Modulation of cdk2, cyclin D1, p16INK4a, p21WAF and p27Kip1 expression in endothelial cells by TNF/IFN gamma.

BACKGROUND: Regional administration of high doses of tumor necrosis factor (TNF) and interferon gamma (IFN gamma) to metastatic melanoma patients causes selective disruption of the tumor vasculature. This effect is paralleled by decreased endothelial cell proliferation and suppressed integrin alpha V beta 3-mediated adhesion in vitro. Overexpression of the cyclin-dependent kinase (cdk) inhibitory protein p16INK4a was reported to interfere with integrin alpha V beta 3-dependent melanoma cell adhesion. MATERIALS AND METHODS: TNF- and IFN gamma-treated HUVEC were analyzed for cell cycle progression and for protein expression by flow cytometry and Western blotting, respectively. p16INK4a was overexpressed by transient transfection, and HUVEC adhesion was tested in short-term adhesion assays. RESULTS: TNF and IFN gamma synergistically induced a G1 arrest associated with reduced levels of cyclin D1 and cdk2, and increased expression of the cdk inhibitors p16INK4a, p21WAF and p27Kip1. p16INK4a overexpression, however, had no effect on alpha V beta 3-mediated adhesion. CONCLUSION: These results implicate the down-regulation of cyclin D1 and cdk-2, and up-regulation of p16INK4a, p21WAF and p27Kip1 in the suppression of endothelial cell proliferation induced by TNF/IFN gamma and demonstrate that increased p16INK4a levels are not sufficient to suppress alpha V beta 3-mediated endothelial cell adhesion.

Combined approach for the management of large vestibular schwannomas: Planned subtotal resection followed by gamma knife surgery in a series of 20 consecutive cases.

INTRODUCTION: The management of large lesions of the skull base, such as vestibular schwannomas (VS) is challenging. Microsurgery remains the main treatment option. Combined approaches (planned subtotal resection followed by gamma knife surgery (GKS) for residual tumor long-term control) are being increasingly considered to reduce the risk of neurological deficits following complete resection. The current study aims to prospectively evaluate the safety-efficacy of combined approach in patients with large VS. MATERIALS AND METHODS: We present our experience with planned subtotal resection followed by gamma knife surgery (GKS) in a consecutive a series of 20 patients with large vestibular schwannomas, treated between 2009 and 2014 in Lausanne University Hospital, Switzerland. Clinical and radiological data and audiograms were prospectively collected for all patients, before and after surgery, before and after GKS, at regular intervals, in dedicated case-report forms. Additionally, for GKS, dose-planning parameters were registered. RESULTS: Twenty patients (6 males and 14 females) with large VS had been treated by this approach. The mean age at the time of surgery was 51.6years (range 34.4-73.4). The mean presurgical diameter was 36.7 (range 26.1-45). The mean presurgical tumor volume was 15.9cm(3) (range 534.9). Three patients (15%) needed a second surgical intervention because of high volume of the tumor remnant considered too large for a safe GKS. The mean follow-up after surgery was 27.2months (range 6-61.3). The timing of GKS was decided on the basis of the residual tumor shape and size following surgery. The mean duration between surgery and GKS was 7.6months (range 413.9, median 6months). The mean tumor volume at the time of GKS was 4.1cm(3) (range 0.5-12.8). The mean prescription isodose volume was 6.3cm(3) (range 0.8-15.5). The mean number of isocenters was 20.4 (range 11-31) and the mean marginal prescription dose was 11.7Gy (range 11-12). We did not have any major complications in our series. Postoperative status showed normal facial nerve function (House-Brackmann grade I) in all patients. Six patients with useful pre-operative hearing (GR class 1) underwent surgery with the aim to preserve cochlear nerve function; of these patients, 5 (83.3%) of them remained in GR class 1 and one (16.7%) lost hearing (GR class 5). Two patients having GR class 3 at baseline remained in the same GR class, but the tonal audiometry improved in one of them during follow-up. Eleven patients (57.8%) were in GR class 5 preoperatively; one patient improved hearing after surgery, passing to GR class 3 postoperatively. Following GKS, there were no new neurological deficits, with facial and hearing function remaining identical to that after surgery. CONCLUSION: Our data suggest that planned subtotal resection followed by GKS has an excellent clinical outcome with respect to retaining facial and cochlear nerve function. This represents a paradigm shift of the treatment goals from a complete tumor excision perspective to that of a surgery designed to preserve neural functions. As long-term results emerge, this approach of a combined treatment (microsurgery and GKS) will most probably become the standard of care in the management of large vestibular schwanomma.

