RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus.

The antiviral endoribonuclease, RNase L, is activated by the mammalian innate immune response to destroy host and viral RNA to ultimately reduce viral gene expression. Herein, we show that RNase L and RNase L-mediated mRNA decay are primarily localized to the cytoplasm. Consequently, RNA-binding proteins (RBPs) translocate from the cytoplasm to the nucleus upon RNase L activation due to the presence of intact nuclear RNA. The re-localization of RBPs to the nucleus coincides with global alterations to RNA processing in the nucleus. While affecting many host mRNAs, these alterations are pronounced in mRNAs encoding type I and type III interferons and correlate with their retention in the nucleus and reduction in interferon protein production. Similar RNA processing defects also occur during infection with either dengue virus or SARS-CoV-2 when RNase L is activated. These findings reveal that the distribution of RBPs between the nucleus and cytosol is dictated by the availability of RNA in each compartment. Thus, viral infections that trigger RNase L-mediated cytoplasmic RNA in the cytoplasm also alter RNA processing in the nucleus, resulting in an ingenious multi-step immune block to protein biogenesis.

Lidocaine Infusion for the Treatment of Headache Associated With Subarachnoid Hemorrhage: A Case Report.

Headache after subarachnoid hemorrhage and corresponding craniotomy with aneurysm clipping can be severe and difficult to treat. Currently accepted analgesic therapies are often ineffective at treating the pain without incurring unacceptable side effects. We present an innovative approach wherein intravenous lidocaine infusions were used to successfully treat 2 patients with hyperalgesia refractory to traditional analgesic therapies. Opioid consumption fell to zero for both patients during lidocaine infusions without lidocaine toxicity. Moreover, after discontinuation of lidocaine infusions, both patients reported good pain control using only standard oral medications.

Comparison between cotton test and tap test for the assessment of coronal syndesmotic instability: A cadaveric study.

INTRODUCTION: In surgically treated rotational malleolar fractures, residual syndesmotic instability is typically assessed following fixation with the widely used intraoperative Cotton test. However, due to its dynamic nature, there are inconsistencies of the magnitude and direction of the distraction force when attempting to pull the fibula away from the tibia using a bone hook. The novel Tap test advances a cortical tap through a drilled hole in the fibula with a stable, unidirectional distraction force applied to the tibia. The objective of this cadaveric study was to compare the Cotton and Tap tests as diagnostic tools for coronal plane syndesmotic instability. METHODS: Tibiofibular Clear Space (TFCS) of 10 cadaveric specimens was measured for: intact, non-stressed; intact, stressed; injured, non-stressed; and injured, stressed (Tap and Cotton tests). In injured conditions, the syndesmotic ligamentous complex was sectioned using an anterolateral longitudinal approach. Perfect fluoroscopic Mortise images were acquired for all conditions. Two independent and blinded Orthopaedic Foot and Ankle Surgeons measured TFCS 1 cm proximal to the ankle joint line. Intra and interobserver reliabilities were assessed by Intraclass Correlation Coefficient. Syndesmotic TFCS values for all conditions were compared by paired Wilcoxon. Diagnostic performance of the Cotton and Tap tests was assessed using a relative increase of TFCS > 2 mm when comparing intact stressed and injured stressed conditions. P-values <0.05 were considered significant. RESULTS: The intraclass correlation coefficient for intraobserver and interobserver reliability was respectively 0.96 and 0.79. TFCS measurements were similar in intact non-stressed, intact stressed (both Cotton and Tap tests) and injured non-stressed conditions, with mean values and 95% Confidence Intervals of: intact non-stressed, 3.5 mm; intact stressed, 3.6 mm (Cotton test) and 4.0 mm (Tap test); injured non-stressed, 3.8 mm. The Cotton test and Tap test had, respectively, 73.3% and 70% sensitivity, 100% and 90% specificity, 86.7% and 80% diagnostic accuracy. CONCLUSIONS: Our cadaveric study compared the Cotton and Tap tests for detection of coronal plane syndesmotic instability. Both tests demonstrated similar increases in the TFCS measurements in stressed injured conditions when compared to intact non-stressed and stressed conditions, as well as injured non-stressed conditions.

Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD. METHODS: We reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment. RESULTS: A total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners. CONCLUSIONS: ATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.

Influence of Cytomegalovirus on the Survival of Cytomegalovirus-Seropositive Lung Transplant.

BACKGROUND: The primary aim of this study was to analyze the survival of patients undergoing lung transplant (LT) with cytomegalovirus (CMV)-positive serologies at the time of transplantation, according to the presence of CMV events and according to the severity of these events. The secondary objective was to assess whether there are differences in the incidence of chronic lung allograft dysfunction (CLAD) according to the presence of these events. METHODS: This was an observational, single-center, retrospective study. The inclusion criterion for the study was having undergone LT at the Hospital Universitario 12 de Octubre from October 2008 to February 2019. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. The incidence of CLAD was compared using the χ2 test. RESULTS: Inclusion criteria were met by 239 LTs. In terms of survival, no difference was found between patients with and without CMV events (log-rank P = .52), with mean survival of 3223 ± 164 days and 3024 ± 146 days, respectively. Nor did we find a difference when stratifying patients according to no CMV events, infection, syndrome, and disease (log-rank P = .6). There was also no difference in the incidence of CLAD between patients with and without CMV events (P > .178). CONCLUSION: In patients with positive CMV serology, the development of CMV events, including severe disease, does not seem to influence survival. The incidence of CLAD also is not increased by the presence of CMV events.

Oxidative Stress, Telomere Shortening, and Apoptosis Associated to Sarcopenia and Frailty in Patients with Multimorbidity.

