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Inflammation is a defense mechanism that restores tissue damage and eliminates pathogens. Among the pattern recognition receptors that recognize danger or pathogenic signals, nucleotide oligomerization domains 1 and 2 (NOD1/2) have been identified to play an important role in innate immunity responses, and inhibition of NOD1 could be interesting to treat severe infections and inflammatory diseases. In this work, we identified the first selective NOD1 versus NOD2 pathway inhibitors at the nanomolar range based on a 4-anilinoquinazoline scaffold. We demonstrated that NOD1 inhibition occurs through the inhibition of receptor interacting protein kinase 2 (RIPK2), which is involved in its downstream signaling pathways. Compound 37 demonstrates no cytotoxicity, a selectivity for RIPK2 over epithelial and vascular endothelial growth factor receptors (EGFR/VEGFR), and a capacity to reduce pro-inflammatory cytokine IL-8 secretion. The structure of the RIPK2-compound 37 complex was resolved by crystallography. The 4-anilinoquinazoline scaffold offers novel perspectives to design NOD1-RIPK2 signaling inhibitors.

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.

A recent debate about Theory of Mind (ToM) concerns whether spontaneous and explicit mentalizing are based on the same mechanisms. However, only a few neuroimaging studies have investigated the neural bases of spontaneous ToM, with inconsistent results. The present study had two goals: first, to investigate whether the right Temporo-Parietal Junction (rTPJ) is crucially involved in spontaneous ToM and second, to gain insight into the role of the rTPJ in ToM. For the first time, we applied rTMS to the rTPJ while participants were engaged in a spontaneous false belief task. Participants watched videos of a scene including an agent who acquires a true or false belief about the location of an object. At the end of the movie, participants reacted to the presence of the object. Results show that, during stimulation of the control site, RTs were affected by both the participant's expectations and the belief of the agent. Stimulation of the rTPJ significantly modulated task performance, supporting the idea that spontaneous ToM, as well as explicit ToM, relies on TPJ activity. However, we did not observe a disruption of the representation of the agent's belief. Rather, the stimulation interfered with participant's predictions, supporting the idea that rTPJ is crucially involved in self-other distinction., (© The Author (2017). Published by Oxford University Press.)

The aim of this study was to develop a method combining chiral separation and biophysical techniques to evaluate the enantioselective affinity of original sulfonamide derivatives towards their therapeutic target, the human carbonic anhydrase II (hACII). The first step consisted in the preparation of the enantiomers by chromatographic separation. The performances of HPLC and Supercritical Fluid Chromatography (SFC) were studied at the analytical scale by optimization of various experimental conditions using adsorbed polysaccharide chiral stationary phases (amylose AD-H and cellulose OD-H). Since SFC allowed obtaining higher enantioresolutions per time unit, it was selected for the semi-preparative scale and successfully used to isolate each enantiomer with a satisfactory enantiomeric purity (>98%). Secondly, microscale thermophoresis (MST) method and surface plasmon resonance (SPR) used as reference method were developed to measure potential enantioselective affinities of these enantiomers towards the hACII. The optimizations of both methods were performed using a reference compound, i.e. acetazolamide, which affinity for hCAII has previously been demonstrated. For all compounds, K D values obtained using MST and SPR were in good agreement, leading to similar affinity scales despite both approaches totally differ (labeling for MST versus immobilization of the protein for SPR). The equilibrium dissociation constants of our original compounds for the hCAII were in the range 100-1000nM and an enantioselectivity was observed using the MST and SPR methods for the diarylpyrazole 2. Finally, by comparing the MST and SPR techniques, MST appears especially adapted for further screening of a series of sulfonamide derivatives due to the lower time required to estimate a binding constant while consuming as little hCAII as SPR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This work was dedicated to the development of a reliable SPR method allowing the simultaneous and quick determination of the affinity and selectivity of designed sulfonamide derivatives for hCAIX and hCAXII versus hCAII, in order to provide an efficient tool to discover drugs for anticancer therapy of solid tumors. We performed for the first time a comparison of two immobilization approaches of hCA isoforms. First one relies on the use of an amine coupling strategy, using a CM7 chip to obtain higher immobilization levels than with a CM5 chip and consequently the affinity with an higher precision (CV% < 10%). The second corresponds to a capture of proteins on a streptavidin chip, named CAP chip, after optimization of biotinylation conditions (amine versus carboxyl coupling, biotin to protein ratio). Thanks to the amine coupling approach, only hCAII and hCAXII isoforms were efficiently biotinylated to reach relevant immobilization (3000 RU and 2700 RU, respectively) to perform affinity studies. For hCAIX, despite a successful biotinylation, capture on the CAP chip was a failure. Finally, concordance between affinities obtained for the three derivatives to CAs isozymes on both chips has allowed to valid the approaches for a further screening of new derivatives., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Persistent control of a transmon qubit is performed by a feedback protocol based on continuous heterodyne measurement of its fluorescence. By driving the qubit and cavity with microwave signals whose amplitudes depend linearly on the instantaneous values of the quadratures of the measured fluorescence field, we show that it is possible to stabilize permanently the qubit in any targeted state. Using a Josephson mixer as a phase-preserving amplifier, it was possible to reach a total measurement efficiency η=35%, leading to a maximum of 59% of excitation and 44% of coherence for the stabilized states. The experiment demonstrates multiple-input multiple-output analog Markovian feedback in the quantum regime.

