Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy.

BACKGROUND: Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis. METHODS: H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin µ, PFTµ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype. RESULTS: Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTµ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTµ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival. CONCLUSION: Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.

Validation of modular endoscopic medial maxillectomies for inverted papilloma of the maxillary sinus.

BACKGROUND: Treatment of inverted papilloma of the maxillary sinus (IPMS) has a lower success rate compared to other IPs. As such, its correct management generally needs trans-nasal endoscopic medial maxillectomy (EMMs) for adequate resection. The aim of this manuscript is to describe outcomes and major prognostic factors of a cohort of patients with IPMS who were treated with EMM. METHODOLOGY: In this multicentric study, patients affected with IPMS and treated with EMMs were included. The site of origin of the IPMS were studied as well as the type of EMM performed. The histological features (IP vs dysplasia), type of mucosal resection (total vs. pedicle oriented), and post-operative complications were analyzed. RESULTS: 310 patients were included (212 primary and 98 recurrent cases). After a mean follow-up of 45.4 months, 15 patients experienced recurrence (4.8%) due to the application of EMMs tailored to the surgical insertion point. Dysplasia was significantly associated with a higher risk of recurrence. The rates of early and late complications were 11.6% and 11.9%, respectively. CONCLUSIONS: IPMS resection via tailored EMM is associated with excellent disease control, thus excluding the systematic use of extended EMMs, which can however be justified in case of dysplastic IPMS given its significant impact on recurrence.

"Big Data" Analyses Underlie Clinical Discoveries at the Aortic Institute.

This issue of the Yale Journal of Biology and Medicine (YJBM) focuses on Big Data and precision analytics in medical research. At the Aortic Institute at Yale New Haven Hospital, the vast majority of our investigations have emanated from our large, prospective clinical database of patients with thoracic aortic aneurysm (TAA), supplemented by ultra-large genetic sequencing files. Among the fundamental clinical and scientific discoveries enabled by application of advanced statistical and artificial intelligence techniques on these clinical and genetic databases are the following: From analysis of Traditional "Big Data" (Large data sets). 1. Ascending aortic aneurysms should be resected at 5 cm to prevent dissection and rupture. 2. Indexing aortic size to height improves aortic risk prognostication. 3. Aortic root dilatation is more malignant than mid-ascending aortic dilatation. 4. Ascending aortic aneurysm patients with bicuspid aortic valves do not carry the poorer prognosis previously postulated. 5. The descending and thoracoabdominal aorta are capable of rupture without dissection. 6. Female patients with TAA do more poorly than male patients. 7. Ascending aortic length is even better than aortic diameter at predicting dissection. 8. A "silver lining" of TAA disease is the profound, lifelong protection from atherosclerosis. From Modern "Big Data" Machine Learning/Artificial Intelligence analysis: 1. Machine learning models for TAA: outperforming traditional anatomic criteria. 2. Genetic testing for TAA and dissection and discovery of novel causative genes. 3. Phenotypic genetic characterization by Artificial Intelligence. 4. Panel of RNAs "detects" TAA. Such findings, based on (a) long-standing application of advanced conventional statistical analysis to large clinical data sets, and (b) recent application of advanced machine learning/artificial intelligence to large genetic data sets at the Yale Aortic Institute have advanced the diagnosis and medical and surgical treatment of TAA.

Drp1/Fis1-Dependent Pathologic Fission and Associated Damaged Extracellular Mitochondria Contribute to Macrophage Dysfunction in Endotoxin Tolerance.

