Intranasal fentanyl for postoperative analgesia after elective Caesarean section.
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Analgesia, Obstetrical↗
Biomedical subjects
P Wong
Publications and source records attributed to P Wong.
Intubation times for using the Bonfils intubation fibrescope.
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Endoscopes↗
Cytostatic potential of novel agents that inhibit the regulation of intracellular pH.
Cells within the acidic extracellular environment of solid tumours maintain their intracellular pH (pHi) through the activity of membrane-based ion exchange mechanisms including the Na(+)/H(+) antiport and the Na(+)-dependent Cl(-)/HCO(3)(-) exchanger. Inhibition of these regulatory mechanisms has been proposed as an approach to tumour therapy. Previously available inhibitors of these exchangers were toxic (e.g. 4,4-diisothiocyanstilbene-2,2-disulphonic acid), and/or non-specific (e.g. 5-N-ethyl-N-isopropyl amiloride). Using two human (MCF7, MDA-MB231) and one murine (EMT6) breast cancer cell lines, we evaluated the influence of two new agents, cariporide (an inhibitor of the Na(+)/H(+) antiport) and S3705 (an inhibitor of the Na(+)-dependent Cl(-)/HCO(3)(-) exchanger) on the regulation of intracellular pH (pHi). The cytotoxicity of the two agents was assessed by using clonogenic assays. Our results suggest that cariporide has similar efficacy and potency to 5-N-ethyl-N-isopropyl amiloride for inhibition of Na(+)/H(+) exchange while S3705 is more potent and efficient than 4,4-diisothiocyanstilbene-2,2-disulphonic acid in inhibiting Na+-dependent Cl(-)/HCO3(-) exchange. The agents inhibited the growth of tumour cells when they were incubated at low pHe (7.0-6.8), but were non-toxic to cells grown at doses that inhibited the regulation of pHi. Our results indicate that cariporide and S3705 are selective cytostatic agents under in vitro conditions that reflect the slightly acidic microenvironment found in solid tumours.
Adenocarcinoma↗
A hypothesis of haemolysis in haemolytic anaemias associated with enzymopathies.
A feature of a previously proposed mechanism of erythrocyte shape control is a control of the shape by the Donnan equilibrium ratio. An enzymopathy of the glycolytic pathway and nucleotide metabolism could alter the Donnan ratio, since it alters levels of phosphate intermediates and of end-products carbonic gas (CO(2)) and ammonia gas (NH(3)) which are ionized at the erythrocyte pH. Thus, a hypothesis of haemolysis in haemolytic anaemias associated with enzymopathies of the glycolytic pathway and nucleotide metabolism would be that it results from an inhibition of the mechanism by a modification of the Donnan ratio. This hypothesis seems plausible as it would explain coherently observations in these haemolytic anaemias.
Anemia, Hemolytic↗
Pitfalls in perinatal shunt surgery: a personal perspective.
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Age Factors↗
Design, synthesis, and SAR of amino acid derivatives as factor Xa inhibitors.
A series of potent and selective factor Xa inhibitors was synthesized using various readily available amino acids as central templates. The most potent compound displays IC(50) of 3 nM.
Drug Design↗
Design and synthesis of glycolic and mandelic acid derivatives as factor Xa inhibitors.
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.
Acetanilides↗
Mitochondria isolated from liver contain the essential factors required for RNA/DNA oligonucleotide-targeted gene repair.
Chimeric RNA/DNA oligonucleotides (ONs) have been used successfully for site-specific modifications of episomal and chromosomal DNA in eukaryotic cells. We explored the possibility of applying this technique to mitochondrial DNA, as single-nucleotide defects in this genome are associated with a series of human diseases. Therefore, we determined whether mitochondria possess the enzymatic machinery for chimeric ON-mediated DNA alterations. We utilized an in vitro DNA repair assay and an Escherichia coli readout system with mutagenized plasmids carrying point mutations in antibiotic resistance genes. RNA/DNA ONs were designed to correct the defects and restore kanamycin and tetracyclin resistance. Using this system, we demonstrated that extracts from highly purified rat liver mitochondria possess the essential enzymatic activity to mediate precise single-nucleotide changes. Interestingly, the frequency of gene conversion was similar in both mitochondrial and nuclear extracts, as well as from quiescent and regenerating liver. The results indicate that mitochondria contain the machinery required for repair of genomic single-point mutations, and suggest that RNA/DNA ONs may provide a novel approach to the treatment of certain mitochondrial-based diseases.
