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.

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.

TLIF is Associated With Lower Rates of Adjacent Segment Disease and Complications Compared to ALIF: A Matched-Cohort Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare the rate of adjacent segment disease (ASD) in patients undergoing anterior lumbar interbody fusion (ALIF) versus transforaminal lumbar interbody fusion (TLIF) for the treatment of degenerative stenosis and spondylolisthesis. SUMMARY OF BACKGROUND DATA: ALIF and TLIF are frequently used to treat Lumbar stenosis and spondylolisthesis. While both approaches have distinct advantages, it is unclear whether there are any differences in rates of ASD and postoperative complications. METHODS: A retrospective cohort study of patients who underwent index 1-3 levels ALIF or TLIF between 2010 and 2022, using the PearlDiver Mariner Database, an all-claims insurance database (120 million patients). Patients with a history of prior lumbar surgery and those undergoing surgery for cancer, trauma, or infection were excluded. Exact 1:1 matching was performed using demographic factors, medical comorbidities, and surgical factors found to be significantly associated with ASD in a linear regression model. The primary outcome was a new diagnosis of ASD within 36 months of index surgery, and secondary outcomes were all-cause medical and surgical complications. RESULTS: Exact 1:1 matching resulted in 2 equal groups of 106,451 patients undergoing TLIF and ALIF. The TLIF approach was associated with a lower risk of ASD (RR 0.58, 95% CI 0.56-0.59, P < 0.001) and all-cause medical complications (RR 0.94, 95% CI 0.91-0.98, P =0.002). All-cause surgical complications were not significantly different between both groups. CONCLUSION: After 1:1 exact matching to control for confounding variables, this study suggests that for patients with symptomatic degenerative stenosis and spondylolisthesis, a TLIF procedure (compared to ALIF) is associated with a decreased risk of developing ASD within 36 months of index surgery. Future prospective studies are needed to corroborate these findings. LEVEL OF EVIDENCE: Level-3.

Preoperative HbA1c and Postoperative Outcomes in Spine Surgery: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To perform a systematic review and meta-analysis of previous studies on HbA1c in preoperative risk stratification in patients undergoing spinal procedures and provide an overview of the consensus recommendations. SUMMARY OF BACKGROUND DATA: Diabetes mellitus (DM) and hyperglycemia have been shown to be independent risk factors for increased surgical complications. Glycated Hemoglobin A1C (HbA1c), a surrogate for long term glycemic control, is an important preoperative parameter that may be optimized to reduce surgical complications and improve patient-reported outcomes. However, comprehensive systematic reviews on preoperative HbA1c and postoperative outcomes in spine surgery have been limited. METHODS: We systematically searched PubMed, EMBASE, Scopus, and Web-of-Science for English-language studies from inception through April 5 th , 2022, including references of eligible articles. The search was conducted according to PRISMA guidelines. Only studies in patients undergoing spine surgery with preoperative HbA1c values and postoperative outcomes available were included. RESULTS: A total of 22 articles (18 retrospective cohort studies, 4 prospective observational studies) were identified with level of evidence III or greater. The majority of studies (n=17) found that elevated preoperative HbA1c was associated with inferior outcomes or increased risk of complications. Random-effect meta-analysis demonstrated that patients with preoperative HbA1c >8.0% had increased risk(s) of postoperative complications (RR: 1.85, 95% CI: [1.48, 2.31], P <0.01) and that patients with surgical site infection (SSI) had higher preoperative HbA1c (Mean Difference: 1.49%, 95% CI: [0.11, 2.88], P =0.03). CONCLUSION: The findings of this study suggest that HbA1c >8.0% is associated with an increased risk of complications. HbA1c was higher by 1.49% on average among patients with SSI when compared to patients who did not experience SSI. These results suggest that elevated HbA1c is associated with less favorable outcomes following spine surgery. LEVEL OF EVIDENCE: IV.

