In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa

The in vitro activity of the novel antimicrobial peptide dendrimer G3KL was evaluated against 32 Acinetobacter baumannii (including 10 OXA-23, 7 OXA-24, and 11 OXA-58 carbapenemase producers) and 35 Pseudomonas aeruginosa (including 18 VIM and 3 IMP carbapenemase producers) strains and compared to the activities of standard antibiotics. Overall, both species collections showed MIC_50/90 values of 8/8 μg/ml and minimum bactericidal concentrations at which 50% or 90% of strains tested are killed (MBC_50/90) of 8/8 μg/ml. G3KL is a promising molecule with antibacterial activity against multidrug-resistant and extensively drug-resistant A. baumannii and P. aeruginosa isolates.     

Release of cardiac bio-markers during high mechanical index contrast-enhanced echocardiography in humans.

BACKGROUND: Recent experimental data have shown that the combined exposure of rodent hearts to high acoustic pressure and ultrasound contrast agents can induce vascular injury and cell damage. The aim of the present work was to test whether similar effects can be observed in humans. METHODS AND RESULTS: Twenty patients underwent simultaneous arterial and coronary sinus blood sampling during contrast-enhanced echocardiography using Perfluorocarbon-enhanced Sonicated Dextrose Albumin. Control subjects were compared to groups of patients exposed to either high mechanical index (MI = 1.5) triggered second harmonic (1.3-2.6 MHz) imaging or low mechanical index (MI = 0.2) real-time power modulation imaging for 15 min. No significant changes arterio-venous differences in lactate, total creatine kinase (CK) and myoglobin occurred over time in the three groups. Similarly, the arterio-venous difference in CK-MB and troponin I remained stable over time in control and low-MI patients. By contrast, these two parameters progressively increased over time in the high-MI group (P < 0.05 vs. baseline and vs. controls). CONCLUSION: Our data suggest that high-MI contrast-enhanced echocardiography can cause subclinical release of cardiac bio-markers in humans, while low-MI real-time imaging appears to be safer.     

Gemcitabine combined with oxaliplatin is safe and effective in patients with previously untreated advanced pancreatic adenocarcinoma

AIM: The aim of this study was to determine the safety and the efficacy of a gemcitabine/oxaliplatin combination (GEMOX) as first line therapy in patients with metastatic or unresectable locally-advanced pancreatic cancer. PATIENTS AND METHODS: Patients received gemcitabine 1000 mg/m2 as a 10-mg/m2/min infusion on day 1 followed on day 2 by oxaliplatin 100 mg/m2 as a 2-hour infusion, each cycle being given every 2 weeks. All patients had measurable disease and histological diagnosis before inclusion. Patients were treated until progression or for 12 cycles in the absence of progression. Tumor lesions were assessed by computed tomography scan every 4 cycles. RESULTS: Between January 2001 and January 2003, 32 patients were eligible for the study. The objective response rate (OR) was 28.1% with a 12.5% complete response rate (CR). Median progression-free survival and median overall survival were 7 and 9 months, respectively. Median overall survival for patients with metastatic disease and locally-advanced disease were 7 and 25 months, respectively (P < 0.0007). Eleven patients were alive at 1 year (34.4%), six at 2 years (18.8%) and two at 3 years (6%). Fourteen (43.8%) of 32 patients experienced a clinical benefit response. CONCLUSION: These results support the safety, the antitumor activity and the possibility of durable responses of the GEMOX regimen in patients with locally-advanced disease.     

Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules

OBJECTIVE The prevalence of sporadic forms of medullary thyroid carcinoma (MTC) has been studied In patients living in an area of moderate iodine deficiency. Such forms of MTC are usually diagnosed after surgery and have little chance of definitive cure. Using the measurement of basal serum calcitonin (CT) levels in a large series of patients with both thyroid disease and normal 24-hour urinary Iodine excretion, we assessed the prevalence of MTC and, in patients affected with the disease, we also evaluated the stage of the disease according to surgical findings and post surgical plasma CT levels. PATIENTS A prospective study of 657 patients with thyroid disease (469 with nodular and 188 with non-nodular thyroid disease). As controls, 40 normal subjects were also studied. MEASUREMENTS In all patients: (1) measurement of basal serum CT, free T4, total T3, TSH levels and serum TSH-receptor, peroxidase and thyroglobulin (Tg) antibody concentrations, (2) thyroid ultrasonography, (3) fine needle aspiration cytology (FNAC). In patients with Increased basal CT levels: (1) measurement of serum CT levels during pentagastrin test prior to surgery, (2) histological examination and immunostaining with both anti-CT and anti-Tg antibodies of all the nodular thyroid tissue surgically removed, (3) measurement of basal and pentagastrin stimulated serum CT values after surgery. RESULTS All the patients with non-nodular thyroid disease had normal basal CT levels. Four patients (0.84%) with nodular thyroid disease (2 with uninodular and 2 with multinodular goitre) had both elevated basal and pentagastrin stimulated CT levels. In the two patients with uninodular goitre, FNAC was suggestive of MTC in 1 (nodular diameter 8.0 cm) and of follicular carcinoma In 1 (nodular diameter 2.5 cm). Histological examination of the nodules confirmed these histotypes. Immunostaining with anti-CT antibodies was positive In the former patient but also In the latter. FNAC was suggestive of benign adenomatous tissues in the two patients with multinodular goitre. Histological examination of all the thyroid nodules confirmed the cytological findings. However, serial sections through the gland in each of these two patients showed an occult follicular carcinoma which had, however, positive staining with anti-CT antibodies. Furthermore, immunostaining with anti-Tg antibodies was negative In the patient with MTC but positive in the 3 patients with follicular carcinoma. Finally, both basal and pentagastrin stimulated CT levels remained elevated after total thyroidectomy only in the patient with FNAC suggesting MTC. CONCLUSIONS This study demonstrates a surprisingly high prevalence of sporadic forms of medullary thyroid carcinoma in patients with nodular thyroid disease. Such forms of medullary thyroid carcinoma seem to be unrelated to iodine intake and may be pure or mixed with a follicular carcinoma. In these mixed thyroid carcinomas, only the neoplastic follicular pattern was seen on both cytological and histological examination. Routine measurements of serum calcitonin levels should therefore be considered an integral part of the diagnostic evaluation of thyroid nodules. Indeed, increasing the accuracy of diagnosis of medullary thyroid carcinoma encourages the surgeon to perform more radical treatment, thus achieving more frequent normalization of post-operative serum calcitonin levels.     

Clinical spectrum and outcomes in families with coronal synostosis and TCF12 mutations

TCF12 mutations have been reported very recently in coronal synostosis. We report several cases of familial coronal synostosis among four families harbouring novel TCF12 mutations. We observed a broad interfamilial phenotypic spectrum with features overlapping with the Saethre–Chotzen syndrome. TCF12 molecular testing should be considered in patients with unilateral- or bilateral-coronal synostosis associated or not with syndactyly, after having excluded mutations in the TWIST1 gene and the p.Pro250Arg mutation in FGFR3.     

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.     

Use of steerable catheters for endovascular procedures: Report of a CASE and literature review

We report a case of a celiac trunk stenting using a steerable guiding catheter, to fix a residual endoleak following fenestrated endovascular repair (FEVAR) of a thoraco‐abdominal aortic aneurysm (TAAA). A systematic search of the literature about the use of steerable catheters was also performed on Pubmed according to the PRISMA Guidelines, including all papers in which the device was used for in vivo endovascular procedures. In our case report, the patient had undergone a failed attempt of cannulation due to the presence of a severely angulated and stenosed ostium of the vessel. A steerable catheter was then used to fix the residual endoleak. The search of the Literature retrieved 544 papers. Of them, 13 met the inclusion criteria and were therefore assessed. The use of steerable sheaths and catheters was reported as effective and safe for the cannulation of 157 target vessels in 131 endovascular procedures, with a success rate of 95.5% and no complications. The use of a steerable guiding catheter in our experience was safe and effective for the selective cannulation of a severely stenosed and angulated celiac trunk, to correct a residual endoleak after FEVAR for TAAA. Steerable catheters could be useful tools for the selective cannulation of target vessels with a challenging ostium.     

