Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity.

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in multiple sclerosis initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we unveil deregulation of astrocytic calcium signaling and astrocyte-to-neuron communication as key pathophysiological mechanisms of cortical dysfunction in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Using two-photon imaging ex vivo and fiber photometry in freely behaving mice, we found that acute EAE was associated with the emergence of spontaneously hyperactive cortical astrocytes exhibiting dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists. Abnormal astrocyte signaling by Gi and Gq protein coupled receptors was observed in the inflamed cortex. This was mirrored by treatments with pro-inflammatory factors both in vitro and ex vivo, suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, deregulated astrocyte calcium activity was associated with an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall, our data identify astrocyte-neuronal network dysfunctions as key pathological features of gray matter inflammation in multiple sclerosis and potentially additional neuroimmunological disorders.

Differences of postextrasystolic behavior of left ventricular and aortic pressures between fixed and dynamic left ventricular outflow tract stenosis.

The dynamic behavior of fixed LV outflow tract stenosis partly resembles that of OCM. To analyze their differences we studied basal and postextrasystolic (post-PVC) peak-to-peak LV aortic gradients, aortic systolic pressure, and pulse pressure in 14 OCM and in 36 pure VAS without two-dimensional echocardiographic findings of OCM. Fifteen mild VAS had basal gradients similar to those of OCM (39 +/- 17 mm Hg vs 24 +/- 16 mm Hg). Patients with OCM show a post-PVC gradient (109 +/- 41 mm Hg) similar to that of VAS (110 +/- 50 mm Hg). However, the latter were departing from much higher gradients (VAS 72 +/- 30 mm Hg vs OCM 24 +/- 16 mm Hg). Decrement of post-PVC aortic systolic pressure and pulse pressure were frequent in both groups, but decrement of pulse pressure greater than 5 mm Hg were more frequent in OCM. We concluded that (1) post-PVC increased aortic gradients and decreased aortic systolic pressure occurred in both VAS and OCM; (2) post-PVC decreased aortic pulse pressure might occur in VAS; and (3) association of post-PVC gradient increment greater than 75 percent and pulse pressure decrement greater than 5 mm Hg are strongly suggestive of OCM.

[Coronary heart disease and lipoprotein (a): relationship with other lipid cardiovascular risk factors]. / Enfermedad cardíaca coronaria y lipoproteína (a): su relación con otros factores lipídicos de riesgo cardiovascular.

BACKGROUND: Lipoprotein (Lp) (a) is considered a risk factor for early coronary heart disease (CHD), and a discriminant cutoff of Lp(a) concentration has been suggested. METHODS: Serum Lp(a) concentrations have been determined by enzymoimmunoassay in 66 men with CHD and in 100 healthy control men. Serum cholesterol, serum triglycerides, high density lipoprotein (HDL)-cholesterol, and apoprotein (apo) A-I were also determined. RESULTS: Serum Lp(a) concentration was 21.7 +/- 16.9 mg/dl (mean +/- SD) in patients and 12.5 +/- 12.5 mg/dl in controls (p less than 0.001). Serum cholesterol was 5.63 +/- 1.22 mmol/l and 5.29 +/- 1.00 mmol/l (p less than 0.05) respectively; serum triglycerides were 1.99 +/- 1.23 mmol/l and 1.29 +/- 0.61 mmol/l (p less than 0.001) respectively; HDL-cholesterol was 0.97 +/- 0.27 mmol/l and 1.07 +/- 0.30 mmol/l (p less than 0.05) respectively; and apo A-I was 94 +/- 15 mg/dl and 144 +/- 41 mg/dl (p less than 0.001) respectively. Lp(a) concentrations were not correlated with other well-recognized cardiovascular risk lipidic factors, nor influenced by age either body mass index. Using 20 mg/dl as discriminant Lp(a) concentration between patients and controls, a ratio 2:1 in patients with respect to controls has been observed and exceeded some more when the threshold level was put on 30 mg/dl. A subset of normocholesterolemic and normotriglyceridemic patients (n = 17) and controls (n = 49) had serum Lp(a) concentration of 22.7 +/- 16.3 mg/dl and 9.1 +/- 8.2 mg/dl (p less than 0.001) respectively. CONCLUSIONS: Increased concentration of Lp(a) constitutes an independent risk factor for CHD. On the other hand, Lp(a) concentrations of 20 mg/dl or 30 mg/dl as risk threshold levels are well-defined.

The Armc10/SVH gene: genome context, regulation of mitochondrial dynamics and protection against Aß-induced mitochondrial fragmentation.

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents Aß-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against Aß-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

[Evaluation of the use of digoxin in a primary care emergency service]. / Evaluación del uso de la digoxina en asistencia primaria en un servicio de urgencias.

Digoxin is a widely used drug. Previous studies suggest a high prevalence of inadequate use, subtherapeutic levels and high toxicity rates. The aim of the present study was to evaluation the use of digoxin in our area. 50 consecutive patients who attended our emergency service and who were receiving digoxin on a chronic basis were prospectively evaluated. There were 37 females and males, with age 78.1 +/- 8.6 years. We found that digoxin was not indicated in 12% of cases. Only 48% had digoxin plasma levels within the therapeutic range. When plasma levels were considered in association with clinical and electrocardiographic findings, 12% of patients were undertreated and 6% had digitalis toxicity. There was no relation between the digoxin plasma level and the dosage schedule, the ECG findings, the renal function, the use of other drugs or the anthropometric data. Emphasis is made on the need to individualize digoxin therapy and to measure plasma levels in particular cases.

Dolor torácico con elevación del segmento ST en un consumidor de cannabis / Chest pain with elevation of the ST segment in a cannabis consumer

La miocarditis se define como una inflamación del miocardio. Frecuentemente se asocia a afectación pericárdica constituyendo una miopericarditis. Su etiología es muy variada, e incluye agentes infecciosos, químicos como drogas de abuso, radiaciones e hipersensibilidad a fármacos. La causa más frecuente es la infección por enterovirus. Es más frecuente en niños, adolescentes y adultos jóvenes, con predominio del sexo masculino. Aunque las manifestaciones clínicas son muy variables, en algunos casos puede semejar un síndrome coronario agudo. Por otro lado, el consumo de cannabis, se ha asociado a vaso espasmo, infarto agudo de miocardio y taquiarrítmias. Se describe el caso de un varón joven, consumidor de cannabis, que consultó por dolor torácico con alteraciones electrocardiográficas y enzimáticas sugestivas de síndrome coronario agudo con elevación del ST. Se discute el diagnóstico diferencial, métodos diagnósticos y actitud terapéutica (AU)

Myocarditis is defined as inflammation of the myocardium, and it is frequently associated with pericardial involvement leading to myopericarditis. Myopericarditis may be due to different etiologies, including infectious and chemical agents, such as drugs of abuse, radiation and hypersensitivity to drugs. Infection caused by enterovirus is the most frequent cause. The disease is more common in children, adolescents and young adults with a predominance of the male sex. Although patients may present different clinical manifestations, in some cases symptoms may resemble an acute coronary syndrome. On the other hand, cannabis consumption has been associated with vasospasm, acute myocardial infarction and tachyarrhythmias. We describe the case of a young man who was a cannabis consumer and presented chest pain with biochemical and electrocardiographic abnormalities suggestive of acute coronary syndrome with an elevated ST segment. The differential diagnosis, diagnostic work-up studies and therapeutic approach are commented on (AU)