Laminectomy With Fusion is Associated With Greater Functional Improvement Compared With Laminectomy Alone for the Treatment of Degenerative Lumbar Spondylolisthesis: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and Meta-analysis. OBJECTIVE: To compare outcomes and complications profile of laminectomy alone versus laminectomy and fusion for the treatment of degenerative lumbar spondylolisthesis (DLS). SUMMARY OF BACKGROUND DATA: Degenerative lumbar spondylolisthesis is a common cause of back pain and functional impairment. DLS is associated with high monetary (up to $100 billion annually in the US) and nonmonetary societal and personal costs. While nonoperative management remains the first-line treatment for DLS, decompressive laminectomy with or without fusion is indicated for the treatment-resistant disease. METHODS: We systematically searched PubMed and EMBASE for RCTs and cohort studies from inception through April 14, 2022. Data were pooled using random-effects meta-analysis. The risk of bias was assessed using the Joanna Briggs Institute risk of bias tool. We generated odds ratio and standard mean difference estimates for select parameters. RESULTS: A total of 23 manuscripts were included (n=90,996 patients). Complication rates were higher in patients undergoing laminectomy and fusion compared with laminectomy alone (OR: 1.55, P <0.001). Rates of reoperation were similar between both groups (OR: 0.67, P =0.10). Laminectomy with fusion was associated with a longer duration of surgery (Standard Mean Difference: 2.60, P =0.04) and a longer hospital stay (2.16, P =0.01). Compared with laminectomy alone, the extent of functional improvement in pain and disability was superior in the laminectomy and fusion cohort. Laminectomy with fusion had a greater mean change in ODI (-0.38, P <0.01) compared with laminectomy alone. Laminectomy with fusion was associated with a greater mean change in NRS leg score (-0.11, P =0.04) and NRS back score (-0.45, P <0.01). CONCLUSION: Compared with laminectomy alone, laminectomy with fusion is associated with greater postoperative improvement in pain and disability, albeit with a longer duration of surgery and hospital stay.

Bariatric Surgery Before Spine Surgery is Associated With Fewer Postsurgical Complications: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To perform a systematic review and meta-analysis investigating the rate of adverse events after spine surgery in patients who underwent bariatric surgery (BS). SUMMARY OF BACKGROUND DATA: Obesity is an established risk factor for postoperative complications after spine surgery. BS has been associated with improvements in health in patients with severe obesity. However, it is not known whether undergoing BS before spine surgery is associated with reduced adverse outcomes. MATERIALS AND METHODS: PubMed, EMBASE, Scopus, and Web-of-Science were systematically searched according to "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" guidelines. The search included indexed terms and text words from database inception to the date of the search (May 27, 2022). Data and estimates were pooled using the Mantel-Haenszel method for random-effects meta-analysis. Risk of bias was assessed using the Joanna Briggs Institute risk of bias tool. The primary outcome was an all-cause complication rate after surgery. Relative risks for surgical and medical complications were assessed. RESULTS: A total of 4 studies comprising 177,273 patients were included. The pooled analysis demonstrated that the all-cause medical complication rate after spine surgery was lower in patients undergoing BS (relative risk: 0.54, 95% CI: 0.39, 0.74, P < 0.01). There was no difference in rates of surgical complications and 30-day hospital readmission rates between the cohort undergoing BS before spine surgery and the cohort that did not. CONCLUSION: These analyses suggest that obese patients undergoing BS before spine surgery have significantly lower adverse event rates. Future prospective studies are needed to corroborate these findings. LEVEL OF EVIDENCE: 4.

Do Obese Patients Lose Weight After Lumbar Spine Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: Obesity is a major health care concern in the United States and is associated with high rates of postoperative complications after spine surgery. Obese patients assert that weight reduction is not possible unless spine surgery first relieves their pain and concomitant immobility. We describe the post-spine surgery effects on patient weight, with an emphasis on obesity. METHODS: PubMed, EMBASE, Scopus, Web of Science, and Cochrane databases were systematically searched according to the PRISMA guidelines. The search included indexed terms and text words from database inception to the date of the search (15 April 2022). Studies chosen for inclusion had to have data reporting on pre- and postoperative patient weight after spine surgery. Data and estimates were pooled using the Mantel-Haenszel method for random-effects meta-analysis. RESULTS: Eight articles encompassing 7 retrospective and 1 prospective cohort were identified. A random effects model analysis demonstrated that overweight and obese patients (body mass index [BMI], >25 kg/m2) had increased odds of clinically significant weight loss after lumbar spine surgery compared with non-obese patients (odds ratio, 1.63; 95% confidence interval, 1.43-1.86, P < 0.0001). There was no significant difference in the raw weight change between BMI categories (mean difference, -0.67 kg, 95% confidence interval, -4.71 to 3.37 kg, P = 0.7463). CONCLUSIONS: Compared with non-obese patients (BMI, <25 kg/m2), overweight and obese patients have higher odds of clinically significant weight loss after lumbar spine surgery. No difference in pre-operative and post-operative weight was found, although statistical power was lacking in this analysis. Randomized controlled trials and additional prospective cohorts are needed to further validate these findings.

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.

Novel transthyretin gene mutation in familial amyloid neuropathy in India: Case.

Familial amyloid polyneuropathy (PN), also known as amyloid transthyretin (TTR)-PN is an autosomal dominant adult-onset fatal disease, if not treated. It occurs due to mutations in (TTR) gene which leads to a faulty TTR protein which folds up to form amyloid and gets deposited mainly on nerves and causes length-dependent PN and autonomic dysfunction. We report a case of a 45-year-old female who presented with symptoms of painful peripheral neuropathy for 5 months, a history of deafness for 5 years, and cardiac pacemaker implantation 2 years ago for complete heart block. She denied any symptoms of autonomic dysfunction. Her brother with similar symptoms died of cardiac arrest at the age of 50 years. Clinical examination was suggestive of symmetrical sensorimotor PN. The nerve conduction study was suggestive of axonal sensorimotor PN. Abdominal fat biopsy was negative for amyloid. Sural nerve biopsy was suggestive of amyloid neuropathy. Genetic analysis showed c. 165G > T mutation encoding amino acid p. Lys55Asn on exon-4 of TTR gene. This mutation has not been reported from India.

Résumé La polyneuropathie amyloïde familiale (NP), également connue sous le nom de transthyrétine amyloïde (TTR) -PN, est une maladie mortelle autosomique dominante de l'adulte, si elle n'est pas traitée. Il se produit en raison de mutations du gène (TTR) qui conduisent à une protéine TTR défectueuse qui se replie pour former de l'amyloïde et se dépose principalement sur les nerfs et provoque une PN dépendante de la longueur et un dysfonctionnement autonome. Nous rapportons le cas d'une femme de 45 ans qui présentait des symptômes de neuropathie périphérique douloureuse depuis 5 mois, des antécédents de surdité depuis 5 ans et l'implantation d'un stimulateur cardiaque il y a 2 ans pour un bloc cardiaque complet. Elle a nié tout symptôme de dysfonctionnement autonome. Son frère présentant des symptômes similaires est décédé d'un arrêt cardiaque à l'âge de 50 ans. L'examen clinique évoquait une NP sensorimotrice symétrique. L'étude de la conduction nerveuse était évocatrice d'une NP sensorimotrice axonale. La biopsie de la graisse abdominale était négative pour l'amyloïde. La biopsie du nerf sural était évocatrice d'une neuropathie amyloïde. L'analyse génétique a montré c. Mutation 165G > T codant pour l'acide aminé p. Lys55Asn sur l'exon-4 du gène TTR. Cette mutation n'a pas été signalée en Inde. Mots clés: Neuropathie amyloïde familiale, tests génétiques, biopsie nerveuse, amylose à transthyrétine.

Automated in vivo compound screening with zebrafish and the discovery and validation of PD 81,723 as a novel angiogenesis inhibitor.

Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.

Estrogen Receptor-ß Agonists Modulate T-Lymphocyte Activation and Ameliorate Left Ventricular Remodeling During Chronic Heart Failure.

BACKGROUND: CD4+ T cells temporally transition from protective to pathological during ischemic heart failure (HF; 8 weeks postmyocardial infarction). Cellular mechanisms mediating this shift are unknown. METHODS: RNA-sequencing of cardiac CD4+ T cells and flow cytometric analysis of immune cells was conducted. RESULTS: RNA-sequencing of CD4+ T cells from the failing hearts of male mice indicated activation of ER (estrogen receptor)-α signaling. Flow cytometric analysis showed that ERα in CD4+ T cells decreases significantly at 3-day postmyocardial infarction but increases during HF. To antagonize ERα, we tested a novel ERß agonist (OSU-ERb-012) to inhibit T cells and blunt left ventricular remodeling. Proliferation assays showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks postmyocardial infarction and treated with either vehicle or drug (60 mg/kg per day; oral). While vehicle-treated HF mice displayed progressive left ventricular dilatation with significantly increased end-systolic and end-diastolic volumes from 4 to 8 weeks postmyocardial infarction, treatment with OSU-ERb-012 significantly blunted these changes and stopped left ventricular remodeling in both the sexes. Reduction in tibia-normalized heart and left ventricular weights, cardiomyocyte hypertrophy and interstitial fibrosis further supported these results. Additionally, OSU-ERb-012 treatment selectively inhibited cardiac, splenic, and circulating CD4+ T cells without affecting other myeloid and lymphoid cells in the HF mice. CONCLUSIONS: Our studies indicate that ERß agonists and OSU-ERb-012, in particular, could be used as selective immunomodulatory drugs to inhibit CD4+ T cells during chronic HF.