Quel système pour quelle classification psychiatrique ? De Linné à Schotte en passant par le DSM et Szondi

Objective

The aim of this article is to define more clearly the different models of classification that have accompanied the history of psychiatry, which will situate the DSM better with regard to the models of classification that preceded it. This will also highlight the originality and interest of the nosographical conception proposed by Jacques Schotte.

Method

This article defends the idea that it is impossible to think about this question of classification without defining more fundamentally the epistemology on which the psychiatric practice is based. Distinguishing and classifying the philosophical systems such as Jules Vuillemin had done permits the better definition of these epistemologies and hence the type of classification that corresponds.

Results

Dogmatic naturalistic classifications are the classifications that medicine and psychiatry had inherited from Linné and Sydenham and that at a time when medicine was assimilated to botany: the diseases were described and defined as substances. The DSM-III represented a profound change in paradigm: attempting to be a-theoretical and limited to a consensus based on the statistics and opinion of the various editorial participants, the DSM was reduced to being a sceptical classification legitimate at a certain period in time and in certain areas. The originality of the works of Jacques Schotte was his attempt to establish a nosography that was neither dogmatic nor sceptical.

Discussion

Based on intuitional epistemology, Schotte's nosography avoids the classical naturalistic-type psychiatric models but also the sceptical model. Using this system, a diagnosis should be composed of psychiatric disorders as a ‘presentification’ and no longer as a ‘representation’. The diagnosis can no longer be detached from the thoughts of the therapist and from a therapeutic method.

Conclusions

The question of the classification of psychiatric pathologies runs throughout the history of the discipline. No classification appears satisfactory; the new version of the DSM only starts up old controversies. This problem of nosography only reflects the great epistemological confusion that prevails in the field of psychiatry. Through the bias of the classification of philosophical systems that distinguish the various epistemologies that are confronted by psychiatry, allows one to understand better in which way the classification models differ and improve our understanding of the interest of the works of Jacques Schotte on psychiatric nosography.     

Inactivation of AMPKα1 induces asthenozoospermia and alters spermatozoa morphology

AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, is present in metabolic tissues (muscle and liver) and has been identified as a modulator of the female reproductive functions. However, its function in the testis has not yet been clearly defined. We have investigated the potential role of AMPK in male reproduction by using transgenic mice lacking the activity of AMPK catalytic subunit α1 gene [α1AMPK knockout (KO)]. In the testis, the α1AMPK subunit is expressed in germ cells and also in somatic cells (Sertoli and Leydig cells). α1AMPK KO male mice show a decrease in fertility, despite no clear alteration in the testis morphology or sperm production. However, in α1AMPK(-/-) mice, we demonstrate that spermatozoa have structural abnormalities and are less motile than in control mice. These spermatozoa alterations are associated with a 50% decrease in mitochondrial activity, a 60% decrease in basal oxygen consumption, and morphological defects. The α1AMPK KO male mice had high androgen levels associated with a 5- and 3-fold increase in intratesticular cholesterol and testosterone concentrations, respectively. High concentrations of proteins involved in steroid production (3β-hydroxysteroid dehydrogenase, cytochrome steroid 17 alpha-hydroxylase/17,20 lysate, and steroidogenic acute regulatory protein) were also detected in α1AMPK(-/-) testes. In the pituitary, the LH and FSH concentrations tended to be lower in α1AMPK(-/-) male mice, probably due to the negative feedback of the high testosterone levels. These results suggest that total α1AMPK deficiency in male mice affects androgen production and quality of spermatozoa, leading to a decrease in fertility.     

Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin-biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs.