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Biomedical subjects

A Sullivan

Publications and source records attributed to A Sullivan.

At least 19 recordsLinked to original sources
PubMed2007

ASPP: a new family of oncogenes and tumour suppressor genes.

The apoptosis stimulating proteins of p53 (ASPP) family consists of three members, ASPP1, ASPP2 and iASPP. They bind to proteins that are key players in controlling apoptosis (p53, Bcl-2 and RelA/p65) and cell growth (APCL, PP1). So far, the best-known function of the ASPP family members is their ability to regulate the apoptotic function of p53 and its family members, p63 and p73. Biochemical and genetic evidence has shown that ASPP1 and ASPP2 activate, whereas iASPP inhibits, the apoptotic but not the cell-cycle arrest function of p53. The p53 tumour suppressor gene, one of the most frequently mutated genes in human cancer, is capable of suppressing tumour growth through its ability to induce apoptosis or cell-cycle arrest. Thus, the ASPP family of proteins helps to determine how cells choose to die and may therefore be a novel target for cancer therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Patients' preferences for adjuvant chemotherapy in early breast cancer: what makes AC and CMF worthwhile now?

BACKGROUND: Studies of women who had adjuvant chemotherapy for early breast cancer 10-20 years ago showed that many judged small benefits sufficient to make it worthwhile. Indications, regimens and supportive care have changed. We sought the preferences of contemporary women who received similar chemotherapy. PATIENTS AND METHODS: Ninety-seven consecutive consenting women who completed adjuvant chemotherapy for early breast cancer 3-34 months previously were interviewed. Preferences were elicited with a structured, scripted interview using the trade-off method. Women were presented with four hypothetical scenarios based on known life expectancies (5 and 15 years) and survival rates (65% and 85% at 5 years) without adjuvant chemotherapy. RESULTS: Improvements of an additional year in life expectancy or 3% in survival rates were judged sufficient to make adjuvant chemotherapy worthwhile by 68-84% of women. Half the women judged 1 day or 0.1% sufficient to make adjuvant chemotherapy worthwhile. Recollections of better well-being during adjuvant chemotherapy, having dependants and having a friend or relative who died from cancer were independently associated with judging smaller benefits sufficient to make adjuvant chemotherapy worthwhile (all P < 0.05). CONCLUSIONS: Preferences were highly variable, but the benefits judged sufficient to make adjuvant chemotherapy worthwhile were even smaller than those found in previous studies. Preferences were influenced by factors other than direct benefits and harms of chemotherapy.

Adult↗
PubMed2005

Probiotics and gastrointestinal diseases.

There is increasing evidence indicating health benefits by consumption of foods containing microorganisms, i.e. probiotics. A number of clinical trials have been performed to evaluate the effects in the prevention and treatment of gastrointestinal diseases caused by pathogenic microorganisms or by disturbances in the normal microflora. Gastrointestinal infections caused by Helicobacter pylori, traveller's diarrhoea, rotavirus diarrhoea, antibiotic-associated diarrhoea (AAD) and Clostridium difficile-induced diarrhoea are conditions that have been studied. There are also studies performed on the preventive effect of probiotics on radiation-induced diarrhoea and diarrhoea in tube-fed patients. Inflammatory bowel disease and irritable bowel syndrome, two idiopathic conditions where alterations in the normal microflora have been implicated as responsible for initiation, are two further areas where the use of probiotics has been regarded as promising. The results from clinical studies have not been conclusive in that the effects of probiotics have been strain-dependent and different study designs have been used. Treatment of acute diarrhoea in children and prevention of AAD are the two most justified areas for the application of probiotics.

Acute Disease↗
PubMed2003

Growth/differentiation factor-15 (GDF-15), a novel member of the TGF-beta superfamily, promotes survival of lesioned mesencephalic dopaminergic neurons in vitro and in vivo and is induced in neurons following cortical lesioning.

