Colitis can be a life-threatening immune-related adverse event (irAE) for patients with metastatic melanoma treated with immune checkpoint blockade, a new anti-cancer immunotherapy. With the increasing use of PD-1/PD-L1 and CTLA-4 inhibitors, particularly in combination in melanoma and other cancers, timely and accurate diagnosis of colitis will become increasingly important for oncologists. The main goal of this study is to understand the clinical presentation of ipilimumab-induced colitis and to validate the use of CT scans as a safe and effective diagnostic tool. We analyzed a cohort of 303 patients who received ipilimumab at Dana Farber Cancer Institute on an expanded access protocol or standard of care between the years of 2008 and 2015. Age, number of doses and frequency of ipilimumab doses were found to be clinical characteristics which could help differentiate patients who develop ipilimumab induced colitis from those who only present with diarrhea and other gastrointestinal symptoms. Of the 303 patients, 100 (33%) developed diarrhea and 43 (14%) received treatment with corticosteroids for ipilimumab-induced colitis. For all patients with suspected immune-related colitis, an effort was made to firmly establish the diagnosis prior to or immediately after initiation of treatment. Forty-one of 43 patients (95%) who received steroids for presumed immune-related colitis had a colonoscopy and 27 of 43 (63%) patients had both computed tomography (CT) of the abdomen/pelvis and a colonoscopy including biopsy. In the 31 patients with a CT and biopsy, CT was highly predictive of the presence of colitis on biopsy (sensitivity 85%, specificity 75%, PPV 96%) and the absence of CT findings was predictive of a negative biopsy (negative LR 0.2). In the 44 patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (sensitivity 85%, specificity 88%, PPV 92%, positive LR 7.3). Fifteen of the 17 patients with negative CT findings did not require steroids to reach resolution of symptoms. In conclusion, CT of the abdomen/pelvis is a fast, reliable, and non-invasive mode of diagnosing ipilimumab-induced immune-related colitis, whereas colonoscopy may not be needed to firmly establish that diagnosis

Made available in DSpace on 2014-06-11T19:25:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-04Bitstream added on 2014-06-13T19:32:58Z : No. of bitstreams: 1 ferreira_jz_me_araca.pdf: 504466 bytes, checksum: dc9b0c70071e970dde9037df9afcd1f8 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Objetivou-se comparar as técnicas de punções única e dupla e estabelecer uma dose (mL/kg) de ropivacaína 0,75% para realização do bloqueio peribulbar em cães. Vinte e dois cães com indicação para cirurgia de catarata, machos ou fêmeas, de diferentes raças, idades e pesos foram utilizados no experimento. Os pacientes foram alocados em três grupos: punção única inferior (PUI), superior (PUS) ou dupla (PD). Em todos os grupos foram realizadas no máximo três punções em intervalo de 20 minutos tendo-se como critério para repetição a não centralização bulbar. Os volumes administrados foram de 0,2 mL/kg (primeira punção) e, caso necessário, de 0,1 mL/kg nas segunda e terceira punções. Avaliou-se a duração dos bloqueios motor e sensitivo (estesiometria) em intervalos de 15 minutos, número de punções e complicações. As variáveis foram submetidas à análise de variância com medidas repetidas e análise de resíduos. Aquelas com distribuição normal foram analisadas pelo teste de Tukey enquanto as não normais foram analisadas pelo teste de Kruskal-Wallis e teste de Friedman com pós-teste de Dunn. As análises foram efetuadas empregando-se o programa SAS e foram consideradas significativas quando P < 0,05. Não houve diferença significativa (P>0,05) entre os grupos PUI, PUS e PD com relação ao número de punções, duração dos bloqueios motor e sensitivo. As complicações foram significativamente menos frequentes no grupo PUI, diferindo dos grupos PUS e PD. O bloqueio peribulbar realizado pela PUI é melhor e mais seguro comparado a PUS e PD sendo o volume ideal de 0,3 mL/kg de ropivacaína a 0,75% / The objective of this study was to compare the techniques of single and double puncture and to establish the dosage (mL/kg) of ropivacaine 0.75% for peribulbar blockade. Twenty two dogs with indication for extracapsular facectomy, of both genders and various breeds and ages were used. The dogs were allocated into three groups: inferior single puncture (PUI), superior single puncture (PUS) and double puncture (PD). In all groups up to three punctures were made at 20 minute intervals, being non centralization of the bulb the criteria for each next puncture. The volumes administered were 0.2 mL/kg (first puncture) and 0.1 mL/kg (second and third punctures). The duration of motor and sensitive (estesiometry) blockades was evaluated at 15 minutes intervals, as well as number of punctures and complications. Variables were submitted to ANOVA. Variables with normal distribution were analyzed using a Tukey’s test, and the ones that didn’t pass normality test were analyzed by using the Kruskal-Wallis and Friedman tests with post-test of Dunn. Such analyses were made by the SAS software (Statistical Analysis System Institut Inc.; Version 9.2, NC, USA) and were considered significant when P < 0.05. There was no significant difference (P>0.05) between groups PUI, PUS and PD concerning number of punctures, duration of motor and sensitive blockades. Complications were significantly lower in the PUI group, differing from groups PUS and PD. Peribulbar blockade performed by PUI is better and safer when compared to PUS and PD, being the ideal volume for it 0.3 mL/kg of ropivacaine 0.75%

