Dosimetric comparison of different treatment modalities for stereotactic radiosurgery of arteriovenous malformations and acoustic neuromas.

PURPOSE: We investigated the influence of beam modulation on treatment planning by comparing four available stereotactic radiosurgery (SRS) modalities: Gamma-Knife-Perfexion, Novalis-Tx Dynamic-Conformal-Arc (DCA) and Dynamic-Multileaf-Collimation-Intensity-Modulated-radiotherapy (DMLC-IMRT), and Cyberknife. MATERIAL AND METHODS: Patients with arteriovenous malformation (n = 10) or acoustic neuromas (n = 5) were planned with different treatment modalities. Paddick conformity index (CI), dose heterogeneity (DH), gradient index (GI) and beam-on time were used as dosimetric indices. RESULTS: Gamma-Knife-Perfexion can achieve high degree of conformity (CI = 0.77 ± 0.04) with limited low-doses (GI = 2.59 ± 0.10) surrounding the inhomogeneous dose distribution (D(H) = 0.84 ± 0.05) at the cost of treatment time (68.1 min ± 27.5). Novalis-Tx-DCA improved this inhomogeneity (D(H) = 0.30 ± 0.03) and treatment time (16.8 min ± 2.2) at the cost of conformity (CI = 0.66 ± 0.04) and Novalis-TX-DMLC-IMRT improved the DCA CI (CI = 0.68 ± 0.04) and inhomogeneity (D(H) = 0.18 ± 0.05) at the cost of low-doses (GI = 3.94 ± 0.92) and treatment time (21.7 min ± 3.4) (p<0.01). Cyberknife achieved comparable conformity (CI = 0.77 ± 0.06) at the cost of low-doses (GI = 3.48 ± 0.47) surrounding the homogeneous (D(H) = 0.22 ± 0.02) dose distribution and treatment time (28.4min±8.1) (p<0.01). CONCLUSIONS: Gamma-Knife-Perfexion will comply with all SRS constraints (high conformity while minimizing low-dose spread). Multiple focal entries (Gamma-Knife-Perfexion and Cyberknife) will achieve better conformity than High-Definition-MLC of Novalis-Tx at the cost of treatment time. Non-isocentric beams (Cyberknife) or IMRT-beams (Novalis-Tx-DMLC-IMRT) will spread more low-dose than multiple isocenters (Gamma-Knife-Perfexion) or dynamic arcs (Novalis-Tx-DCA). Inverse planning and modulated fluences (Novalis-Tx-DMLC-IMRT and CyberKnife) will deliver the most homogeneous treatment. Furthermore, Linac-based systems (Novalis and Cyberknife) can perform image verification at the time of treatment delivery.

Loss of glucose-induced insulin secretion and GLUT2 expression in transplanted beta-cells.

Either 200 or 400 syngeneic islets were transplanted under the kidney capsule of normal or streptozocin-induced diabetic B6/AF1 mice. The diabetic mice with 400 islets became normoglycemic, but those with 200 islets, an insufficient number, were still diabetic after the transplantation (Tx). Two weeks after Tx, GLUT2 expression in the islet grafts was evaluated by immunofluorescence and Western blots, and graft function was examined by perfusion of the graft-bearing kidney. Immunofluorescence for GLUT2 was dramatically reduced in the beta-cells of grafts with 200 islets exposed to hyperglycemia. However, it was plentiful in grafts with 400 islets in a normoglycemic environment. Densitometric analysis of Western blots on graft homogenates demonstrated that GLUT2 protein levels in the islets, when exposed to chronic hyperglycemia for 2 weeks, were decreased to 16% of those of normal recipients. Moreover, these grafts had defective glucose-induced insulin secretion, while the effects of arginine were preserved. We conclude that GLUT2 expression in normal beta-cells is promptly down-regulated during exposure to hyperglycemia and may contribute to the loss of glucose-induced secretion of diabetes.

No variation of physical performance and perceived exertion after adrenal gland stimulation by synthetic ACTH (Synacthen) in cyclists.