This review summarizes the evidence that GDF-15, a recently discovered member of the TGF-beta superfamily, is a trophic factor for nigral dopamine neurons, both in vitro and in vivo. Specifically, GDF-15 promotes survival and differentiation of embryonic rat dopaminergic neurons, but not of other neuron populations, with the exception of serotonergic raphe neurons. The neurotrophic effect of GDF-15 seems to be direct and not mediated through glial cells. In the rat 6-hydroxydopamine model of parkinsonism GDF-15 rescues intoxicated dopaminergic neurons and abolishes abnormal turning behavior. The most prominent site of synthesis of GDF-15 within the brain is the choroid plexus, which secretes GDF-15 into the cerebrospinal fluid, from where the molecule can penetrate through the ependymal layer into the parenchyma. Analysis of mouse mutants lacking GDF-15 will reveal whether the endogenous factor also has a role in promoting embryonic and protecting lesioned nigral dopamine neurons.

Adrenergic Agents↗
PubMed2003

The micro-flora of the small bowel in health and disease.

The micro-flora of the proximal jejunum in healthy volunteers was compared with the micro-flora in patients with gastrointestinal symptoms suggestive of spontaneous bacterial overgrowth in the small intestine. Biopsies were taken distally to the ligament of Treitz with a Watson capsule. The samples were diluted and inoculated on selective and non-selective agar plates that were incubated aerobically and anaerobically. No major differences were found in the small jejunum micro-flora in healthy persons or in a heterogenous group of patients with gastrointestinal disorders. Oropharyngeal micro-organisms dominated the micro-flora in all subjects and colonic micro-organisms were found in low numbers in a few subjects from both groups. Streptococcus intermedius and Haemophilus parahaemolyticus were only found in the micro-flora of healthy subjects while Lactobacillus spp. was more frequently found in the samples from patients. Eight of 20 healthy subjects and five of 18 patients met the criterion of small intestinal overgrowth. Emerging evidence suggests that other factors are involved in the pathogenesis of the irritable bowel syndrome complex. There is a need for better understanding of the complicated interactions between the host and the endogenous micro-flora.

Journal Article↗
PubMed2003

Will triclosan in toothpaste select for resistant oral streptococci?

The aims of the study were to determine the in vitro sensitivity of triclosan against viridans streptococci and the impact of triclosan on the normal oral microflora. Nine subjects used a triclosan-containing toothpaste for 2 weeks. Saliva samples were collected on days 0 and 14 and were analyzed quantitatively. The minimum inhibitory concentrations of triclosan and of several antimicrobial agents were determined for the streptococci isolated on days 0 and 14. No major changes occurred in the normal oral microflora during the study period. There were no differences in susceptibility between streptococcal strains collected at days 0 and 14 against triclosan or antimicrobial agents. Short-term use of triclosan has no major impact on normal oral microflora or on streptococcal susceptibility of antimicrobial agents. The effects of long-term use should be evaluated.

Anti-Infective Agents, Local↗
PubMed2002

Analysis of CHK2 in vulval neoplasia.

Structure and expression of the Rad53 homologue CHK2 were studied in vulval neoplasia. We identified the previously described silent polymorphism at codon 84 (A>G at nucleotide 252) in the germ-line of six out of 72, and somatic mutations in two out of 40 cases of vulval squamous cell carcinomas and none of 32 cases of vulval intraepithelial neoplasia. One mutation introduced a premature stop codon in the kinase domain of CHK2, whereas the second resulted in an amino acid substitution in the kinase domain. The two squamous cell carcinomas with mutations in CHK2 also expressed mutant p53. A CpG island was identified close to the putative CHK2 transcriptional start site, but methylation-specific PCR did not detect methylation in any of 40 vulval squamous cell carcinomas, irrespective of human papillomavirus or p53 status. Consistent with this observation, no cancer exhibited loss of CHK2 expression at mRNA or protein level. Taken together, these observations reveal that genetic but not epigenetic changes in CHK2 occur in a small proportion of vulval squamous cell carcinomas.

