Autophagy: an affair of the heart

Whether an element of routine housekeeping or in the setting of imminent disaster, it is a good idea to get one’s affairs in order. Autophagy, the process of recycling organelles and protein aggregates, is a basal homeostatic process and an evolutionarily conserved response to starvation and other forms of metabolic stress. Our understanding of the role of autophagy in the heart is changing rapidly as new information becomes available. This review examines the role of autophagy in the heart in the setting of cardioprotection, hypertrophy, and heart failure. Contradictory findings are reconciled in light of recent developments. The preponderance of evidence favors a beneficial role for autophagy in the heart under most conditions.     

Involvement of A1 adenosine receptors in the acquisition of fertilizing capacity

Ejaculated mammalian spermatozoa acquire competence to fertilize oocytes by a two-step process: capacitation followed by acrosome reaction. The biochemical and biophysical modifications occurring in vivo in the female reproductive tract can be reproduced in vitro, and previous studies have suggested a capacitative role for adenosine A(1) receptor (A(1)R). Mice with a targeted disruption of the Adora 1 gene (A(1)R-/- mice) provide a useful model for better understanding the role of the A(1)R in fertility. Murine spermatozoa express A(1)R in the head, neck, midpiece region, and tail. The number of capacitated spermatozoa incubated in human tubal fluid was significantly reduced in A(1)R-/- compared with A(1)R+/+ and A(1)R+/- spermatozoa. The difference between A(1) R+/+ and A(1)R-/- mouse spermatozoa was mainly in the time necessary to reach the maximum percentage of capacitation. A(1)R+/+ murine sperm obtained the full state of capacitation within 90 minutes whereas A(1)R-/- sperm required 240 minutes. Caffeine, a known antagonist of A(1) and A(2A) adenosine receptors, lowered the number of capacitated sperm and affected the time of capacitation in a dose-dependent manner, mimicking the effects of the lack of A(1) receptors. Although number, motility, and viability of A(1)R-/- murine sperm was not significantly different from A(1)R+/+ mouse spermatozoa, a significant reduction of the number of pups produced by A(1)R-/- male mice suggests that A(1) receptors must be fully operative to accomplish the optimal degree of capacitation and thereby fertilization.     

Multi-Centre European Experience with Intragastric Balloon in Overweight Populations: 13 Years of Experience

Background

The request to lose weight is expanding not only in obese and morbidly obese patients but also in overweight patients affected by co-morbidities as diabetes and hypertension and who do not tolerate diet regimen or lifestyle changes. The aim of this study is a multicenter evaluation of outcomes of intragastric balloon in overweight patients.

Methods

Patients (BMI 27–30 kg/m²) treated with a BioEnterics Intragastric Balloon (BIB) between 1996 and 2010 were extracted from the database of the participating centres in Rome (Italy), Liège (Belgium) and Madrid (Spain). Primary endpoints were the efficacy and safety at 6 and 42 months from balloon positioning. Secondary endpoints included resolution of co-morbidities.

Results

A total of 261 patients were included in this study. The most common indication for balloon placement was a psychological disorder (54 %). Mean body mass index (BMI) fell from 28.6?±?0.4 at baseline to 25.4?±?2.6 kg/m² at 6 months and to 27.0?±?3.1 kg/m² at 3 years from BIB removal. The mean %EWL was 55.6 % at 6 months and 29.1 % at 3 years. Forty-seven patients (18 %) had complications associated with placement of the intragastric balloon (leak?=?28, intolerance?=?14, duodenal ulcer?=?2, gastritis?=?1, oesophagitis?=?1, duodenal polyps?=?1). The rate of patients with hypertension decreased from 29 % at baseline to 16 % at 3 years. Diabetes decreased from 15 to 10 %, dyslipidaemia decreased from 20 to 18 %, hypercholesterolaemia decreased from 32 to 21 % and osteoarthropathy decreased from 25 to 13 %.

Conclusions

The intragastric balloon is safe and effective in overweight patients, helping to reduce progression to obesity and decreasing the prevalence of a number of important co-morbidities.     

Surgery after intracranial investigation with subdural electrodes in patients with drug-resistant focal epilepsy: outcome and complications

Video-EEG monitoring with intracranial subdural electrodes is a useful assessment tool for the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy. We aimed at assessing the morbidity related to electrode implantation and the surgical outcome in patients who underwent epilepsy surgery after intracranial EEG monitoring. All patients (N?=?58) admitted to our Epilepsy Surgery Centre for drug-resistant focal epilepsy who underwent resective surgery after intracranial monitoring with subdural electrodes and were followed up for at least 2?years were included in the study. Their mean age was 30.4?years (range 8-60?years), 25 (43?%) were female, and 44 (76?%) had a preoperatively detected structural lesion. The mean duration of invasive recording was 2.3?days (range 1-14?days). Extraoperative ECoG allowed the identification of the epileptogenic focus in all cases. The temporal lobe was involved in 21 (36?%) patients, whereas extratemporal foci were identified in 24 (41?%) patients. Thirteen patients (23?%) had multilobar involvement. Functional brain mapping was performed in 15 (26?%) patients. Transient complications related to electrode implantation occurred in three patients. Among patients with evidence of lesion on preoperative MRI, lesionectomy alone was performed in 12 cases (27?%), while it was combined with tailored cortical resection in the remaining cases. Tailored cortical resection was also performed in patients without evidence of lesion on MRI. After resective surgery, transient neurological deficits occurred in five cases, while another patient experienced permanent lateral homonymous hemianopia. At the last follow-up observation, 34 (57?%) patients were seizure-free (Engel class I). This study suggests that invasive EEG recording with subdural electrodes may be useful and fairly safe for many candidates for epilepsy surgery.     

Protein kinase C–delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts

Bone homeostasis requires stringent regulation of osteoclasts, which secrete proteolytic enzymes to degrade the bone matrix. Despite recent progress in understanding how bone resorption occurs, the mechanisms regulating osteoclast secretion, and in particular the trafficking route of cathepsin K vesicles, remain elusive. Using a genetic approach, we describe the requirement for protein kinase C–delta (PKCδ) in regulating bone resorption by affecting cathepsin K exocytosis. Importantly, PKCδ deficiency does not perturb formation of the ruffled border or trafficking of lysosomal vesicles containing the vacuolar‐ATPase (v‐ATPase). Mechanistically, we find that cathepsin K exocytosis is controlled by PKCδ through modulation of the actin bundling protein myristoylated alanine‐rich C‐kinase substrate (MARCKS). The relevance of our finding is emphasized in vivo because PKCδ?/? mice exhibit increased bone mass and are protected from pathological bone loss in a model of experimental postmenopausal osteoporosis. Collectively, our data provide novel mechanistic insights into the pathways that selectively promote secretion of cathepsin K lysosomes independently of ruffled border formation, providing evidence of the presence of multiple mechanisms that regulate lysosomal exocytosis in osteoclasts. © 2012 American Society for Bone and Mineral Research.