Preventing occludin tight-junction disruption via inhibition of microRNA-193b-5p attenuates viral load and influenza-induced lung injury.

Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.

Tiny Guides, Big Impact: Focus on the Opportunities and Challenges of miR-Based Treatments for ARDS.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions.

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Coimmunoprecipitation assays on control neutrophils challenged with interferon-γ and LPS showed that PD-L1 complexes with the p85 subunit of phosphatidyl 3-kinase (PI3K) to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared with wild-type animals, PD-L1-deficient animals presented lower levels of plasma tumor necrosis factor-α and interleukin-6 (IL-6) and higher levels of IL-10 after CLP, and reduced 7-day mortality in CLP PD-L1-knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.

Hepatic artery-related complications after live donor liver transplantation.

BACKGROUND: Hepatic artery-related complications (HARC) after live donor liver transplantation (LDLT) is associated with high morbidity and mortality rate. METHODS: Prospectively maintained data from July 2011 to September 2020 was analyzed for etiology, detection, management, and outcome of HARC. RESULTS: Six hundred fifty-seven LDLT (adult 572/pediatrics 85) were performed during the study period. Twenty-one (3.2%) patient developed HARC; 16 (2.4%) hepatic artery thrombosis (HAT) and 5 (0.76%) non-thrombotic hepatic artery complication (NTHAC). Ninety percent (19/21) HARC were asymptomatic and detected on protocol Doppler. Median time to detection was day 4 (range - 1 to 35), which included 18 early (within 7 days) vs 3 late incidents. Only one pediatric patient had HAT. Seven patients underwent surgical revascularization, 11 had endovascular intervention and 3 with attenuated flow required only systemic anticoagulation. All NTHAC survived without any sequelae. Revascularization was successful in 81% (13/16) with HAT. Biliary complications were seen in 5 (23.8%); four were managed successfully. Overall mortality was 14.8% (3/21). The 1-year and 5-year survival were similar to those who did not develop HARC (80.9% vs 84.2%, p = 0.27 and 71.4% vs 75.19%, p = 0.36 respectively) but biliary complications were significantly higher (23.8% vs 14.2%, p = 0.03). On multivariate analysis, clockwise technique of arterial reconstruction was associated with decreased risk of HAT (1.7% vs 4.1% (p value - 0.003)). CONCLUSION: Technical refinement, early detection, and revascularization can achieve good outcome in patients with HARC after LDLT.

Analysis and approach to renal trauma: A five-year experience at a level I trauma centre in north India.

PURPOSE: Renal trauma constitutes 0.5% - 5% of all trauma patients, and 10% - 20% of abdominal trauma. It is the most commonly injured organ in the genitourinary tract. Road traffic crash (RTC) is the most common cause. In recent years due to the advances in radiological imaging and endovascular techniques, there has been an increase in the nonoperative management of renal trauma. We investigated a large trauma cohort at a level I trauma centre to evaluate patients' demographics with renal trauma, their management, and the outcomes. METHODS: This was a retrospective analysis of the prospectively collected data of renal trauma patients managed from January 2016 to December 2020. Patients who visited the level I trauma centre in north India with renal trauma were included in this study. Patients who were dead on arrival in the emergency department were excluded. Demographics, mechanism of injury, presence of hemorrhagic shock, associated injuries, complications, length of hospital stay (LOS), discharge, and mortality were recorded. The data were entered in Microsoft Excel 365 and analysed using SPSS version 21. RESULTS: This study collected data from 303 renal trauma patients. Males constituted 86.5% of the patients. Most patients were young, aged from 20 - 40 years. Blunt renal trauma was the predominant mode of injury (n = 270, 89.1%). RTCs (n = 190, 62.7%) and falls from height (n = 65, 21.4%) were the 2 most common mechanisms of injury. Focused assessment with sonography in trauma was positive in 68.4% of patients. Grade III (grading by the American Association for the Surgery of Trauma) renal trauma (30.4%) was the most common grade in our study. The liver (n = 104, 34.3%) and splenic trauma (n = 96, 31.7%) were the most commonly associated injuries. Of the 303 patients, 260 (85.8%) were managed nonoperatively. The mean (SD) of the patients' LOS was 12.5 (6.5) days. There were 25 (8.3%) mortalities during the study period and all of them had associated other injuries. The comparison of LOS of isolated renal trauma group and renal trauma with associated injuries group was not statistically significant (p = 0.322). All the patients who died during the study period had renal trauma with associated other organ injuries. None of the patients with isolated renal trauma died during the study. The outcome comparison between both groups was not statistically significant (p = 0.110). CONCLUSION: Renal trauma predominantly occurs in young males, especially due to RTCs followed by fall from height. Focused assessment with sonography in trauma is not reliable in detecting renal injuries, other diagnostic tools such as contrast enhanced computed tomography torso should be considered in diagnosing and grading these injuries. Renal trauma usually does not occur in isolation. Majority are associated with other abdominal and extra abdominal injuries. Most of the times these injuries can be managed nonoperatively, which can achieve a low mortality. The patients who required surgery had high mortality as compared to patients who managed nonoperatively. These patients who required surgery had either severe renal or extra renal trauma and were in hemorrhagic shock. Renal trauma from this large cohort may contribute to improving the quality of care for patients with renal trauma by obtaining knowledge about the patient's characteristics, management, and outcomes.

