Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.

Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both by inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.

Incidence and Predictors of Delirium After Cardiac Surgery.

BACKGROUND: The overall purpose of this study was to determine the incidence and perioperative factors that predispose to cause delirium in postoperative cardiac surgery patients in our Intensive Care Unit. METHODS: We performed a prospective, observational study. Following institutional review board approval, this study included 234 patients above the age of 18 years meeting the inclusion criteria for cardiac surgery in Shahid Gangalal National Heart Center from July 2018 to December 2018. Preoperative, intraoperative and postoperative data for possible risk factors were obtained. Daily assessment of delirium was done during Intensive Care Unit stay of the patient. Collected data were analysed by means of statistical software SPSS-21. RESULTS: The incidence of delirium was 15.6% (35/224) in our study. Delirium was seen in 14 out of 58 (24.1%) patients with age >60 years which was found to be statistically significant. Preoperative risk factor for developing delirium were carotid artery disease and Hemoglobin level <10gm/dl. Intraoperative risk factor for developing delirium were blood transfusion, longer cardiopulmonary bypass time. Post-operative factors for developing delirium included longer Intensive Care Unit stay, mechanical ventilation time ,duration on inotropes , blood transfusion, use of non-invasive ventilation, sleep deprivation, use of intra-aortic balloon pump, Pao2<70. CONCLUSIONS: As shown in our study, delirium is a frequent occurrence in the cardiac surgical population. The incidence of delirium after cardiac surgery was 15.6%. Several risk factors pre-operatively like age>60 years, carotid artery disease, Hb<10gm/dl, intra-operative factors like longer cardiopulmonary bypass time, blood transfusion and post-operatively longer duration of Mechanical ventilation, Intensive Care Unit stay, blood transfusion, use of intra-aortic balloon pump and Non-invasive ventilation were found to be predictors of delirium.

High Prevalence of Biofilms on Retrieved Implants from Aseptic Pseudarthrosis Cases.

INTRODUCTION: Recent literature has associated pseudarthrosis and pedicle screw loosening with subchronic infection at the pedicle of the vertebra. The positive culture results of a previous retrieval analysis show that such patients have a high frequency of bacterial contamination. The objective of this study is to visually capture the architecture of these undiagnosed infections, which have been described in other studies as biofilms on supposedly "aseptic" screw loosening. METHODS: Explants from 10 consecutive patients undergoing revision spine surgery for pseudarthrosis were collected and fixed in glutaraldehyde solution. Each of these implants was imaged thoroughly by using scanning electron microscopy and x-ray spectroscopy to evaluate the architecture of the biofilm. Additionally, eight patient swabs from tissues around the implants were sent for cultures to assess bacterial infiltration in tissues beyond the biofilm. The implants were also analyzed using energy dispersive x-ray spectroscopy. The exclusion criteria included clinically diagnosed infection (current or previous) and/or mechanical failure of the implant due to falls/accidents. RESULTS: The study was successful in capturing the visual architecture of the biofilm on retrieved implants. A total of 77% of pseudarthrosis cases presented with loose pedicle screws, which were diagnosed by a preoperative computed tomography scan showing radiolucency along the screw track and were confirmed intraoperatively, and 72% of the cases showed biofilm on explants. CONCLUSIONS: In the absence of the clinical presentation of infection, impregnated bacteria could form a biofilm around an implant, and this biofilm can remain undetected via contemporary diagnostic methods, including swabbing. Implant biofilm is frequently present in "aseptic" pseudarthrosis cases.

A time to build and a time to burn: glucose metabolism for every season.

Luengo et al. (2020) demonstrate that pyruvate dehydrogenase (PDH) overactivation blunts NAD+ regeneration by overcharging the mitochondrial membrane potential and driving ATP synthesis beyond demand. Under these conditions, some cells prioritize aerobic glycolysis to meet the need for oxidized cofactors in biosynthetic metabolism.

Early and consistent pattern of proximal weakness in GNE myopathy.