Orientador: Valéria Nobre Leal de Souza Oliva / Banca: Celina Tie Nishimori Duque / Banca: Paulo Sérgio Patto dos Santos / Resumo: Objetivou-se comparar as técnicas de punções única e dupla e estabelecer uma dose (mL/kg) de ropivacaína 0,75% para realização do bloqueio peribulbar em cães. Vinte e dois cães com indicação para cirurgia de catarata, machos ou fêmeas, de diferentes raças, idades e pesos foram utilizados no experimento. Os pacientes foram alocados em três grupos: punção única inferior (PUI), superior (PUS) ou dupla (PD). Em todos os grupos foram realizadas no máximo três punções em intervalo de 20 minutos tendo-se como critério para repetição a não centralização bulbar. Os volumes administrados foram de 0,2 mL/kg (primeira punção) e, caso necessário, de 0,1 mL/kg nas segunda e terceira punções. Avaliou-se a duração dos bloqueios motor e sensitivo (estesiometria) em intervalos de 15 minutos, número de punções e complicações. As variáveis foram submetidas à análise de variância com medidas repetidas e análise de resíduos. Aquelas com distribuição normal foram analisadas pelo teste de Tukey enquanto as não normais foram analisadas pelo teste de Kruskal-Wallis e teste de Friedman com pós-teste de Dunn. As análises foram efetuadas empregando-se o programa SAS e foram consideradas significativas quando P < 0,05. Não houve diferença significativa (P>0,05) entre os grupos PUI, PUS e PD com relação ao número de punções, duração dos bloqueios motor e sensitivo. As complicações foram significativamente menos frequentes no grupo PUI, diferindo dos grupos PUS e PD. O bloqueio peribulbar realizado pela PUI é melhor e mais seguro comparado a PUS e PD sendo o volume ideal de 0,3 mL/kg de ropivacaína a 0,75% / Abstract: The objective of this study was to compare the techniques of single and double puncture and to establish the dosage (mL/kg) of ropivacaine 0.75% for peribulbar blockade. Twenty two dogs with indication for extracapsular facectomy, of both genders and various breeds and ages were used. The dogs were allocated into three groups: inferior single puncture (PUI), superior single puncture (PUS) and double puncture (PD). In all groups up to three punctures were made at 20 minute intervals, being non centralization of the bulb the criteria for each next puncture. The volumes administered were 0.2 mL/kg (first puncture) and 0.1 mL/kg (second and third punctures). The duration of motor and sensitive (estesiometry) blockades was evaluated at 15 minutes intervals, as well as number of punctures and complications. Variables were submitted to ANOVA. Variables with normal distribution were analyzed using a Tukey's test, and the ones that didn't pass normality test were analyzed by using the Kruskal-Wallis and Friedman tests with post-test of Dunn. Such analyses were made by the SAS software (Statistical Analysis System Institut Inc.; Version 9.2, NC, USA) and were considered significant when P < 0.05. There was no significant difference (P>0.05) between groups PUI, PUS and PD concerning number of punctures, duration of motor and sensitive blockades. Complications were significantly lower in the PUI group, differing from groups PUS and PD. Peribulbar blockade performed by PUI is better and safer when compared to PUS and PD, being the ideal volume for it 0.3 mL/kg of ropivacaine 0.75% / Mestre

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Many cities have experienced extended and sometimes catastrophic sieges in their history. Troy was besieged for ten years. Carthage fell to the Romans after three years of resistance. The siege of Paris by Prussia in 1970 and 1877 lasted fire-and-a-half months. The story of the blockade of Berlin, however, and the airlift created to combat this blockade, is perhaps the most curious of all such stories. The eleven-month siege was a determined attempt by Soviet Russia to starve the Berliners into surrender. The defense and the eventual victory over this attempt was provided by the miracle of the Berlin Airlift..

The ensuing chaos and power struggles between the East and West following the end of the Second World War in Germany set the stage for the creation of a unique radio station that would broadcast from behind the iron curtain for the duration of the cold war. RIAS, or Radio in the American Sector, would play a key role in the battle over ideology between the West and the Soviet Union. The story of RIAS' birth and development is a unique narrative of unintended consequences as the efforts of the Soviet Union to gain a monopoly over the airwaves of Berlin actually contributed to ensuring a permanent Western radio presence in the city. This paper draws in part upon oral history, personal papers, government documents and the archives of the New York Times to tell the story of the development of RIAS and its role during the Berlin blockade and influence on the cold war.