Assessment of Psychological Well-being Among Medical Professionals Working with Patients Who Suffer from Physical Trauma: An Observational Study from India.

Background: Healthcare providers working with victims of physical trauma are exposed to significant human suffering at work. This may place them at risk of burnout, secondary traumatic stress (STS), and other psychological disturbances. This study aimed to evaluate the professional quality of life and psychological well-being among trauma professionals. Methodology: This was a cross-sectional study conducted among 153 staff members (nursing officers, resident doctors, and faculty) of a Level 1 trauma center in North India. The Professional Quality of Life (ProQoL-5) and Depression, Anxiety, and Stress (DASS-21) Scales were used. Results: More than 50% of the participants had a moderate risk of burnout and STS. In addition, 54% of participants reported having anxiety, 40% stress, and 36% depressive symptoms. Depression, anxiety, and stress were all strongly predicted by burnout and STS. Conclusion: Psychological distress symptoms were seen in a significant portion of professionals working in the trauma center. Workplace interventions for the promotion of psychological well-being among trauma professionals are recommended. How to cite this article: Gupta S, Bhatia G, Sagar R, Sagar S. Assessment of Psychological Well-being Among Medical Professionals Working with Patients Who Suffer from Physical Trauma: An Observational Study from India. Indian J Crit Care Med 2023;27(7):493-502.

Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury.

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.

Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis.

Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.

Estrogenic bias in T-Lymphocyte biology: Implications for cardiovascular disease.

Gender bias in cardiovascular disease has been extensively documented in epidemiological and clinical studies. Despite this, the precise molecular mechanisms underlying these disparities between men and women are poorly understood. It is clear that physiological concentrations of estradiol, such as those present in pre-menopausal women, exert cardioprotective effects that are absent in men or in post-menopausal women. These cardioprotective effects, in part, are due to the estrogen receptor-mediated modulation of the immune system including T-cells. Estrogen receptors (ERs) are widely expressed in different T-cell subsets which are known to play an indispensable role in the progression of cardiovascular disease. Because T-cells can be polarized into several distinct subsets depending on the activation milieu, they can have many different, potentially opposing functions, and it is unclear what roles estrogen receptor signaling may play in mediating these functions. This is further complicated by the discrete and often antagonistic actions of different ERs on T-cell biology which dictate the balance between numerous ER-dependent signaling pathways. While myriad effects of estrogen in T-cells are relevant for many cardiovascular diseases, their widespread effects on several other (patho)physiological systems introduce several obstacles to understanding ER signaling and its precise effects on the immune system. This review aims to provide a more comprehensive summary of the mechanisms of estrogen receptor-mediated modulation of T-cell function, polarization, and cytokine production in the context of cardiovascular disease.

Heat Shock Protein 70 Is Associated With Cardioversion Outcome and Recurrence of Symptomatic Recent Onset Atrial Fibrillation in Hypertensive Patients.

ABSTRACT: Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = -0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503-7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341-7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Intractable Pain Originating From a Lipofibromatous Hamartoma of the Median Nerve.