There is anecdotal evidence that athletes use the banned substance Synacthen because of its perceived benefit with its associated rise in cortisol. To test the performance-enhancing effects of Synacthen, eight trained cyclists completed two, 2-day exercise sessions separated by 7-10 days. On the first day of each 2-day exercise session, subjects received either Synacthen (0.25 mg, TX) or placebo (PLA) injection. Performance was assessed by a 20-km time trial (TT) after a 90-min fatigue period on day 1 and without the fatiguing protocol on day 2. Plasma androgens and ACTH concentrations were measured during the exercise bouts as well as the rate of perceived exertion (RPE). Spot urines were analyzed for androgens and glucocorticoids quantification. Basal plasma hormones did not differ significantly between PLA and TX groups before and 24 h after the IM injection (P > 0.05). After TX injection, ACTH peaked at 30 min and hormone profiles were significantly different compared to the PLA trial (P < 0.001). RPE increased significantly in both groups as the exercise sessions progressed (P < 0.001) but was not influenced by treatment. The time to completion of the TT was not affected on both days by Synacthen treatment. In the present study, a single IM injection of synthetic ACTH did not improve either acute or subsequent cycling performance and did not influence perceived exertion. The investigated urinary hormones did not vary after treatment, reinforcing the difficulty for ACTH abuse detection.

Comunitats vegetals higronitròfiles de la Catalunya pirinenca i de les terres properes

Hygronitrophilous plant communities of Pyrenaean Catalonia and its vicinities. The following communities have been recognized: Alliance Bidention tripartitae: Xanthio italici-Polygonetumpersicarine O. Bolòs 1957, Bidentetum tripartitae W. Koch 1926 (= Polygono hydropiperis-Bidentetum tripartitae Lohm. in Tx. 1950) and Myosoto aquaticae-Bidentetum frondosae, ass. nova. Alliance Convolvulion sepium: Arundini-Convolvuletum sepium (Tx. and Oberd.) O. Bolòs 1962, Oenothero glaziovianae-Asteretum pilosi O. Bolòs and R. Masalles 1983 and Oenothero biennis-Helianthetum tuberosi,ass. nova.

Constraining ACT-R models of decision strategies: An experimental paradigm

It has been repeatedly debated which strategies people rely on in inference. These debates have been difficult to resolve, partially because hypotheses about the decision processes assumed by these strategies have typically been formulated qualitatively, making it hard to test precise quantitative predictions about response times and other behavioral data. One way to increase the precision of strategies is to implement them in cognitive architectures such as ACT-R. Often, however, a given strategy can be implemented in several ways, with each implementation yielding different behavioral predictions. We present and report a study with an experimental paradigm that can help to identify the correct implementations of classic compensatory and non-compensatory strategies such as the take-the-best and tallying heuristics, and the weighted-linear model.

Benefit of anti-HER2-coated paclitaxel-loaded immuno-nanoparticles in the treatment of disseminated ovarian cancer: Therapeutic efficacy and biodistribution in mice.

The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.

Nanomedicines for active targeting: physico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies on target cells.

Paclitaxel (Tx)-loaded anti-HER2 immunonanoparticles (NPs-Tx-HER) were prepared by the covalent coupling of humanized monoclonal anti-HER2 antibodies (trastuzumab, Herceptin) to Tx-loaded poly (dl-lactic acid) nanoparticles (NPs-Tx) for the active targeting of tumor cells that overexpress HER2 receptors. The physico-chemical properties of NPs-Tx-HER were compared to unloaded immunonanoparticles (NPs-HER) to assess the influence of the drug on anti-HER2 coupling to the NP surface. The immunoreactivity of sulfo-MBS activated anti-HER2 mAbs and the in vitro efficacy of NPs-Tx-HER were tested on SKOV-3 ovarian cancer cells that overexpress HER2 antigens. Tx-loaded nanoparticles (NPs-Tx) obtained by a salting-out method had a size of 171+/-22 nm (P.I.=0.1) and an encapsulation efficiency of about of 78+/-10%, which corresponded to a drug loading of 7.8+/-0.8% (w/w). NPs-Tx were then thiolated and conjugated to activated anti-HER2 mAbs to obtain immunonanoparticles of 237+/-43 nm (P.I.=0.2). The influence of the activation step on the immunoreactivity of the mAbs was tested on SKOV-3 cells using 125I-radiolabeled mAbs, and the activity of the anti-HER2 mAbs was minimally affected after sulfo-MBS functionalization. Approximately 270 molecules of anti-HER2 mAbs were bound per nanoparticle. NPs-Tx-HER exhibited a zeta potential of 0.2+/-0.1 mV. The physico-chemical properties of the Tx-loaded immunonanoparticles were very similar to unloaded immunonanoparticles, suggesting that the encapsulation of the drug did not influence the coupling of the mAbs to the NPs. No drug loss was observed during the preparation process. DSC analysis showed that encapsulated Tx is in an amorphous or disordered-crystalline phase. These results suggest that Tx is entrapped in the polymeric matrix and not adsorbed to the surface of the NPs. In vitro studies on SKOV-3 ovarian cancer cells demonstrated the greater cytotoxic effect of NPs-Tx-HER compared to other Tx formulations. The results showed that at 1 ng Tx/ml, the viability of cells incubated with drug encapsulated in NP-Tx-HER was lower (77.32+/-5.48%) than the viability of cells incubated in NPs-Tx (97.4+/-12%), immunonanoparticles coated with Mabthera, as irrelevant mAb (NPs-Tx-RIT) (93.8+/-12%) or free drug (92.3+/-9.3%).

