Let patients have their say: reducing miscommunication.
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Communication↗
Biomedical subjects
S Falk
Publications and source records attributed to S Falk.
Clinical and economic benefits of irinotecan in combination with 5-fluorouracil and folinic acid as first line treatment of metastatic colorectal cancer.
The combination of irinotecan plus 5-fluorouracil and folinic acid has clinical and survival benefits over 5-fluorouracil and folinic acid alone in the setting of first line treatment of metastatic colorectal cancer. The aim of this cost-effectiveness analysis was to compare the economic implications, from a UK health commissioner perspective, of the two treatment arms (de Gramont regimen) in this setting. Resource utilisation data collected prospectively during the study were used as a basis for estimating cumulative drug dosage, chemotherapy administration, and treatment of complications during first line therapy. Resource utilisation associated with further chemotherapy in patients who had progressed during the study was derived from a retrospective case note review. Drug acquisition costs were derived from the British National Formulary (September, 2001) and unit costs for clinical consultation and services were taken from the latest relevant cost database. Cumulative costs per patient associated with further chemotherapy were lower in the irinotecan plus 5-fluorouracil and folinic acid treatment arm. Based on incremental costs per life-year gained of 14 794 pounds sterling, the combination of irinotecan plus 5-fluorouracil and folinic acid can be considered cost-effective by commonly accepted criteria compared with 5-fluorouracil and folinic acid alone. Thus, clinical and economic data demonstrate that irinotecan, either in combination with irinotecan plus 5-fluorouracil and folinic acid in the first line setting or as monotherapy in the second line setting, has a major role in the management of metastatic colorectal cancer.
Antineoplastic Agents, Phytogenic↗
The cell morphogenesis gene ANGUSTIFOLIA encodes a CtBP/BARS-like protein and is involved in the control of the microtubule cytoskeleton.
The ANGUSTIFOLIA (AN) gene is required for leaf hair (trichome) branching and is also involved in polarized expansion underlying organ shape. Here we show that the AN gene encodes a C-terminal binding proteins/brefeldin A ADP-ribosylated substrates (CtBP/BARS) related protein. AN is expressed at low levels in all organs and the AN protein is localized in the cytoplasm. In an mutant trichomes, the organization of the actin cytoskeleton is normal but the distribution of microtubules is aberrant. A role of AN in the control of the microtubule cytoskeleton is further supported by the finding that AN genetically and physically interacts with ZWICHEL, a kinesin motor molecule involved in trichome branching. Our data suggest that CtBP/BARS-like protein function in plants is directly associated with the microtubule cytoskeleton.
Alcohol Oxidoreductases↗
[Color vision defects in patients with arterial hypertension].
PURPOSE: In view of the generally impaired vascular condition in patients with arterial hypertension, we were interested in their colour perception. METHODS: Patients (n = 35, f:m = 14:21, mean age 52 +/- 11 years) with arterial hypertension without damage in end-organs and normal subjects (n = 62, :m = 28:34, mean age 49 +/- 9 years) as a control group were included in this study. Exclusion criteria were other systemic or ophthalmological diseases. In addition to the ophthalmological examinations (visual acuity, refraction, intraocular pressure, slit lamp and fundus examination) the colour vision was tested by the colour arrangement test Roth 28-hue (E) desaturated under standard conditions: The background used was black cardboard, illuminated by two Osram fluorescent lamps (L36 W/12LDL Daylight) providing 2000 lux at the test table. RESULTS: The ophthalmological examinations in the patients and in the control group were normal. The patients with arterial hypertension had a significantly higher mean error score (median +/- mean absolute deviation 150 +/- 56, Mann-Witney U-test: p < 0.001) in the colour arrangement test than the control group (median +/- mean absolute deviation 72 +/- 53.4). A particular colour axis (blue-yellow or red-green) was not found. CONCLUSION: Although the ophthalmological examinations were normal we found a disturbed colour vision in patients with arterial hypertension. This has to be taken into account in colour vision testing to avoid diagnostic interferences between specifically ocular diseases (e.g. glaucoma) and arterial hypertension.