BACKGROUND: GNE myopathy is widely regarded as a distal myopathy. Involvement of proximal musculature in this condition has not been systematically studied. METHODS: The phenotype of genetically confirmed patients with GNE myopathy was analyzed. Fourteen groups of muscles were evaluated with Medical Research Council (MRC) grading and the average muscle scores (AMS:1-10) were calculated. RESULTS: Fully documented AMS data was available in 31 of 65 patients. It showed a consistent pattern of severe weakness of hip adductors, hip flexors, knee flexors, and foot dorsiflexors, with milder weakness of the hip extensors and abductors. The knee extensors were largely unaffected. The proximal weakness appeared early in the course of the disease. Proximal muscle weakness was also present in the remaining 34 patients in whom the data were limited. A variant in exon 13 (c.2179G > A) was very common (81.5%). CONCLUSIONS: The GNE phenotype in this Indian cohort exhibited mixed proximal and distal involvement. Weakness of adductors and flexors of the hip formed an integral part of the phenotype.

Implant Retention or Removal for Management of Surgical Site Infection After Spinal Surgery.

STUDY DESIGN: A literature review. OBJECTIVE: To summarize the implant removal rate, common bacterial organisms found, time of onset, ratio of superficial to deep infection, and regurgitating the prevalence among all the retrospective and prospective studies on management and characterization of surgical site infections (SSIs). METHODS: PubMed was searched for articles published between 2000 and 2018 on the management or characterization of SSIs after spinal surgery. Only prospective and retrospective studies were included. RESULTS: A total of 49 articles were found relevant to the objective. These studies highlighted the importance of implant removal to avoid recurrence of SSI. The common organisms detected were methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermis, Staphylococcus epidermis, Staphylococcus aureus, and Propionibacterium acnes, with prevalence of 1% to 15%. A major proportion of all were deep SSI, with minority reporting on late-onset SSI. CONCLUSION: Long-term antibiotics administration, and continuous irrigation and debridement were common suggestion among the authors; however, the key measure undertaken or implied by most authors to avoid risk of recurrence was removal or replacement of implants for late-onset SSI.

A Multicenter Trial Demonstrating Presence or Absence of Bacterial Contamination at the Screw-Bone Interface Owing to Absence or Presence of Pedicle Screw Guard, Respectively, During Spinal Fusion.

STUDY DESIGN: A prospective multicenter study. OBJECTIVE: The objective of this study was to assess bacterial contamination in current practices of pedicle screw handling and comparing it to a novel method of using an intraoperative, sterile implant guard for screws. SUMMARY OF BACKGROUND DATA: Postoperative infections occur at the higher end of 2%-13%, as cited in the literature, and are underestimated due to various reasons in such publications. Despite concerns associated with vancomycin application immediately before closure, it is theoretically impossible to irrigate the screw-bone interface postimplantation. Consequently, any contamination of pedicle screw before implantation is permanent, and has the potential to cause deep-bone infection, or hardware loosening due to encapsulation of biofilm between the bone and the screw. Therefore, continued vigilance and effective preventive measures should be undertaken if available. MATERIALS AND METHODS: Two groups of presterile individually-packaged pedicle screws, one incased in a sterile, protective guard (group 1: G) and the other without such a guard (group 2: NG), 31 samples in each group were distributed over 28 spinal fusion surgeries at 5 independent hospitals groups. Each were loaded onto the insertion device by the scrub tech and left on the sterile table. Twenty minutes later, the lead surgeon who had just finished preparing the surgical site, handles the pedicle screw, to check the fit with the insertion device. Then, instead of implantation, it was transferred to a sterile container using fresh sterile gloves for bacterial analysis. RESULTS: The standard unguarded pedicle screws presented bioburden in the range of 10 to 10 colonies forming units per screw, whereas the guarded pedicle screws showed no bioburden. CONCLUSION: Standard, current, handling of pedicle screws leads to bacterial contamination, which can be avoided if the screws are sterilely prepackaged with an intraoperative guard (preinstalled).

ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development.

Reactive oxygen species (ROS), despite having damaging roles, serve as signaling molecules regulating diverse biological and physiological processes. Employing in vivo genetic studies in Drosophila, we show that besides causing G1-S arrest by activation of Dacapo, ROS can simultaneously inhibit cell growth by regulating the expression of 4EBP and S6K. This is achieved by triggering a signaling cascade that includes Ask1, JNK, and FOXO independent of the Tsc-TOR growth regulatory pathway. Qualitative and quantitative differences in the types of ROS molecules generated dictate whether cells undergo G1-S arrest only or experience blocks in both cell proliferation and growth. Importantly, during normal development, this signaling cascade is triggered by ecdysone in late larval fat body cells to restrict their growth prior to pupation by antagonizing insulin signaling. The present work reveals an unexpected role of ROS in systemic control of growth in response to steroid hormone signaling to establish organismal size.

Improving Health-Related Quality of Life of Patients With an Ostomy Using a Novel Digital Wearable Device: Protocol for a Pilot Study.

BACKGROUND: Ostomy surgeries involving the placement of an ostomy bag (eg, colostomy, ileostomy, urostomy, etc) have been shown to have a negative impact on health-related quality of life. To date, no studies have been conducted examining what impact, if any, wearable biosensors have on the health-related quality of life of ostomy patients. OBJECTIVE: In the present study, we plan to assess the quality of life of ostomy patients using the Ostom-i alert sensor, a portable, wearable, Bluetooth-linked biosensor that facilitates easier ostomy bag output measurements. We hypothesize that using the Ostom-i alert sensor will result in an improved, ostomy-specific, health-related quality of life as compared to baseline measurement before the use of the sensor. METHODS: A total of 20 ostomy patients will be screened and recruited to participate in this prospective, observational, cross-over pilot study using an Ostom-i alert sensor for one month. The primary outcome of this study will compare ostomy-specific, health-related quality of life at baseline (prior to Ostom-i alert sensor use) to ostomy-specific, health-related quality of life after 2 and 4 weeks of Ostom-i use by utilizing the City of Hope Quality of Life Questionnaire for Patients with an Ostomy. Secondary outcomes of general health-related quality of life and adjustment to ostomy will be evaluated using the Medical Outcomes Study 36-item short form health survey and the Olbrisch Ostomy Adjustment Scale Short Form 2. RESULTS: The project was funded by the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University School of Medicine. Enrollment is currently underway and data analysis is expected to be completed in 2018. CONCLUSIONS: Proposed benefits of mobile, internet-linked personal health monitors, such as the Ostom-i, include a reduction in the cost of care by reducing resource utilization and infection rates, improving patient-provider communication, reducing time spent as an inpatient as well as improved quality of life. Prior studies have demonstrated decreased health-related quality of life in patients with an ostomy bag. We aim to examine the extent to which the Ostom-i alert sensor affects the health-related quality of life of its users. The Ostom-i alert sensor has the potential to improve quality of life of users by giving them the freedom and confidence to partake in daily activities with the knowledge that they can check how full their ostomy bag is in a private, discrete manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT02319434; https://clinicaltrials.gov/ct2/show/NCT02319434 (Archived at WebCite at http://www.webcitation.org/6xhFDThmq).

Nasal inserts containing ondansetron hydrochloride based on Chitosan-gellan gum polyelectrolyte complex: In vitro-in vivo studies.

The aim of this study was the production of ondansetron hydrochloride loaded lyophilized insert for nasal delivery. The nasal insert was prepared by the lyophilisation technique using Chitosan-gellan gum polyelectrolyte complex as the polymer matrix. The ondansetron loaded inserts were evaluated with respect to water uptake, bioadhesion, drug release kinetic study, ex vivo permeation study, and in vivo study. Lyophilised nasal inserts were characterized by differential scanning calorimetry, scanning electron microscopy and X-ray diffraction study. Scanning electron microscopy confirmed the porous sponge like structure of inserts whereas release kinetic model revealed that drug release followed non-fickian case II diffusion. The nasal delivery showed improved bioavailability as compared to oral delivery. In conclusion, the ondansetron containing nasal inserts based on Chitosan-gellan gum complex with potential muco-adhesive potential is suitable for nasal delivery.

Robotic-assisted laparoscopic partial nephrectomy: A single centre Indian experience.