Clinical uses of anti-Müllerian hormone assays : pitfalls and promises

Rapport de synthèse : OBJECTIF : étudier si les fluctuations sériques du taux d'hormone anti-müllérienne (AMH) sont liées à des différences méthodologiques entre les deux tests ELISA commercialement disponibles le kit de Beckman Coulter Immunotech (Fullerton, CA) et le kit de Diagnostic Systems Laboratories (Webster, TX). DESIGN : étude prospective au sein de deux services universitaires de médecine de la reproduction. POPULATION ETUDIEE : cent soixante-huit échantillons sanguins provenant de trois populations différentes ainsi que des dosages itératifs au cours du même cycle menstruel dans une population de dix volontaires. INTERVENTIONS : doubles mesures en aveugle des taux sériques d'AMH dans les 168 sera avec les deux kits commercialement disponibles. Sept dosages itératifs au cours du même cycle menstruel chez 10 volontaires normo-ovulantes. ANALYSE STATISTIQUE : régression linéaire pour l'étude de la corrélation entre les deux méthodes de dosage. Analyse des variances pour les dosages sériés en cours de cycle menstruel. RÉSULTATS : nous avons démontré une relation linéaire entre les deux méthodes, avec un coefficient de corrélation de 0,88 ainsi qu'une diminution faible mais statistiquement significative et concomitante avec l'ovulation du taux d'AMH sérique. CONCLUSION : les variations en cours de cycle menstruel rapportées par certains auteurs ne sont pas liées à des problèmes méthodologiques. La chute du taux d'AMH lors de l'ovulation est faible mais statistiquement significative. Les variations observées en cours de cycle restent toutefois inférieures aux variations intercycles et ne représentent de ce fait pas un obstacle au dosage de l'AMH à n'importe quel jour du cycle menstruel.

Efeito da alimentação de Schizaphis graminum com genótipos de sorgo no desenvolvimento do predador Cycloneda sanguinea

O pulgão Schizaphis graminum (Rondani) (Hemiptera: Aphididae) é uma das principais pragas do sorgo. O objetivo deste trabalho foi determinar o efeito da alimentação deste inseto com genótipos de sorgo resistentes e suscetíveis no desenvolvimento do predador Cycloneda sanguinea (Linnaeus) (Coleoptera: Coccinellidae). O pulgão foi criado em folhas dos genótipos de sorgo GR 11111 e TX 430 x GR 111, resistentes, GB 3B, de resistência moderada e BR 007B, suscetível ao hemíptero. As larvas de C. sanguinea foram alimentadas diariamente, ad libitum, com ninfas e adultos de S. graminum. A duração das fases de desenvolvimento e a sobrevivência de C. sanguinea não foram influenciadas pelo genótipo. Apenas a duração do quarto ínstar, da fase larval e do período de larva a adulto foram afetadas. O peso de larvas de segundo ínstar de C. sanguinea não foi afetado pelo genótipo. Nos demais ínstares e fase adulta, esse parâmetro foi diferenciado conforme o genótipo de sorgo utilizado como hospedeiro ao pulgão. Os genótipos resistentes GR 11111 e TX 430 x GR 111 não afetam adversamente o desenvolvimento e a fecundidade de C. sanguinea, durante uma geração. Estes genótipos demonstram compatibilidade com o predador e viabilizam o manejo de S. graminum na cultura do sorgo.