Adult↗
What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated?
OBJECTIVE AND BACKGROUND: The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF-I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia. DESIGN AND PATIENTS: We set up a prospective study of 30 patients with newly diagnosed unresectable non-small cell lung cancer, together with a cross-sectional comparison group of healthy volunteers. MEASUREMENTS: We examined the relationship between aspects of the IGF system, including IGFBP-3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP-3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments). RESULTS: Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP-3, which correlated with the circulating interleukin-6 (IL-6) concentration. The pattern of IGFBP-3 proteolysis was unusual, with a prominent 17-kDa fragment. Less IGFBP-3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter-regulatory mechanism, increasing IGF-I bioavailability to the tissues. CONCLUSIONS: Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP-3 proteolysis, which may be regulated by IL-6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.
Aged↗
A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus.
BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS: Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle. RESULTS: The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.
Adenocarcinoma↗
Meta-analysis of single agents in the chemotherapy of NSCLC: what do we want to know?
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Antibiotics, Antineoplastic↗
Two-step mechanism of phlorizin binding to the SGLT1 protein in the kidney.
The relationships between phlorizin binding and Na+-glucose cotransport were addressed in rabbit renal brush-border membrane vesicles. At pH 6.0 and 8.6, high affinity phlorizin binding followed single exponential kinetics. With regard to phlorizin concentrations, the binding data conformed to simple Scatchard kinetics with lower apparent affinities of onset binding (Kdi = 12-30 microM) compared to steady-state binding (Kde = 2-5 microM), and the first-order rate constants demonstrated a Michaelis-Menten type of dependence with Km values identical to Kdi. Phlorizin dissociation from its receptor sites also followed single exponential kinetics with time constants insensitive to saturating concentrations of unlabeled phlorizin or D-glucose, but directly proportional to Na+ concentrations. These results prove compatible with homogeneous binding to SGLT1 whereby fast Na+ and phlorizin addition on the protein is followed by a slow conformation change preceding further Na+ attachment, thus occluding part of the phlorizin-bound receptor complexes. This two-step mechanism of inhibitor binding invalidates the recruitment concept as a possible explanation of the fast-acting slow-binding paradigm of phlorizin, which can otherwise be resolved as follows: the rapid formation of an initial collision complex explains the fast-acting behavior of phlorizin with regard to its inhibition of glucose transport; however, because this complex also rapidly dissociates in a rapid filtration assay, the slow kinetics of phlorizin binding are only apparent and reflect its slow isomerization into more stable forms.
Animals↗
Extensive traumatic soft tissue loss: reconstruction in severely injured patients using cultured hyaluronan-based three-dimensional dermal and epidermal autografts.
BACKGROUND: This report demonstrates the potential of two-stage autologous keratodermal grafting as a starting point for noninvasive reconstruction of extensive traumatic soft tissue defects. METHODS: In three severely injured patients, skin biopsies for cell cultivation were taken. Cultured "neodermis" consisting of cultured autologous fibroblasts grown on biocompatible three-dimensional scaffolds made up of benzyl ester of hyaluronan was grafted on conditioned defect areas. After ingrowth of dermal substitutes, transplantation of cultured autologous keratinocytes on hyaluronan-based laser-perforated membranes was performed. Ten days later, a 0.2-mm thin, 1:6 meshed autograft was overlaid. Clinical follow-up, histologic, and immunohistochemical findings were documented. RESULTS: Grafting with cultured autologous fibroblasts revealed a suitable dermal tissue replacement. Epithelialization was evident after transplantation of keratinocytes. Final closure of the defects with "normoelastic" tissue properties was achieved after thin mesh-grafting. CONCLUSION: Preliminary findings with the described method seem to be very promising. As in all fields of tissue engineering, long-term studies and further follow-up are required.
