[Adverse effects of licorice consumed as food: An update]. / Toxicités de l'exposition alimentaire à la réglisse : mise au point.

The word "licorice" refers to the plant, its root, and its aromatic extract. From a commercial point of view, Glycyrrhiza glabra is the most important species with a wide range of uses (herbal medicine, tobacco industry, cosmetics, food and pharmaceutical). Glycyrrhizin is one of the main constituents of licorice. Glycyrrhizin is hydrolyzed in the intestinal lumen by bacterial ß-glucuronidases to 3ß-monoglucuronyl-18ß-glycyrrhetinic acid (3MGA) and 18ß-glycyrrhetinic acid (GA), which are metabolized in the liver. Plasma clearance is slow due to enterohepatic cycling. 3MGA and GA can bind to mineralocorticoid receptors with very low affinity, and 3MGA induces apparent mineralocorticoid excess syndrome through dose-dependent inhibition of 11ß-hydroxysteroid dehydrogenase type 2 in renal tissue. The cases of apparent mineralocorticoid excess syndrome reported in the literature are numerous and sometimes severe, even fatal, most often in cases of chronic high dose consumption. Glycyrrhizin poisonings are characterized by hypertension, fluid retention, and hypokalemia with metabolic alkalosis and increased kaliuresis. Toxicity depends on the dose, the type of product consumed, the mode of consumption (acute or chronic) and a very large inter-individual variability. The diagnosis of glycyrrhizin-induced apparent mineralocorticoid excess syndrome is based on the history, clinical examination, and biochemical analysis. Management is primarily based on symptomatic care and stopping licorice consumption.

Spatio-temporal Analysis of Multichannel Atrial Electrograms Based on a Concept of Active Areas.

Atrial tachycardia and atrial flutter are frequent arrhythmia that occur spontaneously and after ablation of atrial fibrillation. Depolarization waves that differ significantly from sinus rhythm propagate across the atria with high frequency (typically 140 to 220 beats per minute). A detailed and personalized analysis of the spread of depolarization is imperative for a successful ablation therapy. Thus, catheters with several electrodes are employed to measure multichannel electrograms inside the atria. Here we propose a new concept for spatio-temporal analysis of multichannel electrograms during atrial tachycardia and atrial flutter. It is based on the calculation of simultaneously active areas. The method allows to identify atrial tachycardia and to automatically distinguish between subtypes of focal activity, micro-reentry and macro-reentry.

Efficiency of 5-ALA mediated photodynamic therapy on hypoxic prostate cancer: a preclinical study on the Dunning R3327-AT2 rat tumor model.

OBJECTIVES: To evaluate photodynamic therapy (PDT) using 5-ALA-induced protoporphyrin IX (PPIX) in an in vivo hypoxic tumor model and its monitoring using MRI. MATERIAL AND METHODS: Dunning R3327-AT2 tumors were grafted in the neck of Copenhagen rats. PDT using 150 mg 5-ALA/kg i.v. was performed by focal interstitial illumination of the photosensitized tumor (λ=633 nm; fluence=100 J/cm(2)). MRI at baseline and 2 days after treatment (T1, T2 and dynamic gadolinium enhanced sequences) were performed. Necrosis volumes were determined on post-procedure MRI. Tumors were resected 2 days post-PDT and obtained necrosis was determined histopathologically. Intra-tumoral PPIX distribution was evaluated using confocal microscopy and tissue porphyrin quantification. RESULTS: Twenty rats were treated divided into three groups: continuous (n=7), fractionated illumination (n=7), and a control group receiving only light or only ALA or neither (n=6). Baseline MRI confirmed the hypoxic character of tumors. Necrosis volumes determined on posttreatment MRI were not reproducible and presented with important geometric and volumetric variability. Average necrosis volumes of 0.39 cc (0-0.874 cc) in the continuous group, 0.24 cc (0.107-0.436 cc) in the fractionated group and 0.012 cc (0-0.071 cc) in the control group were observed. Intra-tumoral PPIX distribution was heterogeneous and PPIX quantification revealed low intra-tumoral concentration. CONCLUSION: Necrosis volumes induced by 5-ALA-mediated PDT were highly variable and non reproducible, probably because of lack of intra-tissular oxygen. Photosensitizer was poorly represented inside the tumor and its distribution was heterogeneous. Our study suggests that 5-ALA-mediated PDT might not be the best management option for hypoxic prostatic adenocarcinoma.