In this thesis, we studied the self-assembly of nanoparticles at liquid metal-water interfaces and oil-water interfaces. We demonstrated a simple approach to form nanostructured electronic devices by self-assembly of nanoparticles at liquid metal surfaces. In this approach, two liquid-metal droplets, which were coated with a monolayer of ligand-stabilized nanoparticles, were brought into contact. They did not coalesce but instead remained separated by the nanoparticles assembled at the interface. Devices formed by this method showed electron transport between droplets that was characteristic of the Coulomb blockade, where current was suppressed below a tunable threshold voltage because of the energy of charging individual nanoparticles. Further studies of this approach demonstrated the potential of interfacial assembly in fabricating microscopic electronic devices over a large area in a cost-effective and time-efficient fashion. Micrometer-scale Ga droplets coated with nanoparticles were fabricated using ultrasonication and then deposited on patterned substrates to form microscopic devices. I-V measurements showed Coulomb blockade effect in the devices containing more than one nanoparticle junction. The measured threshold voltages increased with number of junctions as expected for devices arranged in series. We also studied experimentally the energy of adsorption of nanoparticles and microparticles at the oil-water and Ga-water interfaces by monitoring the decrease of interfacial tension as the particles bind. For citrate-stabilized gold nanoparticles assembling on a droplet of octafluoropentyl acrylate, we found adsorption energy =-5.1 kBT for particle radius R = 2.5 nm, and adsorption energy scales R^2 for larger sizes. Gold nanoparticles with (1-mercaptoundec-11-yl) tetra(ethylene glycol) ligand had a much larger binding energy (-60.4 kBT) and an energy barrier against adsorption. For polystyrene spheres with R = 1.05 micrometer, we found adsorption energy =-0.9*10^6 kBT. We also found that the binding energy depended on the composition of the oil phase and could be tuned by the salt concentration of the nanoparticle suspension. At Ga-water interfaces, we found that adsorption energy of Au-cit and Au-TEG nanoparticles were much larger. We have also studied desorption of polystyrene microparticles from oil-water interfaces by changing experimental conditions, including addition of nanoparticles, cross-linking ligand molecules or in response to chemical interactions between the particles and the oil. We found that microparticles can desorb even though the adsorption energy is large. We also found that the desorbed particle formed a surprising `tail'-like structure.

No description available.

Abstract Not Provided. / Thesis / Master of Science (MSc)

The mechanisms by which antipsychotics (neuroleptics) produce their therapeutic effects in schizophrenia are largely unknown. Although neuroleptic efficacy is attributed to central dopamine D2 and/or serotonin 5-HT2 receptor antagonism, clinical improvements in schizophrenia are not seen until two or three weeks after daily neuroleptic administration. The mechanisms underlying the neuroleptic response must therefore occur downstream from initial receptor blockade and be a consequence of chronic neurotransmitter receptor blockade. The goal of the present study was to use neuroleptics with varied dopamine vs. serotonergic receptor blocking profiles to elucidate some of these intracellular post receptor mechanisms. Since the final steps of both dopamine and serotonin synthesis require the enzyme aromatic L-amino acid decarboxylase (AADC), the effects of neuroleptics on AADC gene (mRNA) expression were examined in PC12 cells and compared to their effects on the synthetic enzyme tyrosine hydroxylase (TH) and ' c-fos' (an early immediate gene [IEG]) mRNA. The neuroleptics examined did not significantly regulate AADC mRNA in PC12 cells, and only haloperidol upregulated TH and 'c-fos' mRNA. Later studies in rats showed that acute neuroleptic administration increased ' c-fos' mRNA, whereas the immunoreactivity of a related IEG (delta FosB) was increased upon chronic treatment. These studies and a subsequent dose response study demonstrated that upregulation of both 'c-fos' mRNA and delta FosB immunoreactivity was most prominent in dopaminergic projection areas including the striatum and nucleus accumbens. Because it has been suggested that neuroleptic treatment might prevent neurodegeneration in schizophrenia, the effects of neuroleptics on the mRNA expression of neuroprotective target genes of delta FosB were examined both ' in vivo' and 'in vitro'. These genes included brain-derived neurotrophic factor (BDNF), the neuroprotective enzyme superoxide dismutase (SOD), and the low affinity nerve growth factor receptor (p75). While dopamine D2 blockade unfavorably regulated BDNF and p75 mRNA, 5-HT 2 blockade either had no effect on or favorably regulated BDNF, SOD, and p75 mRNA. Thus, although little about the contribution of serotonergic blockade in the neuroleptic response was determined, dopaminergic blockade regulated IEG's and several of their target genes. Future studies will be needed to understand the role of 5-HT2 receptor blockade in the neuroleptic response.