Adjuvants, Immunologic↗
[Modern quality management in pathology--accreditation according to EN DIN 45004: an experience report].
Accreditation according to EN DIN 45004 is a new way of documenting quality assurance and competence in pathology. It comprises a quality assurance program according to ISO 9002 as well as demonstration of diagnostic competence to a panel of experts. Accreditation results in a marked improvement of diagnostic quality and appears suitable to document special competence in pathology according to a flexible internationally recognized norm. We recommend accreditation according to EN DIN 45004 to all competent institutes of pathology.
Accreditation↗
The major head protein of bacteriophage T4 binds specifically to elongation factor Tu.
The Lit protease in Escherichia coli K-12 strains induces cell death in response to bacteriophage T4 infection by cleaving translation elongation factor (EF) Tu and shutting down translation. Suicide of the cell is timed to the appearance late in the maturation of the phage of a short peptide sequence in the major head protein, the Gol peptide, which activates proteolysis. In the present work we demonstrate that the Gol peptide binds specifically to domains II and III of EF-Tu, creating the unique substrate for the Lit protease, which then cleaves domain I, the guanine nucleotide binding domain. The conformation of EF-Tu is important for binding and Lit cleavage, because both are sensitive to the identity of the bound nucleotide, with GDP being preferred over GTP. We propose that association of the T4 coat protein with EF-Tu plays a role in phage head assembly but that this association marks infected cells for suicide when Lit is present. Based on these data and recent observations on human immunodeficiency virus type 1 maturation, we speculate that associations between host translation factors and coat proteins may be integral to viral assembly in both prokaryotes and eukaryotes.
Amino Acid Sequence↗
Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer.
BACKGROUND: In phase II trials, paclitaxel has been shown to have antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). However, the survival and quality-of-life (QOL) benefits of paclitaxel used as a single agent compared with supportive care alone have not been assessed in a randomized clinical trial. METHODS: A total of 157 patients with stage IIIB or IV NSCLC who had received no prior chemotherapy were randomly assigned to receive either best supportive care alone (78 patients) or paclitaxel plus supportive care (79 patients). Paclitaxel was administered as a 3-hour intravenous infusion every 3 weeks. Supportive care included palliative radiotherapy and supportive therapy with corticosteroids, antibiotics, analgesics, antiemetics, transfusions, and other symptomatic therapy as required. The primary end point of the study was survival. Time to disease progression, response rate, adverse events, and QOL were secondary end points. RESULTS: Pretreatment characteristics were evenly distributed between the two arms. Survival was statistically significantly better in the paclitaxel plus supportive care arm than in the supportive care alone arm (two-sided P =.037) (median survival = 6.8 months versus 4.8 months). Cox multivariate analysis showed paclitaxel plus supportive care to be statistically significantly associated with improved survival (two-sided P =.048). QOL was similar for both treatment arms, except for the functional activity score of the Rotterdam Symptom Checklist, where QOL data statistically significantly favored the paclitaxel plus supportive care arm (two-sided P =.043). CONCLUSION: The addition of paclitaxel to best supportive care significantly improved survival and time to disease progression compared with best supportive care in patients with advanced NSCLC and may improve some aspects of QOL.
Adult↗
Implementing LIMS: a "how-to" guide.
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Clinical Laboratory Information Systems↗
Photosynthetic acclimation of the filamentous cyanobacterium, Plectonema boryanum UTEX 485, to temperature and light.