Análise da diversidade genética entre acessos de banco ativo de germoplasma de algodão

O conhecimento da diversidade genética entre um grupo de genitores é importante no melhoramento, sobretudo na identificação de combinações híbridas de maior heterozigose e maior efeito heterótico e, portanto, na recuperação de genótipos superiores nas gerações segregantes. Os métodos preditivos de diversidade têm sido muito utilizados porque dispensam a obtenção de combinações híbridas entre os genitores e normalmente usam uma medida de similaridade para avaliar a diversidade entre eles. Foram avaliados 221 acessos do banco ativo de germoplasma de algodão da Epamig, por meio da distância euclidiana média e posterior agrupamento dos indivíduos, de modo a permitir escolhas mais apropriadas de genitores para cruzamentos. Para isso foram consideradas 11 características morfológicas e de fibra. Foi detectada grande diversidade genética entre os 221 acessos reunidos em dez grupos distintos. A maior distância euclidiana (4,36) ocorreu entre os acessos S 8186 e T-295-1-1 e a menor (0,25) entre os acessos TX CACES 1-81 e TX CDPS 177.

Differential effects of immunosuppressive drugs on effector and regulatory T cells.

Purpose: Current experimental data suggest that CD4+CD25+Foxp3+regulatory T cells (Tregs) based immunotherapy would be of greatinterest to promote donor-specific immune tolerance in transplantation(Tx). Whether and how adoptive transfer of Tregs could be bestcombined with current immunosuppressive regimens in clinicalsettings remains to be defined. Using an experimental Tx model,we had previously shown that the transfer of antigen-specific Tregspromoted long-term skin allograft acceptance in lymphopenic mice,in the absence of any immunosuppressive drug. However, allograftsurvival was only slightly prolonged when Tregs were transferredalone into non-lymphopenic mice, suggesting that in more stringentconditions such as in clinical settings adjuvant therapies may beneeded to effectively control alloreactive T cells (Teff).Methods and Materials: Here we have investigated the effects ofvarious immunosuppressive drugs on the survival, proliferation andeffector function of Teff and Tregs in response to alloantigens in in vitroassays and in our in vivo Tx model.Results: Teff proliferation was inhibited in a dose-dependant mannerby rapamycin and cyclosporine A, while anti-CD154 only marginallyaffected Teff proliferation and survival in vitro. Rapamycin promotedapoptosis of Teff as compared to Tregs that were more resistant underthe same culture conditions. In vivo, the transfer of donor-specificTregs could be advantageously combined with rapamycin andanti-CD154 to significantly prolong MHC-mismatched skin allograftsurvival in non-lymphopenic recipients.Conclusion: Taken together, our data indicate thatimmunosuppressive drugs differentially target T-cell subsets and couldpromote Tregs expansion and/or function while controlling the Teff pool.

Variabilidade genética de Sugarcane mosaic virus, causando mosaico em milho no Brasil

O objetivo deste trabalho foi caracterizar biológica e molecularmente três isolados de Sugarcane mosaic virus (SCMV) de lavouras de milho, analisá-los filogeneticamente e discriminar polimorfismos do genoma. Plantas com sintomas de mosaico e nanismo foram coletadas em lavouras de milho, no Estado de São Paulo e no Município de Rio Verde, GO, e seus extratos foliares foram inoculados em plantas indicadoras e submetidos à análise sorológica com antissoros contra o SCMV, contra o Maize dwarf mosaic virus (MDMV) e contra o Johnsongrass mosaic virus (JGMV). Mudas de sorgo 'Rio' e 'TX 2786' apresentaram sintomas de mosaico após a inoculação dos três isolados, e o DAS-ELISA confirmou a infecção pelo SCMV. O RNA total foi extraído e usado para amplificação por transcriptase reversa seguida de reação em cadeia de polimerase (RT-PCR). Fragmentos específicos foram amplificados, submetidos à análise por polimorfismo de comprimento de fragmento de restrição (RFLP) e sequenciados. Foi possível discriminar os genótipos de SCMV isolados de milho de outros isolados brasileiros do vírus. Alinhamentos múltiplos e análises dos perfis filogenéticos corroboram esses dados e mostram diversidade nas sequências de nucleotídeos que codificam para a proteína capsidial, o que explica o agrupamento separado desses isolados e sugere sua classificação como estirpes distintas, em lugar de simples isolados geográficos.

