Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Unilateral mesial temporal atrophy after a systemic insult as a possible etiology of refractory temporal lobe epilepsy: case report Esclerose mesial temporal unilateral após insulto sistêmico como possível etiologia de epilepsia refratária do lobo temporal: relato de caso

Mesial temporal sclerosis is the main pathological substrate present in refractory temporal lobe epilepsy and its presence is often related to the occurrence of febrile seizures in infancy. There is an on-going discussion on the nature of mesial temporal sclerosis as it related to epilepsy: cause or consequence. A previously normal child developed hyperosmolar coma after abdominal surgery at the age of 6. Three months afterwards he developed simple and complex partial seizures with an increasing frequency and refractory to multiple mono-and polytherapic drug regimens. He was evaluated for surgery at the age of 13. Ictal and interictal recordings showed left temporal lobe abnormalities. Early CT scaning suggested left temporal atrophy. MRI showed mesial temporal sclerosis. Neuropsichological testing showed verbal memory deficits and he passed a left carotid artery amytal injection. He was submitted to a cortico-amygdalo-hippocampectomy and has been seizure-free since then. The clinical data obtained from this patient suggest that at least in this case mesial temporal sclerosis would be related to the cause of epilepsy and not resultant from repeated seizure activity.<br>A esclerose mesial temporal é o principal substrato anatomo-patológico envolvido na epilepsia refratária do lobo temporal e está frequentemente associada à ocorrência de convulsões febris na infância. Persiste até o momento intensa discussão se a esclerose mesial seria causa ou consequência da síndrome epiléptica. Uma criança previamente normal, desenvolveu coma hiperosmolar após intercorrência em cirurgia abdominal aos 6 anos de idade. Após 3 meses iniciaram-se crises parciais simples e complexas em frequência ascendente e refratárias a múltiplos esquemas terapêuticos em mono- e politerapia. Ele realizou investigação pré-operatória para epilepsia aos 13 anos de idade. Registros eletrencefalográficos de superfície ictais e interictais mostraram anormalidades temporais esquerdas. TC de crânio antiga, próxima ao insulto sistêmico, já sugeria atrofia do lobo temporal. RMN demonstrou esclerose mesial temporal. Testagem neuropsicológica mostrou déficit de memória verbal e este paciente apresentou o padrão passa-ipsi/falha contralateralmente no teste de amital sódico. Ele foi submetido a córtico-amígdalo-hipocampectomia e está sem crises desde então. Os achados anátomo-patológicos são de esclerose mesial. Os dados obtidos neste paciente sugerem que, ao menos neste caso, a esclerose mesial temporal está possivelmente relacionada à causa da epilepsia e não à presença de crises recorrentes

Cavernous sinus invasion by pituitary macroadenomas: neuroradiological, clinical and surgical correlation

The classical imaging gold-standard for this diagnosis is the presence of tumor lateral to the carotid artery. Seventeen patients with pituitary macroadenomas with intraoperative confirmation of cavernous sinus invasion were studied with MRI. Only 8 patients had tumor lateral to the carotid artery; 13 had tumor within the carotid syphon and all lacked the ring enhancement of the medial wall of the cavernous sinus. In 10 patients, widening of the posterior double leaflets of the cavernous sinus could be. All patients were operated by the transesphenoidal route. Only one patient was cured by surgery alone. Only 3 patients disclosing the above mentioned MRI features were identified in a series of 250 patients and did not have cavernous sinus invasion. The present criteria proved to be useful in the pre-operative diagnosis of cavenous sinus invasion and patients' counselling. Pre-operative diagnosis of cavernous sinus invasion of pituitary tumors has a great impact in the management of such patients

