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Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

At least 37 records · Page 2Linked to original sources
PubMed2001

Referral of patients with a family history of breast/ovarian cancer--GPs' knowledge and expectations.

BACKGROUND: Primary care is expected to play a significant role in the management of patients with genetic problems. Currently, this particularly involves patients with a family history of cancer. If GPs are to exercise their gatekeeper role efficiently in this area, they must be able to evaluate genetic risk and make appropriate referral decisions. OBJECTIVES: The aim of this study was to examine GPs' ability to assess risk and to make appropriate referral decisions for women with a family history of breast/ovarian cancer, and to determine their expectations of a referral to secondary care. METHOD: A questionnaire survey was carried out of the 282 GP principals working within Bedfordshire Health Authority. GPs were asked to make decisions for six simulated cases of women presenting with a family history of breast or ovarian cancer. RESULTS: A total of 164 (58%) GPs returned completed questionnaires. Across the six family histories, the percentage of GPs making an appropriate risk assessment ranged from 21% [95% confidence interval (CI) 14-27%] to 63% (95% CI 56-71%), and an appropriate referral decision ranged from 40% (95% CI 32-48%) to 80% (95% CI 73-86%). Regardless of their accuracy of risk assessment, most GPs were consistent in deciding not to refer low risk women and to refer moderate and high risk women (range 71-85% of GPs for the six family histories). Only 43 (26%, 95% CI 20-33%) of GPs knew the three most important criteria for risk assessment. CONCLUSIONS: GPs require more help and education to enable them to perform their gatekeeper role satisfactorily when assessing patients with a family history of breast/ovarian cancer.

Adult↗
PubMed2001

The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation.

While the transactivation function of the tumor suppressor p53 is well understood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mSin3a (hereafter designated Sin3) in vivo and that this interaction is critical for the ability of p53 to repress gene expression. In the present study, we demonstrate that expression of Sin3 results in posttranslational stabilization of both exogenous and endogenous p53, due to an inhibition of proteasome-mediated degradation of this protein. Stabilization of p53 by Sin3 requires the Sin3-binding domain, determined here to map to the proline-rich region of p53, from amino acids 61 to 75. The correlation between Sin3 binding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthetic mutant of p53 lacking the Sin3-binding domain has an increased half-life in cells, compared to wild-type p53, supports this premise. Interestingly, unlike retinoblastoma tumor suppressor protein, MDMX, and p14(ARF), Sin3 stabilizes p53 in an MDM2-independent manner. The ability of Sin3 to stabilize p53 is consistent with the model whereby these two proteins must exist on a promoter for extended periods, in order for repression to be an effective mechanism of gene regulation. This model is consistent with our data indicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunologically detectable for prolonged periods following exposure of cells to agents of DNA damage.

Base Sequence↗
PubMed2001

Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation.

Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.

Acetylation↗
PubMed2001

In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review.

A literature search was undertaken for evidence of the effect of succinylcholine (SCH) on the intracranial pressure (ICP) of patients with acute brain injury and whether pretreatment with a defasciculating dose of competitive neuromuscular blocker is beneficial in this patient group. The authors could find no definitive evidence that SCH caused a rise in ICP in patients with brain injury. However, these studies were often weak and small. For those patients suffering acute traumatic brain injury the authors could find no studies that investigated the issue of pretreatment with defasciculating doses of competitive neuromuscular blockers and their effect on ICP in patients given SCH. There is level 2 evidence that SCH caused an increase in ICP for patients undergoing neurosurgery for brain tumours with elective anaesthesia and that pretreatment with defasciculating doses of neuromuscular blockers reduced such increases. It is unknown if this affects neurological outcome for this patient group.

Cerebrovascular Circulation↗
PubMed2001

Interventions for smoking cessation in hospitalised patients: a systematic review.

