A novel method for studying the cortical processing of human swallowing using Synthetic Aperture Magnetometry(SAM)

Background/Aims: Positron emission tomography has been applied to study cortical activation during human swallowing, but employs radio-isotopes precluding repeated experiments and has to be performed supine, making the task of swallowing difficult. Here we now describe Synthetic Aperture Magnetometry (SAM) as a novel method of localising and imaging the brain's neuronal activity from magnetoencephalographic (MEG) signals to study the cortical processing of human volitional swallowing in the more physiological prone position. Methods: In 3 healthy male volunteers (age 28–36), 151-channel whole cortex MEG (Omega-151, CTF Systems Inc.) was recorded whilst seated during the conditions of repeated volitional wet swallowing (5mls boluses at 0.2Hz) or rest. SAM analysis was then performed using varying spatial filters (5–60Hz) before co-registration with individual MRI brain images. Activation areas were then identified using standard sterotactic space neuro-anatomical maps. In one subject repeat studies were performed to confirm the initial study findings. Results: In all subjects, cortical activation maps for swallowing could be generated using SAM, the strongest activations being seen with 10–20Hz filter settings. The main cortical activations associated with swallowing were in: sensorimotor cortex (BA 3,4), insular cortex and lateral premotor cortex (BA 6,8). Of relevance, each cortical region displayed consistent inter-hemispheric asymmetry, to one or other hemisphere, this being different for each region and for each subject. Intra-subject comparisons of activation localisation and asymmetry showed impressive reproducibility. Conclusion: SAM analysis using MEG is an accurate, repeatable, and reproducible method for studying the brain processing of human swallowing in a more physiological manner and provides novel opportunities for future studies of the brain-gut axis in health and disease.

Can you tell your clunis from your cubitus? A benchmark for functional imaging

Advances in functional brain imaging have allowed the development of new investigative techniques with clinical application—ranging from presurgical mapping of eloquent cortex to identifying cortical regions involved in religious experiences. Similarly a variety of methods are available to referring physicians, ranging from metabolic measures such as functional magnetic resonance imaging and positron emission tomography to measurements based on electrical activity such as electroencephalography and magnetoencephalography. However, there are no universal benchmarks by which to judge between these methods. In this study we attempt to develop a standard for functional localisation, based on the known functional organisation of somatosensory cortex. Studies have shown spatially distinct sites of brain activity in response to stimulation of various body parts. Generally these studies have focused on areas with large cortical representations, such as the index finger and face. We tested the limits of magnetoencephalography source localisation by stimulation of body parts, namely the clunis and the cubitus, that map to proximal and relatively poorly represented regions of somatosensory cortex.

Celiac disease-specific TG2-targeted autoantibodies inhibit angiogenesis ex vivo and in vivo in mice by interfering with endothelial cell dynamics

A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2), reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility. © 2013 Kalliokoski et al.

Fluorine-18-labeled estrogens, progestins and corticosteroids for receptor-based imaging of breast tumors and target areas of the brain

Estrogens can be labeled with the positron-emitting radionuclide fluorine-18 (t$\sb{1/2}$ = 110 min) by fluoride ion (n-Bu$\sb4$N$\sp{18}$F) displacement of a 16$\beta$-trifluoromethanesulfonate (triflate) derivative of the corresponding estrone 3-triflate, and purification by HPLC. That sequence has been used to synthesize the 11$\beta$-methoxy 1 and 11$\beta$-ethyl 2 analogues of the breast tumor imaging agent, 16$\alpha$-($\sp{18}$F) fluoro-17$\beta$-estradiol (FES). Tissue distribution studies of 1 and 2 in immature female rats show high selectivity for target tissue (T, uterus) vs non-target (NT, muscle and lung), with T/NT ratios being 43 and 17 at one hour after injection for 1 and 2, respectively. The parent estrogen FES has previously been shown to display an intermediate value for tissue selectivity.

Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models

Abnormalities in brains of Alzheimer's disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this 'preclinical AD' stage relies on biomarkers such as decreased levels of the amyloid-β peptide (Aβ) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20-30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new 'preclinical AD' biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.