Adult↗
PubMed2002

E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia.

In common with other E2F1 responsive genes such as p14(ARF) and B-myb, the promoter of p73 is shown to be positively regulated in cell lines and primary human keratinocytes by E7 proteins from oncogenic human papillomavirus (HPV) types 16, 18, 31 and 33, but not HPV 6. Mutational analysis revealed that transactivation of the p73 promoter by HPV 16E7 requires association with pRb. Expression of p73 in normal cervical epithelium is confined to the basal and supra-basal layers. In contrast, expression in neoplastic lesions is detected throughout the epithelium and increases with grade of neoplasia, being maximal in squamous cell cancers (SCC). Deregulation of expression of the N-terminal splice variant p73Delta2 was observed in a significant proportion of cancers, but not in normal epithelium. The frequent over-expression of p73Delta2, which has recognized transdominant properties, in malignant and pre-malignant lesions suggests a role in the oncogenic process in cervical epithelium.

Carcinoma, Squamous Cell↗
PubMed2002

The place of probiotics in human intestinal infections.

A number of studies have been carried out on the effect of several probiotic species on treatment and prevention of intestinal infections. The most commonly used microorganisms are lactic-acid producing bacteria such as lactobacilli and bifidobacteria belonging to the human normal microflora. In vitro and animal studies have shown that probiotic microorganisms interfere with the colonisation of Helicobacter pylori and of enteropathogenic microorganisms. In humans the significance is more uncertain. Clinically significant benefits of probiotics have been demonstrated in the treatment of rotavirus induced diarrhoea and of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea (AAD). In patients suffering from inflammatory bowel disease, several probiotic strains have been shown to be as effective as traditional medication in preventing relapses. Standardised and well performed studies are needed to elucidate further the mechanisms of action and the clinical significance of probiotics.

Digestive System↗
PubMed2001

p73 is over-expressed in vulval cancer principally as the Delta 2 isoform.

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Delta 2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16(INK4a) in HPV-negative cases. There was a close correlation between expression of p73 and p14(ARF) in cancers with loss of p53 function. The frequent over-expression of p73 Delta 2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2001

Effect of antimicrobial agents on the ecological balance of human microflora.

The normal microflora acts as a barrier against colonisation of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms. Control of growth of opportunistic microorganisms is termed colonisation resistance. Administration of antimicrobial agents, therapeutically or as prophylaxis, causes disturbances in the ecological balance between the host and the normal microflora. Most studies on the impact of antimicrobial agents on normal microflora have been carried out on the intestinal flora. Less is known on the effects on oropharyngeal, skin, and vaginal microflora. Disturbances in the microflora depend on the properties of the agents as well as of the absorption, route of elimination, and possible enzymatic inactivation and/or binding to faecal material of the agents. The clinically most common disturbances in the intestinal microflora are diarrhoea and fungal infections that usually cease after the end of treatment. A well-balanced microflora prevents establishment of resistant microbial strains. By using antimicrobial agents that do not disturb colonisation resistance, the risk of emergence and spread of resistant strains between patients and dissemination of resistant determinants between microorganisms is reduced. In this article, the potential ecological effects of administration of antimicrobial agents on the intestinal, oropharyngeal, and vaginal microflora are summarised. The review is based on clinical studies published during the past 10 years.

Anti-Bacterial Agents↗
PubMed2001

Detection and quantification of HIV-1 specific CD4 helper and CD8 cytotoxic cells: their role in HIV-1-infected individuals and vaccine recipients.

