The cervico-thoracic outlet compression syndrome. Analysis of surgical treatment.

Surgical treatment of the thoracic outlet compression syndrome is being presently reconsidered. Until these last few years, there was the choice between two interventions only: scalenotomy, a simple operation entailing no complication, but with a 60% recurrence rate--or the resection of the first rib through an axillary approach, an efficacious intervention which caused, however, serious nervous complications in 14% of treated cases. The follow-up of 75 cases operated for a TOCS reveals to the authors that--all techniques taken into account--results are unsatisfactory in 33% of cases. These failures are due either to technical deficiencies, or to a complication arising in the course of the operation, or to an erroneous diagnosis. The authors resort to surgery only to treat serious vascular syndromes (absolute indication) or invalidating neurological compression syndromes, after failure of physical therapy (relative indication). They propose a cervical approach--the only one enabling a safe dissection of the brachial plexus--a partial scalenectomy, resection of all fibrous bands pressing on nervous trunks, or the resection of a cervical rib. Should the costo-clavicular space appear anatomically too narrow, the first rib, already partially freed by the cervical approach, will be resected through the axillary route.

Safety and efficacy in gamma knife radiosurgery for trigeminal neuralgia due to megadolichbasilar artery compression: a prospective series of 29 consecutive patients

Purpose: To analyse prospectively the long-term results of Gamma Knife surgery (GKS) in patients with trigeminal neuralgia secondary to megadolichobasilar artery (MBA). Methods: Between December 1992 and November 2010, 33 consecutive patients presenting with ITN secondary to MBA were operated by GKS and followed prospectively in Timone University Hospital. The follow up is at least of 1 year in 29 patients. The median age was 74.90 years (range 51 to 90). The GKS typically was performed using MR and CT imaging guidance and a single 4 mm isocenter. The median of the prescription dose (at the 100%) was 90 Gy (range 80 to 90). The target was placed on the cisternal portion of the Vth nerve. Clinical and dosimetric parameters were analyzed. GKS was the first surgical procedure in 23 patients (79.31%). Results: The median follow- up period was 46.12 months (range 12.95 to 157.93). All the 29 patients (100%) were initially pain free in a median time of 13.5 days (range 0 to 240). The probability of remaining pain free at 0.5, 1, 2 years was 93.1%, 79.3% and 75.7% respectively, reaching at this time the flat part of the curve. Seven patients (24.13%) experienced a recurrence with a median delay of 10.75 months (range 3.77 to 12.62). The actuarial rate of recurrence was not higher than in our population with essential TN although atypical pain was associated with a much higher risk of recurrence (HR= 6.92, p= 0.0117). The hypoesthesia actuarial rates at 0.5 years was 4.3% and at 1 year reach 13% and remains stable till 12 years with a median delay of onset of 7 (5, 12) months. Female patients had a statistically much lower probability of developing a facial numbness (p of 0.03). No patient reported a bothersome hypoesthesia. Conclusion: Retrogaserian, high dose GKS, turned out to be very safe with only 13.04% hypoesthesia, which was never disabling (0%), while achieving high quality pain control. The majority of the patients demonstrated a prolonged effect of radiosurgery in absence of any trigeminal nerve disturbance.

A dramatic lung cancer course in a patient with a rare EGFR germline mutation exon 21 V843I: Is EGFR TKI resistance predictable?

We report on the medical history of a Caucasian smoker woman diagnosed with a stage IV NSCLC adenocarcinoma, characterized by a rare epidermal growth factor receptor (EGFR) point mutation in exon 21 codon 843 (p.V843I/c.2527G>A/COSMIC ID 85894). This genetic alteration revealed to be germline, after its presence was demonstrated in chondroblasts from the bone biopsy. While it is the first description of germline V843I mutation without concomitant additional known EGFR activating mutation, we modeled the EGFR ATP catalytic domain in complex with ATP, gefitinib and erlotinib using computer-aided approaches to estimate possible changes in affinity upon the V843I mutation.

Effects of the social environment on the survival and fungal resistance of ant brood

The phenotype of social animals can be influenced by genetic, maternal and environmental effects, which include social interactions during development. In social insects, the social environment and genetic origin of brood can each influence a whole suite of traits, from individual size to caste differentiation. Here, we investigate to which degree the social environment during development affects the survival and fungal resistance of ant brood of known maternal origin. We manipulated one component of the social environment, the worker/brood ratio, of brood originating from single queens of Formica selysi. We monitored the survival of brood and measured the head size and ability to resist the entomopathogenic fungus Beauveria bassiana of the resulting callow workers. The worker/brood ratio and origin of eggs affected the survival and maturation time of the brood and the size of the resulting callow workers. The survival of the callow workers varied greatly according to their origin, both in controls and when challenged with B. bassiana. However, there was no interaction between the fungal challenge and either the worker/brood ratio or origin of eggs, suggesting that these factors did not affect parasite resistance in the conditions tested. Overall, the social conditions during brood rearing and the origin of eggs had a strong impact on brood traits that are important for fitness. We detected a surprisingly large amount of variation among queens in the survival of their brood reared in standard queenless conditions, which calls for further studies on genetic, maternal and social effects influencing brood development in the social insects.

Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection.

Principal mechanisms of resistance to azole antifungals include the upregulation of multidrug transporters and the modification of the target enzyme, a cytochrome P450 (Erg11) involved in the 14alpha-demethylation of ergosterol. These mechanisms are often combined in azole-resistant Candida albicans isolates recovered from patients. However, the precise contributions of individual mechanisms to C. albicans resistance to specific azoles have been difficult to establish because of the technical difficulties in the genetic manipulation of this diploid species. Recent advances have made genetic manipulations easier, and we therefore undertook the genetic dissection of resistance mechanisms in an azole-resistant clinical isolate. This isolate (DSY296) upregulates the multidrug transporter genes CDR1 and CDR2 and has acquired a G464S substitution in both ERG11 alleles. In DSY296, inactivation of TAC1, a transcription factor containing a gain-of-function mutation, followed by sequential replacement of ERG11 mutant alleles with wild-type alleles, restored azole susceptibility to the levels measured for a parent azole-susceptible isolate (DSY294). These sequential genetic manipulations not only demonstrated that these two resistance mechanisms were those responsible for the development of resistance in DSY296 but also indicated that the quantitative level of resistance as measured in vitro by MIC determinations was a function of the number of genetic resistance mechanisms operating in any strain. The engineered strains were also tested for their responses to fluconazole treatment in a novel 3-day model of invasive C. albicans infection of mice. Fifty percent effective doses (ED(50)s) of fluconazole were highest for DSY296 and decreased proportionally with the sequential removal of each resistance mechanism. However, while the fold differences in ED(50) were proportional to the fold differences in MICs, their magnitude was lower than that measured in vitro and depended on the specific resistance mechanism operating.

Role of Endogenous GLP-1 and GIP in Beta Cell Compensatory Responses to Insulin Resistance and Cellular Stress.

Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.

Temperature-dependent elasticity of microtubules

Central to the biological function of microtubules is their ability to modify their length which occurs by addition and removal of subunits at the ends of the polymer, both in vivo and in vitro. This dynamic behavior is strongly influenced by temperature. Here, we show that the lateral interaction between tubulin subunits forming microtubule is strongly temperature dependent. Microtubules deposited on prefabricated substrates were deformed in an atomic force microscope during imaging, in two different experimental geometries. Microtubules were modeled as anisotropic, with the Young's modulus corresponding to the resistance of protofilaments to stretching and the shear modulus describing the weak interaction between the protofilaments. Measurements involving radial compression of microtubules deposited on flat mica confirm that microtubule elasticity depends on the temperature. Bending measurements performed on microtubules deposited on lithographically fabricated substrates show that this temperature dependence is due to changing shear modulus, implying that the lateral interaction between the protofilaments is strongly determined by the temperature. These measurements are in good agreement with previously reported measurements of the disassembly rate of microtubules, demonstrating that the mechanical and dynamic properties of microtubules are closely related.

Résistance aux antibiotiques chez les pneumocoques [Pneumococcal antibiotic resistance].