BACKGROUND: We summarise our experience with RPN emphasising on learning curve, techniques and outcomes. PATIENTS AND METHODS: A retrospective chart review of 57 patients was done. The preoperative workup included a triple phase CT angiography. The parameters analyzed were demographics, tumor characteristics, operative details, postoperative outcome, histopathology and follow-up. The data were compared with historical cohort of the laparoscopic partial nephrectomy (LPN). RESULTS: 58 renal units in 57 patients (45 males and 12 females) underwent RPN. The mean age was 53.08 ± 13.6 (30-71) years. The mean tumor size was 4.96 ± 2.33 (2-15.5) cm. Average operative time was 129.4 ± 29.9 (70-200) min.; mean warm ischemia time was 20.9 ± 7.34 (9-39) min. 8 renal units in 7 patients were operated with the zero ischemia technique. The average follow-up was 5.15 months (1-18). There was no recurrence. 15 patients underwent LPN. The mean tumor size was 4.3 ± 1.6 (1.6-8) cm. operative time was 230.7 ± 114.8 (150-300) min.; mean warm ischemia time was 31.8 ± 9 min. The nephromerty score in the LPN group was 7.1 ± 0.89, in the RPN group was 8.75 ± 1.21. CONCLUSION: Our results suggest that prior experience of LPN shortens the learning curve for RPN as seen by shorter warm ischemia time and operative time in our series. The nephrometry score in RPN were higher suggesting that complex tumour can be managed with robotic approach.

Once myasthenic, always myasthenic? observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients.

BACKGROUND: The natural history of myasthenia gravis [MG] is unpredictable: In the first few years the disease course is worst with subsequent gradual disease stabilization. However, some patients tend to have continued disease activity or resurgence of the disease many years into the illness. The factors correlating with disease course need further evaluation. AIMS: To study the patterns of remissions, worsening and exacerbations in patients with MG and correlate various factors affecting them. SETTINGS AND DESIGN: Retrospective, Institute Review Board (IRB) approved study in tertiary referral neurology center. MATERIALS AND METHODS: Hundred patients with acquired MG confirming the inclusion criteria were studied. Pharmacological remissions, complete stable remissions, exacerbations, worsening episodes were analyzed with respect to age of onset, disease extent, disease severity at onset and worst of illness, acetyl choline receptor antibody positivity, thymectomy status, period of disease, pharmacotherapy and crisis episodes. RESULTS AND CONCLUSIONS: In this cohort the percentage of new remission rates per year steadily declined after the first year. Ocular myasthenia had lesser clinical worsening episodes and high chance of complete stable remission. Generalized disease had less chance drug free remission. The risk of episodes of worsening persisted at a steady rate over a period of time, being maximum in the first year. The risk of exacerbations was unpredictable and could occur after prolonged clinical quiescence, often was related to reduction of immunosuppression. The disease course did not differ significantly in the juvenile and adult age-groups. There was a strong case for permanent immunomodulation in MG.

Fellow eye vitrectomy for proliferative diabetic retinopathy in an inner city population.

AIM: To describe the rate of fellow eye vitrectomy for proliferative diabetic retinopathy in an inner city population. METHODS: Retrospective interventional case series. Medical and surgical records of 434 consecutive eyes of 358 patients undergoing primary diabetic vitrectomy in an inner city institutional practice were reviewed. Kaplan-Meier statistical analysis was employed to evaluate the rate of fellow eye vitrectomy and visual outcomes were determined for patients with ≥ 3 months follow-up. RESULTS: Fellow eyes underwent diabetic vitrectomy at a rate of 24% within 1 year, 34% within 3 years and 36% within 5 years of primary vitrectomy. A surgical indication of non-clearing vitreous haemorrhage (VH) in the primary eye was associated with a lower rate of fellow eye surgery compared with non-clearing VH with extrafoveal traction retinal detachment (TRD) at years 1, 3 and 5 (p ≤ 0.02), and TRD at years 3 and 5 (p ≤ 0.03). Younger patients underwent fellow eye vitrectomy at a higher rate than older patients (p ≤ 0.01). Surgical intervention was associated with improvement in mean visual acuity (p<0.01). CONCLUSIONS: Approximately a third of fellow eyes required diabetic vitrectomy within 3 years of primary eye vitrectomy. Primary eye surgical indication and younger age were significant predictors of need for fellow eye surgery.

Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A.

An in silico screen of the NIH Molecular Library Small Molecule Repository (MLSMR) of ∼350000 compounds and confirmatory bioassays led to identification of chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogues of 1 uncovered two compounds, talaroderxines A (2) and B (3), with improved activity. These are the first fungal metabolites reported to exhibit BoNT/A inhibitory activity.

Myocardial perfusion single photon emission computed tomography in asymptomatic diabetics.