BACKGROUND: An admission to hospital provides an opportunity to help people stop smoking. Individuals may be more open to help at a time of perceived vulnerability, and may find it easier to quit in an environment where smoking is restricted or prohibited. Providing smoking cessation services during hospitalisation may help more people to attempt and sustain an attempt to quit. The purpose of this paper is to systematically review the effectiveness of interventions for smoking cessation in hospitalised patients. METHODS: We searched the Cochrane Tobacco Addiction Group register, CINAHL, and the Smoking and Health database for studies of interventions for smoking cessation in hospitalised patients. Randomised and quasi-randomised trials of behavioural, pharmacological, or multi-component interventions to help patients stop smoking conducted with hospitalised patients who were current smokers or recent quitters were included. Studies of patients admitted for psychiatric disorders or substance abuse, those that did not report abstinence rates, and those with follow up of less than 6 months were excluded. Two of the authors extracted data independently for each paper, with assistance from others. RESULTS: Intensive intervention (inpatient contact plus follow up for at least 1 month) was associated with a significantly higher cessation rate compared with controls (Peto odds ratio (OR) 1.82, 95% CI 1.49 to 2.22). Any contact during hospitalisation followed by minimal follow up failed to detect a statistically significant effect on cessation rate, but did not rule out a 30% increase in smoking cessation (Peto OR 1.09, 95% CI 0.91 to 1.31). There was insufficient evidence to judge the effect of interventions delivered only during the hospital stay. Although the interventions increased quit rates irrespective of whether nicotine replacement therapy (NRT) was used, the results for NRT were compatible with other data indicating that it increases quit rates. There was no strong evidence that clinical diagnosis affected the likelihood of quitting. CONCLUSIONS: High intensity behavioural interventions that include at least 1 month of follow up contact are effective in promoting smoking cessation in hospitalised patients.

Adult↗
PubMed2001

First-line Herceptin monotherapy in metastatic breast cancer.

The pivotal phase II and III Herceptin trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for > or =6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.

Antibodies, Monoclonal↗
PubMed2001

Use of the pediatric symptom checklist in strategies to improve preventive behavioral health care.

OBJECTIVE: The purpose of this study was to examine the utility of the Pediatric Symptom Checklist (PSC) in identifying youth at risk of behavioral health problems and to develop strategies to meet their mental health needs. METHODS: The PSC was completed by the parents of 570 children aged two to 18 years at three urban health centers in Massachusetts. Follow-up interviews were conducted with the parents of 95 of the children. Multidisciplinary teams held case conferences to review the cases of 43 of the 95 children who were interviewed and who were determined to have moderate to severe behavioral health problems. RESULTS: Of the 570 children in the screening sample, 144 (25 percent) had moderate to severe behavioral health problems, as indicated by a positive score on the PSC, and 2 percent had a serious emotional disturbance. Of the 297 pre-school-aged children (younger than six years), 67 (23 percent) received a positive score. Of the 283 school-aged children (age six and older) from both English- and Spanish-speaking families, 77 (27 percent) received a positive score. About one-third of the severely emotionally disturbed youth were receiving some mental health treatment, but only 20 percent were rated by the multidisciplinary team as receiving adequate treatment. CONCLUSIONS: The study provided further support for the validity and reliability of the PSC and confirmed the results of earlier studies that found a high level of unmet needs for mental health services among this population. Use of the PSC in this study promoted an increase in referrals for children in need.

Adolescent↗
PubMed2001

First-line, single-agent Herceptin(trastuzumab) in metastatic breast cancer: a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Adult↗
PubMed2001

Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity.

An N-acetylcysteine (NAC)/oltipraz (OLZ) combination was studied in healthy volunteer smokers who received daily NAC (1200 mg/day) and were randomized to weekly placebo (Arm A), OLZ 200 mg (Arm B), or 400 mg (Arm C). Treatment was for 12 weeks with follow-up at 16 weeks. The objective was to study toxicity and the modulation of pharmacodynamic end points. After treatment of 19 of a planned 60 subjects, (Arm A, six; Arm B, four; and Arm C, nine), the study was closed because of toxicity. Eight subjects failed to complete 12 weeks of drug administration, (Arm A, two, and Arm C, six). The most frequent side effects were gastrointestinal, fatigue, conjunctival irritation, and skin rash. Pharmacodynamic end points were measured pretreatment and 48 h after the dose of OLZ at weeks 1, 5, and 12 and 4 weeks after the end of treatment. Glutathione (GSH) was measured in plasma and in peripheral blood lymphocytes (PBLs). Other end points measured in PBLs were the enzyme activities of total glutathione-S-transferase (GST), GSTpi, and NAD(P)H:quinone oxidoreductase; and the mRNA expression of gamma-glutamylcysteine synthetase gammaGCS), GSTpi, and NAD(P)H:quinone oxidoreductase. GSH in PBLs, GST (total), and the mRNA of gammaGCS showed increases at some time points in some subjects. Most consistent was the mRNA of gammaGCS, which showed a > or = 30% increase at one or more time points in 11 of 19 subjects. Other end points were unchanged. We concluded that NAC/OLZ modulates some end points related to GSH but is too toxic for chemoprevention at the doses used.