Structure of arabinogalactan-protein from Acacia gum: from porous ellipsoids to supramolecular architectures.

The structure of the arabinogalactan-protein (AGP) fraction of the gum exudate of Acacia senegal (gum Arabic) isolated from hydrophobic interaction chromatography was investigated using HPSEC-MALLS, small angle neutron scattering and TEM observations. Literature reported that the AGP structure of gum Arabic adopts a very compact conformation in solution due to the attachment of short arabinoside side chains and much larger blocks of carbohydrate to the polypeptidic backbone. The present study revealed that AGP in solution had a weight average molecular weight Mw of 1.86×10(6) g mol(-1) and a radius of gyration Rg of 30 nm. In addition, two exponent values were identified in the Rg, [η], Rh and ρ vs. Mw relationships highlighting two types of conformations depending on the molecular weight range considered: a low molar mass population with long-chain branching and a compact conformation and a high molar mass population with short-chain branching and an elongated conformation. AGP would behave in solution as a branched or hyper-branched polymer with conformations ranging from globular to elongated shape depending on the size of the carbohydrate branches. Small angle scattering form factor revealed an elongated average conformation corresponding to a triaxial ellipsoid while inverse Fourier transform of the scattering form factor gave a maximum dimension for AGP of 64 nm. Transmission electron microscopy highlighted the existence of two types of flat objects with thicknesses below 3-5 nm, single particles with a more or less anisotropic spheroidal shape and aggregated structures with a more elongated shape. A remarkable feature of all particle morphologies was the presence of an outer structure combined to an inner more or less porous network of interspersed chains or interacting structural blocks, as previously found for the arabinogalactan (AG) main molecular fraction of Acacia gum. However, clear differences were observed in the density and morphology of the inner porous network, probably highlighting differences in the degree of branching. The existence of assembled AG as part of the AGP family was confirmed using TEM micrographs at high resolution. Fused AGP dimers, trimers, tetramers and multimers were also identified. These molecular assemblies questioned about the nature of interactions involved.

Use of oral supplements in malnourished elderly patients living in the community: a pharmaco-economic study.

BACKGROUND & AIMS: Inadequate nutritional support in elderly patients is likely to be responsible for increased morbidity and increased associated costs. Conversely prescribing oral supplements to ensure sufficient protein and energy intake should be beneficial. Even though this claim makes sense there is a lack of objective data to support the evidence. The objective of the present study was to assess the cost of malnutrition and related comorbidities among elderly patients living in the community and to determine the impact of nutritional support practice on these outcomes. METHODS: Observational, prospective, longitudinal, cohort study with a 12 months follow-up conducted with 90 general practitioners in France. Two groups of physicians were selected based on historical prescribing practice: group 1 with rare and group 2 with frequent prescription of oral nutrition supplements. The resulting study population was 378 elderly malnourished patients aged over 70, living in the community, either at home or in institutions. Nutritional status at baseline was determined using the Mini Nutritional Assessment (MNA) scale. Main outcome measures were nutritional status, malnutrition-related comorbidities and medical care consumption. RESULTS: Populations in the two groups of patients were balanced for age, gender, weight and body mass index but differed significantly in terms of housing status (P < 0.005) and nutritional status (P < 0.001). After adjustment for baseline characteristics, MNA improved within both groups over time but improvement was significantly higher in group 2 than in group 1 (P < 0.01). The adjusted cost per patient of hospital care (EUR -551), nursing care (EUR -145) and other medical care was significantly reduced in group 2 as compared to group 1, with cost savings of EUR -723 per patient (90% CI: EUR -1.444 to EUR -43). Including the costs related to nutritional products, the total cost savings per patient attributable to nutrition support were EUR -195 (90% CI: EUR -929 to EUR +478). CONCLUSION: Appropriate nutrition support can address the problem of malnutrition among elderly individuals living in the community and may contribute to reduce the costs of health care.

Activation patterns in the left atrium during counterclockwise and clockwise atrial flutter.

