Biomedical subjects
Publications and source records attributed to M Gilbert.
In a victim of very deep accidental hypothermia, 9 h of resuscitation and stabilisation led to good physical and mental recovery. This potential outcome should be borne in mind for all such victims.
The purpose of this study was the investigation of cationic nanoparticles as drug delivery systems for antisense oligonucleotides. Cationic monomethylaminoethylmethacrylate (MMAEMA) copolymer nanoparticles were prepared from N-monomethylaminoethylmethacrylate hydrochloride and methylmethacrylate. Oligonucleotides were adsorbed onto MMAEMA nanoparticles. Cell penetration was investigated in vitro with fluorescently labeled oligonucleotides and nanoparticles. Antisense effects of oligonucleotides adsorbed to MMAEMA nanoparticles were evaluated by sequence specific inhibition of ecto-5'-nucleotidase expression. The amount of enzyme expressed in PC12 cells was detected and quantified by immunocytochemistry using fluorescein isothiocyanate-labeled antibodies. Oligonucleotides were adsorbed to MMAEMA nanoparticles by the formation of ion-pairs between the positively charged secondary amino groups located on the particle surface and the anionic phosphodiester or phosphorothioate backbones of the oligonucleotides. Adsorption to nanoparticles led to an increased cellular uptake of oligonucleotides and to a significantly enhanced antisense efficacy of unmodified phosphodiester oligonucleotides as well as phosphorothioates. The results of the cell penetration and the antisense assay demonstrated that MMAEMA nanoparticles are promising carriers for oligonucleotide administration.
Recent publications support the use of preradiation chemotherapy in the treatment of selected primary brain tumors. In the pediatric population, this treatment strategy often delays radiotherapy and may improve the outcome in patients. This manuscript describes the use of a preradiation chemotherapy approach for adult patients with newly diagnosed glioblastoma multiforme. The main objective of this trial was to determine the feasibility of delivering up to 3 monthly cycles of a 72 h continuous simultaneous intravenous infusion of BCNU (40 mg/m2/day) and cisplatin (40 mg/m2/day). Patients were evaluated for tumor response or progression after each cycle. Following the completion of the chemotherapy treatments or evidence of tumor progression, patients underwent external beam radiotherapy. A dose of 45 Gy was delivered to the pretreatment tumor volume plus surrounding edema and a margin of 3.0 cm. An additional 14.4 Gy was delivered to the preoperative volume plus a 2 cm margin. Fifty patients were enrolled, 47 were eligible and analyzable. Overall, 79% of patients were able to complete at least 2 cycles of treatment, exceeding the predefined measure of feasibility. One patient achieved a complete response, 10 patients a partial response and 18 patients had stable disease at completion of the chemotherapy treatments. Twenty-four patients experienced grade 4 toxicity, mostly hematologic. All patients were able to undergo radiotherapy following chemotherapy. These results indicate that a preradiation strategy is feasible. Although responses to the chemotherapy were seen, a phase III trial is needed to determine whether this approach provides an advantage over standard treatment; such a phase III trial has been undertaken by ECOG.
Ganglioside mimicry by Campylobacter jejuni lipo-oligosaccharide (LOS) is thought to be a critical factor in the triggering of the Guillain-Barré and Miller-Fisher syndrome neuropathies after C. jejuni infection. The combination of a completed genome sequence and a ganglioside GM1-like LOS structure makes C. jejuni NCTC 11168 a useful model strain for the identification and characterization of the genes involved in the biosynthesis of ganglioside-mimicking LOS. Genome analysis identified a putative LOS biosynthetic cluster and, from this, we describe a putative gene (ORF Cj1139c), which we have termed wlaN, with a significant level of similarity to a number of bacterial glycosyltransferases. Mutation of this gene in C. jejuni NCTC 11168 resulted in a LOS molecule of increased electrophoretic mobility, which also failed to bind cholera toxin. Comparison of LOS structural data from wild type and the mutant strain indicated lack of a terminal beta-1,3-linked galactose residue in the latter. The wlaN gene product was demonstrated unambiguously as a beta-1,3 galactosyltransferase responsible for converting GM2-like LOS structures to GM1-like by in vitro expression. We also show that the presence of an intragenic homopolymeric tract renders the expression of a functional wlaN gene product phase variable, resulting in distinct C. jejuni NCTC 11168 cell populations with alternate GM1 or GM2 ganglioside-mimicking LOS structures. The distribution of wlaN among a number of C. jejuni strains with known LOS structure was determined and, for C. jejuni NCTC 12500, similar wlaN gene phase variation was shown to occur, so that this strain has the potential to synthesize a GM1-like LOS structure as well as the ganglioside GM2-like LOS structure proposed in the literature.