Acetylcysteine↗
PubMed2001

First-line, single-agent Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Journal Article↗
PubMed2001

Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs.

The aminothiol WR-1065 (the active form of amifostine) protects normal tissues from the toxic effects of certain cancer drugs, while leaving their antitumor effects unchanged. The present data address the mechanism of action of this dichotomous effect. (35)S-Labeled WR-1065 bound directly to the transcription factors nuclear factor-kappaB, activator protein-1, and p53, resulting in enhanced binding of these proteins to target regulatory DNA sequences and subsequent transactivation of a number of downstream genes. Since other small molecular thiols could mimic WR-1065, the redox potential of the sulfhydryl is an important determinant of its activity. In nontransformed cells, WR-1065 protected cells from the cytotoxic effects of paclitaxel in a p53-dependent manner. However, in a transformed human tumor cell line, there was no cytoprotectivity by WR-1065, consistent with the premise that p53-dependent growth arrest is the basis for the protective effect of this compound, and that this pathway is abrogated in human tumors. The combined data support the principle that the cellular effects of the aminothiol WR-1065 are mediated through an impact on transcriptional regulation and are not only a consequence of radical scavenging.

Animals↗
PubMed2001

The safety and effectiveness of the Le Fort I approach to removing central skull base lesions.

The difficulty of gaining access to the central skull base has led to the development of many surgical approaches to this area during the past decade. Yet we believe that the Le Fort I technique, which has been used for almost 140 years in orthognathic surgery, is still an excellent approach to treating anterior skull base lesions. This procedure, which entails the horizontal sectioning of the dentoalveolar maxillary segment, seemed to fall out of favor with otolaryngologists after a few reports of complications surfaced during the past 10 to 15 years. In this article, we report a series of seven patients whom we treated with a Le Fort I approach during a 3-year period for a variety of benign and malignant anterior skull base lesions. We have encountered no significant complications of surgery or recurrence of disease at a maximum postoperative followup of 3 years.

Adult↗
PubMed2001

The utility of a 3-dimensional, large-field-of-view, sodium iodide crystal--based PET scanner in the presurgical evaluation of partial epilepsy.

UNLABELLED: (18)F-FDG PET is an accurate and reliable technique for localizing medically refractory temporal lobe epilepsy, but widespread use has been hindered by limited reimbursement in many countries because of the high cost of traditional PET equipment and radioisotopes. Additionally, the place of FDG PET as a cost-effective tool for presurgical evaluation of epilepsy has been questioned because of limited data showing that FDG PET provides localization information incremental to that provided by more established techniques, particularly MRI and ictal electroencephalography (EEG). Three-dimensional (3D), large-field-of-view, sodium iodide crystal-based scanners have lower equipment and running costs and better multiplanar resolution than traditional 2-dimensional bismuth germinate (BGO) systems but have not yet been validated for evaluation of epilepsy. Our purpose was to investigate the localization rate, accuracy, and prognostic value of FDG PET images acquired on a 3D, large-field-of-view, sodium iodide crystal-based PET scanner in the presurgical evaluation of intractable partial epilepsy. We also wanted to establish the incremental value of FDG PET over established MRI and ictal EEG techniques. METHODS: Fifty-five patients who were surgical candidates because of medically refractory partial epilepsy were examined. For most of these patients, the lesions had not been clearly localized on conventional assessment. The FDG PET scans were reviewed independently by 2 reviewers who were unaware of the patients' clinical details, ictal EEG findings, and volumetric MRI results, and the FDG PET results were correlated with those of MRI and EEG and with postsurgical outcome. RESULTS: Forty-two patients (76%) had localizing FDG PET images (37 temporal, 5 extratemporal). The ictal EEG recordings were localizing in 66%, and the MRI findings were localizing in 27% (which increased to 35% after the MRI findings were reviewed again after PET). Concordance between the site of the PET localizations and the site of the MRI or EEG localizations was 100%. The PET images were localizing in 63% and 69% of patients with nonlocalizing ictal EEG and MRI findings, respectively. Twenty-one of 24 patients who subsequently underwent epilepsy surgery had localizing FDG PET images; of these 21 patients, 18 (86%) had a class I outcome. Multiple regression analysis showed the FDG PET results to be predictive of postsurgical outcome independently of the MRI findings. CONCLUSION: For intractable partial epilepsy, FDG PET using a 3D, large-field-of-view, sodium iodide crystal-based scanner provided clinically useful localizing information that was at least as accurate as the results reported for traditional BGO-based scanners. The PET images provided prognostically significant localization information incremental to that provided by volumetric MRI and ictal EEG, particularly if 1 of these studies was nonlocalizing.

