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Biomedical subjects

M Page

Publications and source records attributed to M Page.

At least 19 recordsLinked to original sources

A new gamma-ray burst classification scheme from GRB 060614.

Gamma-ray bursts (GRBs) are known to come in two duration classes, separated at approximately 2 s. Long-duration bursts originate from star-forming regions in galaxies, have accompanying supernovae when these are near enough to observe and are probably caused by massive-star collapsars. Recent observations show that short-duration bursts originate in regions within their host galaxies that have lower star-formation rates, consistent with binary neutron star or neutron star-black hole mergers. Moreover, although their hosts are predominantly nearby galaxies, no supernovae have been so far associated with short-duration GRBs. Here we report that the bright, nearby GRB 060614 does not fit into either class. Its approximately 102-s duration groups it with long-duration GRBs, while its temporal lag and peak luminosity fall entirely within the short-duration GRB subclass. Moreover, very deep optical observations exclude an accompanying supernova, similar to short-duration GRBs. This combination of a long-duration event without an accompanying supernova poses a challenge to both the collapsar and the merging-neutron-star interpretations and opens the door to a new GRB classification scheme that straddles both long- and short-duration bursts.

Journal Article↗

The association of GRB 060218 with a supernova and the evolution of the shock wave.

Although the link between long gamma-ray bursts (GRBs) and supernovae has been established, hitherto there have been no observations of the beginning of a supernova explosion and its intimate link to a GRB. In particular, we do not know how the jet that defines a gamma-ray burst emerges from the star's surface, nor how a GRB progenitor explodes. Here we report observations of the relatively nearby GRB 060218 (ref. 5) and its connection to supernova SN 2006aj (ref. 6). In addition to the classical non-thermal emission, GRB 060218 shows a thermal component in its X-ray spectrum, which cools and shifts into the optical/ultraviolet band as time passes. We interpret these features as arising from the break-out of a shock wave driven by a mildly relativistic shell into the dense wind surrounding the progenitor. We have caught a supernova in the act of exploding, directly observing the shock break-out, which indicates that the GRB progenitor was a Wolf-Rayet star.

Journal Article↗

Managing the patient journey through enteral nutritional care.

Nutritional support provision does not happen by accident. Clinical dimensions include screening and assessment, estimation of requirements, identification of a feeding route and the subsequent need for monitoring. Patients may need different forms of nutritional intervention during the course of their illness. Furthermore, these may need to be provided in different locations as their clinical status changes. If this is not properly managed there is potential for inappropriate treatment to be given. Clinical processes can only be effectively implemented if there is a robust infrastructure. The clinical team need to understand the different elements involved in effective service provision and this depends on bringing together disciplines which do not feature overtly on the clinical agenda including catering, finance and senior management. Excellent communication skills at all levels, financial awareness and insight into how other departments function are fundamental to success. Practice needs to be reviewed constantly and creativity about all aspects of service delivery is essential. Finally, it is important that key stakeholders are identified and involved so that they can support any successes and developments. This will raise awareness of the benefits of nutritional intervention and help to ensure that the right resources are available when they are needed.

Community Health Services↗

A short gamma-ray burst apparently associated with an elliptical galaxy at redshift z = 0.225.

Gamma-ray bursts (GRBs) come in two classes: long (> 2 s), soft-spectrum bursts and short, hard events. Most progress has been made on understanding the long GRBs, which are typically observed at high redshift (z approximately 1) and found in subluminous star-forming host galaxies. They are likely to be produced in core-collapse explosions of massive stars. In contrast, no short GRB had been accurately (< 10'') and rapidly (minutes) located. Here we report the detection of the X-ray afterglow from--and the localization of--the short burst GRB 050509B. Its position on the sky is near a luminous, non-star-forming elliptical galaxy at a redshift of 0.225, which is the location one would expect if the origin of this GRB is through the merger of neutron-star or black-hole binaries. The X-ray afterglow was weak and faded below the detection limit within a few hours; no optical afterglow was detected to stringent limits, explaining the past difficulty in localizing short GRBs.