Early disturbances of gamma band dynamics in mild cognitive impairment.

Recent studies have indicated that gamma band oscillations participate in the temporal binding needed for the synchronization of cortical networks involved in short-term memory and attentional processes. To date, no study has explored the temporal dynamics of gamma band in the early stages of dementia. At baseline, gamma band analysis was performed in 29 cases with mild cognitive impairment (MCI) during the n-back task. Based on phase diagrams, multiple linear regression models were built to explore the relationship between the cognitive status and gamma oscillation changes over time. Individual measures of phase diagram complexity were made using fractal dimension values. After 1 year, all cases were assessed neuropsychologically using the same battery. A total of 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). When adjusted for gamma values at lag -2, and -3 ms, PMCI cases displayed significantly lower average changes in gamma values than SMCI cases both in detection and 2-back tasks. Gamma fractal dimension of PMCI cases displayed significantly higher gamma fractal dimension values compared to SMCI cases. This variable explained 11.8% of the cognitive variability in this series. Our data indicate that the progression of cognitive decline in MCI is associated with early deficits in temporal binding that occur during the activation of selective attention processes.

Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up.

BACKGROUND: Trigeminal neuralgia (TN) related to multiple sclerosis (MS) is more difficult to manage pharmacologically and surgically. OBJECTIVE: This article aims to evaluate the safety and efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7-14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. RESULTS: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. CONCLUSIONS: GKS proved safe and effective in this special group of patients.

Previous microvascular decompression decreases the chances of pain free in patients treated with Gamma Knife radiosurgery for TIC

Object: The authors sought to establish whether the safety-efficacy of Gamma Knife radiosurgery (GKRS) as a second treatment for intractable trigeminal neuralgia (ITN) are influenced by prior microvascular decompression (MVD) which remains, for some of the authors, the reference technique. Methods: Between July 1992 and November 2010, 737 patients have been operated with GKRS for ITN and prospectively evaluated in Timone University Hospital in Marseille, France. Among these, 54 patients had a previous MVD history. Radiosurgery using a Gamma Knife (model B or C or Perfexion) was performed relying on both MR and CT targeting. A single 4 mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 3.9- 11.9) anteriorly to the emergence of the nerve (retrogasserian target). A median maximum dose of 85 Gy (range 70-90) was delivered. Are further analyzed only 45 patients with previous MVD and a follow-up longer than one year (the patients with megadolichobasilar artery compression and multiple sclerosis were excluded). Results: The median age in this series was 56.75 years (range 28.09-82.39). The median follow-up period was 39.48 months (range 14.10-144.65). All the patients had a past history of surgery, with at least one previous failed MVD, but also a radiofrequency lesion (RFL) in 16 (35.6%) patients, balloon microcompression in 7 (15.6%) patients and glycerol rhizotomy in 1 case (2.2%). Thirty-five patients (77.8%) were initially pain free in a median time of 14 days (range 0, 180). Patients from this group had less probability of being pain free compared to our global population of essential trigeminal neuralgia without previous MVD history (p=0.010, hazard ratio of 0.64). Their probability of remaining pain free at 3, 5, 7 and 10 years was 66.5%, 59.1%, 59.1% and 44.3%, respectively. Twelve patients (34.3%) initially pain free experienced a recurrence with a median delay of 31.21 months (range 3.40-89.93). The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable till 12 years with a median delay of onset of 8 months (range 8-8). Conclusions: Retrogasserian GKRS proofed to be safe and effective on the long-term basis even after failed previous MVD. Even if the initial result of pain free was of only 77.8%, the toxicity was low with only 9.1% hypoesthesia. No patient reported a bothersome hypoesthesia. The probability of maintaining pain relief in long-term was of 44.3% at 10 years.

A neuronal gamma oscillatory signature during morphological unification in the left occipitotemporal junction.

Morphology is the aspect of language concerned with the internal structure of words. In the past decades, a large body of masked priming (behavioral and neuroimaging) data has suggested that the visual word recognition system automatically decomposes any morphologically complex word into a stem and its constituent morphemes. Yet the reliance of morphology on other reading processes (e.g., orthography and semantics), as well as its underlying neuronal mechanisms are yet to be determined. In the current magnetoencephalography study, we addressed morphology from the perspective of the unification framework, that is, by applying the Hold/Release paradigm, morphological unification was simulated via the assembly of internal morphemic units into a whole word. Trials representing real words were divided into words with a transparent (true) or a nontransparent (pseudo) morphological relationship. Morphological unification of truly suffixed words was faster and more accurate and additionally enhanced induced oscillations in the narrow gamma band (60-85 Hz, 260-440 ms) in the left posterior occipitotemporal junction. This neural signature could not be explained by a mere automatic lexical processing (i.e., stem perception), but more likely it related to a semantic access step during the morphological unification process. By demonstrating the validity of unification at the morphological level, this study contributes to the vast empirical evidence on unification across other language processes. Furthermore, we point out that morphological unification relies on the retrieval of lexical semantic associations via induced gamma band oscillations in a cerebral hub region for visual word form processing.