A CE method using dual cationic and neutral cyclodextrins (CD) was optimized for the enantiomeric separation of a compound presenting a diaryl sulfonamide group. Preliminary studies were made to select the optimal CDs and pH of the BGE. Two CDs (amino-β-CD and β-CD) were selected to separate the enantiomers in a 67 mM phosphate buffer at pH 7.4. However, the repeatability of the analyses obtained on bare-fused silica capillary was not acceptable owing to the adsorption of the amino-β-CD to the capillary. To prevent this, a dynamic coating of the capillary was used employing five layers of ionic-polymer (poly(diallyldimethylammonium) chloride (PDADMAC) and poly(sodium 4-styrenesulfonate). The efficiency of the coating was assessed by measuring the EOF stability. Repeatability of the injections was obtained when intermediate coating with PDADMAC was performed between each run. Secondly, this enantioseparation method was optimized using a central composite circumscribed design including three factors: amino-β-CD and β-CD concentrations and the percentage of methanol. Under the optimal conditions (i.e. 16.6 mM of amino-β-CD, 2.6 mM of β-CD, 0% MeOH in 67 mM phosphate buffer (pH 7.4) as BGE, cathodic injection 0.5 psi, 5 s, separation voltage 15 kV and a temperature of 15°C), complete enantioresolution of the analyte was obtained. It is worth mentioning that the design of experiments (DOE) protocol employed showed a significant interaction between CDs, highlighting the utility of DOE in method development. Finally, small variations in the ionic-polymer concentrations did not significantly influence the EOF, confirming the robustness of the coating method., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Several regulatory and signaling molecules governing angiogenesis are targets of interest for the development of drugs in the cancer, including growth factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF). A series of 4-aryloxy-6,7-dimethoxyquinazolines, previously synthesized in our laboratory, has shown a nanomolar inhibition of kinase enzymatic activity of VEGFR, PDGFR and c-Kit. We have therefore studied the impact of the variation in the 7-position substitution of the quinazoline core. Substitution by aminoalkoxy chains led to new highly potent ATP-competitive inhibitors of VEGFR, PDGFR and c-Kit enzyme with IC50 values in the nanomolar range and this substitution has increased greatly antiproliferative activity on cancer cell lines (PC3, MCF7, HT29) and HUVEC (human umbilical vein endothelial cells). One of the most promising compounds (36) was assessed for its ability to limit the induction of web like network of capillary tubes by the human umbilical vascular endothelial cells (HUVEC) and for its ability to inhibit invasion., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

This work describes the development of biophysical unbiased methods to study the interactions between new designed compounds and carbonic anhydrase II (CAII) enzyme. These methods have to permit both a screening of a series of sulfonamide derivatives and the identification of a lead compound after a thorough study of the most promising molecules. Interactions data were collected using surface plasmon resonance (SPR) and thermal shift assay (TSA). In the first step, experiments were performed with bovine CAII isoform and were extended to human CAII. Isothermal titration calorimetry (ITC) experiments were also conducted to obtain thermodynamics parameters necessary for the processing of the TSA data. Results obtained with this reference methodology demonstrate the effectiveness of SPR and TSA. KD values obtained from SPR data were in perfect accordance with ITC. For TSA, despite the fact that the absolute values of KD were quite different, the same affinity scale was obtained for all compounds. The binding affinities of the analytes studied vary by more than 50 orders of magnitude; for example, the KD value determined by SPR were 6 ± 4 and 299 ± 25 nM for compounds 1 and 3, respectively. This paper discusses some of the theoretical and experimental aspects of the affinity-based methods and evaluates the protein consumption to develop methods for the screening of further new compounds. The double interest of SPR, that is, for screening and for the quick thorough study of the interactions parameters (ka , kd , and KD ), leads us to choose this methodology for the study of new potential inhibitors., (Copyright © 2013 John Wiley & Sons, Ltd.)

Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX. Pharmacological studies revealed high hCA IX inhibitory potency in the parameters nanomolar range. This study showed that the position of sulfonamide group in meta of the 1-phenylpyrazole increase a selectivity hCA IX versus hCA II of our compounds. An in vitro antiproliferative screening has been performed on the breast cancer MDA-MB-231 cell using doxorubicin as cytotoxic agent and in presence of selected CA IX inhibitor. The results shown that the cytotoxic efficiency of doxorubicin in an hypoxic environment, expressed in IC50 value, is restored at 20% level with 1μM CA IX inhibitor., (Copyright © 2012. Published by Elsevier Ltd.)

In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series.

Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core. Substitution by aryloxy groups led to new compounds which are selective inhibitors of VEGFR-2 enzyme with IC(50) values in the nanomolar range in vitro., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents. We studied the strength and mode of binding to DNA of these molecules by DNA melting temperature measurements, fluorescence emission, and circular dichroism. The results of various spectral and gel electrophoresis techniques obtained with the different compounds, in particular compounds 5g and 22f, revealed significant DNA interaction. These experiments confirm that the N-aminoalkyl(anilino)-6,7-dimethoxyquinazoline nucleus is an efficient pharmacophore to trigger binding to DNA, via an intercalative binding process.

Objectives: To propose an objective approach in order to determine the number of beds required for a hospital department by considering how recruitment fluctuates over time. To compare this approach with classical bed capacity planning techniques., Methods: A simulated data-based evaluation of the impact that the variability in hospital department activity produces upon the performance of methods used for determining the number of beds required. The evaluation criteria included productive efficiency measured by the bed occupancy rate, accessibility measured by the transfer rate of patients due to lack of available beds and a proxy of clinical effectiveness, by the proportion of days during which there is no possibility for unscheduled admission., Results: When the variability of the number of daily patients increases, the Target Occupancy Rate favors productive efficiency at the expense of accessibility and proxy clinical effectiveness. On the contrary, when the variability of the department activity is marginal, the Target Activity Rate penalizes the proxy of clinical effectiveness, and the Target Occupancy Rate underoptimizes productive efficiency. The method we propose led to a superior performance in terms of accessibility and proxy of clinical effectiveness at the expense of productive efficiency. Such a situation is suitable for intensive care units. In the case of other departments, a weighting procedure should be used to improve productive efficiency., Conclusions: This approach could be considered as the first step of a family of methods for quantitative healthcare planning.

Objective: The aim of this retrospective study was to identify the risk factors for catheter-associated bloodstream infection (CABSI) in neonates., Method and Results: Fifteen episodes of CABSI occurred in 108 central catheters over a period of one year (2002). The univariate analysis risk factors were birth weight (1.064 vs 1.413 g; P<0.001), gestation age (28 vs 31 weeks; P<0.001), blood transfusion (8/15 vs 3/34; P<0.01), corticosteroids (7/15 vs 3/34; P<0.01), nasal CPAP duration (13.6 vs 2 days; P<0.01). Nasal CPAP duration was the only risk factor independently associated with CASBI (OR=1.2, 95% confidence interval=1.09-1.5) in the multivariate logistic regression analysis., Conclusions: The risk of infection associated with low birth weight is multifactorial suggesting that host-related factors are important. Prevention remains difficult and a policy of strict aseptic catheter care must be promoted.

Objective: The number of acute hospital beds is determined by health authorities using methods based on ratios and/or target bed occupancy rates. These methods fail to consider the variability in hospitalization demands over time. On the other hand, the implementation of sophisticated models requires the decision concerning the number of beds to be made by an expert. Our aim is to develop a new method that is as simple to use as the ratio method while minimizing the roundabout approaches of these methods., Method: A score was constructed with three parameters: number of transfers due to lack of space, number of days with no possibility for S unscheduled admissions and number of days with at least a threshold of U unoccupied beds. The optimal number of beds is the number for which both the mean and the standard deviation of the score reach their minimum. We applied this method to two internal medicine departments and one urological surgery department and we compared the solutions proposed by this method with those put forward by the ratio method., Results: The solutions proposed by this method were intermediate to those calculated by the local and national length of Stays ratio methods. Simulating an unusual increase in admission requests had no consequence on the bed number selected, indicating that the method was robust., Conclusion: Our tool represents a real alternative to the ratio methods. A software has been developed and is now available for use.

Despite their prevalence and longevity in many forms of social organization, most research on formal meetings suggests that they do not fulfil the instrumental purposes (e.g. setting strategy) that their constitutions propose. A three-year study of the Joint Commissioning Board for mental health in Somerset, UK, revealed that it was no exception. However, many of the participants on the Board suggested that it fulfilled important purposes that drew attention to its role as ritual. This paper examines the role of the Board in the light of the literature on ritual--in particular the work of the neo-Durkheimian tradition flowing from the work of Douglas--and locates the importance of the meeting in the formation of social solidarity. This theoretical perspective illuminates issues around classification and language which explain the disempowerment felt by some members of the Board. Finally, this paper identifies the challenges in engaging a broader range of stakeholders (including users and carers) in these rituals.