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.

Differential Regulation of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGEs) and Its Ligands S100A8/A9 Four Weeks Post an Exercise Intervention in a Cohort of Young Army Recruits.

Apart from its beneficial effects on cardiovascular risk factors, an anti-inflammatory effect of exercise is strongly implicated. Yet, data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a physical activity intervention on the soluble form of the receptor for advanced glycation end products (sRAGEs) and its ligands S100A8/A9. A total of 332 young army recruits volunteered and 169 completed the study. The participants underwent the standard basic training of Greek army recruits. IL-6, IL-1ß, S100A8/A9, and sRAGEs were measured at the beginning and at the end of the training period. Primary rodent adult aortic smooth muscle cells (ASMCs) were analyzed for responsiveness to direct stimulation with S100A8/A9 alone or in combination with sRAGEs. At the end of the training period, we observed a statistically significant reduction in S100A8/A9 (630.98 vs. 472.12 ng/mL, p = 0.001), IL-1ß (9.39 [3.8, 44.14] vs. 5.03 [2.44, 27.3] vs. pg/mL, p = 0.001), and sRAGEs (398.38 vs. 220.1 pg/mL, p = 0.001). IL-6 values did not change significantly after exercise. S100A8/A9 reduction was positively correlated with body weight (r = 0.236 [0.095, 0.370], p = 0.002) and BMI (r = 0.221 [0.092, 0.346], p = 0.004). Direct stimulation of ASMCs with S100A8/A9 increased the expression of IL-6, IL-1ß, and TNF-α and, in the presence of sRAGEs, demonstrated a dose-dependent inhibition. A 4-week military training resulted in significant reduction in the pro-inflammatory cytokines IL-1ß and S100A8/A9 complex. The observed reduction in sRAGEs may possibly reflect diminished RAGE axis activation. Altogether, our findings support the anti-inflammatory properties of physical activity.

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.

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.

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.

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.

Mesenchymal Stem/Stromal Cells Increase Cardiac miR-187-3p Expression in a Polymicrobial Animal Model of Sepsis.

ABSTRACT: Sepsis-induced myocardial dysfunction (MD) is an important pathophysiological feature of multiorgan failure caused by a dysregulated host response to infection. Patients with MD continue to be managed in intensive care units with limited understanding of the molecular mechanisms controlling disease pathogenesis. Emerging evidences support the use of mesenchymal stem/stromal cell (MSC) therapy for treating critically ill septic patients. Combining this with the known role that microRNAs (miRNAs) play in reversing sepsis-induced myocardial-dysfunction, this study sought to investigate how MSC administration alters miRNA expression in the heart. Mice were randomized to experimental polymicrobial sepsis induced by cecal ligation and puncture (CLP) or sham surgery, treated with either MSCs (2.5 × 105) or placebo (saline). Twenty-eight hours post-intervention, RNA was collected from whole hearts for transcriptomic and microRNA profiling. The top microRNAs differentially regulated in hearts by CLP and MSC administration were used to generate a putative mRNA-miRNA interaction network. Key genes, termed hub genes, within the network were then identified and further validated in vivo. Network analysis and RT-qPCR revealed that septic hearts treated with MSCs resulted in upregulation of five miRNAs, including miR-187, and decrease in three top hit putative hub genes (Itpkc, Lrrc59, and Tbl1xr1). Functionally, MSC administration decreased inflammatory and apoptotic pathways, while increasing cardiac-specific structural and functional, gene expression. Taken together, our data suggest that MSC administration regulates host-derived miRNAs production to protect cardiomyocytes from sepsis-induced MD.

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.