There is a strong link between virus specific CD8 T-cell function and the efficiency of regulatory CD4 helper T cells. Controlling viraemia in HIV-1-infected individuals requires the maintenance of strong CD4 and CD8 T-cell responses. These responses should be elicited by prophylactic vaccination and by postexposure immunotherapy. This review will examine the methods that are available for the detection and quantification of HIV-1 specific CD4 and CD8 T-cell responses. We will also discuss the methods that should be used to identify these responses in HIV-1-infected individuals, seropositive recipients of immunotherapy and seronegative vaccinees. Finally, we will give examples of how responses observed in vitro relate to those known to occur in vivo.

AIDS Vaccines↗
PubMed2001

Cost effectiveness of bedside fetal fibronectin testing varies according to treatment algorithm.

OBJECTIVE: To determine the cost effectiveness of implementing fetal fibronectin testing in women with threatened preterm labor. METHODS: We developed a cost analysis model based upon our institution's experience with threatened preterm labor. Model estimates related to fetal fibronectin were obtained from the literature. The model considered hospital admission and assay cost. RESULTS: Approximately 2000 women deliver annually at our tertiary care facility. In the prior 11 months, 340 (19%) presented for threatened preterm labor with 45 (13%) admissions. In a group of individuals with threatened preterm labor and < 3 cm cervical dilatation, approximately 25% can be expected to have a positive fetal fibronectin test. If fetal fibronectin testing were used to influence the decision of admission, 93 (25%) would have a positive test over a 12-month period, potentially increasing admissions by 94%. At a cost of $225 per test, our institution's antepartum admission cost of $1919, a prevalence of threatened preterm labor of 19% and admission rate of 13%, fetal fibronectin testing applied prior to the decision to admit would result in a total cost of $262 583 with 373 assays performed, and 93 admissions. If only those who would have been admitted based on traditional criteria are considered, > 25% should have a positive fetal fibronectin test. If we assume a positive rate of 70%, fetal fibronectin testing employed after the decision to admit would result in a total cost of $75 963, with 48 assays performed and 34 admissions. Without using the assay, total costs are $92 950 for 48 admissions. CONCLUSION: This cost analysis suggests that fetal fibronectin testing on all patients presenting with threatened preterm labor significantly increases the cost, while fetal fibronectin testing after the decision to admit may reduce the cost.

Adult↗
PubMed2001

X-ray crystal structure of a monoclonal antibody that binds to a major autoantigenic epitope on thyroid peroxidase.

Thyroid peroxidase (TPO) catalyzes the production of thyroid hormones and is a major autoantigen in autoimmune thyroid disease (AITD). It is believed that the majority of TPO autoantibodies bind to an immunodominant region consisting of two overlapping domains. Precise location of these domains would help our understanding of the interaction between TPO and TPO autoantibodies. 4F5 is a mouse monoclonal antibody (IgG1, kappa) that reacts with high affinity (2.6 x 10(10) mol/L(-1)) with one of the major autoantigenic regions on TPO. Heavy chain genes of 4F5 were from the VH1 germline gene family, germline genes for the D region could not be assigned and the J region was from the JH2 germline. Light chain genes were from Vkappa4/5 and Jkappa2, germline gene families. The Fab fragment of 4F5 was prepared by papain digestion, purified, crystallized, and the structure solved to 1.9 A using molecular replacement. The refined structure had an R factor of 19.5% and a free R factor of 23.9%. Deduced amino acid sequence and amino acid sequence obtained from diffraction analysis were compared and used to finalize the 4F5 Fab model. Structural analysis indicated that the structure of 4F5 is that of a standard Fab and its combining site is flat and is rich in tyrosine residues. Comparison of the structure of 4F5 with that of a TPO autoantibody Fab, TR1.9 suggests that the two antibodies are unlikely to recognise the same structures on TPO.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Increased medial thalamic choline in pediatric obsessive-compulsive disorder as detected by quantitative in vivo spectroscopic imaging.