Objective: Most methods used to estimate ICU bed needs rely either on simple formulas that do not consider the actual needs of the population or on simulations that are too specific to be applicable to all hospitals. We sought to develop a universally applicable nonparametric method., Design and Setting: For each day, the number of immediate patient transfers to other ICUs because of a full unit and the number of patients treated in the ICU were collected. The number of beds needed was selected according to the minimization of both the mean and the variance of three parameters (accessibility, safety, and efficiency). This method was applied to the ICU of a general hospital. Robustness of the model was assessed using outliers., Main Results: During the 5-month study period, 215 ICU stays were collected. The method selected a ten-bed model whereas length-of-stay ratio and case-mix methods selected a twelve- and height-bed models respectively. An unusual increase in admission requests had no consequence on the bed number selected, indicating that the method was robust. None of the parameters were dependent on specific ICU characteristics, establishing that this method is applicable to any type of hospital ward., Conclusion: Our model is reliable for determining the number of beds needed in any type of ICU and can be used by all ICU managers. The software is available.

The determination of the number of beds needed for a hospital department is a complex problem that try to take into account efficiency, forecasting of needs, appropriateness of stays. Health authority used methods based on ratios that do not take into account local specificities and use rather to support an economic decision. On the other side, the models developed are too specific to be applied to all type of hospital department. Moreover, all the solutions depend on the LoS (Length of Stay). We have developed a non parametric method to solve this problem. This modelisation was successfully tested in teaching and non teaching hospitals, for an Intensive Care Unit, two Internal Medicine and a surgical departments. A software easy to use was developed, working on Windows available on our website www.sante.univ-nantes.fr/med/stat/.

Background: The modified French version of the Appropriateness Evaluation Protocol (AEPf) has been validated. Inappropriate days according to simple medical and technical criteria are identified with this tool. The aim of this study is to highlight the interest of investigating the reasons for inappropriate days and to assess the inter-observers reliability of the questionnaire developed for this purpose., Methods: This questionnaire collects on one hand the needs of patients - distinguishing health care and accommodation needs - and on the other hand the reasons for inappropriate hospital days. The data were collected from January to September 1998 in nine voluntary medical and surgical departments. For each day of study randomly selected, each inappropriate hospital day according to AEPf has been included. Data were collected by two health professionals (a nurse and a physician), using a concurrent design., Results: The reliability of the over-ride option of the appropriateness assessment of the 345 hospital days was good (overall Kappa coefficient: 0.66; 95% CI: 0.55-0.78). The comparison of the two expert judgments on health care needs fulfilled during the hospital day was acceptable; the Kappa coefficient was 0.62 (95% CI: 0.52-0.72). The reliability of expert assessment on patient accommodation needs (home, housing facilities or hospital) was good (Kappa coefficient: 0.67; 95% CI: 0.60-0.75). When hospital was not the accommodation the most adapted for patient, the reliability of the reasons for inappropriate days was high (Kappa coefficient: 0.75; 95% CI: 0.61-0.80). Kappa coefficients were different between hospitals, indicating a center effect., Conclusion: This instrument has been found to be reliable and should be used in complement of the first part of the AEPf which assess the prevalence of inappropriate days. It might help to detect dysfunctions within or outside the hospital and thus be used for evaluation or planning of health care.

Cobalamin deficiency increases with advancing age. The cut-off point of serum concentration should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in cobalamin. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended. Cobalamin deficiency may result in a variety of atypical symptoms. Hematological changes typical of megaloblastic anemia are absent in a majority of patients with neuropsychiatric disorders. Generally underlying pernicious anemia is not the main cause of cobalamin deficiency in the elderly. Protein-bound cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria is a common cause of cobalamin deficiency in elderly people. An important manifestation of cobalamin deficiency is cognitive impairment. Much controversy exists on the subject of the association of dementia of the Alzheimer type with cobalamin deficiency. In several studies dementia has been related to low serum cobalamin levels. Physicians should be liberal of cobalamin therapy. The window of opportunity for effective intervention may be as short as one year from the onset of medical symptoms. At last a compilation of recommendations is given.