Journal Article↗

Spatial and temporal variability of cytotoxic metabolites in populations of the New Zealand sponge Mycale hentscheli.

Intraspecific variation in the composition of three cytotoxic secondary metabolites from the New Zealand marine sponge Mycale hentscheli collected at two sites in central New Zealand was quantified by 1H NMR techniques. A total of 275 sponges were analyzed bimonthly over 15 mo to compare intersite (approximately 100 km) and intrasite (approximately 100 m) spatial and temporal variations in the metabolites. Biological and physical characteristics of sponge size, morphology, depth, and temperature were recorded at each site. Metabolite concentrations were found to vary in space and time. Metabolite composition was site-specific; mycalamide A, pateamine, and peloruside A were present at Pelorus Sound, whereas pateamine was absent from sponges at Kapiti Island. Pateamine and peloruside A concentrations in sponges at Pelorus Sound varied seasonally; no such patterns were observed at Kapiti Island. Relationships of compound concentration with volume and depth were complex. High levels of peloruside A in Pelorus Sound sponges from between 8 and 10 m depth coincided with a density boundary layer and chlorophyll a maximum.

Adaptation, Physiological↗

Is midwife workload associated with quality of process of care (continuous electronic fetal monitoring [CEFM]) and neonatal outcome indicators? A prospective study in consultant-led labour wards in Scotland.

Evidence for staffing recommendations in labour wards is scant. This study aimed to test association between midwife workload with adjusted process of continuous electronic fetal monitoring (CEFM) and neonatal outcome indicators. This was a prospective workload study in 23 consultant-led labour wards in Scotland. There were 3489 livebirths during September 2000, and 1561 consecutively delivered women with CEFM case review during the mid-two weeks. Process measures were: adjusted rates of CEFM, appropriate CEFM, and time to medical response for a serious fetal heart trace abnormality. Neonatal outcome indicators were: Apgar score < 7 at 5 minutes, admission to neonatal unit (NNU) > 48 hours, and neonatal resuscitation. Complete information was available for 99% (2553/2576) of workload time points, 99% (1559) of CEFM process, and 3083 eligible neonates. There were no associations between occupancy or staffing ratios and adjusted CEFM process, Apgar < 7 at 5 minutes (0.98 [0.83, 1.15]) or admission to NNU for > 48 hours (0.97 [0.95, 1.00]). However, there was association between increasing staffing ratios and lower odds of adjusted neonatal resuscitation (excluding bag and mask only) (0.97 [0.94, 0.99]). The direction of effect of increasing workload suggests detriment to outcome indicators, although the size of effect may be small.

Apgar Score↗

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.

Adrenal Cortex↗

Modeling comparative mapping using objects and associations.

Spatial information on genome organization is essential for both gene prediction and annotation among species and a better understanding of genomes functioning and evolution. We propose in this article an object-association model to formalize comparative genomic mapping. This model is being implemented in the GeMCore knowledge base, for which some original capabilities are described. GeMCore associated to the GeMME graphical interface for molecular evolution was used to spatially characterize the minor shift phenomenon between human and mouse.

Animals↗

Expression of nuclear factor kappa B components in human endometrium.

Nuclear factor kappa B (NFkappaB) is a family of transcription factors involved in signalling between IL1 and TNFalpha receptors and cytokines and adhesion molecules in a number of cell types, including those of the human endometrium. In this study, we used immunocytochemistry to investigate the in vivo expression of the p50, IkappaBalpha and IkappaBbeta NFkappaB components in endometrium obtained from normal fertile women throughout the menstrual cycle. All three components were expressed by both the stromal and epithelial cells of the endometrium and staining was predominately seen in the cytoplasm of the cells. Staining for p50 was more intense in the epithelial compartment than the stromal compartment. Staining in the stromal compartment was low to moderate throughout the cycle but, in the epithelial compartment, staining was cycle dependent and increased slightly during the mid-secretory phase. The staining patterns for IkappaBalpha and IkappaBbeta were similar. As for p50, staining for both proteins was greater in the epithelial compartment compared to the stromal compartment and stromal cell staining was low to moderate throughout the cycle. However, in contrast to p50, staining for the IkappaB proteins in epithelial cells decreased during the mid-secretory phase of the cycle. Although the immunocytochemistry technique used is only semi-quantitative, the results suggest an increased expression of the active and a decreased expression of the inhibitory NFkappaB components by the endometrium at the time of implantation. If confirmed, it would suggest that NFkappaB is involved in the control of factors important in the implantation process.