OBJECTIVES: Recent publications have shown that mitochondrial dynamics can govern the quality and quantity of extracellular mitochondria subsequently impacting immune phenotypes. This study aims to determine if pathologic mitochondrial fission mediated by Drp1/Fis1 interaction impacts extracellular mitochondrial content and macrophage function in sepsis-induced immunoparalysis. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: C57BL/6 and BALB/C mice. INTERVENTIONS: Using in vitro and murine models of endotoxin tolerance (ET), we evaluated changes in Drp1/Fis1-dependent pathologic fission and simultaneously measured the quantity and quality of extracellular mitochondria. Next, by priming mouse macrophages with isolated healthy mitochondria (MC) and damaged mitochondria, we determined if damaged extracellular mitochondria are capable of inducing tolerance to subsequent endotoxin challenge. Finally, we determined if inhibition of Drp1/Fis1-mediated pathologic fission abrogates release of damaged extracellular mitochondria and improves macrophage response to subsequent endotoxin challenge. MEASUREMENTS AND MAIN RESULTS: When compared with naïve macrophages (NMs), endotoxin-tolerant macrophages (ETM) demonstrated Drp1/Fis1-dependent mitochondrial dysfunction and higher levels of damaged extracellular mitochondria (Mitotracker-Green + events/50 µL: ETM = 2.42 × 106 ± 4,391 vs NM = 5.69 × 105 ± 2,478; p < 0.001). Exposure of NMs to damaged extracellular mitochondria (MH) induced cross-tolerance to subsequent endotoxin challenge, whereas MC had minimal effect (tumor necrosis factor [TNF]-α [pg/mL]: NM = 668 ± 3, NM + MH = 221 ± 15, and NM + Mc = 881 ± 15; p < 0.0001). Inhibiting Drp1/Fis1-dependent mitochondrial fission using heptapeptide (P110), a selective inhibitor of Drp1/Fis1 interaction, improved extracellular mitochondrial function (extracellular mitochondrial membrane potential, JC-1 [R/G] ETM = 7 ± 0.5 vs ETM + P110 = 19 ± 2.0; p < 0.001) and subsequently improved immune response in ETMs (TNF-α [pg/mL]; ETM = 149 ± 1 vs ETM + P110 = 1,150 ± 4; p < 0.0001). Similarly, P110-treated endotoxin tolerant mice had lower amounts of damaged extracellular mitochondria in plasma (represented by higher extracellular mitochondrial membrane potential, TMRM/MT-G: endotoxin tolerant [ET] = 0.04 ± 0.02 vs ET + P110 = 0.21 ± 0.02; p = 0.03) and improved immune response to subsequent endotoxin treatment as well as cecal ligation and puncture. CONCLUSIONS: Inhibition of Drp1/Fis1-dependent mitochondrial fragmentation improved macrophage function and immune response in both in vitro and in vivo models of ET. This benefit is mediated, at least in part, by decreasing the release of damaged extracellular mitochondria, which contributes to endotoxin cross-tolerance. Altogether, these data suggest that alterations in mitochondrial dynamics may play an important role in sepsis-induced immunoparalysis.

Use Characteristics and Triage Acuity of a Digital Symptom Checker in a Large Integrated Health System: Population-Based Descriptive Study.

BACKGROUND: Pressure on the US health care system has been increasing due to a combination of aging populations, rising health care expenditures, and most recently, the COVID-19 pandemic. Responses to this pressure are hindered in part by reliance on a limited supply of highly trained health care professionals, creating a need for scalable technological solutions. Digital symptom checkers are artificial intelligence-supported software tools that use a conversational "chatbot" format to support rapid diagnosis and consistent triage. The COVID-19 pandemic has brought new attention to these tools due to the need to avoid face-to-face contact and preserve urgent care capacity. However, evidence-based deployment of these chatbots requires an understanding of user demographics and associated triage recommendations generated by a large general population. OBJECTIVE: In this study, we evaluate the user demographics and levels of triage acuity provided by a symptom checker chatbot deployed in partnership with a large integrated health system in the United States. METHODS: This population-based descriptive study included all web-based symptom assessments completed on the website and patient portal of the Sutter Health system (24 hospitals in Northern California) from April 24, 2019, to February 1, 2020. User demographics were compared to relevant US Census population data. RESULTS: A total of 26,646 symptom assessments were completed during the study period. Most assessments (17,816/26,646, 66.9%) were completed by female users. The mean user age was 34.3 years (SD 14.4 years), compared to a median age of 37.3 years of the general population. The most common initial symptom was abdominal pain (2060/26,646, 7.7%). A substantial number of assessments (12,357/26,646, 46.4%) were completed outside of typical physician office hours. Most users were advised to seek medical care on the same day (7299/26,646, 27.4%) or within 2-3 days (6301/26,646, 23.6%). Over a quarter of the assessments indicated a high degree of urgency (7723/26,646, 29.0%). CONCLUSIONS: Users of the symptom checker chatbot were broadly representative of our patient population, although they skewed toward younger and female users. The triage recommendations were comparable to those of nurse-staffed telephone triage lines. Although the emergence of COVID-19 has increased the interest in remote medical assessment tools, it is important to take an evidence-based approach to their deployment.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Postoperative long-term morbidity of extended endoscopic maxillectomy for inverted papilloma.