Adolescent↗
PubMed2000

Reproductive factors, subfertility, and risk of neural tube defects: a case-control study based on the Oxford Record Linkage Study Register.

Periconceptual exposure to subfertility treatments is increasingly common, raising concerns about the possibility of malformations in the offspring. The authors conducted a case-control study to determine whether subfertility or its treatment was associated with increased risk of neural tube defects (NTDs). Cases were 694 women diagnosed with an NTD-affected pregnancy in Oxfordshire or West Berkshire, England, between 1970 and 1987. Cases were individually matched on maternal year of birth and year of index pregnancy to controls randomly selected from a computerized database. Data on demographic, reproductive, and obstetric factors were abstracted from patient hospital records. Overall, the period prevalences of subfertility and of subfertility treatment were 7% and 3%, respectively, No evidence was found that the risk of NTD-affected pregnancies was increased by either subfertility (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.7, 2.1) or its treatment (OR = 0.9, 95% CI: 0.4, 2.0). After adjustment, NTD-affected pregnancies were associated with female offspring (OR = 2.3, 95% CI: 1.8, 3.1), multiple birth (OR = 4.8, 95% CI: 1.2, 18.8), and higher numbers of pregnancies (p for trend = 0.005). The findings from this large, population-based study were wholly consistent with those from smaller studies that found no increased risk of NTD associated with exposure to fertility treatments but reported associations with various pregnancy outcomes.

Adult↗
PubMed2000

Molecular cloning of an Atlantic salmon nucleoside diphosphate kinase cDNA and its pattern of expression during embryogenesis.

To gain insight into the process of development in Atlantic salmon (Salmo salar), we sought to identify genes that were differentially expressed at gastrulation. A polymerase chain reaction-based differential screening strategy allowed for the isolation of an Atlantic salmon nucleoside diphosphate kinase cDNA (nm23). Structural characterisation showed a high degree of homology with a large number of previously isolated nucleoside diphosphate kinases (NM23s), both prokaryote and eukaryote, though it represents the first teleost nucleoside diphosphate kinase identified. Highest similarities were found with the type 1 and type 2 NM23 isoforms of mammals. Phylogenetic analysis indicates that the duplication event that gave rise to these isoforms occurred after the splitting of tetrapods and fish, suggesting that the salmon NM23 represents a more ancestral isoform. The position of the salmon sequence on the phylogenetic tree indicates that the salmon genome is expected to have at least three copies of genes from the nm23 gene family. Northern blot analysis showed a single transcript of approximately 0.7 kb in both embryonic and adult tissues. Examination of the temporal pattern of expression of salmon nucleoside diphosphate kinase during embryonic development revealed that this gene is first expressed at the time of gastrulation. Nucleoside diphosphate kinases are thought to have a vital role in regulatory processes such as signal transduction, proliferation and differentiation. Taken together, these results suggest that nucleoside diphosphate kinases have an important role to play in early embryogenic development in vertebrates.

Amino Acid Sequence↗
PubMed2000

Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors.

We describe four patients with galactorrhoea as an isolated endocrine abnormality after use of protease inhibitors (PIs) as part of both highly active antiretroviral therapy (HAART) and postexposure prophylaxis (PEP). This reaction may be a direct effect of PIs or may be indirectly mediated by the effect of PIs on the cytochrome P450 system, thus potentiating the dopamine antagonist effects of other drugs.

Anti-HIV Agents↗
PubMed2000

Large-scale purification of antisense oligonucleotides by high-performance membrane adsorber chromatography.

Very high flux ion-exchange membranes were utilized for a novel purification of antisense oligonucleotides (20-mer). Strong anion-exchange membranes were produced by attaching polymeric ligands onto a microporous cellulosic matrix. The oligonucleotides purified were therapeutic single-stranded phosphorothioates deoxyribonucleotides. Although small-scale membrane devices (15 cm2) had similar resolution to traditional chromatographic columns; their throughputs were superior. Greater than a 1300-fold scale-up produced very similar purity and yields of the phosphorothionate product. Scale-up experiments were conducted with a 2 m2 surface area membrane module. These modules were easily capable of very high throughputs of 0.5 to 2 l/min. High purity and yields were achieved by both step and linear gradient elution.

Chromatography, Ion Exchange↗