Adult↗

A soluble transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses.

Transforming growth factor-beta (TGF-beta) signaling requires a ligand-dependent interaction of TGF-beta receptors Tau beta R-I and Tau beta R-II. It has been previously demonstrated that a soluble TGF-beta type II receptor could be used as a TGF-beta antagonist. Here we have generated and investigated the biochemical and signaling properties of a soluble TGF-beta type I receptor (Tau beta RIs-Fc). As reported for the wild-type receptor, the soluble Tau beta R-I does not bind TGF-beta 1 on its own. Surprisingly, in the absence of TGF-beta1, the Tau beta RIs-Fc mimicked TGF-beta 1-induced transcriptional and growth responses in mink lung epithelial cells (Mv1Lu). Signaling induced by the soluble TGF-beta type I receptor is mediated via the obligatory presence of both TGF-beta type I and type II receptors at the cell surface since no signal was observed in Mv1Lu-derivated mutants for TGF-beta receptors R-1B and DR-26. The comparison between the structures of TGF-betas and a three-dimensional model of the extracellular domain of Tau beta RI has shown that five residues of the supposed binding site of TGF-beta 1 (Lys(31), His(34), Glu(5), Tyr(91), and Lys(94)) were found with equivalent biochemical properties and similar spatial positions.

Amino Acid Sequence↗

The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.

Animals↗

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme.

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Adult↗

Utilization of colorectal cancer screening tests: a 1997 survey of Massachusetts internists.

BACKGROUND: Physician noncompliance with screening recommendations has been a major barrier to effective colorectal cancer control. The overall objectives of this study were to assess the current attitudes and screening behavior of primary care physicians in light of new efficacy data, revised guidelines, improved technology, and more widespread insurance coverage. METHODS: Questionnaires inquiring about knowledge, beliefs, and practice patterns related to colorectal cancer screening were mailed in mid-1997 to 700 randomly selected Massachusetts internists. RESULTS: The overall response rate was 63%. Nearly 60% of respondents reported an increase in screening behavior during the past 5 years. Most (80%) were aware of at least one set of screening guidelines and 90% reported utilizing one or more recommended screening strategies. Fecal occult blood testing (FOBT), alone (47%) or in combination with flexible sigmoidoscopy (50%), was the preferred strategy for most respondents. Colonoscopy was rarely utilized (5%) despite high perceived effectiveness. Concern about patient compliance was a significant determinant of FOBT utilization, whereas perceived effectiveness, concerns about time or efficacy data, prior procedural training, date of licensure, and use of instructional materials were independent determinants of sigmoidoscopy utilization. CONCLUSION: Massachusetts' internists report high rates of utilization of select colorectal cancer screening strategies. Future studies must validate self-reported compliance and explore barriers to screening colonoscopy.

Adult↗

Reduced incidence of radiocontrast-induced nephropathy in ICU patients under theophylline prophylaxis: a prospective comparison to series of patients at similar risk.