Cerebral misery perfusion diagnosed using hypercapnic blood-oxygenation-level-dependent contrast functional magnetic resonance imaging: a case report

Introduction Cerebral misery perfusion represents a failure of cerebral autoregulation. It is animportant differential diagnosis in post-stroke patients presenting with collapses in the presence of haemodynamically significant cerebrovascular stenosis. This is particularly the case when cortical or internal watershed infarcts are present. When this condition occurs, further investigation should be done immediately. Case presentation A 50-year-old Caucasian man presented with a stroke secondary to complete occlusion of his left internal carotid artery. He went on to suffer recurrent seizures. Neuroimaging demonstrated numerous new watershed-territory cerebral infarcts. No source of arterial thromboembolism was demonstrable. Hypercapnic blood-oxygenation-level-dependent-contrast functional magnetic resonance imaging was used to measure his cerebrovascular reserve capacity. The findings were suggestive of cerebral misery perfusion. Conclusions Blood-oxygenation-level-dependent-contrast functional magnetic resonance imaging allows the inference of cerebral misery perfusion. This procedure is cheaper and more readily available than positron emission tomography imaging, which is the current gold standard diagnostic test. The most evaluated treatment for cerebral misery perfusion is extracranial-intracranial bypass. Although previous trials of this have been unfavourable, the results of new studies involving extracranial-intracranial bypass in high-risk patients identified during cerebral perfusion imaging are awaited. Cerebral misery perfusion is an important and under-recognized condition in which emerging imaging and treatment modalities present the possibility of practical and evidence-based management in the near future. Physicians should thus be aware of this disorder and of recent developments in diagnostic tests that allow its detection.

Cáncer gástrico en pacientes de Méderi – Hospital Universitario Mayor entre los años 2011 - 2014

Introducción: El cáncer gástrico es uno de los más frecuentes a nivel mundial y Colombia se sitúa entre los países de mayor incidencia en este tipo de patología. Objetivo: Describir las características epidemiológicas, clínicas, el tratamiento administrado y los desenlaces inmediatos de los pacientes con diagnóstico de cáncer gástrico atendidos en el Hospital Universitario Mayor de Bogotá entre los años 2011 y 2014. Metodología: Se realizó un estudio observacional descriptivo con diagnóstico de cáncer gástrico. Se realizaron análisis univariados por medio de proporciones para las variables cualitativas y medidas de tendencia central para las variables cuantitativas según la distribución. Resultados: Un total de 189 pacientes fueron analizados. El dolor fue el síntoma más frecuente en los pacientes (30.7%) y el principal signo encontrado fue una masa palpable en abdomen (9,5%). Los pacientes fueron sometidos a diferentes abordajes terapéuticos, la mayoría recibieron manejo paliativo no quirúrgico (52.9%) y la opción quirúrgica más usada en los pacientes fue la gastrectomía total (20.6%), y la subtotal (16,4) seguidas de quimioterapia y/o radiación perioperatoria. Los pacientes que sobrevivieron a los 2 años fueron 7,4% del total. Conclusiones: El registro de los pacientes con cáncer gástrico es bueno en el Méderi-Hospital Universitario Mayor es bueno y permite caracterizar los pacientes, la presentación de la patología y los resultados del tratamiento que concuerdan con los presentados en contextos similares en la literatura.

Utilidade da PET/CT, (18F-FDG), no estudo do linfoma Hodgkin e linfoma não Hodgkin

Os linfomas são tumores estabelecidos a nível do sistema linfático. Devido à sua heterogeneidade classificam-se como Linfoma Hodgkin (LH) e Linfoma não Hodgkin (LNH), apresentando diferente prognóstico e seguimento quimioterapêutico. Actualmente, a Photon Emission Tomography/Computed Tomography (PET/CT, do acrónimo inglês) é considerada “imagem” de excelência no estudo desta patologia. Neste contexto, é objectivo deste artigo verificar a utilidade da técnica PET/CT e correlacionar o valor de Standard Uptake Value (SUV), obtido pela PET, com o estadio histológico do linfoma e com a resposta ao tratamento quimioterapêutico. Metodologia - Analisaram-se retrospectivamente 356 estudos respeitantes a 231 pacientes, aos quais se realizou uma PET/CT para estadiamento, estudo de massa ou avaliação da resposta ao tratamento. Após a administração de uma actividade média de 18F-FDG de 288,6 MBq, foram adquiridas imagens numa PET/CT GE Discovery ST. Os resultados obtidos foram comparados com os dados clínicos dos pacientes. Resultados - Foram encontradas diferenças significativas entre a idade Vs tipo de linfoma. Não foram encontradas diferenças significativas entre: valor de SUVmáx ganglionar, lesões extra-ganglionares e seu valor de SUV relativamente ao tipo de linfoma. Comprovou-se a influência da PET/CT na alteração do estadio do linfoma e atitude terapêutica. Em última análise, obtiveram-se respectivamente os seguintes valores de sensibilidade, especificidade e exactidão: 98%, 79% e 88%. Conclusões - Os resultados obtidos permitem verificar a importância da imagem PET/CT no estadiamento, monitorização e alteração da atitude terapêutica dos LH e LNH.