Qualitative and quantitative outcomes were assessed clinically and radiographically in 41 patients (46 thumbs) with thumb basal joint arthritis limited to the trapeziometacarpal joint treated with hemiresection arthroplasty of the trapezium, flexor carpi radialis ligament reconstruction, and allograft costochondral interposition graft. Results of the validated Disability of Arm, Shoulder, and Hand questionnaire at a mean follow-up time of 42 months (range, 24-48 months) revealed that 90% of the patients had a high level of function with minimal symptoms. Important improvements in web space with increased palmar and radial abduction and grip and pinch strength measurements were observed. The trapeziometacarpal space had decreased 21% after surgery while trapeziometacarpal subluxation was 16% compared with 21% before surgery. There was an inverse correlation between the loss of trapezial height and subluxation and clinical outcome. The results of this study demonstrate that although the preoperative trapezial height was not maintained, the reconstructed thumbs remained stable, with little subluxation and improved clinical outcomes. (J Hand Surg 2000; 25A:61-76.
BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.
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The purpose of this study was to investigate, in an anesthetized pig model of low-flow myocardial ischemia, the electrophysiologic effects of the class III drug d-sotalol during myocardial ischemia. Serial monophasic action potential (MAPD90) recordings and refractory period determinations from the anterior and posterior left ventricular wall were taken in 25 pigs during baseline, after low-flow posterior wall ischemia, after d-sotalol infusion under nonischemic conditions, and after repeated posterior wall ischemia while continuing the drug. Measurements were done at 60 and 150 beats/min after radiofrequency ablation of atrioventricular conduction. At baseline, MAPD90 and refractory periods were comparable in the anterior and posterior wall (323 +/- 15 vs. 318 +/- 10 ms, and 267 +/- 10 vs. 262 +/- 11 ms at 60 beats/min, respectively). In the absence of d-sotalol, low-flow regional ischemia was associated with a significant shortening of MAPD90 in the posterior versus the anterior wall (267 +/- 20 vs. 317 +/- 20 ms at 60 beats/min; p = 0.006). Similarly, ischemia-induced shortening of the refractory periods in the posterior wall was apparent (230 +/- 16 ms in the posterior wall vs. 274 +/- 14 ms in the anterior wall at 60 beats/min). In contrast, ischemia was no longer associated with shortening of MAPD90 (360 +/- 17 ms posterior wall and 360 +/- 20 ms anterior wall at 60 beats/min) and refractory periods (304 +/- 19 ms posterior wall vs. 316 +/- 15 ms anterior wall at 60 beats/min) during combined posterior wall ischemia and d-sotalol infusion. Similar findings were obtained during pacing at 150 beats/min. d-Sotalol attenuates ischemia-induced action potential shortening. This property should decrease dispersion of cardiac repolarization and be antiarrhythmic. On the other hand, longer APD under ischemic conditions may favor calcium overload, which may trigger new arrhythmias.
The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions.
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BACKGROUND: Calcipotriol has been combined with a number of systemic antipsoriatric treatments, improving efficacy or reducing the systemic treatment required. Although studies on calcipotriol and UVB have also been performed, there are no data on the UVB-saving effect of calcipotriol combined with broad-band UVB to reduce overall UVB exposure, while maintaining efficacy. OBJECTIVES: To assess the efficacy and safety of calcipotriol cream (50 microg/g) combined with twice weekly broad-band UVB and to determine if this treatment would require fewer UVB treatments and lower cumulative UVB irradiance when compared to a standard 3 times weekly broad-band UVB regime in patients with extensive psoriasis. METHODS: This multicentre, prospective, randomised, parallel-group, vehicle-controlled, single-blind (investigator) study consisted of a 1-week wash-out phase, 12-week treatment phase and 12-week follow-up phase. Broad-band UVB equipment was standardised and calibrated prior to the study. The UVB starting dose was based on the patient's minimal erythema dose. Assessments included PASI, extent, severity and investigator and patient's overall assessments of the psoriasis. RESULTS: Fewer exposures (12 vs. 19) and less cumulative UVB irradiance (1,570 vs. 5,430 mJ/cm(2)) were required by the calcipotriol + twice weekly UVB group to achieve 80% reduction in PASI (p < 0.001). Similarly, fewer exposures (22 vs. 25) and less cumulative UVB irradiance (4,147 vs. 9,670 mJ/cm(2)) were required by this group to achieve total clearance (p < 0.001). There was no difference in the PASI, patient's and investigator's overall assessments and number of adverse events recorded by either group for both the treatment and follow-up phases. CONCLUSION: Calcipotriol cream + twice weekly broad-band UVB phototherapy is an effective and safe antipsoriatric treatment, resulting in fewer UVB exposures, lower cumulative irradiance and a saving of time.