Quality of life in simultaneous pancreas-kidney transplant recipients

Currently, simultaneous pancreas-kidney transplantation (SPK Tx) is the treatment of choice in selected patients with type 1 diabetes mellitus (DM1) and terminal kidney failure (TRF). A functioning SPK transplant allows dialysis and insulin therapy to be discontinued and stabilizes or improves the complications of DM1. Nevertheless, to a greater or lesser degree, these complications (physical and psychological alterations, secondary effects of immunosuppressive therapy and the need for lifelong medication and medical follow-up) can persist after SPK Tx. Health professionals have mainly investigated the clinical features of transplant recipients. However, in the last few years, interest in analyzing perceived health and health-related quality of life (QoL) has increased. This latter concept includes the features of QoL most closely associated with a particular disease, its treatment and follow-up and therefore those elements most susceptible to modification by the health system. The general aim of this study was to measure health-related QoL in our population with SPK Tx and to determine whether there are significant differences between these patients and those with DM1 and TRF who continue to receive renal replacement therapy (RRT) and insulin therapy. More specific aims were to evaluate whether there are significant differences between the study groups and the means of the Spanish reference population in the distinct dimensions of a QoL questionnaire and whether other variables such as age, sex, years" duration of DM1, length of dialysis, and time since SPK Tx significantly affect health-related QoL.

Impact of simultaneous pancreas-kidney transplantation: patients' perspectives

Background: Few qualitative studies of simultaneous pancreas-kidney transplantation (SPK Tx) have been published. The aims of this study were to explore from the perspective of patients, the experience of living with diabetes mellitus type 1 (T1DM), suffering from complications, and undergoing SPK Tx with good outcome; and to determine the impact of SPK Tx on patients and their social and cultural environment. Methods: We performed a focused ethnographic study. Twenty patients were interviewed. Data were analyzed using content analysis and constant comparison following the method proposed by Miles and Huberman. Results: A functioning SPK Tx allowed renal replacement therapy and insulin to be discontinued. To describe their new situation, patients used words and phrases such as"miracle","being reborn" or"coming back to life". Although the complications of T1DM, its surgery and treatment, and associated psychological problems did not disappear after SPK Tx, these were minimized when compared with the pretransplantation situation. Conclusion: For patients, SPK Tx represents a recovery of their health and autonomy despite remaining problems associated with the complications of T1DM and SPK Tx. The understanding of patients" existential framework and their experience of disease are key factors for planning new intervention and improvement strategies.

Quality of life in simultaneous pancreas-kidney transplant recipients

Currently, simultaneous pancreas-kidney transplantation (SPK Tx) is the treatment of choice in selected patients with type 1 diabetes mellitus (DM1) and terminal kidney failure (TRF). A functioning SPK transplant allows dialysis and insulin therapy to be discontinued and stabilizes or improves the complications of DM1. Nevertheless, to a greater or lesser degree, these complications (physical and psychological alterations, secondary effects of immunosuppressive therapy and the need for lifelong medication and medical follow-up) can persist after SPK Tx. Health professionals have mainly investigated the clinical features of transplant recipients. However, in the last few years, interest in analyzing perceived health and health-related quality of life (QoL) has increased. This latter concept includes the features of QoL most closely associated with a particular disease, its treatment and follow-up and therefore those elements most susceptible to modification by the health system. The general aim of this study was to measure health-related QoL in our population with SPK Tx and to determine whether there are significant differences between these patients and those with DM1 and TRF who continue to receive renal replacement therapy (RRT) and insulin therapy. More specific aims were to evaluate whether there are significant differences between the study groups and the means of the Spanish reference population in the distinct dimensions of a QoL questionnaire and whether other variables such as age, sex, years" duration of DM1, length of dialysis, and time since SPK Tx significantly affect health-related QoL.