This case report presents an application of peripheral nerve stimulation to the median nerve to treat a patient with intractable pain due to a lipofibromatous hamartoma of the left upper extremity. Ultra high-frequency ultrasound was used to determine the boundaries of the hamartoma. The patient then underwent an ultrasound-guided implantation of 2 stimulator electrodes distal to the elbow along the median nerve with stimulation coverage achieved at 1.2 and 1.4 mA, respectively. After an uneventful procedure, the pain score immediately decreased from 9 out of 10 to less than 6 on a numeric rating scale. Two weeks after the procedure, the patient reported substantial pain relief, with an average pain level of 5 to 6 out of 10. Twelve months after implantation, the patient maintained significant pain relief, rating her average pain level as a 4 to 6 out of 10. Placement of a percutaneous peripheral nerve stimulator was safe and effective with no adverse events being reported at the 12-month follow-up.

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology.

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.

Epigenetic Profiling in Severe Sepsis: A Pilot Study of DNA Methylation Profiles in Critical Illness.

OBJECTIVES: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. DESIGN: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on "Day 1" of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as ß values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. SETTING: Tertiary care hospitals. SUBJECTS: Critically ill septic and nonseptic patients. INTERVENTIONS: Observational study. MEASUREMENTS AND MAIN RESULTS: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR ß I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ ß I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region-associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. CONCLUSIONS: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis.

GPIbα is required for platelet-mediated hepatic thrombopoietin generation.

Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα-/- mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα-/- platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα-/-, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα-/- mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα-/- platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα-/- platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbα-transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias.

Ultrasound-Guided Intercostal Peripheral Nerve Stimulator Implantation: Technique Report and Feasibility Study in a Cadaver.

OBJECTIVE: This study aimed to describe and validate a novel ultrasound-guided intercostal peripheral nerve stimulator implantation technique. METHODS: The fifth to tenth ribs on both sides of an unembalmed cadaveric specimen were localized using a 15-6-MHz linear array transducer, counting distally from T-1 bilaterally. A single interventionist then implanted 12 peripheral nerve stimulators on the fifth through tenth ribs, six MicroLeads on the left side and six StimRouters on the right side, using an in-plane lateral to medial approach to the inferior border of the corresponding rib. After all the stimulators were implanted, their location was confirmed using fluoroscopy. Gross anatomic dissection was later performed for each of the stimulators placed, and the distance of the lead from the intercostal nerve and pleura was noted. RESULTS: All leads were noted in an accurate position in the plane between the inner and innermost intercostal muscle, without any intrapleural placement. The distance of the leads from the intercostal nerves was on average 2.3 mm and 1.1 mm for MicroLead and StimRouter, respectively. CONCLUSIONS: To our knowledge, this study is the first to determine the feasibility of ultrasound-guided peripheral nerve stimulator placement in close proximity to the pleura. All the stimulator leads were accurately placed using our ultrasound-guided technique and were within 0.5-3 mm from the intercostal nerve. Although this technique might prove technically challenging, the use of ultrasound for intercostal peripheral nerve stimulator implantation appears feasible and warrants further investigation to establish this as an acceptable technique for patients.

Circulating Ligands of the Receptor for Advanced Glycation End Products and the Soluble Form of the Receptor Modulate Cardiovascular Cell Apoptosis in Diabetes.

We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided into two age groups: young = <35 years old or middle-aged (36-64 years old) and stratified based on normal glucose tolerance (NGT), impaired (IGT), and T2D. Plasma titers of sRAGE, the RAGE ligands, AGEs, S100B, S100A1, S100A6, and the apoptotic marker Fas ligand Fas(L) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic potential of the above RAGE ligands and sRAGE were assessed in cultured adult rat aortic smooth muscle cells (ASMC). In NGT individuals, aging increased the circulating levels of AGEs and S100B and decreased sRAGE, S100A1 and S100A6. Middle-aged patients with T2D presented higher levels of circulating S100B, AGEs and FasL, but lower levels of sRAGE, S100A1 and S100A6 than individuals with NGT or IGT. Treatment of ASMC with either AGEs or S100B at concentrations detected in T2D patients increased markers of inflammation and apoptosis. Responses attenuated by concomitant administration of sRAGE. In middle-aged patients with T2D, lower circulating plasma levels of sRAGE may limit decoy and exogenous trapping of deleterious pro-apoptotic/pro-inflammatory RAGE ligands AGEs and S100B, increasing the risk for diabetic complications.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation for the Treatment of Lower Extremity Pain: A Rare Case Report.