Nuclear well logging in soils. Calibration of slim hole nuclear tools gamma-gamma and neutron-thermal neutron.

The calculation of elasticity parameters by sonic and ultra sonic wave propagation in saturated soils using Biot's theory needs the following variables : forpiation density and porosity (p, ø), compressional and shear wave velocities (Vp, Vs), fluid density, viscosity and compressibility (Pfi Ilfi Ki), matrix density and compressibility (p" K), The first four parameters can be determined in situ using logging probes. Because fluid and matrix characteristics are not modified during core extraction, they can be obtained through laboratory measurements. All parameters necessitate precise calibrations in various environments and for specific range of values encountered in soils. The slim diameter of boreholes in shallow geophysics and the high cost of petroleum equipment demand the use of specific probes, which usually only give qualitative results. The measurement 'of density is done with a gamma-gamma probe and the measurement of hydrogen index, in relation to porosity, by a neutron probe. The first step of this work has been carried out in synthetic formations in the laboratory using homogeneous media of known density and porosity. To establish borehole corrections different casings have been used. Finally a comparison between laboratory and in situ data in cored holes of known geometry and casing has been performed.

Fat poetry: a kingdom for PPAR gamma.

Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARgamma agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARgamma in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARgamma modulators.

The murine interleukin-2 receptor gamma chain gene: organization, chromosomal localization and expression in the adult thymus.

Defects in the interleukin-2 receptor gamma (IL-2R gamma) chain in the man result in an X-linked severe combined immunodeficiency, SCIDX1, characterized by an absence of T-cell differentiation. This phenotype may result from pertubations in IL-2, IL-4-, IL-7- or IL-15-mediated signaling, as the IL-2R gamma chain forms an integral component of these receptor systems. We have isolated and characterized cDNA and genomic clones for the murine IL-2R gamma. The gene (Il2rg) is well conserved between mouse and man with respect to overall structure and size, and contains regions of high conservation in the promoter region as well. Il2rg maps to mouse X chromosome region 40, in a region of synteny with human Xq12-13.1. We have also explored the expression of the IL-2R gamma during thymocyte development. IL-2R gamma transcripts are detected in the earliest thymocyte precursor cells and persist throughout intrathymic development into the mature peripheral compartment. Genomic clones for the murine IL-2R gamma will allow for further studies on the regulation and function of this gene in vivo.

Role of high normal gamma-glutamyltransferase level in identifying heavy alcohol use in young men.

The objective of the current study was to determine the predictive value of high normal gamma-glutamyltransferase (GGT) level as an indication of heavy drinking in young men. In a sample of 577 men attending a one-day army recruitment process mandatory for all Swiss men at age 19 years, GGT level was evaluated as the dependent variable for each of eight dichotomous classifications of individuals on the basis of meeting cut-off criteria for five indexes of alcohol use, two indexes of alcohol-related problems, and one index of body mass. The sensitivity, specificity, and predictive values of GGT level in identifying subjects as either heavy drinkers or being overweight were determined. Compared with findings for their counterparts, GGT level was higher in subjects reporting consumption of more than 14 drinks per week (20.5 +/- 7.81 vs. 18.9 +/- 7.60, P <.05), in those reporting being drunk at least once during the past 30 days (20.3 +/- 7.80 vs. 18.3 +/- 7.43, P <.001), and in individuals with body mass indexes >or=25 kg/m(2) (25.8 +/- 10.84 vs. 18.3 +/- 6.59, P <.001). At a GGT level cut-off of 20 U/l, the sensitivity, specificity, and positive and negative predictive values of either being a heavy drinker or overweight were 48.2%, 70.2%, 67.7%, and 51.2%, respectively. Exclusion of subjects with body mass indexes of >or=25 kg/m(2) revealed similar results. High normal GGT level in young men is indicative of heavy alcohol use or being overweight; when present, subjects should be screened further for potential concomitant drinking problems.