Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Asymmetrically coupled resonators for mass sensing

Mechanically coupled resonators have been applied in the last years to the development of nanomechanical mass-sensors based on the detection of the different vibration modes of the system by measuring on a single resonator. Their sensitivity and capability for detecting multiple analytes strongly depends on the design and coupling strength between the mechanically coupled resonators in an array format. We present a theoretical and experimental study of the behavior of an asymmetrically coupled array of four different resonators. These doubly clamped beam resonators are elastically coupled by an overhang region of varying length along the transversal axis of the array. The results show that parameters such as the gap between microbeams and the overhang length affect the coupling strength, tuning the system from highly disordered and highly localized (weak coupling) to highly delocalized (strong coupling). In the strong coupling and partially localized case, the distances between resonant peaks are larger, reaching higher eigenfrequency values. In this case, relative changes in a specific eigenstate, due to an added mass, can be markedly large due to the energy distribution over a single microbeam. A strong coupling also facilitates performing the detection on the relative frequency shift mode, which can usually be resolved with better precision than the amplitude changes

The role of dystroglycan in PDGF-BB-dependent migration of activated hepatic stellate cells/myofibroblasts

Hepatic stellate cells are embedded in the loose connective tissue matrix within the space of Disse. This extracellular matrix contains several basement membrane components including laminin, but its composition changes during liver injury because of the production of extracellular matrix components found in scar tissue. These changes in extracellular matrix composition and in cell-extracellular matrix interactions may play a key role in hepatic stellate cell transdifferentiation. In this communication we used early passages of mouse hepatic stellate cells (activated HSC/ myofibroblasts) to study the platelet-derived growth factor BB (PDGF-BB)-dependent expression and regulation of ?-dystroglycan and its role in activated HSC/myofibroblast migration. We used Northern and Western analysis to study dystroglycan expression and confocal microscopy to investigate changes in subcellular distribution of the protein. Activated HSC migration was investigated using an in vitro wound-healing assay. PDGF-BB induced significant changes in dystroglycan regulation and subcellular distribution of the protein. Whereas steady-state levels of dystroglycan mRNA remained constant, PDGF-BB increased dystroglycan transcription but shortened the t1/2 by 50%. Moreover, PDGF-BB changed dystroglycan and ?5-integrin cellular distribution. Cell migration experiments revealed that PDGF-BB-dependent migration of activated HSC/myofibroblasts was completely blocked by neutralizing antibodies to fibronectin, ?5-integrin, laminin, and ?-dystroglycan. Overall, these findings suggest that both laminin and fibronectin and their receptors play a key role in PDGF-BB-induced activated HSC migration. � 2011 the American Physiological Society

Iliac artery reconstruction secondary to incidental injury in open hernia repair: A case report and literature review

Introduction: Inguinal hernia repair is one of the most common surgeries performed worldwide by general surgeons. More than 750,000 inguinal hernia repairs are performed each year in the United States. Complications of inguinal or femoral hernia are relatively rare, depending on the clinical circumstances in which the patient is admitted to the operating room and the type of hernia. The complications are classified as: intraoperative, short term and long term. Arterial lesions are the rarest but most dangerous. Objective: To describe surgical techniques used to repair injuries to the external iliac artery during an inguinal hernia repair that is reproducible by general surgeons. Materials and methods: A case report of an intraoperative external iliac artery injury is presented in which is a polytetrafluoroethylene (PTFE) graft was used over the length of the lesion. Different techniques may be used for revascularisation: autogenous vein graft, synthetic grafts, revascularisation with ipsilateral or contralateral internal iliac artery and femoro-femoral crossover graft. Conclusion: The surgical technique using PTFE grafts is effective for repairing arterial injuries and it results in timely revascularisation that promotes satisfactory progress. Resumen: Introducción: La plastia inguinal es una de las cirugías más frecuente realizadas a nivel mundial por cirujanos generales. En Estados Unidos más de 750,000 hernioplastias inguinales se realizan por año. Las complicaciones de una hernia inguinal o femoral son relativamente infrecuentes, depende de las circunstancias clínicas en las que se ingresa a quirófano y el tipo de la hernia. Las complicaciones se clasifican en: intraoperatoría, a corto plazo y a largo plazo. Las lesiones arteriales son las más raras pero más graves. Objetivo: Describir técnicas quirúrgicas para reparación de lesiones de la arteria iliaca durante una plastia inguinal y reproducible por cirujanos generales. Material y método: Se presenta un caso clínico con lesión de arteria iliaca externa intraoperatoría la cual se realiza injerto de politetrafluoroetileno (PTFE) por la longitud de la lesión. Se puede utilizar diferentes técnicas para la revascularización: injerto de vena autóloga, injertos sintéticos, revascularización con arteria hipogástrica ipsi o contralateral e injerto cruzado femoro-femoral. Conclusión: La técnica quirúrgica utilizando injerto de PTFE es eficaz para la reparación de lesión arterial y tener una revascularización oportuna que favorece una satisfactoria evolución. Keywords: Hernia, Inguinal, Iliac artery, Injury, Grafts, Palabras clave: Hernia, Inguinal, Arteria iliaca, Lesión, Injerto

Performance evaluation of CCOs for the optimization of low-power pressure-based implantable wireless systems

Implantable biomedical devices intended for remote follow-up of Cardiovascular Diseases (CVD) are often based on MEMS pressure sensors and the corresponding CMOS electronics, which are responsible for powering, signal conditioning and data transmission. This kind of heterogeneous systems achieves reduced dimensions and consumption by monolithic integration on the same silicon substrate. The objective of this work is to analyze and fully characterize several Capacitor-Controlled Oscillator (CCO) topologies that can be used for the aforementioned implantable applications, by comparison of their most relevant performance parameters. The results will allow the design optimization of low-power wireless implants, aimed at a future development of embedded systems with real-time data acquisition. Five topologies have been chosen for the evaluation: a standard ring oscillator; a current-starved ring oscillator; a Lee-Kim fully-differential oscillator; a coupled Sawtooth oscillator, and a modified Sawtooth oscillator designed for CCOs biased by a ramped voltage signal. Comprehensive simulations allowed the estimation of the output frequency, percentage tuning range, maximum linearity error, phase noise and power consumption for each design, as well as a Figure of Merit, for every CCO. For the calculation of these performance metrics, the impact of biasing circuits and different tuning strategies has also been considered.This work was carried out in collaboration with the Hospital Marqués de Valdecilla and its medical research institute IDIVAL, in the context of the “Self-Expanding Dual-Anchor Umbrella with Wireless Monitoring Feature of Intra-Atrial Pressure” project (DTS19/00094). Financial support is provided by the Ministerio de Ciencia, Innovación y Universidades (Spanish Goverment), by means of its annual call for Technological Development Projects in Health (DTS2019) under the framework of the Health Research and Development Strategy (AES) that, in turn, belongs to the State Plan for Scientific and Technical Research and Innovation 2017-2020, whose objectives are aligned with the ones highlighted by the European Union under Horizon 2020

Supplementary Material for: Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study

<p><b><i>Background:</i></b> An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. <b><i>Methods:</i></b> The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. <b><i>Results:</i></b> Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. <b><i>Conclusions:</i></b> Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.</p