Projeto para a aquisição de um equipamento PET-CT: análise da viabilidade financeira

Projeto de mestrado em Gestão de Unidades de Saúde

Effects of continuous positive airway pressure treatment on coronary vasoreactivity measured by (82)Rb cardiac PET/CT in obstructive sleep apnea patients.

PURPOSE: Obstructive sleep apnea syndrome (OSA) increases the risk of cardiovascular disease. We aimed at evaluating the effect of continuous positive airway pressure (CPAP) treatment on coronary endothelium-dependent vasoreactivity in OSA patients by quantifying myocardial blood flow (MBF) response to cold pressure testing (CPT). METHODS: In the morning after polysomnography (PSG), all participants underwent a dynamic (82)Rb cardiac positron emitting tomography/computed tomography (PET/CT) scan at rest, during CPT and adenosine stress. PSG and PET/CT were repeated at least 6 weeks after initiating CPAP treatment. OSA patients were compared to controls and according to response to CPAP. Patients' characteristics and PSG parameters were used to determine predictors of CPT-MBF. RESULTS: Thirty-two untreated OSA patients (age 58 ± 13 years, 27 men) and 9 controls (age 62 ± 5 years, 4 men) were enrolled. At baseline, compared to controls (apnea-hypopnea index (AHI) = 5.3 ± 2.6/h), untreated OSA patients (AHI = 48.6 ± 19.7/h) tend to have a lower CPT-MBF (1.1 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.09). After initiating CPAP, CPT-MBF was not different between well-treated patients (AHI <10/h) and controls (1.3 ± 0.3 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.83), but it was lower for insufficiently treated patients (AHI ≥10/h) (0.9 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.0045). CPT-MBF was also higher in well-treated than in insufficiently treated patients (1.3 ± 0.3 mL/min/g vs. 0.9 ± 0.2 mL/min/g, p = 0.001). Mean nocturnal oxygen saturation (β = -0.55, p = 0.02) and BMI (β = -0.58, p = 0.02) were independent predictors of CPT-MBF in OSA patients. CONCLUSIONS: Coronary endothelial vasoreactivity is impaired in insufficiently treated OSA patients compared to well-treated patients and controls, confirming the need for CPAP optimization.

Increased expression of "peripheral-type" benzodiazepine receptors in human temporal lobe epilepsy: implications for PET imaging of hippocampal sclerosis.

Increased binding sites for "peripheral-type" benzodiazepine receptor (PTBR) ligands have been described in a wide range of neurological disorders including both human and experimental epilepsy. This study was undertaken to assess PTBR expression in relation to the presence of hippocampal sclerosis in human temporal lobe epilepsy (TLE). For this purpose, hippocampal CA1 subfields were dissected from surgical samples from patients with therapy-refractive TLE with (n = 5) or without (n = 2) hippocampal sclerosis and from age-matched nonepileptic postmortem controls (n = 5). PTBR expression was assessed by immunohistochemistry and reverse-transcription polymerase chain reaction. Receptor sites were evaluated using an in vitro binding assay and the selective PTBR ligand [3H]PK11195. Epileptic patients with hippocampal sclerosis showed increases in PTBR binding sites, immunoreactivity, and mRNA expression compared to both nonsclerotic TLE patients and postmortem nonepileptic controls. Induction of PTBR expression and binding sites were directly correlated with the presence of hippocampal sclerosis and the accompanying reactive gliosis.

Neue 18 F-markierte Liganden zur Visualisierung des GABA A, alpha 5-Rezeptorstatus mittels PET

