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Biomedical subjects

A Henry

Publications and source records attributed to A Henry.

At least 19 recordsLinked to original sources
PubMed2007

A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer.

BACKGROUND: This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity. PATIENTS AND METHODS: Thirty-five patients received escalating doses of PTK/ZK (range 500-2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage. RESULTS: Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months. CONCLUSION: The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.

Adult↗
PubMed2006

Dislocation of the hips in children with bilateral spastic cerebral palsy, 1985-2000.

The aim of this study was to assess the rate of hip dislocation at different ages in children with bilateral spastic cerebral palsy attending special schools in southern Derbyshire, UK, between 1985 and 2000. The medical notes of 110 individuals (68 males, 42 females) were obtained. They were divided into four groups according to the Gross Motor Function Classification System (GMFCS). We determined whether or not their hips were dislocated at the ages of 5, 10, and 15 years, and the kind of surgery performed in each case. The percentage of individuals with one or both hips dislocated increased with age and with severity of disease. Of those in GMFCS Level II (n=18), none had dislocations; Level III (n=16), none had dislocations at ages 5 and 10, but 11% had by the age of 15; Level IV (n=35), 8% had dislocations by age 5, 19% by age 10, and 30% by age 15; Level V (n=41), 22% had dislocations by age 5, 48% by age 10, and 50% by age 15. Forty-two per cent of individuals with hip dislocation had not had previous preventive surgery. Twenty-one per cent of hips operated on still proceeded to dislocation. We conclude that there was a high rate of hip dislocation, especially in GMFCS groups Levels IV and V, and that this often occurred very early. Preventive surgery avoided dislocation in many children. However, orthopaedic referral was often not made before dislocation was discovered, or the referral was made too late for surgery on soft tissue to be successful. These results may be compared with those from current programmes of hip management, involving radiological surveillance and early use of conservative and surgical interventions.

Adolescent↗
PubMed2006

Use of a chronic disease management programme in COPD to reduce hospital admissions.

Chronic obstructive pulmonary disease (COPD) accounts for a large number of hospital admissions and numerous interventions have attempted to reduce exacerbations requiring hospitalization. This paper describes the implementation of a community based COPD management programme led by a respiratory physiotherapist to improve home management of COPD and its effect on reducing readmissions and/or length of stay in hospital. One-hundred and twenty-five patients (median age 73) referred with COPD exacerbations met the criteria for the service; 95 received the intervention and data were available for 80. Median FEV1 was 0.86 L. Admission data, length of stay and total hospitalization days with COPD were compared for one year before and after the intervention. Overall there was no reduction in length of stay, admission frequency, or adjusted total hospitalization days with COPD, but median time interval to next exacerbation increased by 29%. In those who had had previous admissions (mean FEV1 0.58 L) total hospitalization days fell by 27%, length of stay fell by 58% despite an increase in admission frequency from one to two per year, and there was no change in median time interval to next hospitalized exacerbation. In our patients implementation of a Chronic Disease Management programme increased the time to next hospitalized exacerbation. Benefit was seen in the more severe patients however, with a significant reduction in both length of stay and total hospitalization days.

Aged↗
PubMed2006

Developments in and experience of kilovoltage X-ray cone beam image-guided radiotherapy.

This paper offers a realistic review of kilovoltage X-ray cone beam tomography integrated with the treatment machine for image-guided radiotherapy in the light of experience taking a commercial system from prototype development into clinical use. It shows that key practicalities cannot be ignored, in particular the regular characterization of mechanical flex during gantry rotation, the mapping of defects in flat panel image transducers and their response to X-ray exposure. The number of X-ray projections and the doses required for clinically useful cone beam reconstruction at different therapy sites are considered in the context of imaging that is fit for purpose. Three roles for cone beam tomography in radiotherapy are identified: patient setup in three dimensions (3D), where even low dose cone beam tissue detail is superior to megavoltage imaging; disease targeting where, despite wide field scatter and slow scanning, it is possible to generate images that are suitable for tumour delineation even at challenging sites; adaptive treatment planning, where calibrated cone beam images have been shown to provide sufficient target detail to support "plan of the day" selection and have the potential for planning with bulk corrections. With frequent use in mind, the need to limit patient dose during setup, yet maximize much needed image quality in the target zone, is considered. Finally, it is noted that the development of cone beam tomography for radiotherapy is far from complete, with X-ray source, image transducer, reconstruction algorithms and techniques for image profile collection still being researched.

