Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. METHODS: Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1G93A and TDP43A315T) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. RESULTS: Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. CONCLUSIONS: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.

[Coronary endovascular prostheses (stents) in the treatment of imminent or acute occlusion as a complication of coronary angioplasty]. / Protesis endovasculares coronarias (stents) en el tratamiento de la oclusion inminente o aguda como complicacion de angioplastia coronaria.

Acute coronary occlusion as a consequence of dissection or thrombosis occurs in 2 to 11% of patients treated with percutaneous transluminal coronary angioplasty (PTCA), and continues to be the principal cause of early morbidity and mortality. In this study the experience of one center is presented with the application of two types of stents, Wiktor (Medtronic Inc.) or Gianturco-Roubin (Cook Inc.) for bailout of acute or threatening coronary occlusion that persisted after treatment with prolonged balloon inflation. All patients received a complete anticoagulation scheme with heparin, dextran, dipyridamole, aspirin and coumadin. From January to November 1993, 26 patients with 27 prosthesis were included. There were 21 men and 5 women with mean age of 58 years (range 36 to 73). The indications for stenting were: total occlusion in five (19%) threatening occlusion in 13 (50%) and severe persistent dissection in eight (31%). Initial implantation success was 93% (25/27). Procedure related clinical complications were death in one patient, bypass surgery in two (8%) and myocardial infarction in four (15%). Acute stent thrombosis occurred in three cases and subacute in one (11 and 4% respectively). Three patients, had non-fatal bleeding complications. Final clinical success without myocardial infarction, bypass surgery or death was 77%. In conclusion, coronary stenting for bailout of acute or threatening coronary occlusion after PTCA is a good alternative to emergency surgery. New antithrombotic strategies and better anticoagulation schemes may improve further this procedure.

[Percutaneous coronary angioscopy: 200 observations in 100 candidates for angioplasty]. / Angioscopía coronaría percutánea: 200 observaciones en 100 pacientes candidatos a angioplastía.

Due to the recent technological advances, it is possible to perform percutaneous coronary angioscopy in a straightforward fashion in most patients. To know the safety and usefulness of this technique we present 200 observations in 100 patients candidates for coronary intervention. We used a coronary angioscope (Baxter, Edwards LIS Division), that can be placed using the conventional technique for percutaneous coronary angioplasty. The system incorporates a proximal occluding balloon, and distally a movable optical fiber. Case selection considered non-ostial coronary segments relatively straight. It was possible to obtain adequate images in 86 percent of cases. The technique is safe in experienced hands: there were two cases of ventricular fibrillation, and two cases of local dissection occurred, none of these associated with clinical consequences. No myocardial infarction, surgery or death, related to this procedure occurred. Valuable diagnostic information is derived from angioscopy as the method provides some histopathological correlation. Stable plaques are usually uniformly white or yellow. Unstable plaques are yellow and ulcerated. Thrombus can be easily recognized in acute coronary syndromes. Also in percutaneously treated segments, the final result and the presence of dissection or hemorrhage can be visualized. Coronary percutaneous angioscopy is safe and brings useful clinical information. Its applications in the clinical practice are still to be determined.