Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents : a role for long-term prevention of infective endocarditis in humans?

BACKGROUND: Infective endocarditis (IE) mostly occurs after spontaneous low-grade bacteremia. Thus, IE cannot be prevented by circumstantial antibiotic prophylaxis. Platelet activation following bacterial-fibrinogen interaction or thrombin-mediated fibrinogen-fibrin polymerization is a critical step in vegetation formation. We tested the efficacy of antiplatelet and antithrombin to prevent experimental IE. METHODS: A rat model of experimental IE following prolonged low-grade bacteremia mimicking smoldering bacteremia in humans was used. Prophylaxis with antiplatelets (aspirin, ticlopidine [alone or in combination], eptifibatide, or abciximab) or anticoagulants (antithrombin dabigatran etexilate or anti-vitamin K acenocoumarol) was started 2 days before inoculation with Streptococcus gordonii or Staphylococcus aureus. Valve infection was assessed 24 hours later. RESULTS: Aspirin plus ticlopidine, as well as abciximab, protected 45%-88% of animals against S. gordonii and S. aureus IE (P < .05). Dabigatran etexilate protected 75% of rats against IE due to S. aureus (P < .005) but failed to protect against S. gordonii (<30% protection). Acenocoumarol was ineffective. CONCLUSIONS: Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.

Outcome and Prognostic Factors in Adenosquamous Carcinoma of the Head and Neck - a Multicenter Rare Cancer Network Study

Background: Adenosquamous carcinoma (AC) of the head and neck is a distinct entity first described in 1968. Its natural history is more aggressive than squamous-cell carcinoma. The aim of this study was to assess the clinical profile, patterns of failure, and prognostic factors in patients with AC of the head and neck treated by radiation therapy (RT) with or without chemotherapy (CT).Materials and Methods: Data from 19 patients with stage I (n = 3), II (n = 1), III (n = 4), or IVa (n = 11) AC, treated between 1989 and 2009, were collected in a retrospective multicenter Rare Cancer Network study. Median age was 60 years (range, 48−73). Fifteen patients were male, and 4 female. Risk factors, including perineural invasion, lymphangitis, vascular invasion, positive margins were present in the majority (83%) of the patients. Tumour sites included oral cavity in 4, oropharynx in 4, hypopharynx in 2, larynx in 2, salivary glands in 2, nasal vestibule in 2, maxillary sinus in 2, and nasopharynx in 1 patient. Surgery (S) was performed in all but 5 patients. S alone was performed in only 1 patient, and definitive RT alone in 3 patients. Fifteen patients received combined modality treatment (S+RT in 11, RT+CT in 2, and all of the three modalities in 2 patients). Median RT dose to the primary and to the nodes was 66 Gy (range, 50−72) and 53 Gy (range, 44−66), respectively (1.8−2.0 Gy/fr., 5 fr./week). In 4 patients, the planning treatment volume included the primary tumour site only. Eight patients were treated with 2D RT, 7 with 3D conformal RT, and 2 with intensity-modulated RT.Results: After a median follow-up period of 39 months (range, 9−62), 9 patients developed distant metastases (lung, bone, mediastinum, and liver), 7 presented nodal recurrences, and only 4 had a local relapse at the primary site (all in-field recurrences). At last follow-up, 7 patients were alive without disease, 1 alive with disease, 9 died from progressive disease, and 2 died from intercurrent disease. The 3-year and median overall survival, disease-free survival (DFS), and locoregional control rates were 55% (95% confidence interval [CI]: 32−78%) and 39 months, 34% (95% CI: 12−56%) and 22 months, and 50% (95% CI: 22−78%) and 33 months, respectively. In multivariate analysis (Cox model), DFS was negatively influenced by the presence of extracapsular extension (p = 0.01) and advanced stage (IV versus I−III, p = 0.002).Conclusions: Overall prognosis of locoregionally advanced AC remains poor, and distant metastases and nodal relapse occur in almost half of the cases. However, local control is relatively better, and early stage AC patients had prolonged DFS when treated with combined-modality treatment.