The thalamus has been implicated in the pathophysiology of obsessive-compulsive disorder. Using a multislice spectroscopic imaging sequence, we reported reductions in right and left medial thalamic N-acetylaspartate/cytosolic choline + creatine/phosphocreatine and N-acetylaspartate/cytosolic choline levels in 11 pediatric patients with obsessive-compulsive disorder, 8 to 15 years, versus 11 case-matched healthy controls. These changes may reflect a change in N-acetylaspartate, cytosolic choline, or creatine concentrations. Therefore, using a validated phantom replacement methodology, we obtained absolute measures (mmol/L) of N-acetylaspartate, a putative marker of neuronal viability, cytosolic choline, and creatine in these subjects. A significant increase in cytosolic choline was observed in right and left medial but not lateral thalami in patients with obsessive-compulsive disorder versus controls. N-acetylaspartate and creatine did not differ significantly between case-control pairs in the medial or lateral thalamus. These findings provide new evidence of cytosolic choline abnormalities in the thalamus in pediatric obsessive-compulsive disorder.

Adolescent↗
PubMed2001

Effect of perorally administered pivmecillinam on the normal oropharyngeal, intestinal and skin microflora.

To study the ecological effects of pivmecillinam on the human oropharyngeal, intestinal and skin microflora, 15 healthy volunteers were given pivmecillinam tablets 400 mg twice daily for 7 days. Saliva, stool and skin specimens were taken before (days -3 and 0) and on the 2nd, 4th and 7th days during the administration period and 14 and 21 days after the start of administration. Mecillinam caused no major changes in the aerobic or anaerobic oropharyngeal microflora. In the aerobic intestinal microflora there was a decrease in the numbers of Escherichia coli while no changes occurred in the anaerobic microflora. In the skin microflora there was a transient decrease in the numbers of Propionibacterium spp. underneath the wing of the nose. The major effect of pivmecillinam was seen on E. coli and to some extent on Propionibacterium spp. No further ecological disturbances were noticed in the oropharyngeal, intestinal or skin microflora.

Administration, Oral↗
PubMed2001

Cardioprotective effect of propranolol from alcohol-induced heart muscle damage as assessed by plasma cardiac troponin-t.

BACKGROUND: Heavy alcohol consumption from either long-term misuse or binge drinking is associated with poor cardiac contractility, mitochondrial dysfunction, and ventricular arrhythmias. The aim of this study was to measure circulating cardiac troponin-T as a marker for myocardial damage following acute and chronic alcohol administration. METHODS: In acute studies, male Wistar rats were treated with alcohol (75 mmol/kg body weight, intraperitoneal) and plasma was collected 2.5 hr after alcohol administration for analysis of rat cardiac troponin-T. In addition, rats were pretreated with cyanamide (an inhibitor of acetaldehyde dehydrogenase), various beta-blockers, xanthine oxidase inhibitors, or lisinopril before acute alcohol dosing. In chronic studies, rats were fed alcohol (as 35% of total dietary calories) for 6 weeks. RESULTS: The results of the time course study showed that acute alcohol administration significantly raised plasma cardiac troponin-T levels after 2.5 hr and 6 hr, but not after 24 hr. The effects of alcohol on cardiac troponin-T were potentiated with cyanamide pretreatment. Acute ethanol, alone or with cyanamide pretreatment, decreased systolic blood pressure and increased heart rates. Beta-blocker pretreatment with propranolol reduced the alcohol-induced increase in plasma troponin-T, whereas lisinopril potentiated this effect. The beta-blockers, atenolol and metoprolol, and the xanthine oxidase inhibitors, allopurinol and oxypurinol, were unable to reduce elevated troponin-T. However, pretreatment with the beta-blocker timolol moderated the acute alcohol-induced increase in troponin-T. In the chronic alcohol rat model, no differences were observed between alcohol and control pair-fed rats, suggesting the inducement of tolerance. CONCLUSIONS: In conditions of acute exposure, ethanol-induced lesions are characterized by raised plasma cardiac troponin-T possibly due to beta1 and/or beta2 adrenergic activation.

Adrenergic beta-Antagonists↗