Background: The Appropriateness Evaluation Protocol (AEP) is a tool used to identify hospitalization days that are appropriate with respect to simple technical criteria, and the reasons for hospitalization days that do not meet these criteria. The goal of the study was to validate the clinical criteria of AEPf, required for identifying the reasons which explain these inappropriate hospital days., Methods: The validity of a French version of criteria of appropriateness (AEPf) was assessed in a sample of 502 hospital days in medical and surgical wards of six French teaching hospitals. The reliability of the AEPf-based conclusions was studied by the measure of the concordance between two independent measures of AEPf for the same hospital day. Validity of AEPf was studied by the measure of the concordance between AEPf-based conclusions and the judgments of physicians using implicit criteria to assess the necessity of the hospital day studied. The degree of concordance was estimated by the Kappa coefficient., Results: AEPf reproducibility was high (Kappa coefficient: 0.81; 95% confidence interval (95% CI): 0.76-0.87). Validity was also high (Kappa coefficient: 0.61; 95% CI: 0.53-0.68)., Conclusion: The French version of the AEP was thus shown to be both reliable and valid to identify hospitalisation days appropriate with respect to hospital's technical equipment and specific resources. However, the reproducibility of the assessment of reasons for hospital days that did not meet AEP criteria will require a validation.

Objectives: A prospective longitudinal study was conducted to investigate the influence of prolonged suppressive L-thyroxin therapy on bone density and biochemical markers of bone remodeling., Patients and Methods: Seventy-one patients (including 28 menopaused women) taking long-term L-T4 for thyroid carcinoma were divided into 3 groups according to their TSH level: low (TSH < 0.04 mlU/l), moderate (0.04 TSH < or = 0.10 mlU/l) and high (TSH > 0.10 mlU/l). Bone density was measured in lumbar vertebrae annually for a mean 4.5 years. Bone metabolism markers were measured over a 4 year period. Bone density measurements of the femur were also obtained for 2 years in 16 menopaused women., Results: Lumbar bone density did not decline whatever the TSH level or the duration of L-T4 treatment. Likewise for menopaused women without substitution estroprogesterone therapy. Over the 4 years, biochemical markers of bone formation, including bone alkaline phosphatases and osteocalcin, or of bone resorption, including urinary hydroxyprolin, did not vary. In addition, in menopaused women, femoral bone density was not significantly lowered over the 2 years follow-up. No lumbar or femoral osteopenia was observed in these patients taking L-thyroxin, even for those with complete TSH blockade. Biochemical markers did not demonstrate a significant acceleration of bone turnover during prolonged administration of L-T4 at suppressive levels.

This article presents the predictors for living at home 3 months, 6 months, 12 months, and 24 months after hospitalization in a geriatric clinic. The multivariate regression analysis revealed the predictive factors for living at home after 3 months: Incontinence, functional status judged by the physician, and balance performance. For living at home at 6 months, balance performance, handgrip were predictive, and at 12 months, balance performance, physicians judgement of functional abilities and Barthel-Index had the most predictive value. The only factor that was recognized to be predictive for living at home at 24 months was the physician's judgement of the functional abilities of the patient. It is concluded that the functional status measured by observation but preferably by performance is of predictive value for living at home from 6 months to 12 months after acute hospitalization.

The risk of falling increases with age and with many of the disorders common in late life. Approximately 35 to 40% of community-dwelling people over the age of 65 and up to 50% of institutionalized elderly fall at least once every year. The incidence is highest in women and the very old. Hip fracture, one of the most serious injuries associated with falls, assumes epidemic proportions in old people. In addition to physical injury, falls can have other serious consequences for the older person. Repeated falls are a common reason for the admission of previously independent elderly persons to long-term care institutions. This article examines why older people fall and what factors place persons at risk for falling. The multiple reasons for an inconsistency of the epidemiological data are discussed.

In senile dementia the clinical presentation is not only determined by the mental deficits but also by affective, behavioral and somatic symptoms. Some sequelae are regularly associated with the process and the course of dementia, and therefore largely predictable and preventable. Identification of the complications commonly associated with this disease complex allows prevention and early treatment of states incriminating the natural course of the disease. By this approach a rational management of senile dementia can be achieved.

Gait disorders in the elderly are a major cause of falls and accidents. They also interfere badly with the quality of life and the psychosocial well-being. The prevalence of these disorders is very high: 15% of the persons over 65 years and about 25% of those over 75 years suffer from gait disorders. The cause of gait disorders can be a specific disease, but in the elderly, multiple causes are much more frequent. In the elderly, the analysis of gait disorders consists not only of a diagnostic work-up, but also of a comprehensive geriatric and functional gait assessment. A minimal gait assessment includes a special clinical examination, an instrumental analysis of gait speed and a functional assessment of gait and balance by standard tests. In this article the relevant methods of a practical gait assessment are presented and some basic aspects of treatments are discussed.

Postural hypotension, defined as a fall in systolic pressure of 20 mmHg or more on standing, and other hypotensive conditions are major problems in geriatric medicine. In this article the physiology and the pathology of orthostatic blood pressure regulation in the elderly are reviewed. Proposals are made for the diagnostic evaluation of patients with postural hypotension and for steps to be taken in therapeutic management.

