, phage type, and was common in Salmonella Typhimurium. Salmonella Typhimurium predominated among isolates from cattle and pigs (n = 213 [58%]), while Salmonella Livingstone (n = 327) and S. Kentucky (n = 227) were predominant in isolates from poultry (total n = 554 [43%]). This paper discusses trends, and their implications, in Irish salmonella isolates since the establishment of the Reference Laboratory.

Animals↗
PubMed2003

An outbreak of Norwalk-like viral gastroenteritis in holidaymakers travelling to Andorra, January-February 2002.

A retrospective cohort study was conducted to investigate an outbreak of Norwalk-like viral gastroenteritidis that occurred in Irish holidaymakers visiting Andorra, in January-February 2002. Preliminary results showed the risk exposure was higher for tourists who stayed in Soldeu and consumed ice cubes in their drinks (OR = 2.5, 95% CI [1.3-4.6)], after logistic regression and adjusting for sex and water consumption).

Adolescent↗
PubMed2001

Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen.

N-Acetyl-4-S-cysteaminylphenol 1 is an analogue of a biosynthetic intermediate in the pathway to melanin. It is probably oxidized to an o-quinone which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. It is reported to have useful anti-melanoma activity. We previously synthesized a range of analogues of 1 by varying the acyl portion of the amide. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. Thirteen new analogues of 1 containing two methyl groups at the alpha-position of the amino component and various acyl groups have now been prepared and assessed for anti-melanoma activity against six human melanoma cell lines. Most of the new compounds displayed greater cytotoxicity than the lead compound 1. The highest cytotoxicity against the cell lines was observed for the cyclohexylacetamide 11 followed by the cyclohexylcarboxamide 10 and the 2,2-dimethylpropanamide 6. The IC50 values of the most cytotoxic compound 11 against the cell lines were comparable with those of cisplatin. Small variations in the acyl components of these analogues, such as reducing the ring size, lengthening the carbon chain and reducing the amount of chain branching, resulted in a considerable loss of cytotoxicity. The moderate activity of 6, 10 and 11 against SK-Mel-24 cells (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be their only mode of action.

Antineoplastic Agents↗
PubMed2000

Elastin: mutational spectrum in supravalvular aortic stenosis.

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.

Alternative Splicing↗
PubMed2000

Synthesis and antiproliferative activity of unsaturated quinoline derivatives.

In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-carbaldehyde with malononitrile derivatives was used to produce a series of heteroarylidene malononitrile derivatives. Some of these heteroaromatic tyrphostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase. This work has now been extended by using 6-, 7-, and 8-quinolinecarbaldehyde to prepare 23 new quinoline-tyrphostins 1-23. Most of these compounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6 > 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with electron deficiency at the 7-position in the quinoline ring. The most active compound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 microM. Compounds 1-23 showed similar IC50 values against the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased protein tyrosine kinase activity) except for the compounds 1 and 15 formed from 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no association was found between growth inhibition and inhibition of the EGFR protein tyrosine kinase (PTK), using a cell-free assay. In addition, new compounds were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugation in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29). These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 microM, but similar values were observed against both cell lines. No association was found between inhibition of PTK and growth inhibition, again indicating that their mode of action may not be specific for the EGF receptor.

Antineoplastic Agents↗
PubMed2000

Synthesis and antimelanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol.

N-Acetyl-4-S-cysteaminylphenol (1) has been shown by Jimbow and co-workers to possess useful antimelanoma activity. It is an analogue of a biosynthetic intermediate in the pathway to melanin and probably acts as a prodrug, being oxidized to an o-quinone which reacts with essential enzymes containing sulphydryl groups resulting in interference with cell growth and proliferation. We have synthesized a range of analogues of 1 by varying the acyl portion of the amide with the intention of increasing the lipophilicity of the compounds. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. The most active of these compounds, N-[2-[(4-hydroxyphenyl)thiol]ethyl]cyclohexanecarboxamide (9), showed promising selectivity (lack of cytotoxicity) on the non-melanotic cell line SK-Mel-24 and on an ovarian cell line. A significant improvement in antimelanoma activity was observed with a new type of analogue containing three carbon atoms between the sulphur and nitrogen. The most active of these new analogues, N-[3-[(4-hydroxyphenyl)-thiolpropyl]-1-cyclohexanecarboxamide (15), had activity comparable to cisplatin against several cell lines and low cytotoxicity towards the non-melanotic cell line.

Antineoplastic Agents↗
PubMed1997

Neural transplantation as an experimental treatment modality for cerebral ischemia.

