No energy, no autophagy-Mechanisms and therapeutic implications of autophagic response energy requirements.

Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and substrates for energy metabolism during nutrient or energy deficiency, which are the main stimuli for autophagy induction. However, like most biological processes, autophagy itself requires ATP, and there is an energy threshold for its initiation and execution. We here present the first comprehensive review of this often-overlooked aspect of autophagy research. The studies in which ATP deficiency suppressed autophagy in vitro and in vivo were classified according to the energy pathway involved (oxidative phosphorylation or glycolysis). A mechanistic insight was provided by pinpointing the critical ATP-consuming autophagic events, including transcription/translation/interaction of autophagy-related molecules, autophagosome formation/elongation, autophagosome fusion with the lysosome, and lysosome acidification. The significance of energy-dependent fine-tuning of autophagic response for preserving the cell homeostasis, and potential implications for the therapy of cancer, autoimmunity, metabolic disorders, and neurodegeneration are discussed.

High prevalence of risk factors for chronic kidney disease in Balkan endemic nephropathy foci.

BACKGROUND/AIMS: The aim of this study was to find out the prevalence of the most frequent risk factors for chronic kidney disease (CKD) and the prevalence of urinary abnormalities in adult inhabitants of three Balkan endemic nephropathy (BEN) villages near Bijeljina, Bosnia and Herzegovina. METHODS: The survey consisted of an interview, blood pressure measurement, and urine dipstick test for proteinuria, hematuria, and glycosuria. RESULTS: The study involved 1625 (739 males, aged 51 ± 16 years) subjects: 319 (19.6%) with positive family history for BEN, 585 (36%) with hypertension, 604 (37.2%) above 60 years, 146 (9%) with diabetes, and 566 (34.8%) with none of these risk factors. Proteinuria was present in 6.2-7.1% of the subjects with risk factors for CKD but in 3.4% of those without risk factors. Systolic blood pressure and BEN in brother/sister were found to be significant variables associated with proteinuria, but female gender and history of kidney disease with hematuria. CONCLUSION: In addition to a family burden for BEN, other risk factors for CKD were highly prevalent in BEN villages of the Bijeljina municipality. The frequency of proteinuria was higher in the at-risk group than in the group without risk factors and increased with the number of risk factors.

Modulation of Cancer Cell Autophagic Responses by Graphene-Based Nanomaterials: Molecular Mechanisms and Therapeutic Implications.

Graphene-based nanomaterials (GNM) are plausible candidates for cancer therapeutics and drug delivery systems. Pure graphene and graphene oxide nanoparticles, as well as graphene quantum dots and graphene nanofibers, were all able to trigger autophagy in cancer cells through both transcriptional and post-transcriptional mechanisms involving oxidative/endoplasmic reticulum stress, AMP-activated protein kinase, mechanistic target of rapamycin, mitogen-activated protein kinase, and Toll-like receptor signaling. This was often coupled with lysosomal dysfunction and subsequent blockade of autophagic flux, which additionally increased the accumulation of autophagy mediators that participated in apoptotic, necrotic, or necroptotic death of cancer cells and influenced the immune response against the tumor. In this review, we analyze molecular mechanisms and structure-activity relationships of GNM-mediated autophagy modulation, its consequences for cancer cell survival/death and anti-tumor immune response, and the possible implications for the use of GNM in cancer therapy.

Influence of Syrgical Trauma on Nitric Oxide and Nitrotyrosine Serum Levels in Patients Undergoing Laparoscopic Or Conventional Cholecystectomy.