Thy-1-mediated cell-cell contact induces astrocyte migration through the engagement of αVβ3 integrin and syndecan-4.

Cell adhesion to the extracellular matrix proteins occurs through interactions with integrins that bind to Arg-Gly-Asp (RGD) tripeptides, and syndecan-4, which recognizes the heparin-binding domain of other proteins. Both receptors trigger signaling pathways, including those that activate RhoGTPases such as RhoA and Rac1. This sequence of events modulates cell adhesion to the ECM and cell migration. Using a neuron-astrocyte model, we have reported that the neuronal protein Thy-1 engages αVβ3 integrin and syndecan-4 to induce RhoA activation and strong astrocyte adhesion to their underlying substrate. Thus, because cell-cell interactions and strong cell attachment to the matrix are considered antagonistic to cell migration, we hypothesized that Thy-1 stimulation of astrocytes should preclude cell migration. Here, we studied the effect of Thy-1 expressing neurons on astrocyte polarization and migration using a wound-healing assay and immunofluorescence analysis. Signaling molecules involved were studied by affinity precipitation, western blotting and the usage of specific antibodies. Intriguingly, Thy-1 interaction with its two receptors was found to increase astrocyte polarization and migration. The latter events required interactions of these receptors with both the RGD-like sequence and the heparin-binding domain of Thy-1. Additionally, prolonged Thy-1-receptor interactions inhibited RhoA activation while activating FAK, PI3K and Rac1. Therefore, sustained engagement of integrin and syndecan-4 with the neuronal surface protein Thy-1 induces astrocyte migration. Interestingly we identify here, a cell-cell interaction that despite initially inducing strong cell attachment, favors cell migration upon persistent stimulation by engaging the same signaling receptors and molecules as those utilized by the extracellular matrix proteins to stimulate cell movement.

A-kinase anchoring proteins: scaffolding proteins in the heart.

The pleiotropic cyclic nucleotide cAMP is the primary second messenger responsible for autonomic regulation of cardiac inotropy, chronotropy, and lusitropy. Under conditions of prolonged catecholaminergic stimulation, cAMP also contributes to the induction of both cardiac myocyte hypertrophy and apoptosis. The formation of localized, multiprotein complexes that contain different combinations of cAMP effectors and regulatory enzymes provides the architectural infrastructure for the specialization of the cAMP signaling network. Scaffolds that bind protein kinase A are called &quot;A-kinase anchoring proteins&quot; (AKAPs). In this review, we discuss recent advances in our understanding of how PKA is compartmentalized within the cardiac myocyte by AKAPs and how AKAP complexes modulate cardiac function in both health and disease.

Analysis of Functional and Anatomic Success Following Endonasal Dacryocystorhinostomy

Objectives: The aim of this study was to assess the concomitant perioperative procedures, the causes of nasolacrimal duct obstruction, the success rate, and the complications associated with endonasal dacryocystorhinostomy (ENDCR).Methods: In this single-center retrospective study, 98 patients underwent 104 ENDCRs between January 1994 and February 2006. There were 78 patients with 84 nasolacrimal duct obstructions who were included in this study.Results: The overall functional success rate with improvement in symptoms was 94.9% for primary surgery (59 of 84 obstructions) and 63.6% for salvage surgery after failure of primary surgery performed in another hospital (25 of 84 obstructions). The mean follow-up time was 36.8 +/- 17.11 months. Primary surgery showed better results, with a complete success rate of 93.2%, than did salvage surgery, with a success rate of only 68%. Persistent symptoms, despite an open rhinostomy, were found in 1.7% of patients with primary surgery and in 12% of those with salvage surgery. Failure of ENDCR was observed in 3.4% of patients after primary surgery and in 20% after salvage surgery. We encountered only minimal perioperative complications, and these were essentially related to lacrimal intubation.Conclusions: Because of the possibility of treating concomitant sinonasal disorders, the cosmetic advantages, and the excellent results, ENDCR represents the procedure of choice for treating nasolacrimal duct obstructions. The main challenge lies in the exact preoperative assessment, as well as postoperative evaluation in case of failure.