INTRODUCTION: Activation of the left atrium (LA) in patients with isthmus-dependent right atrial flutter (AFL) has not yet been studied. The aim of this study was to analyze the activation patterns in the LA in patients with counterclockwise and clockwise AFL. METHODS AND RESULTS: The study population consisted of 12 patients (10 men and 2 women; mean age 61+/-13 years) with documented AFL and atrial fibrillation referred for ablation. The LA was mapped with a 64-electrode basket catheter inserted through a transseptal approach (10 patients) or an open foramen ovale (2 patients). In patients with counterclockwise AFL (10 episodes), the LA was activated for a mean of 133+/-28 msec. Two endocardial breakthroughs of earliest activity on the left side of the interatrial septum, separated in time by an interval of 38+/-15 msec, were observed in 9 episodes (90%). Two wavefronts originated from these breakthroughs, which activated the posterior and the anterior LA walls, respectively. In one patient, the entire LA was activated from the inferior breakthrough. In patients with clockwise AFL (five episodes), the LA activation time was 130+/-13 msec. During ongoing episodes, two early electrical breakthroughs, separated in time by an interval of 41+/-15 msec, appeared in the high anteroseptal and low posteroseptal LA regions. The superior wavefront that emerged from the high anterolateral LA region was the dominant activation pathway in 4 (80%) of 5 episodes. CONCLUSION: In patients with AFL, the LA is activated by two wavefronts originating from the high anterior and the low posterior regions of the interatrial septum. The sequence of activation of these interatrial connections in counterclockwise or clockwise AFL and the conductive properties of the LA conduction pathways determine the activation patterns in the LA.

Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcgammaRIIB.

We previously found that low affinity receptors for the Fc portion of IgG, FcgammaRIIB, which are widely expressed by hematopoietic cells, can negatively regulate receptor tyrosine kinase-dependent cell proliferation. We investigated here the mechanisms of this inhibition. We used as experimental models wild-type mast cells, which constitutively express the stem cell factor receptor Kit and FcgammaRIIB, FcgammaRIIB-deficient mast cells reconstituted with wild-type or mutated FcgammaRIIB, and Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1)-deficient mast cells. We found that, upon coaggregation with Kit, FcgammaRIIB are tyrosyl-phosphorylated, recruit SHIP1, but not SHIP2, SH2 domain-containing protein tyrosine phosphatase-1 or -2, abrogate Akt phosphorylation, shorten the duration of the activation of mitogen-activated protein kinases of the Ras and Rac pathways, abrogate cyclin induction, prevent cells from entering the cell cycle, and block thymidine incorporation. FcgammaRIIB-mediated inhibition of Kit-dependent cell proliferation was reduced in SHIP1-deficient mast cells, whereas inhibition of IgE-induced responses was abrogated. Cell proliferation was, however, inhibited by coaggregating Kit with FcgammaRIIB whose intracytoplasmic domain was replaced with the catalytic domain of SHIP1. These results demonstrate that FcgammaRIIB use SHIP1 to inhibit pathways shared by receptor tyrosine kinases and immunoreceptors to trigger cell proliferation and cell activation, respectively, but that, in the absence of SHIP1, FcgammaRIIB can use other effectors that specifically inhibit cell proliferation.

ECG changes in a 25-year-old woman with hypocalcemia due to hypoparathyroidism. Hypocalcemia mimicking acute myocardial infarction.

The case of a 25-year-old woman presenting with chest pain, ECG changes, and laboratory findings suggestive of myocardial infarction is reported. Cardiac catheterization showed impaired left ventricular performance but otherwise normal coronary arteries. Laboratory analyses revealed primary hypoparathyroidism, and supplementation with calcium and vitamin D(3) was initiated. There was subsequent improvement in laboratory findings as well as echocardiographically determined left ventricular performance. Thereafter, the patient remained asymptomatic. Apart from some persisting ECG repolarization disturbances, there was complete normalization of the initial changes. This case demonstrates a combination of clinical, blood biochemical, and ECG findings mimicking acute myocardial infarction.

Irinotecan in second-line treatment of metastatic colorectal cancer: improved survival and cost-effect compared with infusional 5-FU.