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.

Animals↗
PubMed1996

Synthesis and antiproliferative activity of tyrphostins containing quinoline moieties.

Tyrphostins are a series of benzylidenemalononitrile derivatives synthesized by condensing aromatic aldehydes with malononitrile derivatives. The use of heteroaromatic aldehydes in this process has received little attention. Accordingly, 27 tyrphostins containing a 2-, 3- or 4-substituted quinoline moiety were synthesized, of which 21 are novel compounds Compounds containing the 2-aminoethene-1, 1-dinitrile moiety in each series were the most potent inhibitors of the EGF receptor kinase in a cell-free enzyme assay (compounds 2, 11 and 20), having IC50 values of 1.7, 27.0 and 4.7 microM respectively. For each R group substitution the order of potency was 2-quinolines > 4-quinolines > 3-quinolines. Compounds 2, 11 and 20 were unable to inhibit the epidermal growth factor (EGF) receptor autophosphorylation in intact cells; however, they were able to inhibit the EGF-dependent phosphorylation of a 50 kDa protein. These three compounds were able to inhibit EGF-dependent proliferation in a fibroblast cell more efficiently than serum-stimulated proliferation, suggesting that their mechanism of action may be linked to the EGF receptor signalling pathway. Compound 2 exhibited a degree of cell line selectivity in the US National Cancer Institute in vitro human tumour cell line panel. The majority of non-small cell lung cancer lines were relatively resistant to compound 2, while most of the colon, CNS, melanoma and renal lines were relatively sensitive. Further work is required to elucidate the mechanism of action of this interesting group of substituted-quinoline compounds and to determine whether for compounds 2, 11 and 20 this is related to inhibition of EGF receptor function.

Adenocarcinoma↗
PubMed1991

Effectiveness of double bolus alteplase in the treatment of acute myocardial infarction.

Fifty-nine consecutive patients presenting within 6 hours of the onset of symptoms of an acute myocardial infarction were treated with 150 mg of soluble aspirin orally, and either 70 or 100 mg of alteplase divided into 2 intravenous bolus injections separated by 30 minutes. Dosage regimens were either 20 followed by 50 mg (group A), 50 followed by 20 mg (group B), or 50 followed by 50 mg (group C). Coronary angiography 60 minutes after the first bolus showed infarct-related coronary artery patency (Thrombolysis in Myocardial Infarction score 2 or 3) in 13 of 16 (81%) patients in group A, 12 of 17 (71%) in group B, and 10 of 11 (91%) in group C (overall patency rate at 60 minutes: 35 of 44 [80%] patients; 95% confidence interval 68 to 91%). At 90 minutes, patency rates were 15 of 20 (75%) patients in both groups A and B, and 18 of 19 (95%) in group C (overall patency rate 48 of 59 [81%] patients; 95% confidence interval 72 to 91%). Residual thrombus was identified with the 90-minute angiogram in 7 patients in group A, 5 in group B, and 3 in group C. Although there was no statistically significant difference in patency between the 3 dosage regimens at either 60 or 90 minutes there was a trend toward increased patency and more complete thrombolysis at 90 minutes in group C. No episodes of bradyarrhythmia, hypotension or cerebrovascular bleeding were observed after double bolus therapy. There were 7 episodes (12%) of reocclusion, and 3 deaths (5%) within 1-month follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Results of emergent versus elective cardiac transplantation procedures.

Twenty-six patients underwent emergent (Group I) and 34 patients elective (Group II) cardiac transplantation (C. Tx.) from June 1985 through June 1989. Age, sex, etiology, presence of diabetes, renal failure and pulmonary artery pressures were comparable for both groups (P greater than 0.5). Twenty-two patients were in New York Heart Association (NYHA) Class IV for Group I and 17 for Group II. Group I included 12 patients on inotropic agents, five on intra-aortic balloon pump (IABP) and one on IABP and cardiopulmonary bypass (CPB). Elective patients were stable at home. Location of the donor heart and mean ischemic times were comparable for both groups. Early mortality (within 30 days) included four patients for Group I and two for Group II. There were four late deaths for Group I patients and six for Group II. Four deaths were due to infection, six to rejection, two to malignancy, two neurological and one each to suicide and multisystem failure. Immunosuppression regimen was similar for both groups. The number and severity of early and late rejection episodes were similar despite blood group crossing in 11 patients for Group I (P less than .01). Incidence of infection was comparable. Favorable lifestyles were comparable, including employment of 12 patients for Group I and 16 for Group II. Cumulative survival for the entire series was 70% at two years. The study indicates that the results of emergent and elective cardiac transplantation procedures are equally gratifying, that mortality is mainly related to rejection and sepsis complications and blood group crossing does not significantly increase the number of rejection episodes.