OBJECTIVE: To investigate whether the adenosine-antagonist theophylline reduces the incidence of contrast-induced nephropathy (CIN). DESIGN AND SETTING: Prospective, comparison to series of patients at similar risk of CIN in a university hospital medical ICU. PATIENTS: 78 ICU patients with at least one risk factor for CIN undergoing 150 consecutive contrast examinations. INTERVENTIONS: Administration of 200 mg theophylline/70 kg BW intravenously 30 min before that of 100 ml or more low-osmolarity contrast medium (CM). MEASUREMENTS AND RESULTS: Concentrations of serum creatinine and blood urea nitrogen (BUN), urine volume, fluid balance, and the incidence of CIN [increase in creatinine > or =20.5 mg/dl (= 44.2 micromol/l) within 48 h] were monitored for 48 h. Despite the large number of risk factors (6.8 per patient) including a high dose of CM (169.4 ml), impaired renal function (51%), diabetes (38%), aminoglycosides (61%), vancomycin (53%), catecholamines (52%), creatinine concentrations were not increased 24 h (1.40+/-0.92 mg/dl) or 48 h (1.38+/-0.88 mg/dl) after CM [1.47+/-1.0 mg/dl (= 130+/-88 micromol/l)] vs. baseline. The fluid balance was not different before (+3 ml/h) and after CM (-9 ml/h). The urine volume slightly increased after CM and theophylline (184 ml/h vs. 164 ml/h). Only three patients (2%) developed CIN. The incidence was significantly lower than that of 14% (78/565) in the control series with patients at comparable risk of CIN (p < 0.0001). CONCLUSIONS: Using a theophylline prophylaxis the incidence of CIN in patients with increased risk of CIN is as low as 2%.

Adenosine↗

What constitutes a histological confirmation of cancer? A survey of terminology interpretation in two English regions.

AIMS: To compare interpretation by cancer registries and histopathologists of phrases that might confirm a diagnosis of cancer. METHODS: One hundred and thirty one consultant pathologists were sent a questionnaire containing 37 phrases used in pathology reports, including those indicating cancer and those not. Pathologists were asked to indicate whether each phrase confirmed the disease, ruled it out, or was uncertain, together with a subjective estimate of how frequently they used the phrase. RESULTS: There was a 58% response rate with similar interpretation between regions. There were some differences in frequency of use. At least 50% of respondents considered 12 terms as confirmatory (for nine the lower 95% confidence limit was greater than 66%). CONCLUSIONS: The registry should consider ignoring four of the 13 terms currently regarded as confirmatory. Terminology used in pathology reports should be standardised across registries. Registries and coding departments should use empirical evidence to assess which phrases confirm a diagnosis.

Communication↗

A novel, recombinant triple antigen hepatitis B vaccine (Hepacare).

Infection with hepatitis B virus (HBV) continues to be a major problem in the human population. There remains a specific requirement for HBV vaccines capable of circumventing the non-responder/inadequate responder status of some vaccinees. Hepacare has been primarily developed to (1) improve anti-SHBs antibody titres in low responders, to conventional SHBsAg vaccinees, (2) overcome difficulties of non-compliance seen with existing SHBsAg vaccine regimens. Hepacare is a novel recombinant particle produced in eukaryotic cells, consisting of pre-S1, pre-S2 and S proteins of HBV and is adjuvanted with alhydrogel. It has been demonstrated to be highly immunogenic for both B and T cells in mice, chimpanzees and humans and induces higher anti-S 'a' determinant antibody titres than SHBsAg vaccines in mice and humans. Hepacare has proven to be at least as efficacious as current SHBsAg vaccines in chimpanzees. Clinical trials in both Europe and the USA have clearly demonstrated its superior ability to induce anti-SHBs antibody seroconversion in low-responder groups, compared with SHBsAg vaccines.

Animals↗

Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member.

Heparan sulfate proteoglycans are important constituents of the extracellular matrix and basement membrane. Cleavage of heparan sulfate by heparanase, an endoglycosidase, is implicated in the extravasation of leukocytes and metastatic tumour cells, identifying this enzyme(s) as a target for anti-inflammatory and anti-metastatic therapies. The cloning of a cDNA encoding human heparanase (Hpa1) was reported recently, together with evidence indicating that the hpa1 gene is unique and unlikely to belong to a family of related genes. Here we report the cloning of a cDNA encoding a novel human protein, HPA2, with significant homology to Hpa1. Alternative splicing of the hpa2 transcript yields three different mRNAs, encoding putative proteins of 480, 534, and 592 amino acids. Sequence analyses predict that all three Hpa2 proteins are intracellular, membrane-bound enzymes. Hpa2 also shows a markedly different mRNA distribution to Hpa1 in both normal and cancer tissues. The difference in expression profiles and predicted cellular locations suggests that Hpa2 and Hpa1 proteins have distinct biological functions.

Alternative Splicing↗