BACKGROUND: Oxidative stress represents tissue damage caused by reactive forms of oxygen and nitrogen due to the inability of antioxidant mechanisms to reduce reactive forms into more stable ones. The aim of the study was to evaluate the influence of surgical trauma on nitric oxide (NO) and nitrotyrosine (NT) values in patients undergoing conventional and laparoscopic cholecystectomy. METHODS: A prospective study included sixty patients from the Department of Emergency Surgery, Clinical Centre of Serbia who were operated for gallstone related chronic cholecystitis. All the patients enrolled in the study underwent cholecystectomy; the first group was operated conventionally (30 patients - control group), while the second group was operated laparoscopically (30 patients - treatment group). RESULTS: There were no statistically significant differences in the values of NO and its postoperative changes in both groups, the conventionally operated group (p=0.943) and the laparoscopically operated group (p=0.393). We found an increase in NT values 24 hours postoperatively (p=0.000) in the conventionally operated patients, while in the group operated laparoscopically we didn't find statistically significant changes in the values of NT (conventionally operated group (p=0.943) and laparoscopically operated group (p=0.393)). CONCLUSIONS: In our study, we found a significant increase in NT values 24 hours postoperatively in conventionally operated patients i.e. the control group, vs. the treatment group. Further randomized studies are needed for a better understanding of the impact of surgical trauma on oxidative stress response.

Rectosigmoid prolapse--A case report.

INTRODUCTION: Many factors have been indentified as a possible cause of rectal prolaps. Despite the fact that it is not a life- threating condition, its clinical presentation varies, and sometimes it can present as an emergency. We presented a patient with prolapse of an unusually large segment of the rectosigmoid colon caused by chronic constipation, as an incarcerated segment repaired surgically. CASE REPORT: A 62-year-old female patient was referred to the Emergency Department in bad condition with severe pain in the perianal region. On examination a complete rectal prolaps as well as a part of sigmoid colon were found. Macroscopically, the prolapsed segment appeared edematous, livid, with ulcerations. An attempt to manually reduce prolapse failed, therefore resection of 50 cm of sigmoid colon with rectopexy had to be performed. No complications occurred and the patient was without symptoms six months later. Colonoscopy did not reveal any abnormality. CONCLUSION: Although the preoperative management and preparation of the patient was limited, emergancy surgical intervention for such a case was the strategy of choice due to magnitude of the prolapsing segment. It provided a successful and permenant solution.

Single access laparoscopic right hemicolectomy.

Single Access Laparoscopic Colectomy (SALC) were reported in several studies. The first Single Access laparoscopic right colectomy was descibed by Remzi et Al. We report our experience in SALC describing our approach for Right Colectomy. In our experience we perform as well an extracorporeal side-to-side anastomosis, in contrast wit a conventional laparoscopic right colectomy in which we perform an intra-corporeal anastomosis. We think that an important limit of this approach is represented by the difficult to perform a safe intra-corporeal anastomosis. In conclusion we think that right SALC is a safe and feasible approach. However, many issues will be established, as well as technological, economical and educational aspects, before its introduction in the daily clinical practice.

Use of recombinant factor VIIa in the treatment of massive retroperitoneal bleeding due to severe necrotizing pancreatitis.

BACKGROUND: Recently, a growing number of case reports and case series have suggested that the use of recombinant activated factor VII (rFVIIa) may be effective in treatment of patients with non-hemophilic acquired coagulopathy not responding to conventional treatment such as major surgery, major trauma, sepsis, necrotizing pancreatitis and bleeding due to cerebral arteriovenous malformations. CASE REPORT: We presented a septic patient with massive, life-threatening bleeding caused by retroperitoneal necrosis, due to severe acute necrotizing pancreatitis. As conservative treatment (blood, plasma, cryoprecipitates and platelet transfusions) failed to induce cessation of bleeding, the patient was urgently operated on. In spite of usual procedures of surgical hemostasis (ligation, suture, thermocauterisation, fibrin glue, temporary tamponade), hemorrhage could not be stopped. The patient manifested the signs of hypothermia and metabolic acidosis and, therefore, the decision was made to use recombinant activated factor VII (Novo Seven). The application of rFVIIa resulted in significant discontinuation of hemorrhage, restoration to normal blood count as well as other relevant coagulation parameters. CONCLUSION: Although application of rFVIIa is still in the initial clinical phase, and the experience is based mainly on uncontrolled series as well as on individual observations, it seems that this drug can be promising, potent and attractive adjunctive prohemostatic agent. This drug may play a beneficial role in the treatment of serious and unresponsive, "nonsurgical", life-threatening bleeding due to severe acute necrotizing pancreatitis.