50 chronic alcoholics reporting to the medical emergency ward of Basle University Hospital with alcohol-related illness were examined with respect to thiamine nutritional status by means of the transketolase activation test of erythrocytes (ETK). 46% of the chronic alcoholics, compared to only 2% of the control population (1152 healthy adults), had transketolase activation quotients indicating a strong probability of thiamine deficiency (alphaETK greater than 1.25). The most important symptoms associated with the biochemical parameters of thiamine deficiency were: anemia, pathologic liver functions (bilirubin, gamma-globulins), low diastolic blood pressure and Wernicke's encephalopathy. There was a statistically significant correlation (p less than 0.05) between these symptoms and the biochemical parameters for thiamine deficiency. Therefore, when treating chronic alcoholics, these symptoms should direct attention to a possible vitamin B1 deficiency. Since the enzymatic vitamin B1 parameters correlate with the patients' hemoglobin, our results would be consistent with anemia influenced by provision of thiamine.

This work undertakes, in a second part, the clinical exploration of 947 serum digoxin levels of 281 hospitalized patients on a cardiology ward. Our results, which coincide with those of other researchers, have led us to draw certain practical conclusions: the posology is determined first of all according to kidney function, weight and age of the patient. When the treatment is insufficient or, on the other hand, poorly tolerated, a serum digoxin level is performed permitting thus: 1) in the case of ineffective treatment: to be sure of the patient's cooperation, to increase the posology if the serum digoxin level is not in the toxic zone, to discover an eventual pharmacokinetic problem; 2) to establish the responsibility of digitalis (when there are signs of intolerance or of intoxication), in case of arrhythmia, in patients with pacemakers, when associated drugs are capable of causing similar adverse effects; 3) to better manage a digitalis treatment in a high risk patient (unstable renal function, advanced myocardial disease, chronic obstructive disease).

Our aim was to assess the usefulness of tests of reversibility of airways obstruction (AO) in the differential diagnosis of asthma (A) and chronic bronchitis (CB). We selected on strict clinical criteria 20 CB and 32 A patients with stable AO and measured maximal forced expiratory flows before and after increasing doses of inhaled salbutamol. The highest sensitivity (Se), specificity (Sp) and likelihood ratio (L) were obtained when the improvement in forced expiratory volume in one second (FEV1) was expressed as a percentage of predicted FEV1. Se, Sp and L were 0.97, 0.95 and 19.3 (highest possible L: 20) for an increase of 10% of predicted FEV1 on 0.2 mg of salbutamol, and 1.0, 1.0 and 20, respectively, for an increase of 15% on 1 mg of salbutamol. Conversely, L was only 2.8 when the widely used increase in FEV1 of 20% over baseline was tested. In a second group of 42 unselected patients, who were referred to the laboratory for routine lung function testing with a presenting diagnosis of A or CB, L was only 5.5 when the 10% increase in predicted FEV1 was used and even lower for the classical 20% increase over baseline FEV1. We submit that routine tests of reversibility of AO have little diagnostic usefulness in unselected patients with AO and that the commonly used criteria of 15 or 20% increase in FEV1 over baseline are of no value in separating A from CB.

The frequency of chronic terminal renal failure (CTRF) (serum creatinine greater than or equal to 4,5 mg/dl) in an unselected autopsy material was about 1.7% from 1968 to 1976. Based on this figure, the estimated yearly incidence is 160 to 200/10(6) inhabitants of the Basel area. In inhabitants of Basel, analgesic nephropathy (42.2%) was the most important cause of CTRF (excluding obstructive nephropathy). Pyelonephritis (without evidence of analgesic abuse) represented only 25.7%. All other nephropathies were less common: glomerulonephritis 14.6%, diabetic nodular glomerulosclerosis 11.6%, cystic kidney disease and vascular nephropathies (each 4.5%). By contrast, in patients treated by hemodialysis and renal transplantation glomerulonephritis (28.7%) is the most important cause of CTRF, followed by analgesic nephropathy (20%), pyelonephritis (15%) and cystic disease of the kidney (12.5%). The difference between the two groups can be explained by the lower mean age of patients treated by hemodialysis and transplantation. Incidence and disease course can be affected significantly only in analgesic nephropathy. It is therefore very important to prohibit legally the use of phenacetin or paracetamol containing analgesics without medical prescription. In addition, these drugs should be replaced by other analgesic compounds.

A computer analysis of several solution methods for secular equations leads to a determination of their optimum conditions. The results contribute to the application of a new preliminary method of frequency assignment to the vibrational study of the heavy atoms coordination sphere in complex biological structures, such as metalporphyrins and adenosine triphosphate.

Sixty cases of Parkinson's disease were treated with piribedil alone (dose : 274 mg/day, duration : 20,4 months). The overall clinical improvement, confirmed by recordings of tremor and EMG, was 34%, tremor being improved of 59%. Before treatment, an intravenous test does of piribedil with recording made it possible to predict the effectiveness of oral treatment. Side-effects (vasomotor, digestive, psychiatric) were moderate. Orthostatic hypotension, dyskinesia and fluctuations were exceptional. The basic indication for piribedil lies in forms of recent onset in which tremor predominates, patients in whom L-dopa is contraindicated and a certain number in whom the latter has failed (tremor, fluctuating action).

Thiopental was used in long-term infusion (3-4.5 mg . kg-1 . h-1 during 4-8 days) to protect the brain from injury following trauma. Thiopental plasma concentrations were measured during infusion (48 patients) and after infusion (14 patients) to determine the kinetics of the drug in continuous infusion. All mean values were mean +/- SD. Steady state concentrations (Css) were 31.8 +/- 10.7 mg/l for an infusion rate of 3.05 +/- 0.37 mg . kg-1 . h-1 and 48.9 +/- 14.6 mg/l for a rate of 4.2 +/- 0.3 mg . kg-1 . h-1. Corresponding steady state clearance decreased when Css increased, indicating possible saturation of the metabolic enzymatic system. Michaelis-Menten kinetics were confirmed by postinfusion data that give, for higher Css, a nonlinear decay of log C versus time. First-order kinetics were only obtained with Css below 30 mg/l. The maximum rate of elimination (Vm) was 1.76 +/- 1.15 mg . l-1 . h-1 (n = 11), and the Michaelis constant (Km) was 26.7 +/- 22.9 mg/l (n = 11). Hepatic enzyme saturation was between 35 and 85%. The volume of distribution at steady state was 4.35 +/- 1.83 l/kg (n = 11). Apparent half-lives of elimination were between 18 and 36 h at the end of infusion, and predicted terminal half-lives were 10.15 +/- 5.43 h (n = 11). Phases of burst-suppression were observed on electroencephalographic traces for concentrations greater than 40 mg/l. The authors' results suggest that a continuous infusion at a dose of 4 mg . kg-1 . h-1 induces EEG changes consistent with a near-maximum reduction in cerebral metabolism. Because of the thiopental Michaelis-Menten kinetics at doses above 4 mg . kg-1 . h-1, the authors suggest that thiopental plasma concentrations be measured and/or the drug effect be measured with the EEG to prevent excessive thiopental overdosage, causing a prolonged recovery time.

Case report of a 35-year-old female patient who was admitted in Addisonian crisis and in whom primary adrenal, ovarian and thyroid failure was detected. Antibodies against the adrenals and the thyroid were found, together with dinished serum IgA levels. The patient had been treated for 20 years with diphenylhydantoin, a drug known to induce immunological disturbances, e.g. depression of serum IgA levels. The IgA deficiency and pluriglandular failure may be due to prolonged therapy with diphenylhydantoin. The coincidence of IgA deficiency and autoimmune diseases is well known. As far as is known this is the first case of IgA deficiency associated with autoimmune polyendocrinopathy.

Two histopathologic grading systems for prostatic adenocarcinomas are reevaluated: the Gleason system and the Gaeta system. Two pathologists reviewed 234 specimens to assess reproducibility. Exact agreement is achieved in 88% with the Gaeta system, in 65% with the Gleason system. Nevertheless, agreement to within one score unit is achieved in 94% with the Gleason grading. One pathologist's autoreproducibility exceed 80% with either system. Actuarial survival curves and mortality index (deaths per patient-year of follow-up) provided evidence of their predictive value. Regardless of the clinical stage these two grading systems select groups of patients sharing a good, intermediate or bad prognosis but none can predict a given patient's accurate survival. The Gleason system would allow a better discrimination between poorly and highly aggressive tumors of intermediate grade.

The effects of flurbiprofen on various coagulation and haemostasis parameters were studied in 19 patients adequately anticoagulated on a fixed dose of phenprocoumon. Laboratory controls were performed 5 times at weekly intervals. Flurbiprofen 50 mg 3-times daily was given for 2 weeks after an initial control period of 2 weeks. The last control followed 1 week after cessation of flurbiprofen. All changes observed during the administration of flurbiprofen were quantitatively moderate; some reached statistical significance. The prothrombin time (%) Factor II and Factor X values fell; Factor II values remained unchanged. Factor IX values fell only in the first week on flurbiprofen and reached control values thereafter. Phenprocoumon concentration remained constant throughout. There was no change in spontaneous platelet aggregation. Although there was a slight, statistically significant increase in the Ivy bleeding time, it remained within the normal range. These findings suggest that the interference of flurbiprofen with oral anticoagulation is minimal and probably of no clinical relevance.