Animals↗
Tumour-stromal interactions. Integrins and cell adhesions as modulators of mammary cell survival and transformation.
Stromal-epithelial interactions modulate mammary epithelial cell (MEC) growth and apoptosis by influencing cell adhesion and tissue organization. Perturbations in the mammary stroma and cell adhesion characterize breast tumors and underlie the altered tissue organization, disrupted tissue homeostasis and enhanced survival phenotype of the disease. Apoptosis resistance likely arises during malignant transformation via genetic and epigenetic modification of cell adhesion pathways induced by a changing tissue microenvironment. Acquisition of adhesion-linked survival networks that enhance MEC viability in the absence of basement membrane interactions probably promote malignant transformation, and may render breast tumors sufficiently resistant to exogenous apoptotic stimuli to generate multidrug resistance.
Apoptosis↗
Dynamic tuning of T cell reactivity by self-peptide-major histocompatibility complex ligands.
Intrathymic self-peptide-major histocompatibility complex class II (MHC) molecules shape the T cell repertoire through positive and negative selection of immature CD4(+)CD8(+) thymocytes. By analyzing the development of MHC class II-restricted T cell receptor (TCR) transgenic T cells under conditions in which the endogenous peptide repertoire is altered, we show that self-peptide-MHC complexes are also involved in setting T cell activation thresholds. This occurs through changes in the expression level of molecules on thymocytes that influence the sensitivity of TCR signaling. Our results suggest that the endogenous peptide repertoire modulates T cell responsiveness in the thymus in order to enforce tolerance to self-antigens.
Animals↗
Cutting edge: antigen-independent CD8 T cell proliferation.
Recent analyses of CD8 T cell responses to Listeria monocytogenes infection demonstrate that the duration of in vivo T cell proliferation is not determined by the amount or duration of Ag presentation. However, the extent to which T lymphocytes are capable of proliferating in the absence of Ag is unknown. Herein we demonstrate that CD8 T lymphocytes undergo up to eight rounds of proliferation in the absence of Ag following transient, 2.5-h in vitro antigenic stimulation. Ag-independent expansion of CD8 T cells is driven by IL-2 and is further augmented by IL-7 or IL-15. These experiments clearly demonstrate that CD8 T cells undergo prolonged proliferation following transient Ag exposure and support the notion that in vivo CD8 T cell expansion following infection can be uncoupled from Ag presentation.
Animals↗
Validity of an ELISA for N-acetyltransferase-2 (NAT2) phenotyping.
A competitive antigen ELISA was previously developed for NAT2 phenotyping, using caffeine as the probe drug. The ELISA phenotypes by measuring the ratio of 5-acetamido-6-amino-3-methyluracil (AAMU) and 1-methylxanthine (1X) after transformation of 5-acetamido-6-formylamino-3-methyluracil (AFMU) to AAMU, in contrast to capillary electrophoresis high-pressure liquid chromatography (HPLC) which phenotype by measuring the AFMU/1X ratio. The ELISA phenotyping was previously determined in 30 samples and correlated well with phenotypes determined by capillary electrophoresis (29/30). The correlation was extended with the standard HPLC methodology by expanding the data set by 146 in order to test the validity of the ELISA methodology. The correlation with HPLC in this larger sample size was 96%; whereas the correlation between the two methods for determination of 1X was high (r(2)=0.90), that for determination of AAMU by ELISA and AFMU by HPLC was low (r(2)=0.53). The poor correlation between the two methodologies could not be attributed to the age of urine samples, nor to a significant decomposition of AFMU in the body prior to collection of the urine sample. The addition of a simple caffeine metabolite extraction method, originally developed for HPLC analysis of metabolites, to the ELISA phenotyping protocol produced a methodology with absolute correlation to the standard HPLC method.
Arylamine N-Acetyltransferase↗
[Hemialloarthroplasty of the knee joint. Results of 2 different gliding prosthesis models].