Bacterial Infections↗
PubMed1987

Professional depression, 'burnout' and personality in longstay nursing.

Conceptualizations of 'burnout' vary between authors. Some descriptions of burnout show strong similarities to depression in the work setting, or 'professional depression' as described by Oswin [Children Living in Long Stay Hospitals, 1978. Heinemann, London]. This study supported such a similarity, and demonstrated a considerable extent of depressed mood amongst nursing staff in longstay settings, which was particularly significant amongst male staff. A number of distinct 'burnout' responses were evident amongst staff including not only 'professional depression' and depersonalization but also the avoidance of problems and decisions. Ambiguity about supervisors' expectations and success in meeting such expectations were associated with increased scores on each of these variables. Personality appeared to be related to staff's responses. Staff prone to direct hostility inwards on themselves were more likely to show an avoidance of problems and decisions. Those staff prone to direct hostility outwards were more likely to report an awareness of depersonalization toward others. Both these processes may in different ways affect patient care and relationships with other professionals.

Adult↗
PubMed1986

Interpersonal support amongst nurses at work.

The needs for support of staff in human services work are often stated, but less often is the nature of such support clearly specified. This study attempts to clarify the nature of effective support from a superior, as perceived by qualified nursing staff working in psychiatric, mental handicap and medical settings. 'Personal respect', 'empathic attention' and 'absence of interpersonal defensiveness' appeared to be important components to such support. Staff on the same ward showed a high degree of agreement in judgements of their superior's personal respect and empathic attention, but perceived interpersonal defensiveness appeared more specific to perceptions or interactions between particular staff. Greater degrees of 'personal respect' experienced by staff were associated with reduced role ambiguity and reduced emotional exhaustion ('burnout'). The empathic attention reported as given by ward charge nurses was highly correlated with the personal respect they reported receiving from their own superior. These results support approaches which see respect, empathy and genuineness as important ingredients in helping relationships.

Adult↗
PubMed1986

Burnout and professional depression: related concepts?

In 1978 Oswin documented a process of 'professional depression' affecting some nursing staff in long-stay hospitals. This study tested the hypothesis that 'professional depression' in long-stay nursing and 'emotional exhaustion' as a component of burnout describe a similar phenomenon. This hypothesis was supported. The results are consistent with Cherniss' characterization of burnout, which appears to show considerable similarities to the concept of depression. In this study professional depression demonstrated a substantial correlation with depressed mood. Personality demonstrated significant relationships with burnout variables, extrapunitive hostility correlating with hardening toward others, intropunitiveness with avoidance as a coping response. These findings, although confined to hospital nurses, support the usefulness of approaches stressing the interaction between the work environment and the individual.

Adult↗
PubMed1982

Porcine cardiac xenograft valves: analysis of survival, valve failure, and explantation.

Porcine cardiac xenografts were used for cardiac valve replacement in 1,093 patients. Hospital mortality for aortic valve replacement (AVR) was 3.7%; for mitral valve replacement (MVR), 7.8%; and for AVR + MVR, 4.7%. Total follow-up was 2,036 patient-years; maximum, 7.3 years; and mean, 1.89 years. Actuarial survival (+/- standard error of the mean) for AVR was 84% +/- 2% at 56 months; for MVR, 84% +/- 3% at 56 months; and for AVR + MVR, 86% +/- 4% at 30 months. Nonfatal thromboembolism occurred in 8 of 1,030 patients (0.78%). Anticoagulation was not routinely employed. Fifty hospital survivors (4.8%) experienced valve dysfunction; 18 of the survivors (1.7%) died; and 32 of the survivors (3.1%) underwent reoperation. The rate of dysfunction increased slowly until the sixth year when an increased rate was observed (p less than 0.0001). Patients less than 34 years old had a higher incidence of dysfunction (p less than 0.01). Thirty-two hospital survivors (3.1%) underwent explantation of the porcine valve for late dysfunction. Valve dysfunction secondary to endocarditis and paravalvular leak occurred early, while leaflet deterioration or thrombosis was more gradual in onset and was noted later. The porcine valve has functioned well for 1 to 7 years with a low incidence of valve related morbidity and mortality without routine anticoagulation in patients older than 34 years of age.

Aortic Valve↗