Humans↗
PubMed2006

Incidence of injury in elite Gaelic footballers.

The purpose of this study was to undertake a comprehensive prospective epidemiological study of injuries sustained by elite Gaelic Football players over one season. The pattern of injury is strikingly similar across all teams with 47% of all injuries occurring in the final quarter of games and training. Injuries to the lower limb, particularly the hamstrings muscles accounted for the majority of injuries. 65% of players were unable to participate fully in Gaelic Football activity for between one and three weeks as a result of injury. The high incidence of injury especially hamstrings injuries in the latter stages of training and games warrants further investigation.

Adolescent↗
PubMed2005

An operational method for the real-time monitoring of E. coli numbers in bathing waters.

The aim of this study was to investigate the potential application of the beta-d-glucuronidase (GLUase) activity measurement for the routine detection and quantification of E. coli in marine bathing waters. GLUase activity was measured as the rate of hydrolysis of 4-methylumbelliferyl-beta-d-glucuronide. Culturable E. coli were quantified by the most probable number (MPN) microplate method. Both methods were applied to a large set of seawater samples. Significant correlation was found between the log of GLUase activity and the log of culturable E. coli. The mean coefficient of variation (CV) of the GLUase activity was less than 15% at concentrations around the current standards of International regulations whereas the CV of the microplate method was around 30%. When samples were stored at 4 degrees C and 20 degrees C, the mean CV of the GLUase activity remained below 15% up to 6 hours after sample collection whereas the range of variation of the microplate method varied between 10 and 50%. We concluded that the GLUase activity is an operational, reproducible, simple, very rapid and low cost method for the real-time enumeration of E. coli in bathing waters and should be preferred to the microplate method. The GLUase activity method should be routinely applied to the rapid enumeration of E. coli in recreational waters and recommendations for its application were suggested to water quality managers.

Analysis of Variance↗
PubMed2005

Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials.

BACKGROUND: Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases. PATIENTS AND METHODS: Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for > or =2 months were categorized as 'non-progressors'. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and C(max) of PTK/ZK on day 1, cycle 1 and clinical outcome. RESULTS: A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and C(max) was characterized by an E(max) model, suggesting that a change of > or =150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF-A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P=0.027). CONCLUSIONS: In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.

Aged↗
PubMed2004

Development of a stabilized low temperature infrared absorption cell for use in low temperature and collisional cooling experiments.

We have constructed a stabilized low temperature infrared absorption cell cooled by an open cycle refrigerator, which can run with liquid nitrogen from 250 to 80K or with liquid helium from 80K to a few kelvin. Several CO infrared spectra were recorded at low temperature using a tunable diode laser spectrometer. These spectra were analyzed taking into account the detailed effects of collisions on the line profile when the pressure increases. We also recorded spectra at very low pressure to accurately model the diode laser emission. Spectra of the R(2) line in the fundamental band of 13CO cooled by collisions with helium buffer gas at 10.5K and at pressures near 1 Torr have been recorded. The He-pressure broadening parameter (gamma(0) = 0.3 cm(-1) atm(-1)) has been derived from the simultaneous analysis of four spectra at different pressures.

Argon↗
PubMed2002

Diode laser emission linewidth determination: application to H2O line profile studies in the 5 and 1.4 microm regions.

In order to study absorption line profiles using the stabilized diode laser spectrometer of Laboratoire de Physique Moléculaire et Applications (LPMA), a reliable determination of the emission line shape of different diodes laser is needed. In the near infrared region (1.39 and 1.66 microm) we used Distributed Feed Back diode lasers which operate around room temperature and in the middle infrared (5 and 8 microm) we used lead salt diode lasers cooled in a helium closed cycle cryostat or in a liquid nitrogen dewar. Some results obtained in H2O line profile studies in the 1.39 and 5 microm regions are presented as examples demonstrating how absorption line profile measurements can lead to erroneous values of the spectroscopic parameters when the contribution of the diode laser emission line width is neglected.