Die heutige Verfügbarkeit der molekularen Bildgebung ermöglicht einen signifikanten Einfluss auf die Diagnostik und die Therapiekontrolle von neurodegenerativen Erkrankungen, die unter anderem durch Fehlsteuerungen im GABAergen System auftreten können. Die Visualisierung und Quantifizierung des GABAA-alpha5-Subtyps durch PET könnte dabei zu einem besseren Verständnis von Erkrankungen wie Alzheimer und traumatischen Neurosen (emotionales Langzeitgedächtnis) beitragen. Ferner eröffnen GABAA/alpha5-subtypselektive Liganden die Möglichkeit, wesentliche Grundlagen der elementaren Vorgänge von Lernen und Erinnern zu untersuchen. 7,8,9,10-Tetrahydro-(7,10-ethan)-1,2,4-triazol[3,4-alpha]phthalazine stellen sich als vielverspre-chende Leitstrukturen zur Entwicklung neuer 18F-markierter alpha5-subtypselektiver GABAA-Rezeptorliganden für die PET dar. Um diese neuartigen Substanzen hinsichtlich ihrer Potenz als GABAA-alpha5-subtypselektive Radioliganden zu verifizieren, wurden zunächst die entsprechenden 19F-Derivate TC07-TC12 synthetisiert. Diese Referenzverbindungen wurden in Rezeptor-bindungsassays und in Autoradiographien mit [3H]Ro 15-4513 als zu verdrängender Radioligand evaluiert. In beiden Experimenten als auch in in vivo-Verdrängungsexperimenten an Ratten konnte eine hohe Affinität im nanomolaren Bereich als auch eine hohe Selektivität bezüglich der GABAA/alpha5-Untereinheit für einige der dargestellten Referenzverbindungen nachgewiesen werden. Gemäß diesen vielversprechenden Ergebnissen wurden verschiedene Markie-rungsvorläufer für eine 18F-Direktmarkierung der relevantesten Substanz TC07 in einer mehrstufigen organischen Synthese dargestellt. Die anschließende 18F-Markierung erfolgte über eine nukleophile Substitution mit [18F]Fluorid. Die Reaktionsparameter wurden hinsichtlich Reaktionstemperatur und dauer, Markierungsvorläuferkonzentration, Basenabhängigkeit und verschiedenen Markierungsmethoden optimiert. Daraus resultierend konnte [18F]TC07 mit bis zu 45 % radiochemischer Ausbeute erhalten werden. Die zerfallskorrigierte, gesamtradiochemische Ausbeute von nca [18F]TC07 in isotonischer NaCl-Lösung betrug 15 %. Basierend auf den bisher erhaltenen Ergebnissen wurde der Radioligand in in vitro-, ex vivo- und in vivo µPET-Experimenten evaluiert. Die zunächst durchgeführten in vitro-Experimente deuteten auf eine homogene Verteilung der Aktivität hin und zeigten keine spezifische Anreicherung. Diese Ergebnisse wurden sowohl in ex vivo- als auch in in vivo-µPET-Studien bestätigt. Auch hier konnte nur eine niedrige Aktivitätsanreicherung, eine homogene Verteilung im gesamten Gehirn und keine Übereinstimmung mit der bekannten GABAA/alpha5-Subtypverteilung gefunden werden. Eine im Anschluss durchgeführte Metabolismusstudie zeigte eine langsame Metabolisierungsrate des [18F]TC07 und auch eine Organverteilungsstudie zeigte keine außergewöhnlichen Anreicherungen. Aus den erhaltenen Ergebnissen kann geschlossen werden, dass der Radioligand [18F]TC07 kein geeigneter Tracer zur in vivo-Visualisierung der alpha5-Untereinheit des GABAA-Rezeptors ist.

Controlo de qualidade de matrizes de fotodíodos de avalanche no projecto "PET - Desenvolvimento de tecnologia PET para mamografia"

Dissertação mest. em Imagiologia Médica, Faculdade de Ciências e Tecnologia da Univ. do Algarve, 2006

Toxicological effects related to a novel heated tobacco product

The tobacco epidemic is a public health burden. Nicotine-Delivery-Systems(NDS) are devices designed to help people replace conventional cigarette(CC) and among these devices we find electronic cigarettes(e-cig), which are classified as Electronic-NDS(ENDS). E-cigs use different technologies to vaporize a liquid or to heat the tobacco avoiding the combustion phenomenon(IQOS). The US Food and Drug Administration(FDA) has labelled IQOS as modified risk tobacco products(MRTPs), indirectly encouraging the perception of safety in the consumers, but IQOS smoke, although to a lesser extent than conventional, still presents a great deal of harmful or potentially harmful compounds. My PhD thesis aims to study the toxic effects related to IQOS exposure. I sought to answer the question of whether the toxic compounds released by IQOS, albeit in reduced concentrations, could lead to genotoxicity and damage to the airways and liver in vivo. At the University of Nottingham, I have investigated in vitro the effects generated by the IQOS, e-cigs and CC exposure on PBMCs and human lung epithelial cell line. Finally, at University of Milano–Bicocca, I have developed a in vivo Positron Emission computed Tomography(PET) imaging procedure meant to be applied to the monitoring of ENDS toxicity, particularly in the brain. These results indicate that IQOS is not a low-risk product in vivo, for primary target organs but also for secondary organs, although we have observed a small impact in vitro. Labelling as MRTP may mislead consumers who interpret “a lower level of toxic compounds” as an indication of “harmlessness” when there is a health risk for users. In the last part, I set up a methodology for studying temporal fluctuations of regional brain metabolism and connectivity derived from mice of different ages allowing researchers to obtain normative values in investigations of the efficacy or toxicity of substances at the functional level of the CNS.