The outcome of 2 different unicompartimental knee arthroplasty procedures (St. Georg, Link AG, and Wessinghage, Sulzer Medica AG) is presented. The clinical results were evaluated by use of the Insall Score (Knee Society Rating System). According to this system, the subjective opinion of the patients are presented as a "Function Score" and the clinical evaluations is shown as a "Knee Score". In this study, the median follow-up for the St. Georg implant was 7 years and 6 months with good results reported by both scores. The median follow-up for the Wessinghage implant was 3 years and 2 months and it also showed good results. Despite the high average age of the patients in this study as well as the high percentage of female patients, both types of prostheses produced good results. If any, partial or complete radioluciencies were mainly observed in the tibial component. However, they had no clinical consequence. It should be noted, however, that arthritis in the compartment not receiving arthroplasty surgery progressed in almost 2/3 of the patients. By implantation of both implants a physiological axis of the leg could be achieved. The survivorship of the St. Georg implant was 88.92% (10 years survivorship). For the Wessinghage implant it was 98.35% (5 years survivorship).
Aged↗
Development, test reliability and validation of a classification for revision hip arthroplasty.
The objective of the study was to develop a valid and reliable classification system for failed hip arthroplasties. The study uses research principals derived from multi-attribute utility theory and consensus group techniques. The development of the severity measure was done in two phases. Phase I of the study included: (a) questionnaire development, (b) submission of the questionnaire to the respondents, (c) data synthesis of the responses and item reduction, and (d) classification development and inter-observer reliability testing. Phase II included: (a) resubmission of the instrument to the respondents for suggestions/feedback, (b) instrument revision by the co-investigators based on the respondents' second feedback, and (c) inter-observer reliability testing and intraoperative validity testing of the instrument. The questionnaires sought to capture expert opinion as to what clinical determinants obtained preoperatively (during patient interview, physical exam and review of plain radiographs - AP pelvis and hip lateral) that would in their clinical experience reveal intraoperative severity. There was an 80% (16/20) response rate from the outside experts invited to participate in the study. Based on item reduction and test retest analysis, a five-grade radiographic classification for the acetabulum as well as the femur was developed. This system was then reviewed by 13 of the initial outside experts (16, 80%) who participated in the first round. Inter-rater reliability testing of the final format of the classification revealed a weighted kappa statistic value of 0.88 between the two-blinded raters (inter-rater reliability) and 0.87 between the blinded raters and the reference standard (intraoperative validity). We conclude that the study developed a reliable and valid radiographic classification system for failed hip arthroplasty.
Arthroplasty, Replacement, Hip↗
A comparison of the shuttle and 6 minute walking tests with measured peak oxygen consumption in patients with heart failure.
This study investigated the use of an incremental, externally-paced 10 m shuttle walk test (SWT) as an objective, reliable and predictive test of functional capacity in patients with heart failure (CHF). The SWT was compared to a 6 minute walk test (6WT) and a maximal symptom-limited treadmill peak oxygen consumption (VO2peak) test. Experiment 1 examined the reproducibility of the SWT. Two SWF trials were performed and distance ambulated (DA), heart rate (HR) and rate of perceived exertion (RPE) results compared. In experiment 2, SWT, 6WT, and VO2 peak tests were performed and HR. RPE and ambulatory VO2 compared. The SWT demonstrated strong test/retest reliability for DA (r = 0.98). HR (r = 0.96) and RPE (r = 0.89). Treadmill VO2 peak was significantly correlated with DA during the SWT (r = 0.83, P < 0.05), but not the 6WT. SWT peak VO2 (18.5 +/- 1.8 ml.kg(-1) x min(-1)) and treadmill VO2 peak (18.3 +/-2.0 ml.kg(-1) x min(-1)) were also highly correlated (r = 0.78, P < 0.05). Conversely, 6WT peak VO2 and treadmill VO2 peak were not significantly correlated. This study suggests the SWT is a reliable, objective test, highly predictive of VO2 peak which may be a more optimal field exercise test than the self paced 6WT.
Exercise Test↗
The level of accuracy and agreement in measures of FEO2, FECO2 and VE between the Cosmed K4b2 portable, respiratory gas analysis system and a metabolic cart.