Brain dendritic cells

Dendritic cells (DCs) are a subset of leukocytes highly specialized in antigen-presentation to T cells, thus promoting the immune response. DCs occur in the meninges and choroid plexus. Brain DCs and brain-derived antigens are drained by cerebrospinal fluid in the afferent lymphatic vessels of cervical lymph nodes (cLNs) for antigen presentation. Information on the role of DCs in intracerebral immune response is still limited. We recently demonstrated (Laperchia et al., 2013) that in thy1GFP-M transgenic mice, engineered for the expression of green fluorescent protein (GFP) in a proportion of neurons, also myeloid DCs are GFP-tagged. Our in vivo analysis by two-photon microscopy on young (3-6 months) thy1GFP-M mice showed DCs floating in the cerebrospinal fluid or static at the pia mater/parenchyma interface. We are using this animal model to study brain DCs trafficking by two-photon microscopy in two different inflammatory conditions. The first concerns chronic encephalitis caused by the extracellular parasite Trypanosoma brucei. During the first, hemolymphatic stage of this infection, direct interactions between DCs and parasites were seen within meningeal and cortical microvessels. In the second stage, determined by parasite neuroinvasion, DCs invaded the brain parenchyma, exhibiting a random motion for target antigen recognition. With disease progression, intraparenchymal brain DCs were instead mainly arranged in static clusters which incorporated parasites for efficient antigen capture, and extravasated cytotoxic CD8+ T cells established contact with parasites. Ex vivo analysis on cLNs shown that the subcapsular zone was invaded by migratory DCs, and both migratory and resident DCs preferentially contacted CD8+ T cells. The second condition concerns normal aging (18-20 month old mice), which is known to be associated with low-grade chronic inflammation level and with functional impairments of the immune system, also known as immunosenescence. In these mice we observed that DCs infiltrate the brain parenchyma by transmigration from blood vessels and exhibit a motile behavior suggesting a scanning motion. Moreover, some DCs showed a progressive reduction of their motility until convergence, in about 30 minutes, into clusters whose functional significant has yet to be elucidated. Taken together, our studies enlightens key events of the intracerebral immune response both in presence of pathogens and in physiological aging

Chronic Epidural Hematoma Of The Vertex.

Epidural hematomas of the cranial vertex can be rarely found in patients victims of head trauma. The diagnosis of the vertex hematoma may be delayed by the odd location of the bleeding site and the absence of a clear localization symptomatology. The current method of choice for investigation of head trauma patients, the computed tomography (CT) scans, may also give misleading diagnostic clues. Epidural hematomas of the vertex can be also encountered in a chronic form, and re-bleeding is possibly the underlying mechanism for the long term permanence of the hematoma. We report a case of a patient with a chronic epidural hematoma of the cranial vertex with a long interval between the trauma and the symptoms onset. We review the current literature focusing on the diagnostic pitfalls and forms of treatment of the chronic epidural hematoma of the vertex.10669-7

Insular epilepsy: similarities to temporal lobe epilepsy case report Epilepsia insular: similaridades à epilepsia do lobo temporal - relato de caso

