Can we reliably use markers of cell cycle regulation (e.g. Ki-67, p21, p27, p53) to differentiate between benign and malignant skin tumors?
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Biomarkers, Tumor↗
Biomedical subjects
M Murphy
Publications and source records attributed to M Murphy.
Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension.
AIMS: To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. METHODS: One-hundred and forty-five patients with mild to moderate hypertension and a mean (+/- s.e.mean) age of 51 +/- 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. RESULTS: Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 +/- 2 vs 30 +/- 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P < 0.01) and rate-pressure product (3.1 +/- 0.2 vs 3.6 +/- 0.3 x 10(3) mmHg x beats min(-1), difference 0.5, 95% CI (0.1, 0.9), P < 0.01) during handgrip compared with amlodipine. Similar results were observed during cold pressor. Plasma noradrenaline levels were lower with verapamil compared with amlodipine at rest and after both tests, but the increases in plasma noradrenaline were not significantly different. CONCLUSIONS: Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.
Adult↗
The incidence of hydroxyethyl starch-associated pruritus.
BACKGROUND: Pruritus due to hydroxyethyl starch (HES) is reported with a very variable frequency but appears to be relatively uncommon in the U.K. compared with other European countries. OBJECTIVES: To determine the frequency of HES-related pruritus in patients discharged from intensive care units (ICUs) in two U.K. hospitals. METHODS: A questionnaire survey was given to 253 patients after discharge from ICU. Questions were designed to exclude pre-existing skin disease and other causes of pruritus. RESULTS: One hundred and fifty-nine completed questionnaires were suitable for analysis. Seventeen of 135 (12.6%) subjects who had received HES reported itch, as did one of 24 who had not received HES. There was no apparent relationship between the occurrence of HES-related pruritus and either the surgical indication or the brand or volume of HES infused. CONCLUSIONS: HES-related pruritus is a problem that dermatologists need to recognize; however, its frequency in the U.K., when other causes of itch are excluded, appears to be lower than suggested in some previous reported studies.
Drug Eruptions↗
Fatal toxic epidermal necrolysis associated with hydroxychloroquine.
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Adult↗
Fibroblast growth factors in the developing central nervous system.
1. It is now clear that members of the fibroblast growth factor (FGF) family have multiple roles during the formation of the central nervous system (CNS). 2. There are at least 23 members of the FGF family and, of these, 10 are expressed in the developing CNS, along with four FGF receptors (FGFR-1-4). 3. The present review discusses the roles of these FGFs, with emphasis on FGF-2, FGF-8, FGF-15 and FGF-17. Fibroblast growth factors-2 and -15 are generally expressed throughout the developing CNS, whereas FGF-8 and FGF-17 are tightly localized to specific regions of the developing brain and are only expressed in the embryo during the early phases of proliferation and neurogenesis. 4. Expression studies on FGFRs in the chick and mouse indicate that FGFR-1 is most generally expressed, whereas FGFR-2 and FGFR-3 show highly localized but changing patterns of expression throughout CNS development. The FGFR-4 has been localized to the developing CNS in fish but not at a detailed level, as yet, in chick or mouse. 5. A picture is emerging from these studies that particular FGFs signal through specific receptors in a highly localized manner to regulate the development of different regions of the brain. 6. This picture has been demonstrated so far for the developing cortex (FGF-2-/- mice), the forebrain and midbrain (FGF-8 hypomorphs) and the cerebellum (FGF-17/FGF-8 mutant mice). In addition, generation of mutant animals deleted for FGFR-1 and FGFR-2b IIIb demonstrate their importance in FGF signalling. 7. However, there are significant gaps in our knowledge of the localization of members of the FGF family and their receptors. More detailed information on the spatio-temporal mapping of FGFs and FGFR isoforms is required in order to understand the molecular mechanisms through which FGFs signal.
Animals↗
Multimodality image-guided epilepsy surgery.
Co-registration of imaging modalities in the diagnosis of epilepsy is now commonly used in major epilepsy centres. However, the incorporation of these registrations into an image-guided system has only recently been developed. Using techniques of segmentation, surface matching and/or voxel-based matching, we have been able to co-register FLAIR MRI, SPECT, PET, and subdural grids into the 3-D space of the volumetric MRI and use these images on the StealthStation Image-Guided System to resect these foci. This greatly aids the surgeon in performing a more precise tailoring of the cortical resection so as to maximize the excision of the epileptogenic zone while minimizing the impact on eloquent cortex and epileptogenic foci.
Adult↗
An initial investigation of the reliability of the Rivermead Extended ADL index in patients presenting with neurological impairment.