OBJECTIVE: This case report presents an application of percutaneous peripheral nerve stimulation to the right superficial peroneal nerve to treat a patient with chronic intractable L5-S1 radiculopathy pain that conventional treatment failed to ameliorate. METHODS: The patient underwent an uneventful implantation of a percutaneous peripheral nerve stimulator. The implanted lead (15 cm in length and 1.2 mm in diameter) containing the receiver coil and 3 stimulation electrodes (Bioness Stimrouter® , Valencia, CA, U.S.A.) was implanted parallel with the trajectory of the right superficial peroneal nerve. RESULTS: Two weeks after implantation of the percutaneous peripheral nerve stimulator, the patient experienced excellent pain relief and reported a significant increase in mobility. At the 3-month follow-up consultation, the patient reported maintenance of the reduction of pain in his right lower extremity as well as improved performance in his daily activities. CONCLUSION: Percutaneous peripheral nerve stimulation offers an alternative treatment option for intractable pain associated with chronic radiculopathy, especially for patients in whom conventional treatment options have been exhausted. Further clinical series involving larger numbers of patients are warranted in order to assess the definitive role of percutaneous peripheral nerve stimulation for the treatment of chronic intractable radiculopathy pain.

DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.

RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.

Urtica dioica modulates hippocampal insulin signaling and recognition memory deficit in streptozotocin induced diabetic mice.

Diabetes mellitus has been associated with functional abnormalities in the hippocampus and performance of cognitive function. Urtica dioica (UD) has been used in the treatment of diabetes. In our previous report we observed that UD extract attenuate diabetes mediated associative and spatial memory dysfunction. The present study aimed to evaluate the effect of UD extract on mouse model of diabetes-induced recognition memory deficit and explore the possible mechanism behind it. Streptozotocin (STZ) (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes followed by UD extract (50 mg/kg, oral) or rosiglitazone (ROSI) (5 mg/kg, oral) administration for 8 weeks. STZ induced diabetic mice showed significant decrease in hippocampal insulin signaling and translocation of glucose transporter type 4 (GLUT4) to neuronal membrane resulting in cognitive dysfunction and hypolocomotion. UD treatment effectively improved hippocampal insulin signaling, glucose tolerance and recognition memory performance in diabetic mice, which was comparable to ROSI. Further, diabetes mediated oxidative stress and inflammation was reversed by chronic UD or ROSI administration. UD leaves extract acts via insulin signaling pathway and might prove to be effective for the diabetes mediated central nervous system complications.

Resveratrol Protects against Sepsis-Associated Encephalopathy and Inhibits the NLRP3/IL-1ß Axis in Microglia.

Sepsis-associated encephalopathy (SAE) is characterized as brain dysfunction associated with sepsis. In this study we sought to investigate the effects of resveratrol in mice with SAE, as well as its effects in NLRP3 inflammasome and IL-1ß, which were critical in the pathogenesis of SAE. SAE was induced in mice via cecal ligation and puncture (CLP), and resveratrol was administered at two doses after surgery. Spatial learning memory functions were evaluated by Morris water maze testing. Apoptosis in the hippocampus was quantified using TUNEL assay. Inflammation in the hippocampus was quantified by measuring the levels of microglial activation, NLRP3, and IL-1ß. CLP mice treated with resveratrol demonstrated a better spatial memory during water maze training. The TUNEL assay demonstrated significantly attenuated rates of apoptosis, in resveratrol treated mice, while decreasing the number of iba-1 positive microglia in the hippocampus region. NLRP3 expression and IL-1ß cleavage were well inhibited by resveratrol dose-dependently. The in vitro results showed that in the BV2 cell lines resveratrol prevents ATP induced NLRP3 activation and IL-1ß cleavage, which were reversed by the sirtuin 1 inhibitor, nicotinamide. In conclusion, resveratrol improves the spatial memory in mice with SAE and inhibits the NLRP3/IL-1ß axis in the microglia.