In 1875, 7 years prior to the description of the Koch bacillus, Klebs visualized the first Streptococcus pneumoniae in a pleural fluid. Since then, this organism has played a determinant role in biomedical science. From a biological point of view, it was largely implicated in the development of passive and active immunization by serotherapy and vaccination, respectively. Genetic transformation was also first observed in S. pneumoniae, leading to the discovery of DNA. From a clinical point of view, S. pneumoniae is still today a prime cause of otitis media in children and of pneumonia in all age groups, as well as a predominant cause of meningitis and bacteremia. In adults, bacteremia is still entailed with a mortality of over 25%. Although S. pneumoniae remained very sensitive to penicillin for many years, penicillin-resistance has emerged and increased dramatically over the last 15 years. During this period of time, the frequency of penicillin-resistant isolates has increased from < or = 1% to frequencies varying from 20 to 60% in geographic areas as diverse as South Africa, Spain, France, Hungary, Iceland, Alaska, and numerous regions of the United States and South America. In Switzerland, the current frequency of penicillin-resistant pneumococci ranges between 5 and > or = 10%. The increase in penicillin-resistant pneumococci correlates with the intensive use of beta-lactam antibiotics. The mechanism of resistance is not due to bacterial production of penicillinase, but to an alteration of the bacterial target of penicillin, the so-called penicillin-binding proteins. Resistance is subdivided into (i) inter mediate level resistance (minimal inhibitory concentration [MIC] of penicillin of 0.1-1 mg/L) and (ii) high level resistance (MCI > or = 2 mg/L). The clinical significance of intermediate resistance remains poorly defined. On the other hand, highly resistant strains were responsible for numerous therapeutical failures, especially in cases of meningitis. Antibiotics recommended against penicillin-resistant pneumococci include cefotaxime, ceftriaxone, imipenem and in some instances vancomycin. However, penicillin-resistant pneumococci tend to present cross-resistances to all the antibotics of the beta-lactam family and could even become resistant to the last resort drugs mentioned above. Thus, in conclusion, the explosion of resistance to penicillin in pneumococci is a ubiquitous phenomenon which must be fought against by (i) a strict utilization of antibiotics, (ii) the practice of microbiological sampling of infected foci before treatment, (iii) the systematic surveillance of resistance profiles of pneumococci against antibiotics and (iv) the adequate vaccination of populations at risk.

Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state.

Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and β-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal β-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower pro-inflammatory state as determined by lower plasma levels and IL-1β and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal β-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state.

Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model.

The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4(+) T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4(+) Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4(+) Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4(+) T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.

Transcriptional regulation of MDR1, a gene involved in antifungal drug resistance in Candida albicans