Photosynthetic acclimation to temperature and irradiance was studied in the filamentous, non-heterocystous cyanobacterium Plectonema boryanum UTEX 485. Growth rates of this cyanobacterium measured at ambient CO2 were primarily influenced by temperature with minimal effects of irradiance. Both growth temperature and irradiance affected linolenic (18:3) and linoleic acid (18:2) levels in the four major lipid classes in an independent but additive manner. In contrast, photosynthetic acclimation was not due to either growth temperature or irradiance per se, but rather, due to the interaction of these environmental factors. P. boryanum grown at low temperature and moderate irradiance mimicked cells grown at high light. Compared to cells grown at either 29 degrees C/150 micromol m(-2) s(-1) (29/150) or 15/10, P. boryanum grown at either 15/150 or 29/750 exhibited: (1) reduced cellular levels of Chl a and phycobilisomes (PBS), and concomitantly higher content of an orange-red carotenoid, myxoxanthophyll; (2) higher light saturated rates (Pmax) when expressed on a Chl a basis but lower apparent quantum yields of oxygen evolution and (3) enhanced resistance to high light stress. P. boryanum grown at 15/150 regained normal blue-green pigmentation within 16 h after a temperature shift to 29 degrees C at a constant irradiance of 150 micromol m(-2) s(-1). DBMIB and KCN but not DCMU and atrazine partially inhibited the change in myxoxanthophyll/Chl a ratio following the shift from 15 to 29 degrees C. We conclude that P. boryanum responds to either varying growth temperature or varying growth irradiance by adjusting the ability to absorb light through decreasing the cellular contents of Chl a and light-harvesting pigments and screening of excessive light by myxoxanthophyll predominantly localized in the cell wall/cell membrane to protect PSII from over-excitation. The possible role of redox sensing/signalling for photosynthetic acclimation of cyanobacteria to either temperature or irradiance is discussed.
Acclimatization↗
Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: role of humoral factors.
BACKGROUND: The ability of leukocytes to release proinflammatory cytokines on lipopolysaccharide stimulation in vitro is impaired after cardiopulmonary bypass (CPB). This study tested contribution and interaction of humoral factors in altered leukocyte responsiveness to lipopolysaccharide. METHODS: Whole blood and isolated peripheral-blood mononuclear cells (PBMCs) from 10 patients obtained after induction of anesthesia (T1) and 20 min (T2) and 24 h (T3) after CPB were cultured in the absence or presence of lipopolysaccharide and assessed for release of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta and their functional antagonists, IL-1 receptor antagonist (IL-1ra) and IL-10. In addition, dose-response characteristics and interaction of IL-10 and norepinephrine as modulators of TNF-alpha release were studied. RESULTS: Cardiopulmonary bypass induced release of antiinflammatory (T2: IL-10: median 25 pg/ml, 25th-75th percentile 9-42; IL-1ra: median 1,528 pg/ml, 25th-75th percentile 1,075-17,047; P < 0.05 compared with T1) but failed to induce proinflammatory cytokines (T2: TNF-alpha: median 0 pg/ml, 25th-75th percentile 0-6; IL-1beta: median 1 pg/ml, 25th-75th percentile 0-81; nonsignificant). Removal of plasma at T2 increased TNF-alpha response to lipopolysaccharide (+83.8%; P < 0.05), whereas it suppressed IL-10 (-36.8%; P < 0.05). Similarly, incubation of PBMCs (T1) with plasma obtained after CPB (T2) as well as addition of IL-10 or norepinephrine in concentrations present in plasma after CPB led to a reduced lipopolysaccharide-stimulated TNF-alpha and an increased IL-10 response. Coadministration of norepinephrine and IL-10 had synergistic effects. Although pretreatment with an anti-IL-10 antibody and labetalol before addition of plasma obtained at T2 largely restored the TNF-alpha response in vitro, their addition post-treatment failed to restore the monocytic TNF-alpha response. CONCLUSIONS: Plasma contains interacting factors that inhibit the release of TNF-alpha and increase the release of IL-10, presumably attenuating the inflammatory response to CPB. Although norepinephrine fails to induce a cytokine response in the absence of other stimuli, its administration seems to augment the antiinflammatory IL-10 response while attenuating the TNF-alpha response.
Adult↗
Real-time fluorimetric analysis of gramicidin D- and alamethicin-induced K+ efflux from Sf9 and Cf1 insect cells.