Spectrophotometry↗
PubMed2002

Pressure broadening study at low temperature: application to methane.

We studied the R(0) line profile in the CH4 v4 band from room temperature to 188 K with N2 as a perturber, to 100 K with O2 as perturber, and from room temperature to 15 K using He as a perturber. The N2 and O2 measurements were performed over a total pressure range of 15-110 mbar, and for the He measurements the maximum sample pressure at 15 K was 1.10 mbar. Broadening parameters were determined, taking into account the confinement narrowing (Dicke effect), and narrowing parameters, deduced from the soft or hard collision model, are compared with the dynamic friction coefficient calculated values. We also obtained preliminary values for the temperature dependence of the N2, O2 and He line broadening parameters for this transition.

Cold Temperature↗
PubMed2001

Reduced antibody response to streptavidin through site-directed mutagenesis.

Streptavidin provides an effective receptor for biotinylated tumoricidal molecules, including radionuclides, when conjugated to an antitumor antibody and administered systemically. Ideally, one would like to administer this bacterial protein to patients repeatedly, so as to maximize the antitumor effect without eliciting an immune response. Therefore, we attempted to reduce the antigenicity of streptavidin by mutating surface residues capable of forming high energy ionic or hydrophobic interactions. A crystallographic image of streptavidin was examined to identify residues with solvent-exposed side chains and residues critical to streptavidin's structure or function, and to define loops. Mutations were incorporated cumulatively into the protein sequence. Mutants were screened for tetramer formation, biotin dissociation, and reduced immunoreactivity with pooled patient sera. Patient antisera recognized one minor continuous epitope with binding locus at residue E101 and one major discontinuous epitope involving amino acid residues E51 and Y83. Mutation of residues E51, Y83, R53, and E116 reduced reactivity with patient sera to <10% that of streptavidin, but these mutations were no less antigenic in rabbits. Mutant 37, with 10 amino acid substitutions, was only 20% as antigenic as streptavidin. Rabbits immunized with either streptavidin or mutant 37 failed to recognize the alternative antigen. Biotin dissociated from mutant 37 four to five times faster than from streptavidin. Residues were identified with previously undescribed impact on biotin binding and protein folding. Thus, substitution of charged, aromatic, or large hydrophobic residues on the surface of streptavidin with smaller neutral residues reduced the molecule's ability to elicit an immune response in rabbits.

Amino Acid Sequence↗
PubMed2000

Patterns of medication use during and prior to pregnancy: the MAP study.

We interviewed 140 pregnant women of any gestational age attending antenatal clinics at the Women's and Children's Hospital in Adelaide during September-October 1999 to elicit information about their patterns of medication use during and in the 3 months prior to their current pregnancy. Demographic information, information on women's prescribed, non-prescribed, and non-medicinal drug use during and in the 3 months prior to pregnancy, and information about both their general sources of information on medication use and their specific reasons for medication uptake/cessation during pregnancy were obtained. The women used an average of 0.7 0.8 prescribed and 2.3-2.6 non-prescribed medications (total 3.1-3.3) in the 3 pregnancy trimesters, compared with 1.0 prescribed and 2.2 non-prescribed prior to pregnancy. Use of a prescribed or non-prescribed medication was 96-97% across trimesters. Simple analgesics, vitamin/mineral supplements, and antacids were the most commonly taken medications. Antibiotics were the most commonly prescribed medication. Use of class A medications increased during pregnancy while use of non-class A medications decreased. Peri-conceptional folate supplementation was 31%. Alcohol consumption and cigarette smoking decreased after diagnosis of pregnancy. Both prescribed and non-prescribed medication use is common during all trimesters of pregnancy. However, overall use changes little compared with pre-pregnancy values. Rates of peri-conceptional folate supplementation are low.