BACKGROUND: Coronary artery disease (CAD) is the most important cause of mortality in diabetic patients. Diabetes mellitus (DM) due to autonomic neuropathy leads to asymptomatic CAD. Hence, it is important to screen the patients with DM for CAD. AIM: To study the prevalence of asymptomatic CAD by Myocardial Perfuision SPECT (Single Photon Emission Computed Tomography) (MPS) in diabetics. METHODS: This prospective study included 88 asymptomatic patients (58 males and 30 females) of Type 2 DM of more than 5 years duration in the age group of 40-65 years. Risk factors like hypertension, dyslipidemia, smoking, family history of CAD and Body Mass Index > or = 25 kg/sq.m were assessed. All these patients underwent MPS study as two day standard protocol. Thirty eight patients underwent invasive Coronary Angiography (CAG) and stenosis greater than 50% was considered significant. RESULTS: Abnormal perfusion was detected in 38 (43%) diabetics and 4 (11%) controls. A total of 81 perfusion defects were identified (19 fired and 62 reversible). CAG showed significant coronary stenosis in 26 (68.4%), insignificant in 8 (21%) and no stenosis in 4 (10.6%) patients. A total of 114 coronaries were analysed, significant stenosis in 67 (58.8%) coronaries, 21 (18.4%) had insignificant lesions and 26(22.8%) were normal. In comparison to CAG, MPS had sensitivity of 86.6% and specificity of 51%. CONCLUSION: The Myocardial Perfusion SPECT is a sensitive diagnostic tool to identify ischemia in asymptomatic diabetics. MPS can be used as screening test for risk stratification. It has a prognostic value in predicting the outcome of CAD and can be useful for long-term follow up too.

Comparison of two imaging protocols for acute stroke: unenhanced cranial CT versus a multimodality cranial CT protocol with perfusion imaging.

The aim of the study was to validate a multimodality cranial computed tomography (CCT) protocol for patients with acute stroke in the United Arab Emirates as a basic imaging procedure for a stroke unit. Therefore, a comparative study was conducted between two groups: retrospective, historical group 1 with early unenhanced CCT and prospective group 2 undergoing a multimodality CCT protocol. Follow-up unenhanced CCT>48 h served as gold standard in both groups. Group 1: Early unenhanced CCT of 50 patients were evaluated retrospectively, using Alberta Stroke Program Early CT Score, and compared with the definite infarction on follow-up CCT. Group 2: 50 patients underwent multimodality CCT (unenhanced CCT, perfusion studies: cerebral blood flow, cerebral blood volume, mean transit time and CT angiography)<8 h after clinical onset and follow-up studies. Modified National Institute of Health Stroke Scale was used clinically in both groups. Group 1 showed 38 men, 12 women, clinical onset 2-8 h before CCT and modified National Institute of Health Stroke Scale 0-28. Group 2 included 38 men, 12 women, onset 3-8 h before CCT, modified National Institute of Health Stroke Scale 0-28. Sensitivity was 58.3% in group 1 and 84.2% in group 2. Computed tomography angiography detected nine intracranial occlusions/stenoses. The higher sensitivity of the multimodality CCT protocol justifies its use as a basic diagnostic tool for the set-up of a first-stroke unit in the United Arab Emirates.

Purtscher's retinopathy that occurred 6 months before acute pancreatitis.

PURPOSE: To report Purtscher's retinopathy in a patient with chronic pancreatitis 6 months before the development of fulminant acute pancreatitis. DESIGN: Observational case report. METHODS: Review of clinical chart, photographs, fluorescein angiography, and optical coherence tomography. RESULTS: A 45-year-old man with a history of alcohol abuse with a 3-day history of decreased vision in both eyes was examined. Diffuse retinal whitening and intraretinal hemorrhages that were consistent with Purtscher's retinopathy were present in both eyes. Serum amylase and lipase levels were normal. Six months later, he experienced intractable abdominal pain. Serum amylase and lipase levels were elevated markedly. Abdominal computed tomography and endoscopic retrograde cholangiopancreatography confirmed acute pancreatitis, with evidence of coexisting chronic pancreatitis. His funduscopic examination after the development of acute pancreatitis was improved, with almost complete resolution of retinal whitening and hemorrhages. Visual acuity remained poor because of retinal ischemia. CONCLUSIONS: Purtscher's retinopathy can be associated with chronic pancreatitis and can precede the development of fulminant acute pancreatitis.