BACKGROUND: Extended endoscopic maxillectomy (Sturmann-Canfield procedure) allows full visualization of the maxillary sinus by sectioning the lacrimal duct and removing the medial part of the anterior maxillary wall. The aim of this study is to evaluate the morbidity of Sturmann-Canfield procedure in patients treated for inverted papilloma. METHODOLOGY: The clinical records of all patients treated with a Sturmann-Canfield procedure for inverted papilloma from October 2000 to September 2015 at two teaching hospitals were reviewed. All patients were evaluated by nasal endoscopy and lacrimal system patency was assessed. Pre-maxillary cutaneous sensitivity was tested with a Semmes-Weinstein aesthesiometer and thermic stimulation. The SNOT-22 questionnaire was administered. Patients were also asked to report any other post-surgical complaints. RESULTS: Fifty-nine patients were identified. Mean follow-up after surgery was 66.3 months. Mean SNOT-22 score was 5.94 (range 0-20); the majority of patients (86%) had a SNOT-22 symptom score of 3 or lower. Mucocoele occurred in 3 (5%) cases. Lacrimal pathway obstruction was observed in 7 (12%) patients. Fourteen (24%) patients complained of paraesthesia in the malar area; hypoesthesia was present in only 5 (8%) cases. Hypoesthesia in the region innervated by the anterior superior alveolar nerve was detected in 17 (29%) patients. One patient reported a slight depression of paralateronasal soft tissues. CONCLUSIONS: Although nasal function outcomes and the results from SNOT-22 questionnaires were favourable, a high rate of neurologic and lacrimal complications was observed. Potential morbidity of the intervention, including the possibility of negative aesthetic sequelae, should be discussed during preoperative counselling.

Experimental Investigation of the Collective Raman Scattering of Multiple Laser Beams in Inhomogeneous Plasmas.

Experiments have been performed evidencing significant stimulated Raman sidescattering (SRS) at large angles from the density gradient. This was achieved in long scale-length high-temperature plasmas in which two beams couple to the same scattered electromagnetic wave further demonstrating for the first time this multiple-beam collective SRS interaction. The collective nature of the coupling and the amplification at large angles from the density gradient increase the global SRS losses and produce light scattered in novel directions out of the planes of incidence of the beams. These findings obtained in plasmas conditions relevant of inertial confinement fusion experiments similarly apply to the more complex geometry of these experiments where anomalously large levels of SRS were measured.

Expanded endoscopic endonasal surgery for advanced stage juvenile angiofibromas: a retrospective multi-center study.