Insular epilepsy has been rarely reported and its clinical and electrographic features are poorly understood. The electrographic study of the insula is difficult since it is hidden from the brain surface by the frontal and temporal lobe. A 48 years-old woman started having simple partial autonomic and complex partial seizures with automatisms and ictal left arm paresis 8 years prior to admission. Seizure's frequency was 1 per week. Pre-operative EEG showed a right temporal lobe focus. Neuropsychological testing disclosed right fronto-temporal dysfunction. MRI showed a right anterior insular cavernous angioma. Intraoperative ECoG obtained after spliting of the sylvian fissure showed independent spiking from the insula and temporal lobe and insular spikes that spread to the temporal lobe. The cavernous angioma and the surrounding gliotic tissue were removed and the temporal lobe was left in place. Post-resection ECoG still disclosed independent temporal and insular spiking with a lower frequency. The patient has been seizure-free since surgery. Insular epilepsy may share many clinical and electroencephalographic features with temporal lobe epilepsy.<br>A epilepsia insular tem sido raramente relatada e suas características clínicas e eletrencefalográficas são pobremente conhecidas. O estudo eletrográfico da ínsula é difícil já que ela se encontra recoberta pelos lobos frontal e temporal. Uma paciente, de 48 anos, começou a ter crises parciais simples autonômicas e crises parciais complexas com automatismos e paresia crítica de membro superior esquerdo 8 anos antes desta internação. A frequência de crises era de 1/semana . O EEG pré-operatório mostrou foco temporal direito. Testagem neuropsicológica demonstrou disfunção fronto-temporal direita. RMN demonstrou cavernoma insular anterior direito. A eletrocorticografia intraoperatória obtida após a abertura da fissura sylviana demonstrou a presença de espículas independentes na ínsula e no lobo temporal, além de descargas que se originavam na ínsula e espraiavam ao lobo temporal. O angioma cavernoso e a área gliótica ao seu redor foram removidos e o lobo temporal foi deixado em seu lugar. A eletrocorticografia após a ressecção ainda demonstrou a presença de descargas nestas regiões, em menor frequência. A paciente está sem crises desde a cirurgia. A epilepsia insular pode compartilhar diversos aspectos clínicos e eletrográficos com a epilepsia do lobo temporal

Two-Photon Microscopy Imaging of <em>thy1</em>GFP-M Transgenic Mice: A Novel Animal Model to Investigate Brain Dendritic Cell Subsets <em>In Vivo</em>

<div><p>Transgenic mice expressing fluorescent proteins in specific cell populations are widely used for <em>in vivo</em> brain studies with two-photon fluorescence (TPF) microscopy. Mice of the <em>thy1</em>GFP-M line have been engineered for selective expression of green fluorescent protein (GFP) in neuronal populations. Here, we report that TPF microscopy reveals, at the brain surface of these mice, also motile non-neuronal GFP+ cells. We have analyzed the behavior of these cells <em>in vivo</em> and characterized in brain sections their immunophenotype.</p> <p>With TPF imaging, motile GFP+ cells were found in the meninges, subarachnoid space and upper cortical layers. The striking feature of these cells was their ability to move across the brain parenchyma, exhibiting evident shape changes during their scanning-like motion. In brain sections, GFP+ cells were immunonegative to antigens recognizing motile cells such as migratory neuroblasts, neuronal and glial precursors, mast cells, and fibroblasts. GFP+ non-neuronal cells exhibited instead the characteristic features and immunophenotype (CD11c and major histocompatibility complex molecule class II immunopositivity) of dendritic cells (DCs), and were immunonegative to the microglial marker Iba-1. GFP+ cells were also identified in lymph nodes and blood of <em>thy1</em>GFP-M mice, supporting their identity as DCs. Thus, TPF microscopy has here allowed the visualization for the first time of the motile behavior of brain DCs <em>in situ</em>. The results indicate that the <em>thy1</em>GFP-M mouse line provides a novel animal model for the study of subsets of these professional antigen-presenting cells in the brain. Information on brain DCs is still very limited and imaging in <em>thy1</em>GFP-M mice has a great potential for analyses of DC-neuron interaction in normal and pathological conditions.</p> </div

<i>In vivo</i> observation of motile GFP-labeled cells in the cortex of <i>thy1</i>GFP-M mice.

<p>(A) GFP+ cell (white arrowhead) above the pial surface rapidly changing its morphology. Time-lapse sequence of maximum intensity projections of a set of optical sections acquired at 2 µm z-step. The right column shows the depth of the cell through a digital rotation of the corresponding images on the left. The white dotted lines indicate the dura and pia mater.The frame acquired at 45′ shows fluorescent cells (blue arrowheads) passing above the pia through the CSF. (B) GFP+ cell rolling inside a blood vessel on the pial surface. The blood vessel walls (shown in red) were labeled by the intravital dye SR101. Fluorescent cells showing motility at the pial surface (C) and deep in the brain parenchyma (D–E). E) GFP+ cells showing translation across the field of view. Scale bars 10 µm.</p