La ventilation non invasive dans l'insuffisance respiratoire aiguë : de la broncho-pneumonie chronique obstructive au syndrome de détresse respiratoire aiguë

RESUME : L'application d'une ventilation non-invasive (VNI) à pression positive chez des patients avec une insuffisance respiratoire aiguë hypoxémique non liée à une broncho-pneumopathie chronique obstructive (BPCO), reste controversée malgré les résultats encourageants apparus dans de récentes études. Ce travail de thèse est composé d'une introduction qui comprend un historique de la VNI et une revue de ces applications principales dans l'insuffisance respiratoire aiguë avec, en particulier, une analyse des études cliniques principales concernant son utilisation dans l'exacerbation de la BPCO, dans l'asthme aigu sévère, dans les syndromes restrictifs et dans l'insuffisance respiratoire aiguë hypoxémique. La première partie aborde également les aspects pratiques de l'utilisation de la VNI, avec une description de l'équipement et des techniques utilisées. Ce travail de thèse a ensuite pour but d'analyser dans une étude personnelle l'application d'une VNI à pression positive chez des patients avec une insuffisance respiratoire aiguë hypoxémique non liée à une BPCO. Il s'agit d'une étude prospective et observationnelle, dans laquelle nous avons voulu analyser l'efficacité de la VNI chez un groupe de patients sélectionnés et coopérants, stables du point de vue hémodynamique, présentant un syndrome de détresse respiratoire aiguë (SDRA) primaire (atteinte pulmonaire directe). Les échanges gazeux, le taux d'intubation, la mortalité et la durée de séjour dans l'unité de soins intensifs ont été enregistrés. Dans notre travail, la VNI a été appliquée de manière prospective à 12 patients, stables du point de vue hémodynamique, présentant les critères diagnostiques pour un SDRA primaire (SDRAP) et une indication pour une ventilation mécanique classique. Leur évolution a été comparée avec celle d'un groupe contrôle de 12 patients avec SDRAP. et précédemment traités dans la même unité de soins intensifs, ayant des caractéristiques similaires à l'admission : âge, score SAPS II, rapport Pa02/Fi02 et valeurs de pH . Un échec de la VNI fut observé chez 4 patients (33%), tous bactériémiques et nécessitant une intubation endotrachéale. Un facteur prédictif négatif. Les patients traités avec succès ont présenté un temps cumulatif de ventilation (p=0.001) et une durée de séjour aux soins intensifs (p=0.004) inférieure à ceux du groupe contrôle. Pendant la première période d'observation de la ventilation, l'oxygénation après 60 minutes s'est améliorée de manière plus importante dans le groupe VNI par rapport au groupe contrôle (PaO2/FiO2 : 146 +/- 52 mmHg vs. 109 +/- 34 mmHg ; p=0.05). Le taux de mortalité globale aux soins intensifs ne fut pas différent entre le groupe VNI et le groupe de patients intubés. Le taux de complications graves fut plus élevé chez les patients du groupe contrôle. Nos résultats suggèrent que chez des patients stables et coopérants, avec une pneumonie étendue, sans bactériémie à l'admission et remplissant les critères diagnostiques d'un SDRAp, la VNI représente une alternative valable à l'intubation endotrachéale.

mTORC2 regulates PGE2-mediated endothelial cell survival and migration.

Prostaglandin E(2) (PGE(2)) promotes angiogenesis by in part inducing endothelial cell survival and migration. The present study examined the role of mTOR and its two complexes, mTORC1 and mTORC2, in PGE(2)-mediated endothelial cell responses. We used small interfering RNA (siRNA) to raptor or rictor to block mTORC1 or mTORC2, respectively. We observed that down-regulation of mTORC2 but not mTORC1 reduced baseline and PGE(2)-induced endothelial cell survival and migration. At the molecular level, we found that knockdown of mTORC2 inhibited PGE(2)-mediated Rac and Akt activation two important signaling intermediaries in endothelial cell migration and survival, respectively. In addition, inhibition of mTORC2 by prolonged exposure of endothelial cells to rapamycin also prevented PGE(2)-mediated endothelial cell survival and migration confirming the results obtained with the siRNA approach. Taken together these results show that mTORC2 but not mTORC1 is an important signaling intermediary in PGE(2)-mediated endothelial cell responses.