OBJECTIVES: Endoscopic resection has become an established surgical option for most juvenile nasopharyngeal angiofibromas (JNA). However, surgical management of JNA with intracranial extension remains challenging. This retrospective multicenter study reviews a series of patients with advanced stage JNA treated via endonasal/endoscopic approach. METHODS: The experience of five academic tertiary or quaternary care ORL-HNS Departments were included. Medical records of all patients operated for JNA staged as Radkowski stage IIIA or IIIB were reviewed. Main outcome measures included intraoperative blood loss, length of hospital stay, complication rate, and rate of persistence or recurrence. RESULTS: A total of 74 male patients with stages IIIA and IIIB were included. The mean age was 16.4 years and preoperative embolization was performed in 71 patients. The mean blood loss in 45 patients for whom the data was available was 1279.7 ml. The more anatomic subsites were involved, the higher the risk was of intraoperative bleeding. The mean follow-up for 54 out of 73 patients was 37.9 months. Patients with residual disease are significantly linked to involvement of combined (anterior-lateral and posterior) anatomic subsites and to a higher number of affected subsites. At last follow-up, all patients were asymptomatic and those with residual tissue displayed no imaging signs of growth. CONCLUSIONS: This retrospective multicenter study supports the notion that expanded endonasal endoscopic approaches for advance staged JNA are a feasible option associated with good long-term results.

Symmetrical anatomical variant of the anterior belly of the digastric muscle: clinical implicat.

The digastric muscle is an important surgical landmark. Several anatomical variants of the digastric muscle are reported in literature and, in particular, the presence of accessory anterior bellies of the muscle is not uncommon. Here, an unreported symmetrical variant of the digastric muscle was found during a dissection of the suprahyoid region. The dissection showed digastric muscles with an accessory anterior belly, which originated from the anterior belly of muscles in proximity and anteriorly to the intermediate tendon. The accessory bellies were fused together on the midline and were attached with a unique tendon to the inner surface of the mental symphysis. These muscles completely filled the submental triangle. This unreported anatomical variant could be considered an additional contribution to description of the anatomical variants of the digastric muscle, with several implications in head and neck pathology, diagnosis and surgery.

Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD.

ABSTRACT: Despite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APCs. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of major histocompatibility complex II (MHC-II), costimulatory CD86, and proinflammatory cytokines, resulting in increased donor T-cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC-mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggest that pre-HSCT conditioning results in extracellular release of damaged mitochondria, which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria after conditioning could serve as a novel strategy for GVHD prevention.

Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart.

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury.

A machine learning approach for predicting complications in descending and thoracoabdominal aortic aneurysms.

OBJECTIVE: To use machine learning to predict rupture, dissection, and all-cause mortality for patients with descending and thoracoabdominal aortic aneurysms in an effort to improve on diameter-based surgical intervention criteria. METHODS: Retrospective data from 1083 patients with descending aortic diameters 3.0 cm or greater were collected, with a mean follow-up time of 3.52 years and an average descending diameter of 4.13 cm. Six machine learning classifiers were trained using 44 variables to predict the occurrence of dissection, rupture, or all-cause mortality within 1, 2, or 5 years of initial patient encounter for a total of 54 (6 × 3 × 3) separate classifiers. Classifier performance was measured using area under the receiver operator curve. RESULTS: Machine learning models achieved area under the receiver operator curves of 0.842 to 0.872 when predicting type B dissection, 0.847 to 0.856 when predicting type B dissection or rupture, and 0.820 to 0.845 when predicting type B dissection, rupture, or all-cause mortality. All models consistently outperformed descending aortic diameter across all end points (area under the receiver operator curve = 0.713-0.733). Feature importance inspection showed that other features beyond aortic diameter, such as a history of myocardial infarction, hypertension, and patient sex, play an important role in improving risk prediction. CONCLUSIONS: This study provides surgeons with a more accurate, machine learning-based, risk-stratification metric to predict complications for patients with descending aortic aneurysms.

Bicuspid aortopathy does not require earlier surgical intervention.