ABSTRACT Upregulation of the Major Facilitator transporter gene MDR1 (Multi_drug Resistance 1) is one of the mechanisms observed in Candida albicans clinical isolates developing resistance to azole antifungal agents. To better understand this phenomenon, the cis-acting regulatory elements present in a modulatable reporter system under the control of the MDR1 promoter were characterized. In an azole-susceptible strain, transcription of this reporter is transiently upregulated in response to either benomyl or H2O2, whereas its expression is constitutively high in an azole-resistant strain (FR2). Two cis-acting regulatory elements, that are necessary and sufficient to convey the same transcriptional responses to a heterologous promoter (CDR2), were identified within the MDR1promoter. The first element, called BRE (for Benomyl Response Element, -296 to -260 with respect to the ATG start codon), is required for benomyl-dependent MDR1 upregulation and for constitutive high expression of MDR1 in FR2. The second element, termed HRE (for H2O2 Response Element, -561 to -520), is required for H2O2-dependent MDR1 upregulation, but is dispensable for constitutive high expression. Two potential binding sites (TTAG/CTAA) for the blip transcription factor Cap1p lie within the HRE. Moreover, inactivation of CAP1 abolished the transient response to H2O2 and diminished significantly the transient response to benomyl. Cap1p, which has been previously implicated in cellular responses to oxidative stress, may thus play a transacting and positive regulatory role in benomyl- and H2O2-dependent transcription of MDR1. However, it is not the only transcription factor involved in the response of MDR1 to benomyl. A minimal BRE element (-290 to -273) that is sufficient to detect in vitro sequence-specific binding of protein complexes in crude extracts prepared from C. albicans was also delimited. Genome-wide transcript profiling analyses undertaken with a matched pair of clinical isolates, one of which being azole-resistant and upregulating MDR1, and with an azole-susceptible strain exposed to benomyl, revealed that genes specifically upregulated by benomyl harbour in their promoters Cap1p binding site(s). This strengthened the idea that Cap1p plays a role in benomyl-dependent upregulation of MDR1. BRE-like sequences were also identified in several genes co-regulated with MDR1 in both conditions, which was consistent with the involvement of the BRE in both processes. A set of 147 mutants lacking a single transcription factor gene was next screened for loss of MDR1response to benomyl. Unfortunately, none of the tested mutants showed a loss of benomyl-dependent MDR1 upregulation. Nevertheless, a significant diminution of the response was observed in the mutants in which the MADS-box transcription factor Mcm1p and the C2H2 zinc finger transcription factor orf19.13374p were inactivated, suggesting that Mcm1p and orf19.13374p are involved in MDR1response to benomyl. Interestingly, the BRE contains a perfect match to the binding consensus of Mcm1p, raising the possibility that MDR1may be a direct target of this transcriptional activator. In conclusion, while the identity of the trans-acting factors that bind to the BRE and HRE remains to be confirmed, the tools we have developed during characterization of the cis-acting elements of the MDR1promoter should now serve to elucidate the nature of the components that modulate its activity. RESUME La surexpression du gène MDR1 (pour Résistance Multidrogue 1), qui code pour un transporteur de la famille des Major Facilitators, est l'un des mécanismes observés dans les isolats cliniques de la levure Candida albicans développant une résistance aux agents antifongiques appelés azoles. Pour mieux comprendre ce phénomène, les éléments de régulation agissant en cis dans un système rapporteur modulable sous le contrôle du promoteur MDR1 ont été caractérisés. Dans une souche sensible aux azoles, la transcription de ce rapporteur est transitoirement surélevée en réponse soit au bénomyl soit à l'agent oxydant H2O2, alors que son expression est constitutivement élevée dans une souche résistante aux azoles (souche FR2). Deux éléments de régulation agissant en cis, nécessaires et suffisants pour transmettre les mêmes réponses transcriptionnelles à un promoteur hétérologue (CDR2), ont été identifiés dans le promoteur MDR1. Le premier élément, appelé BRE (pour Elément de Réponse au Bénomyl, de -296 à -260 par rapport au codon d'initiation ATG) est requis pour la surexpression de MDR1dépendante du bénomyl et pour l'expression constitutive de MDR1 dans FR2. Le deuxième élément, appelé HRE (pour Elément de Réponse à l'H2O2, de -561 à -520), est requis pour la surexpression de MDR1 dépendante de l'H2O2, mais n'est pas impliqué dans l'expression constitutive du gène MDR1. Deux sites de fixation potentiels (TTAG/CTAA) pour le facteur de transcription Cap1p ont été identifiés dans l'élément HRE. De plus, l'inactivation de CAP1 abolit la réponse transitoire à l'H2O2 et diminua significativement la réponse transitoire au bénomyl. Cap1p, qui est impliqué dans les réponses de la cellule au stress oxydatif, doit donc jouer un rôle positif en trans dans la surexpression de MDR1 dépendante du bénomyl et de l'H2O2. Cependant, ce n'est pas le seul facteur de transcription impliqué dans la réponse au bénomyl. Un élément BRE d'une longueur minimale (de -290 à -273) a également été défini et est suffisant pour détecter une interaction spécifique in vitro avec des protéines provenant d'extraits bruts de C. albicans. L'analyse du profil de transcription d'une paire d'isolats cliniques comprenant une souche résistante aux azoles surexprimant MDR1, et d'une souche sensible aux azoles exposée au bénomyl, a révélé que les gènes spécifiquement surexprimés par le bénomyl contiennent dans leurs promoteurs un ou plusieurs sites de fixation pour Cap1p. Ceci renforce l'idée que Cap1p joue un rôle dans la surexpression de MDR1dépendante du bénomyl. Une ou deux séquences ressemblant à l'élément BRE ont également été identifiées dans la plupart des gènes corégulés avec MDR1 dans ces deux conditions, ce qui était attendu compte-tenu du rôle joué par cet élément dans les deux processus. Une collection de 147 mutants dans lesquels un seul facteur de transcription est inactivé a été testée pour la perte de réponse au bénomyl de MDR1. Malheureusement, la surexpression de MDR1 dépendante du bénomyl n'a été perdue dans aucun des mutants testés. Néanmoins, une diminution significative de la réponse a été observée chez des mutants dans lesquels le facteur de transcription à MADS-box Mcm1p et le facteur de transcription à doigts de zinc de type C2H2 orf19.13374p ont été inactivés, suggérant que Mcm1p et orf19.13374p sont impliqués dans la réponse de MDR1au bénomyl. Il est intéressant de noter que la BRE contient une séquence qui s'aligne parfaitement avec la séquence consensus du site de fixation de Mcm1p, ce qui soulève la possibilité que MDR1 pourrait être une cible directe de cet activateur transcriptionnel. En conclusion, alors que l'identité des facteurs agissant en trans en se fixant à la BRE et à la HRE reste à être confirmée, les outils que nous avons développés au cours de la caractérisation des éléments agissant en cis sur le promoteur MDR1 peut maintenant servir à élucider la nature des composants modulant son activité.

Résistance aux diurétiques de l'anse en clinique [Resistance to loop diuretics in clinical practice]

Loop diuretics belong to the most common medications used in ambulatory and hospitalized patients, especially in situation of hypervolemia and chronic renal failure. Prolonged used of these agents in particular medical conditions can lead to attenuation of their diuretic effect, commonly known as "resistance" to diuretics. This article intends to review the main mechanisms of resistance to loop diuretic and the ways to counteract them in clinical practice.

Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein.

Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6(gag)-p6(pol) region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6(Gag)), or by changes in activation of the viral protease (p6(Pol)). Duplication of the proline-rich p6(Gag) PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6(Pol)), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.