Gramicidin D and alamethicin are pore-forming peptides which exhibit lethal properties against a large spectrum of cells. Despite a wealth of experimental data from artificial membranes, the time course and quantitative analysis of the activity of these ionophores are not well described in living cells. In the present study, the newly described fluorescent dye CD-222 was used to monitor extracellular potassium ion concentration and report the effects of these antibiotics on the K+ permeability of the plasma membrane of Spodoptera frugiperda (Sf9) and Choristoneura fumiferana (Cf1) insect cells. Both peptides induced a rapid efflux of intracellular K+ as a consequence of ion channel formation in the cell membrane. K+ efflux began without any measurable delay. While the final extracellular K+ concentration was unaffected by ionophore concentration, the rate of K+ efflux was dose dependent. Using a model describing the partition of the peptides in lipid membranes, the K+ efflux kinetic parameters were determined for both cell types and both pore formers. The proposed stoichiometry for the channel formed by gramicidin in living cells is in good agreement with the two-monomers model based on data from artificial membrane systems. The K+-permeable channel formed by alamethicin in insect cells appears to involve three monomers.
Alamethicin↗
Kinetic mechanisms of inhibitor binding: relevance to the fast-acting slow-binding paradigm.
Although phlorizin inhibition of Na+-glucose cotransport occurs within a few seconds, 3H-phlorizin binding to the sodium-coupled glucose transport protein(s) requires several minutes to reach equilibrium (the fast-acting slow-binding paradigm). Using kinetic models of arbitrary dimension that can be reduced to a two-state diagram according to Cha's formalism, we show that three basic mechanisms of inhibitor binding can be identified whereby the inhibitor binding step either (A) represents, (B) precedes, or (C) follows the rate-limiting step in a binding reaction. We demonstrate that each of mechanisms A-C is associated with a set of unique kinetic properties, and that the time scale over which one may expect to observe mechanism C is conditioned by the turnover number of the catalytic cycle. In contrast, mechanisms A and B may be relevant to either fast-acting or slow-binding inhibitors. However, slow-binding inhibition according to mechanism A may not be compatible with a fast-acting behavior on the steady-state time scale of a few seconds. We conclude that the recruitment hypothesis (mechanism C) cannot account for slow phlorizin binding to the sodium-coupled glucose transport protein(s), and that mechanism B is the only alternative that may explain the fast-acting slow-binding paradigm.
Animals↗
Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation.
In the present study we have investigated the mechanisms of pulmonary edema caused by platelet-activating factor (PAF) in isolated rat lungs as well as in mice in vivo. In blood-free perfused and ventilated rat lungs, PAF increased lung weight by 0.59 +/- 0.18 g. The cyclooxygenase inhibitor aspirin (500 microM) blocked this response by one-third, and the quinolines quinine (330 microM), quinidine (100 microM), and chloroquine (100 microM) by two-thirds. Lipoxygenase inhibition (10 microM AA861) alone or in combination with thromboxane receptor antagonism (10 microM SQ29548) had no effect on PAF-induced weight gain. In combination with aspirin, quinine or quinidine completely prevented PAF-induced weight gain and the concomitant increase of the capillary filtration coefficient (K(f,c)). Pretreatment with quinine in vivo prevented not only PAF-, but also endotoxin-induced edema formation as assessed by Evans Blue extravasation. In addition, in vivo quinine prevented the endotoxin-induced release of tumor neurosis factor (TNF). Furthermore, in perfused lungs quinine reduced the PAF-induced increases in airway and vascular resistance, as well as thromboxane release. These findings demonstrate the following anti-inflammatory properties of quinolines: reduction of thromboxane and TNF formation; reduction of PAF-induced vasoconstriction and bronchoconstriction; and attenuation of PAF- and lipopolysaccharide (LPS)-induced edema formation. We conclude that the PAF- induced edema consists of two separate mechanisms, one dependent on an unknown cyclooxygenase metabolite, the other one sensitive to quinolines.
Airway Resistance↗