BACKGROUND: This study was performed to determine if the accuracy of screw placement was improved with use of the Herbert-Whipple cannulated screw compared with use of the AO/ASIF cannulated screw and also to evaluate the functional results in patients with an acute displaced fracture of the waist of the scaphoid treated with open reduction and internal fixation with a cannulated screw. METHODS: We retrospectively reviewed the results for thirty-five patients in whom an acute displaced fracture of the waist of the scaphoid had been treated with internal fixation with use of a cannulated screw. The patients were divided into two groups; Group 1 consisted of nineteen patients managed with a 3.5-millimeter cannulated AO/ASIF screw from 1990 through 1997, and Group 2 consisted of sixteen patients managed with a Herbert-Whipple screw from 1993 through 1997. RESULTS: There were no clinical or radiographic differences between the two groups. The average time to union (and standard deviation), confirmed with tomography, was 4.2 +/- 1.2 months for Group 1 and 4.0 +/- 1.2 months for Group 2. Both screws significantly improved the alignment of the scaphoid and decreased carpal collapse (p < 0.01). Importantly, the use of either cannulated screw improved the height-to-length ratio and the lateral intrascaphoid angle, which were correlated with an increase in the range of motion of the wrist (r = 0.584 and 0.625). In addition, both screws allowed for accurate placement in the central portion of the proximal pole. Regardless of the type of screw used, the time to union increased with increasing age of the patient (r = 0.665) and with increasing initial displacement of the fracture (r = 0.541). Within both groups, the time to union was longer for the patients who smoked (p < 0.01). CONCLUSIONS: Within both groups, cannulated screw fixation maintained the corrected fracture alignment and promoted healing and return of function. Our study shows cannulated screws to be a safe and effective method of treatment.
BACKGROUND: Long QT syndrome is a congenital abnormality of cardiac repolarization causing syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. This hereditary cardiac disorder often shows an increase of the value of the QT interval corrected for heart rate over 0.45 s in a 12-lead electrocardiogram. OBJECTIVE: To find and identify pertinent mutations occurring in French Canadians by extracting genomic DNA from blood samples and performing a combination of polymerase chain reaction (PCR), single-strand conformational polymorphism and DNA sequencing. RESULTS: A novel mutation was identified in the S5 region of the HERG potassium channel. In codon 564 CTA, T was replaced by C, resulting in a leucine to proline substitution. Two family members had the mutation in two distinct generations. A new restriction site was created at this position and therefore enabled the development of a rapid diagnostic test using PCR. HERG wild type and mutant potassium channel mRNAs were then expressed in Xenopus laevis oocytes. CONCLUSION: This electrophysiological study suggests that coexpression of HERG wild type and mutant L564P results in a dominant negative effect of the mutation.
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Although primary brain tumors are relatively uncommon types of adult cancer, their location and resistance to treatment can significantly affect the patient's physical and cognitive function. Consequently, quality of life (QOL) issues are extremely important in the design and evaluation of clinical trials of high-grade glioma treatment. Although a number of studies have examined QOL in patients with primary brain tumors, very little is known about QOL in these patients. These studies often use either poorly validated instruments or tools, such as the Karnofsky performance scale, that do not fully evaluate the effects of the tumor on QOL. Recent attempts to better evaluate QOL in brain tumor patients have led to the development of brain tumor-specific QOL instruments, such as the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire-Brain Cancer Module and the Functional Assessment of Cancer Therapy-Brain, which offer more insight into the QOL aspects of cancer and its treatment. Instruments such as quality time without symptoms or toxicity (Q-TWiST) provide a means of integrating both quality of time of survival and absence of symptoms or toxicity.
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As part of our program to design, develop and prepare protective vaccines against the bacterial pathogens Group B Streptococcus, we report the synthesis of a disialylated hexasaccharide. This hexasaccharide represents a portion of the serotype-specific capsular polysaccharide of Type VIII that has the tetrasaccharide repeat unit [beta-L-Rhap-(1-->4)-beta-D-Glcp-(1-->4)-[alpha-Neu5Ac-(2--> 3)]-beta-D- Galp-(1-->4)]n. A tetrasaccharide corresponding to this repeat unit has been synthesized by us [E. Eichler, H.J. Jennings, D.M. Whitfield, J. Carbohydr. Chem., 16 (1997) 385-411]. Since the protective epitopes are believed to involve several repeat units, methods to extend this tetrasaccharide were examined. This objective requires a glycosylation of the unreactive OH-4 of the beta-L-Rhap, which was accomplished by coupling a D-Galp glycosyl trichloroacetimidate donor with a beta-L-Rhap-(1-->4)-D-Glcp acceptor. Subsequent coupling of this trisaccharide as a donor to an alpha-Neu5Ac-(2-->3)-D-Galp disaccharide acceptor gave a pentasaccharide. The pentasaccharide was deprotected and enzymatically sialylated using an alpha-(2-->3)-sialyltransferase from Campylobacter jejuni to give the title hexasaccahride alpha-Neu5Ac-(2-->3)- beta-D-Galp-(1-->4)-beta-L-Rhap-(1-->4)-beta-D-Glcp-(1-->4)-[alpha -Neu5Ac- (2-->3)]-beta-D-Galp-(1-->O)-(CH2)3N3.