Hypertension portate et infection par le VIH [Portal hypertension and HIV infection]

In the era of antiretroviral therapies, the outcome of patients with chronic HIV infection has considerably changed and their prolonged survival allows the development of chronic liver diseases as a major cause of mortality. Although viral hepatitis, alcoholic and non alcoholic steatohepatitis account forthe majority of chronic liver damage in these patients, there is a growing number of cases with unexplained liver disease, many of which are associated with clinical manifestations of portal hypertension. Inthissituation, nodularregenerative hyperplasia is a frequent finding, characterized at histology by the presence of a nodular architecture in the absence of significant fibrosis, resulting from progressive obliteration of small portal veins. This article describes the clinical presentation, diagnostic aspects, pathogenic mechanisms, as well as the management of this emergent non cirrhotic liver disease in HIV-infected patients.

Transcutaneous carbon dioxide tension in newborn infants: reliability and safety of continuous 24-hour measurement at 42 degrees C.

In 58 newborn infants a new iridium oxide sensor was evaluated for transcutaneous carbon dioxide (tcPCO2) monitoring at 42 degrees C with a prolonged fixation time of 24 hours. The correlation of tcPCO2 (y; mm Hg) v PaCO2 (x; mm Hg) for 586 paired values was: y = 4.6 + 1.45x; r = .89; syx = 6.1 mm Hg. The correlation was not influenced by the duration of fixation. The transcutaneous sensor detected hypocapnia (PaCO2 less than 35 mm Hg) in 74% and hypercapnia (PCO2 greater than 45 mm Hg) in 74% of all cases. After 24 hours, calibration shifts were less than 4 mm Hg in 90% of the measuring periods. In 86% of the infants, no skin changes were observed; in 12% of infants, there were transitional skin erythemas and in 2% a blister which disappeared without scarring. In newborn infants with normal BPs, continuous tcPCO2 monitoring at 42 degrees C can be extended for as many as 24 hours without loss of reliability or increased risk for skin burns.

Delirium auf der Intensivstation [Delirium in the intensive care unit.]

The prevalence of delirium in the Intensive Care Unit (ICU) is reported to vary from 20 to 80 %. Delirium in the ICU is not only a frightening experience for the patient and his or her family, it is also a challenge for the nurses and physicians taking care of the patient. Furthermore, it is also associated with worse outcome, prolonged hospitalisation, increased costs, long-term cognitive impairment and higher mortality rates. Thus, strategies to prevent ICU-delirium in addition to the early diagnosis and treatment of delirium are important. The pathophysiology of delirium is still incompletely understood, but numerous risk factors for the development of delirium have been identified in ICU-patients, among which are potentially modifiable factors such as metabolic disturbances, hypotension, anaemia, fever and infection. Key factors are the prevention and management of common risk factors, including avoiding overzealous sedation and analgesia and creating an environment that enhances reintegration. Once delirium is diagnosed, treatment consists of the use of typical and atypical antipsychotics. Haloperidol is still the drug of choice for the treatment of delirium and can be given intravenously in incremental doses of 1 to 2 to 5 (to 10) mg every 15 - 20 minutes.

Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Physiological differences between cycling and running

This review compares the differences in systemic responses (VO2max, anaerobic threshold, heart rate and economy) and in underlying mechanisms of adaptation (ventilatory and hemodynamic and neuromuscular responses) between cycling and running. VO2max is specific to the exercise modality. Overall, there is more physiological training transfer from running to cycling than vice-versa. Several other physiological differences between cycling and running are discussed: HR is different between the two activities both for maximal and sub-maximal intensities. The delta efficiency is higher in running. Ventilation is more impaired in cycling than running due to mechanical constraints. Central fatigue and decrease in maximal strength are more important after prolonged exercise in running than in cycling.

Poly-epsilon-caprolactone intravitreous devices: an in vivo study.