This study aimed to assess the accuracy of the Cosmed K4b2 (Cosmed, Italy) portable metabolic system that measures FEO2, FECO2 and VE on a breath by breath basis. For gas concentration comparisons, expired air from 20 subjects performing treadmill running was collected in a 600 litre chain compensated Collins Tissot tank and analysed for FEO2 and FECO2 using a laboratory metabolic cart and the Cosmed K4 b2 metabolic system. For ventilation comparisons, serial steady state VE (STPD) values were measured on 10 subjects using the Cosmed K4b2 ventilation turbine and a Morgan ventilation monitor during a continuous treadmill running protocol at ascending speeds of 8, 11 and 14 km x h(-1). The Cosmed K4b2 FEO2 and FECO2 measures were significantly lower (P < 0.001) than the metabolic cart values. Pearson correlation coefficients (r) and the standard error of measurement (SEM) demonstrated a high association between the Cosmed and the metabolic cart measures (FEO2 r =0 .971, SEM 0.071: FECO2 r = 0.925, SEM 0.087). Cosmed VE (l x min(-1)) measures were significantly greater than Morgan values at running speeds of 8 kmh(-1) (P < 0.001) and 11 kmh(-1) (P < 0.001) but not significantly different at 14 km x h(-1) (P > 0.05). When VE measures at the three running speeds were combined, the mean difference between instrument measures ranged between 3.5 - 4.0 l x min(-1) but the values were highly correlated (r= 0.982, P<0.01; SEM 3.03). Linear regression analysis revealed the following regression equations to predict metabolic cart values from Cosmed measures: FEO2 = 0.852+0.963 Cosmed (R2 = 0.940, P<0.00 1), FECO2 = 0.627+0.878 Cosmed (R2=0.856, P<0.001), VE = -2.50+0.984 Cosmed (R2 = 0.965. P < 0.001). The results indicated that the Cosmed K4b2 unit assessed here produced measures of FEO2, FECO2 and VE that had strong correlation to values obtained from a metabolic cart. However, linear regression analysis may further improve the accuracy of Cosmed K4b2 measures when compared to metabolic cart values.
Adolescent↗
A simple method to estimate the required dialysis time for cases of alcohol poisoning.
BACKGROUND: Conventional dialysis management of ethylene glycol and methanol poisoning includes frequent intradialytic determinations of serum toxin concentration. Dialysis is continued until a target toxin concentration is reached. Initially, the required dialysis duration is unknown, making planning difficult. We devised a simple method to estimate the duration of dialysis required and avoid quantitation of multiple toxin samples. METHODS: Using the assumption that toxic alcohols would have a dialysis clearance similar to urea, we proposed that required dialysis time (hours) to reach a 5 mmol/L toxin concentration target would be: [-V ln(5/A)]/0.06k, where V (liters) is the Watson estimate of total body water, A is the initial toxin concentration (mmol/L), and k is 80% of the manufacturer-specified dialyzer urea clearance (mL/min) at the initial observed blood flow rate. Directly measured dialysis and renal toxin clearance, and true dialysis requirement by conventional treatment protocol were compared with our estimate in two methanol and three ethylene glycol poisonings treated with Fresenius F8 dialyzers. RESULTS: There were no clinically or statistically significant differences between predicted dialysis duration (7.6 +/- 1.9 hours, +/-SD) and that actually provided using hourly toxin concentration sampling (7.4 +/- 1.9 hours). Renal toxin clearance was negligible compared to that of dialysis, and predicted dialysis clearance did not differ significantly from that observed. CONCLUSIONS: The simple estimate method is sufficiently valid to guide the prescription of dialysis for toxic alcohol poisoning. Data required at dialysis start include only the initial toxin concentration, dialyzer manufacturer's specified urea clearance at initial observed blood pump speed, and patient demographics to estimate total body water. This approach allows for planned dialysis therapy, without the need for additional toxin concentration measurements until dialysis is completed.
Ethylene Glycol↗
Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production.
BACKGROUND & AIMS: Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. METHODS: Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2. RESULTS: Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo). CONCLUSIONS: Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.
Adult↗