The objective of this study was to establish the reliability and sensitivity of both postal and interviewer-administrated versions of the Rivermead Extended Activities of Daily Living (READL) index, which assesses six domestic activities and six community activities. Sixty patients with stable neurological impairment were recruited. In one group (n = 40), every patient was assessed face-to-face using the READL, the Barthel index (BI) and the short orientation memory and concentration test (SOMC). One week later, the READL was repeated by the same person, in the same place. In the second group (n = 20), all the patients were first sent a postal form of the READL and were then seen face-to-face for assessment as in group 1. To be included patients had to score at least 18/28 points on the SOMC. Scores were compared using scatterplots, Bland and Altman plots and correlation coefficients, and difference scores were calculated. Sensitivity was established comparing groups of patients expected to differ in their activities. Repeated assessment score, both face-to-face and by post, showed significant correlation (Pearson coefficient = 0.97 and 0.88, respectively). Most scores were within four points of each other, with no systematic bias, although patients tended to rate themselves more independent. Both methods were able to detect differences in the level of activities as predicted between more and less dependent groups (t-test: p < 0.00001 and p = 0.00087). The READL index appears to be a reliable and sensitive measure, with some evidence for validity, but further research is needed.
Activities of Daily Living↗
The long form of CDK2 arises via alternative splicing and forms an active protein kinase with cyclins A and E.
We have reinvestigated the long form of cyclin-dependent kinase (CDK)2 that is expressed in many rodent cells. We show that the mRNA encoding CDK2L arises by alternative splicing and that the encoded protein can bind to, and be activated by, cyclins A and E. The complex of CDK2L with cyclin A has about half the specific activity of the equivalent CDK2-cyclin A complex. Also, CDK2L--cyclin A is inhibited to the same extent and by the same concentrations of p21(CIP1) as CDK2--cyclin A. The nucleotide sequences of intron V in the human and murine CDK2 genes, where the sequences encoding the 48-residue insert in CDK2L are located, show very high conservation in the position of the alternatively spliced exon and its surroundings. Despite this, we were not able to detect significant expression of CDK2L in human cell lines, although a low level is expressed in COS-1 cells from monkeys.
Alternative Splicing↗
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↗
Poncet's disease in a patient with AIDS.
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AIDS-Related Opportunistic Infections↗
Identification of optimal lung volume during high-frequency oscillatory ventilation using respiratory inductive plethysmography.
OBJECTIVES: First, to define the relationships between critical opening and closing pressures and oxygenating efficiency, and second, to address whether respiratory inductive plethysmography (RIP) could be used to monitor changes in thoracic volume that follow changes in mean airway pressure during high- frequency oscillatory ventilation (HFOV). DESIGN: Prospective, interventional animal study. SETTING: University research laboratory. SUBJECTS: Five anesthetized, paralyzed, and ventilated pigs. INTERVENTIONS: The animals were ventilated by using HFOV after lung injury. Pre- and post-HFOV pressure-volume curves were obtained by supersyringe. A pressure-volume curve was constructed during HFOV as mean airway pressure was increased from 10 to 40 cm H(2)O and then weaned back down to the minimum sustainable. Hemodynamic and oxygenation data were obtained at each data point. MEASUREMENTS AND MAIN RESULTS: RIP-derived thoracic volumes correlated with known lung volumes during supersyringe (r(2) =.78, p <.00001). During HFOV, three of five animals had an identifiable critical opening pressure of the lung, and four of five had an identifiable critical closing pressure. No consistent relationship between critical opening and critical closing pressures was observed. During the weaning phase of HFOV, a relative decrease in RIP-measured volume of >10% predicted the decrease in oxygenation associated with reaching the critical closing pressure. CONCLUSIONS: The ability of RIP to detect optimal lung volume during the weaning of mean airway pressure may allow clinicians to more directly monitor lung volume changes during HFOV and use the lowest possible airway pressures after lung recruitment.
Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
T/NK cell non-Hodgkin's lymphoma of the sinonasal tract.
Non-Hodgkin's lymphoma of the sinonasal tract is now recognized as an important cause of destructive midfacial lesions formally designated as idiopathic inflammatory processes, and commonly treated with local radiotherapy in a bid to halt the destructive process. However, left untreated, the natural history of this disease remains largely unknown. We report a case which demonstrates the slow and apparently indolent natural course that these lymphomas, if left untreated, may display, before finally evolving into overwhelming and fatal disease. We also take the opportunity to present a brief synopsis of the evolution of our understanding of this condition and to review the modern literature on it.
Disease Progression↗