PURPOSE: The objective of this study was to evaluate the long-term safety and pharmacokinetic profile of a dexamethasone-loaded poly-epsilon-caprolactone (PCL) intravitreous implant. METHODS: The PCL devices were prepared by compression and were inserted into the vitreous of pigmented rabbits. At different time points, vitreous samples were retrieved, and dexamethasone concentration was analyzed by high-performance liquid chromatography. The biodegradation of the implants was evaluated by scanning electron microscopy, and the dexamethasone remaining was evaluated at the end of follow-up. Clinical and histologic examinations were performed to evaluate the implant's tolerance. RESULTS: The PCL implant allows for a controlled and prolonged delivery of dexamethasone in rabbits eyes since it released the drug within the therapeutic range for at least 55 weeks. At 55 weeks approximately 79% of the drug was still present in the implant. Biodegradation study showed that PCL implants degradation is very slow. Clinical and histologic observations showed that the devices were very well tolerated in the rabbit eye. CONCLUSIONS: This study demonstrates the feasibility and tolerance of intravitreous PCL drug delivery systems, which can offer a wide range of applications for intraocular drug delivery because of their controlled and prolonged release over months or even years.

Colorectal cancer and thoracic surgeons: close encounters of the third kind.

Resection of lung metastases from colorectal cancer (CRC) is increasingly performed with a curative intent. This strategy was made possible in the 1990s by the development of new chemotherapeutic approaches, improved surgical techniques and better imaging modalities. However, evidence-based data showing clinical benefits of lung metastasectomy in this setting are nonexistent, and there are no prospective randomized trials to support the routine performance of these procedures for stage IV CRC. Current evidence suggests that resection of pulmonary metastases in combination with new cytotoxic agents, such as oxaliplatin, irinotecan and bevacizumab, may result in prolonged survival for many, and cure for a small minority of CRC patients who experienced tumor spread beyond the limits of the abdomen. This review focuses on the results of surgical management of CRC patients with lung metastases: we report the outcome of published series according to the presence or the absence of liver metastasis (and hepatic resection) prior to lung resection.

Exogenous mRNA delivery and bioavailability in gene transfer mediated by piggyBac transposition.

BACKGROUND: Up to now, the different uptake pathways and the subsequent intracellular trafficking of plasmid DNA have been largely explored. By contrast, the mode of internalization and the intracellular routing of an exogenous mRNA in transfected cells are poorly investigated and remain to be elucidated. The bioavailability of internalized mRNA depends on its intracellular routing and its potential accumulation in dynamic sorting sites for storage: stress granules and processing bodies. This question is of particular significance when a secure transposon-based system able to integrate a therapeutic transgene into the genome is used. Transposon vectors usually require two components: a plasmid DNA, carrying the gene of interest, and a source of transposase allowing the integration of the transgene. The principal drawback is the lasting presence of the transposase, which could remobilize the transgene once it has been inserted. Our study focused on the pharmacokinetics of the transposition process mediated by the piggyBac transposase mRNA transfection. Exogenous mRNA internalization and trafficking were investigated towards a better apprehension and fine control of the piggyBac transposase bioavailability. RESULTS: The mRNA prototype designed in this study provides a very narrow expression window of transposase, which allows high efficiency transposition with no cytotoxicity. Our data reveal that exogenous transposase mRNA enters cells by clathrin and caveolae-mediated endocytosis, before finishing in late endosomes 3 h after transfection. At this point, the mRNA is dissociated from its carrier and localized in stress granules, but not in cytoplasmic processing bodies. Some weaker signals have been observed in stress granules at 18 h and 48 h without causing prolonged production of the transposase. So, we designed an mRNA that is efficiently translated with a peak of transposase production 18 h post-transfection without additional release of the molecule. This confines the integration of the transgene in a very small time window. CONCLUSION: Our results shed light on processes of exogenous mRNA trafficking, which are crucial to estimate the mRNA bioavailability, and increase the biosafety of transgene integration mediated by transposition. This approach provides a new way for limiting the transgene copy in the genome and their remobilization by mRNA engineering and trafficking.