In a recent multicentre, randomised, controlled, open-label study (Rougier and colleagues, Lancet 1998, 352, 1407-1412), irinotecan significantly increased survival without any deterioration in quality of life compared with best-estimated infusional 5-fluorouracil (5-FU) therapy in the setting of second-line treatment for metastatic colorectal cancer. The aim of the cost-effectiveness analysis reported here was to compare the economic implications, from a U.K. perspective, of replacing 5-FU therapy [either as a single agent (Lokich regimen, B2) or in combination with folinic acid (de Gramont regimen, B1, or AIO regimen, B3)] with irinotecan as second-line therapy for metastatic colorectal cancer. Resource utilisation data collected prospectively during the study, supplemented by both a questionnaire to investigators and local expert clinical opinion, were used as a basis for estimating cumulative drug dosage, chemotherapy administration and treatment of complications. Drug acquisition costs were derived from the British National Formulary (March 1998), and unit costs for clinical consultation and services were derived from relevant 1996/1997 cost databases. Although cumulative drug acquisition costs per patient were higher with irinotecan than with infusional 5-FU therapy, these were at least partially offset by lower cumulative costs per patient associated with administration of therapy and treatment of complications in the irinotecan arm than in the 5-FU arm. Based on the incremental costs per life year gained (LYG), irinotecan was considered to be cost-effective by commonly accepted criteria compared with either the B1 or B2 regimens. Irinotecan was cost-saving compared with the B3 regimen (that is significant survival gain and a reduction in costs). Thus, not only is there strong evidence for the use of irinotecan as standard second-line therapy in metastatic colorectal cancer,but the results of this prospective economic evaluation have shown that irinotecan also represents good value for money in this clinical setting.

The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans.

PURPOSE: The present investigation retrospectively evaluates the use of human hepatocytes to classify compounds into low, intermediate or high hepatic extraction ratio in man. METHODS: A simple approach was used to correlate the in vivo hepatic extraction ratio of a number of compounds in man (literature and in-house data) with the corresponding in vitro clearance which was determined in human hepatocytes. The present approach assumes that, for compounds eliminated mainly through liver metabolism, intrinsic clearance is the major determinant for their in vivo hepatic extraction ratio and subsequently their bioavailability in man. The test compounds were selected to represent a broad range of extraction ratios and a variety of metabolic pathways. RESULTS: The present data show that in vitro clearances in human hepatocytes are predictive for the hepatic extraction ratios in vivo in man. Most of the test compounds (n = 19) were successfully classified based upon human hepatocyte data into low, intermediate or high hepatic extraction compounds, i.e. compounds with potential for high, intermediate or low bioavailabilities in humans. CONCLUSIONS: The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.

Initial experience with implantation of internal cardioverter/defibrillators under local anaesthesia by electrophysiologists.

This study was designed to evaluate the implantation of internal cardioverter/defibrillators under local anaesthesia by electrophysiologists and to compare this to our former experience of implants with general anaesthesia. Forty-seven internal cardioverter/defibrillators were implanted at our institution by electrophysiologists. Twenty-nine operations were performed under general anaesthesia (isoflurane 0.4-0.6%), and 18 under local anaesthesia (mepivacain 1%). The defibrillator leads were introduced by venotomy of the cephalic vein (n = 25), puncture of the subclavian vein (n = 17) or both (n = 5). All devices were implanted beneath the pectoral muscles. The mean operation time was 99 +/- 29 min. In the group with local anaesthesia the operation time was significantly shorter than with general anaesthesia (86 +/- 20 min vs 107 +/- 31 min; P = 0.027). The defibrillation threshold with biphasic shock application was below 24 J in all patients; thus, the implantation of an additional subcutaneous patch electrode was unnecessary. There were no major complications in either group. However, modifications were required in four patients: in one a set screw had to be re-tightened after delivery of an erroneous shock in the early postoperative phase; in another, device migration occurred several weeks after implantation, but no therapeutic intervention was required; in another, a rise in pacing threshold and partial sensing loss were noted ten days postoperatively; in the fourth, a minor pneumothorax occurred after subclavian puncture, but no further treatment was necessary. There was no intra-operative or postoperative mortality in either group. Implantation of internal cardioverter/defibrillators under local anaesthesia and mild sedation is feasible, and can be safely performed by electrophysiologists experienced in basic surgery. The newly developed smaller devices allow implantation in the subpectoral region, and with "active can' configuration and biphasic shock application, subcutaneous patch electrodes become unnecessary.

Bosentan, a new endothelin receptor antagonist: prediction of the systemic plasma clearance in man from combined in vivo and in vitro data.

1. Accurately predicting the kinetics in man greatly improves the design of the phase I clinical studies. This was particularly crucial in the case of bosentan, a new endothelin receptor antagonist, as very large interspecies differences in systemic clearance were observed in the animal species investigated, namely from 1.5ml/min/kg in the dog up to 70 ml/min/kg for the rabbit. 2. Bosentan was shown to be metabolized by the hepatic cytochrome P450, therefore the rate of metabolism was investigated in vitro in liver microsomes and hepatocytes, across the species which had been tested in vivo. The same rank-order of metabolism was found for the laboratory animals both in vitro and in vivo, and hepatocytes appeared to be more representative of the in vivo situation than liver microsomes. The in vitro clearance in human hepatocytes was very close to that observed in dog hepatocytes. 3. A plasma clearance for bosentan in man of 1-2 ml/min/kg was predicted by combining the in vivo and in vitro data from a few animal species with the in vitro data in man. This expectation was subsequently found to agree reasonably well with the plasma clearance observed in healthy volunteers: ca 2 ml/min/kg. Integrating this prediction into the design of the first clinical protocols substantially improved the quality of the human pharmacokinetic data obtained.

[Radiofrequency ablation in permanent ectopic left atrial tachycardia]. / Radiofrequenzablation bei permanenter ektoper linksatrialer Tachykardie.

HISTORY AND FINDINGS: A 35-year-old symptom-free woman was known since childhood to have an increased resting heart rate (130-150/min). In the ECG there was a negative P in leads I and aVL, with a shortened P-Q interval of 90 ms. Previous treatment with beta-receptor blockers and calcium antagonists had failed. Clinical examination and echocardiography, as well as levels of thyroid hormone were unremarkable. During electrophysiological studies the earliest atrial activity was localised by endocardial leads in the region of the distal coronary sinus and the arrhythmia could not be terminated by atrial over-stimulation. TREATMENT AND COURSE: After transseptal puncture the ablation catheter was introduced into the left atrium and, the exact site of the origin of the atrial tachycardia having been established, radiofrequency ablation of this point was successfully performed. Subsequently the patient was always found to be in stable sinus rhythm at around 80/min. CONCLUSION: To prevent tachycardia-induced cardiomyopathy, radiofrequency ablation can be indicated even in symptom-free patients with atrial tachycardia.

Canine bone marrow as a potential thermal sanctuary during the plateau phase of 41.8 degrees C whole body hyperthermia.

Whole body hyperthermia (WBH) is currently being evaluated as an adjunct to various forms of antineoplastic therapy. In this regard, the uniformity of temperature in an individual subject, induced by any given WBH system, is a significant factor. Preliminary animal investigations suggested that the bone marrow temperature may differ from core temperature during 41.8 degrees C WBH. To quantitatively evaluate this possible phenomena, dogs were utilized in conjunction with a radiant heat WBH system. It was found that mean bone marrow temperature was significantly less than core (i.e. rectal) temperature (p < 0.001), i.e. 0.27 degree C for the ilium 0.40 degree C for the humerus and 0.95 degree C for the tibia. The implications of these results to current clinical trials are discussed.

Initial management of recurrent vulvovaginal candidiasis with oral ketoconazole and topical clotrimazole.

In a randomized study, 151 women with a history of recurrent vulvovaginal candidiasis and suffering from an acute episode of candidal vaginitis were assigned to receive either oral ketoconazole, 400 mg daily for 14 days, or clotrimazole vaginal suppositories, 100 mg daily for 7 days. One week after completion of therapy, evaluation revealed a clinical cure or improvement in 86.4% of ketoconazole- and 81.7% of clotrimazole-treated patients (P > .5), with a mycologic response in 80.3% and 81.7%, respectively. In the absence of maintenance suppressive antimycotic therapy, further follow-up for two months revealed an extremely high rate of clinical and mycologic failure in both groups, reaching 52.5% after ketoconazole and 62.6% after clotrimazole (NS). Adverse effects were significantly more common with systemic ketoconazole than accompanying topical clotrimazole therapy. Although both forms of antifungal therapy were highly successful in inducing clinical and mycologic remission in patients with recurrent vulvovaginal candidiasis, this study emphasized the need for immediate initiation of maintenance therapy following an initial clinical improvement.