Adolescent↗
PubMed1999

Identification of three oligosaccharide binding sites in ricin.

The galactoside-binding sites of ricin B chain can be blocked by affinity-directed chemical modification using a reactive ligand derived from asialoglycopeptides containing triantennary N-linked oligosaccharides. The terminal galactosyl residue of one branch of the triantennary oligosaccharide is modified to contain a reactive dichlorotriazine moiety. Two separate galactoside-binding sites have been clearly established in the ricin B chain by X-ray crystallography [Rutenber, E., and Robertus, J. D. (1991) Proteins 10, 260-269], and it is necessary to covalently attach two such reactive ligands to the B chain to block its binding to galactoside affinity matrixes. A method was developed using thiol-specific labeling of the ligand combined with subsequent immunoaffinity chromatography which allowed the isolation of ricin B chain peptides covalently linked to the ligand from proteolytic digests of purified blocked ricin. The sites of covalent attachment of the two ligands in blocked ricin were inferred from sequence analysis to be Lys 62 in domain 1 of the B chain and Tyr 148 in domain 2. A minor species of blocked ricin contains a third covalently attached ligand. From the analysis of peptides derived from blocked ricin enriched in this species, it is inferred that Tyr 67 in domain 1 is the specific site on the ricin B chain where a third reactive ligand becomes covalently linked to the protein. These results are interpreted as providing support for the notion that the ricin B chain has three oligosaccharide binding sites.

Amino Acid Sequence↗
PubMed1999

Recombinant human amyloid precursor-like protein 2 (APLP2) expressed in the yeast Pichia pastoris can stimulate neurite outgrowth.

The human amyloid precursor-like protein 2 (APLP2) is a member of the Alzheimer's disease amyloid precursor protein (APP) gene family. The human APLP2 ectodomain (sAPLP2) was expressed in the yeast Pichia pastoris and the recombinant sAPLP2 was purified from the culture medium in a single step by metal-chelating Sepharose chromatography. The neuritotrophic activity of APLP2 was compared to the APP isoforms sAPP695 and sAPP751 on chick sympathetic neurones. APLP2 had neurite outgrowth-promoting activity similar to that of the APP isoforms. This suggests that APP and APLP2 have a similar or related role and supports the idea of a redundancy in function between the APP-gene family proteins.

Amyloid beta-Protein Precursor↗
PubMed1999

Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.

Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.

Alzheimer Disease↗
PubMed1999

The amyloid beta-protein precursor of Alzheimer's disease is degraded extracellularly by a Kunitz protease inhibitor domain-sensitive trypsin-like serine protease in cultures of chick sympathetic neurons.

The amyloid beta-protein precursor (APP) of Alzheimer's disease (AD) is cleaved either by alpha-secretase to generate an N-terminally secreted fragment, or by beta- and gamma-secretases to generate the beta-amyloid protein (Abeta). The accumulation of Abeta in the brain is an important step in the pathogenesis of AD. Alternative mRNA splicing can generate isoforms of APP which contain a Kunitz protease inhibitor (KPI) domain. However, little is known about the physiological function of this domain. In the present study, the metabolic turnover of APP was examined in cultured chick sympathetic neurons. APP was labelled by incubating neurons for 5 h with [35S]methionine and [35S]cysteine. Intracellular labelled APP decayed in a biphasic pattern suggesting that trafficking occurs through two metabolic compartments. The half-lives for APP in each compartment were 1.5 and 5.7 h, respectively. A small fraction (10%) of the total APP was secreted into the culture medium where it was degraded with a half-life of 9 h. Studies using specific protease inhibitors demonstrated that this extracellular breakdown was due to cleavage by a trypsin-like serine protease that was secreted into the culture medium. Significantly, this protease was inhibited by a recombinant isoform of APP (sAPP751), which contains a region homologous to the Kunitz protease inhibitor (KPI) domain. These results suggest that KPI forms of APP regulate extracellular cleavage of secreted APP by inhibiting the activity of a secreted APP-degrading protease.

Alzheimer Disease↗