This work undertakes, in a second part, the clinical exploration of 947 serum digoxin levels of 281 hospitalized patients on a cardiology ward. Our results which coincide with those of other researchers, have led us to draw certain practical conclusions: the posology is determined first of all according to kidney function, weight and age of the patient. When the treatment is insufficient or on the other hand, poorly tolerated, a serum digoxin level is performed permitting thus: 1) in the case of ineffective treatment: to be sure of the patient's cooperation, to increase the posology if the serum digoxin level is not in the toxic zone, to discover an eventual pharmacokinetic problem; 2) to establish the responsibility of digitalis (when there are signs of intolerance or of intoxication), in case of arrhythmia, in patients with pacemakers, when associated drugs are capable of causing similar adverse effects; 3) to better manage a digitalis treatment in a high risk patient (unstable renal function, advanced myocardial disease, chronic obstructive disease).

In the geriatric patient differential diagnosis of low back pain with sciatica includes degenerative lumbar spinal stenosis, affecting the central canal, the lateral recesses or both. Symptoms usually begin in the sixth decade, but may occur earlier if spinal degeneration is superimposed on congenital stenosis. In the elderly early diagnosis is more difficult to establish, because of the bewildering medical problems and the multiple symptoms rooted in the polypathy and polymorbidity of old age. Typical symptoms include low back pain, claudicatory pains, and paraesthesias of the legs, typically aggravated by standing and relieved by rest. In our series they were present in 100%, 94% and 56% respectively. In our series, the most important clinical investigations confirming diagnosis were pain provocation by reclining and pain relief by inclination (present in 69% of patients) and combined radiographic examination including plain films, computed tomography and myelography. In our experience myelography proved the best single method for early diagnosis. In our elderly patients lateral stenosis was predominant, and therefore lateral decompression by foraminotomy, generally combined with flavectomy, was the most important surgical procedure. In cases with combined lateral and central stenosis, hemilaminectomy or facetectomy was also performed. In follow-up 1 to 5 years after the operation the success rate, determined by very restrictive criteria, was 87%. Therefore, and because failure to establish early diagnosis potentially leads to definitive invalidity, degenerative lumbar spinal stenosis should be considered more frequently in the differential diagnosis of low back pain of the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

In incorporation experiments used for the determination of glycosyltransferase activities, we demonstrated that the nucleoside diphosphate sugars are decomposed in three different ways: 1, transfer of the monosaccharide to acceptor molecule, catalyzed by glycosyltransferases; 2, degradation of the glycosyl nucleotides by nucleotide pyrophosphatase into monosaccharide 1-phosphates which are further hydrolyzed into free monosaccharides by phosphatases; 3, chemical decomposition of UDP-D-[14C]Gal; UDP-D-[14C]Glc and UDP-D-[14C]GlcUA into 1,2-cyclic phosphate derivatives of the corresponding monosaccharide. All the breakdown products of the nucleoside mono- and diphosphate sugars which are obtained during the incorporation experiments may be separated by paper chromatography and their amounts may be determined. Galactosyltransferase assays on human and rat serum have shown that the three different ways of decomposition of the nucleoside diphosphate sugars are dependent mostly on the concentration of divalent cations (Mn2+, Mg2+). Inhibition of the nucleotide pyrophosphatase activity is obtained with low concentrations of UMP, but increasing concentrations of UMP inhibit also the galactosyltransferase activity and consequently enhance the formation of galactose 1,2-monophosphate. A partial elimination of the nucleotide pyrophosphatase activity was achieved by the addition of increasing concentrations of UDP-D-Gal. These results demonstrate that the determination of glycosyltransferase activities in tissues and in biological fluids is not possible without a concomitant determination of the nucleotide pyrophosphatase activity present in the assay.

Visco-elastic parameters of the bronchi system are represented by the viscous modulus and the recoil static pressure. In several generations, values of the cross-sectional area of the bronchi are defined at various moments by the results obtained with dynamical tracheo-bronchography. By means of these measures and the use of a model describing the air flow in elastic bronchi, a calculation procedure of the visco-elastic parameters has been established.

This paper describes a Medical Information System (conversational in real-time). SIGMED, which is used in the French hospital of Angers. Its main feature is its original organization which (i) allows one to follow a patient's history in space and time with a limited number of medical items and the whole set of administration ones and makes it possible to carry and (ii) the possibility of various epidemiological studies relating to medical speciality records which contain all the medical information related to a patient's examination and/or hospitalization.

A 35-year-old woman had an addisonian crisis and primary adrenal, ovarian, and thyroid failures were detected. Antibodies against the adrenal glands and the thyroid were found, together with consistently low IgA levels. The patient had been receiving phenytoin, a drug known to induce an IgA deficiency, for 20 years. The question arises as to whether this substance was responsible for an immunological defect leading to an autoimmune process that damaged the adrenal glands, the ovaries, and the thyroid.