BACKGROUND: The presence of oxidative stress, telomere shortening, and apoptosis in polypathological patients (PP) with sarcopenia and frailty remains unknown. METHODS: Multicentric prospective observational study in order to assess oxidative stress markers (catalase, glutathione reductase (GR), total antioxidant capacity to reactive oxygen species (TAC-ROS), and superoxide dismutase (SOD)), absolute telomere length (aTL), and apoptosis (DNA fragmentation) in peripheral blood samples of a hospital-based population of PP. Associations of these biomarkers to sarcopenia, frailty, functional status, and 12-month mortality were analyzed. RESULTS: Of the 444 recruited patients, 97 (21.8%), 278 (62.6%), and 80 (18%) were sarcopenic, frail, or both, respectively. Oxidative stress markers (lower TAC-ROS and higher SOD) were significantly enhanced and aTL significantly shortened in patients with sarcopenia, frailty or both syndromes. No evidence of apoptosis was detected in blood leukocytes of any of the patients. Both oxidative stress markers (GR, p = 0.04) and telomere shortening (p = 0.001) were associated to death risk and to less survival days. CONCLUSIONS: Oxidative stress markers and telomere length were enhanced and shortened, respectively, in blood samples of polypathological patients with sarcopenia and/or frailty. Both were associated to decreased survival. They could be useful in the clinical practice to assess vulnerable populations with multimorbidity and of potential interest as therapeutic targets.

Effects of propofol on ischemia-reperfusion and traumatic brain injury.

Oxidative stress exacerbates brain damage following ischemia-reperfusion and traumatic brain injury (TBI). Management of TBI and critically ill patients commonly involves use of propofol, a sedation medication that acts as a general anesthetic with inherent antioxidant properties. Here we review available evidence from animal model systems and clinical studies that propofol protects against ischemia-reperfusion injury. However, evidence of propofol toxicity in humans exists and manifests as a rare complication, "propofol infusion syndrome" (PRIS). Evidence in animal models suggests that brain injury induces expression of the p75 neurotrophin receptor (p75NTR), which is associated with proapoptotic signaling. p75NTR-mediated apoptosis of neurons is further exacerbated by propofol's superinduction of p75NTR and concomitant inhibition of neurotrophin processing. Propofol is toxic to neurons but not astrocytes, a type of glial cell. Evidence suggests that propofol protects astrocytes from oxidative stress and stimulates astroglial-mediated protection of neurons. One may speculate that in brain injury patients under sedation/anesthesia, propofol provides brain tissue protection or aids in recovery by enhancing astrocyte function. Nevertheless, our understanding of neurologic recovery versus long-term neurological sequelae leading to neurodegeneration is poor, and it is also conceivable that propofol plays a partial as yet unrecognized role in long-term impairment of the injured brain.

Atrioesophageal Fistula After Radiofrequency Ablation Presenting With Status Epilepticus: A Case Report.

Radiofrequency (RF) ablation for atrial fibrillation is commonly performed. Atrioesophageal fistulas are an uncommon complication of RF ablation and can present with status epilepticus due to an extensive vascular air embolus. Initial treatment may require a high level of suspicion of this rare occurrence to help prevent further injury and increase the likelihood of a meaningful recovery.

Impact of Sarcopenia and Frailty in a Multicenter Cohort of Polypathological Patients.

The prevalence, relationships and outcomes of sarcopenia and frailty in polypathological patients remain unknown. We performed a multicenter prospective observational study in six hospitals in order to assess prevalence, clinical features, outcome and associated risk factors of sarcopenia and frailty in a hospital-based population of polypathological patients. The cohort was recruited by performing prevalence surveys every 14 days during the inclusion period (March 2012-June 2016). Sarcopenia was assessed by means of EWGSOP criteria and frailty by means of Fried's criteria. Skeletal muscle mass was measured by tetrapolar bioimpedanciometry. All patients were followed for 12 months. Factors associated with sarcopenia, frailty and mortality were analyzed by multivariate logistic regression, and Kaplan-Meier curves. A total of 444 patients (77.3 ± 8.4 years, 55% males) were included. Sarcopenia was present in 97 patients (21.8%), this being moderate in 54 (12.2%), and severe in 43 (9.6%); frailty was present in 278 patients (62.6%), and 140 (31.6%) were pre-frail; combined sarcopenia and frailty were present in the same patient in 80 (18%) patients. Factors independently associated to the presence of both, sarcopenia and frailty were female gender, older age, different chronic conditions, poor functional status, low body mass index, asthenia and depressive disorders, and low leucocytes and lymphocytes count. Mortality in the 12-months follow-up period was 40%. Patients with sarcopenia, frailty or both survived significantly less than those without these conditions. Sarcopenia and frailty are frequent and interrelated conditions in polypathological patients, shadowing their survival. Their early recognition and management could improve health-related outcomes in this population.

Inhibition of cardiac Na+ current by primaquine.

The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na(+) channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked I(Na)(+) in a dose-dependent manner, with a K(d) of 8.2 microM. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of I(Na)(+) inactivation, and (iii) slowed the fast component for recovery of I(Na)(+) from inactivation. Primaquine had no effect on: (i) the shape of the I - V curve, (ii) the reversal potential for Na(+), (iii) the steady-state inactivation and g(Na)(+) curves, (iv) the fast time constant of inactivation of I(Na)(+), and (v) the slow component of recovery from inactivation. Block of I(Na)(+) by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na(+) channels by primaquine. These results suggest that primaquine blocks cardiac Na(+) channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na(+) channels, with subsequent disturbances of impulse conductance and contractility.