Blood pressure regulation in Alzheimer's disease.

Brain neurons which regulate blood pressure (BP), including the C-1 tonic vasomotor neurons, degenerate in Alzheimer's disease (AD). This study determines whether BP is decreased in AD. We reviewed records of three autopsy proven AD patients. Medical causes for decreased BP were investigated. Yearly averages for systolic (SBP), diastolic (DBP), mean arterial (AP) blood pressure and pulse pressure (PP) were calculated. BP in the year of diagnosis was compared to the sum of all BP in subsequent years. In addition, each yearly measurement through the course of AD was compared to its counterpart in the year of diagnosis. Three BP measurements were significantly decreased by from 6.9% to 15.9% in all patients when BP in the year of diagnosis was compared to the sum of each pressure in subsequent years. Sustained BP declines started in the third to fourth year after diagnosis of AD and continued for up to 9 years. The PP was decreased by 19.9% in one patient. There was a strong correlation between the number of C-1 neurons in these cases and their AP and SBP in the years after diagnosis. Hypothalamic phenylethanolamine N-methyltransferase activity was decreased by 63% in AD compared to control cases. Neurofibrillary tangles were found in the paraventricular nucleus of the hypothalamus in an AD case. We postulate that BP is altered in AD as neurons which regulate it degenerate.

A new technological approach to radiant heat whole body hyperthermia.

A new methodology for administering radiant heat whole body hyperthermia (WBH) in humans is described. The technology utilized circulates hot water in a cylinder constructed from copper tubing; the design incorporates a counter current distribution system to maintain thermal constancy. The tubing is coated with a temperature resistant high emissivity finish. Other features include a humidification system to eliminate evaporative heat losses. Data accrued from initial evaluation of this apparatus with a canine model shows that there was no detectable WBH-related hematological, biochemical or physiological toxicity. The perceived advantages of this WBH-system are discussed.

Phase I clinical trial of carboplatin and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial. PATIENTS AND METHODS: Thirty assessable patients with cancer refractory to conventional therapy were treated. During induction therapy, patients received WBH alone in week 1, WBH plus carboplatin in week 2, and carboplatin alone in week 5. Carboplatin dose was escalated (three patients per group) as follows: 100, 150, 200, 250, 300, 350, 400, 480, and 575 mg/m2; three additional patients were entered at 480 mg/m2. Carboplatin was administered at target temperature. RESULTS: Comparisons of the mean/median WBC and platelet nadirs for carboplatin alone and carboplatin plus WBH demonstrated no enhancing effect by WBH. Toxicities including nausea and/or vomiting, as well as myelosuppression, were within acceptable limits, allowing for escalation to a dose of 575 mg/m2; three of three patients at this dose level experienced grade 4 myelosuppression with no associated infection or bleeding. No renal toxicity was observed. Analysis of platinum in plasma ultrafiltrate and urine showed only slight effects of WBH on the pharmacokinetics and renal excretion of platinum. Responses included the following: lung--minor response (200 mg/m2); gastrointestinal neuroendocrine--complete response (CR) (400 mg/m2); pancreatic--partial response (PR) (480 mg/m2); small bowel--PR (575 mg/m2); ovarian--CR, two patients (575 mg/m2), with marker data suggesting WBH enhancement of carboplatin cytotoxicity. Another three patients experienced clinical improvement after WBH plus carboplatin, but progression with carboplatin alone (lung, 400 mg/m2; gastrointestinal neuroendocrine, 480 mg/m2; melanoma, 480 mg/m2). CONCLUSION: We conclude that carboplatin with WBH is well tolerated even at conventional carboplatin doses. Clinical results are consistent with preclinical predictions of an increased therapeutic index for this combination, which encourages future clinical studies.