OBJECTIVES: Guidelines for surgical correction of patients with ascending thoracic aortic aneurysm (ATAA) with a bicuspid aortic valve (BAV) have oscillated over the years. In this study, we outline the natural history of the ascending aorta in patients with BAV and trileaflet aortic valve (TAV) ATAA followed over time, to ascertain if their behavior differs and to determine if a different threshold for intervention is required. METHODS: Aortic diameters and long-term complications (ie, adverse aortic events) of 2428 patients (554 BAV and 1874 TAV) with ATAA before operative repair were reviewed. Growth rates, yearly complication rates, event-free survival, and risk of complications as a function of aortic size were calculated. Long-term follow-up and precise cause of death granularity was achieved via a comprehensive 6-pronged approach. RESULTS: Aortic growth rate in patients with BAV vs TAV ATAA was 0.20 and 0.17 cm/year, respectively (P = .009), with the rate increasing with increasing aortic size. Yearly adverse aortic events rates increased with ATAA size and were lower for patients with BAV. The relative risk of adverse aortic events exhibited an exponential increase with aortic diameter. Patients with BAV had a lower all-cause and ascending aorta-specific adverse aortic events hazard. Age-adjusted 10-year event-free survival was significantly better for patients with BAV, and BAV emerged as a protective factor against type A dissection, rupture, and ascending aortic death. CONCLUSIONS: The threshold for surgical repair of ascending aneurysm with BAV should not differ from that of TAV. Prophylactic surgery should be considered at 5.0 cm for patients with TAV (and BAV) at expert centers.

Haptic feedback in OP:Sense - augmented reality in telemanipulated robotic surgery.

In current research, haptic feedback in robot assisted interventions plays an important role. However most approaches to haptic feedback only regard the mapping of the current forces at the surgical instrument to the haptic input devices, whereas surgeons demand a combination of medical imaging and telemanipulated robotic setups. In this paper we describe how this feature is integrated in our robotic research platform OP:Sense. The proposed method allows the automatic transfer of segmented imaging data to the haptic renderer and therefore allows enriching the haptic feedback with virtual fixtures based on imaging data. Anatomical structures are extracted from pre-operative generated medical images or virtual walls are defined by the surgeon inside the imaging data. Combining real forces with virtual fixtures can guide the surgeon to the regions of interest as well as helps to prevent the risk of damage to critical structures inside the patient. We believe that the combination of medical imaging and telemanipulation is a crucial step for the next generation of MIRS-systems.

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury.

Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.

Magnetically guided fast electrons in cylindrically compressed matter.

Fast electrons produced by a 10 ps, 160 J laser pulse through laser-compressed plastic cylinders are studied experimentally and numerically in the context of fast ignition. K(α)-emission images reveal a collimated or scattered electron beam depending on the initial density and the compression timing. A numerical transport model shows that implosion-driven electrical resistivity gradients induce strong magnetic fields able to guide the electrons. The good agreement with measured beam sizes provides the first experimental evidence for fast-electron magnetic collimation in laser-compressed matter.

Isolated sphenoid inflammatory diseases associated with visual impairment: 15-year experience at a single institution.

We present a retrospective series of 11 patients treated for isolated sphenoid inflammatory disease (ISID) with visual impairment in the period between 1994 and 2008. The series included 7 females and 4 males. All patients, preoperatively assessed by CT or MR, underwent endoscopic sinus surgery and broad-spectrum antibiotic therapy. The procedure was always performed in an emergency setting, with an interval from the onset of visual impairment ranging between 1 and 40 days (mean 9 days). The possibility of recovery was related to both the modality of onset and severity of the deficit. All patients with reduction of the visual field reported significant improvement after surgery. Patients with decreased visual acuity obtained partial or complete resolution, while in patients with preoperative blindness no improvement was observed. Moreover, no postoperative improvement was noticed in the case of severe deficits with sudden onset, whereas the treatment of mild deficits was successful even some weeks after their occurrence. In conclusion, although some factors may predict the likelihood of recovery, any patient with ISID associated with visual impairment should receive immediate medical and surgical treatment. Endoscopic surgery should be considered the technique of choice.