Light Alcohol Consumption Promotes Early Neurogenesis Following Ischemic Stroke in Adult C57BL/6J Mice.

Ischemic stroke is one of the leading causes of death and disability worldwide. Neurogenesis plays a crucial role in postischemic functional recovery. Alcohol dose-dependently affects the prognosis of ischemic stroke. We investigated the impact of light alcohol consumption (LAC) on neurogenesis under physiological conditions and following ischemic stroke. C57BL/6J mice (three months old) were fed with 0.7 g/kg/day ethanol (designed as LAC) or volume-matched water (designed as control) daily for eight weeks. To evaluate neurogenesis, the numbers of 5-bromo-2-deoxyuridine (BrdU)+/doublecortin (DCX)+ and BrdU+/NeuN+ neurons were assessed in the subventricular zone (SVZ), dentate gyrus (DG), ischemic cortex, and ischemic striatum. The locomotor activity was determined by the accelerating rotarod and open field tests. LAC significantly increased BrdU+/DCX+ and BrdU+/NeuN+ cells in the SVZ under physiological conditions. Ischemic stroke dramatically increased BrdU+/DCX+ and BrdU+/NeuN+ cells in the DG, SVZ, ischemic cortex, and ischemic striatum. The increase in BrdU+/DCX+ cells was significantly greater in LAC mice compared to the control mice. In addition, LAC significantly increased BrdU+/NeuN+ cells by about three folds in the DG, SVZ, and ischemic cortex. Furthermore, LAC reduced ischemic brain damage and improved locomotor activity. Therefore, LAC may protect the brain against ischemic stroke by promoting neurogenesis.

An Anatomic Assessment of the Intercavernous Sinuses and Review of the Literature.

Introduction As expanded endoscopic endonasal approaches are gaining popularity, a thorough understanding of the anatomy of the intercavernous sinuses is pertinent to avoid bleeding complications. There have been few studies reporting the presence and dimensions of the anterior intercavernous sinus (AIS), posterior intercavernous sinus (PIS), and inferior intercavernous sinus (IIS). We performed a cadaveric study to better understand these structures. Methods Colored latex was injected into the arterial and venous trees of 17 cadaveric heads. Dissections assessed the presence and dimensions of the AIS, PIS, and IIS. In an additional three specimens, the sellar contents were subjected to histological analysis. Results Of the 20 total specimens, 13 (65%) demonstrated the gross presence of all three sinuses. In six specimens (30%), only the AIS and PIS could be identified, and in one specimen, only an AIS and IIS were identified. An AIS was identified in all 20 (100%) specimens, PIS in 18 (88%), and an IIS in 14 (70%). In two specimens (10%), the AIS covered the entire face of the sella. Dimensions of the AIS averaged 1.7 × 11.7 × 2.8 mm, PIS averaged 1.5 × 10.8 × 1.7 mm, and IIS averaged 8.7 × 11.8 × 1.0 mm when present. Conclusion All examined specimens demonstrated the presence of an AIS, and most had a PIS. The presence of an IIS was more variable. Preoperative awareness of these sinuses is helpful in planning transsphenoidal surgery to minimize the risk of bleeding.

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress.

Myocardial ischemia-reperfusion injury (I/R) causes damage to cardiomyocytes through oxidative stress and apoptosis. We investigated the cardioprotective effects of MnTnBuOE-2-PyP5+ (BMX-001), a superoxide dismutase mimic, in an in vitro model of I/R injury in H9c2 cardiomyocytes. We found that BMX-001 protected against hypoxia/reoxygenation (H/R)-induced oxidative stress, as evident by a significant reduction in intracellular and mitochondrial superoxide levels. BMX-001 pre-treatment also reduced H/R-induced cardiomyocyte apoptosis, as marked by a reduction in TUNEL-positive cells. We further demonstrated that BMX-001 pre-treatment significantly improved mitochondrial function, particularly O2 consumption, in mouse adult cardiomyocytes subjected to H/R. BMX-001 treatment also attenuated cardiolipin peroxidation, 4-hydroxynonenal (4-HNE) level, and 4-HNE adducted proteins following H/R injury. Finally, the pre-treatment with BMX-001 improved cell viability and lactate dehydrogenase (LDH) activity in H9c2 cells following H/R injury. Our findings suggest that BMX-001 has therapeutic potential as a cardioprotective agent against oxidative stress-induced H/R damage in H9c2 cardiomyocytes.

The Autotaxin-LPA Axis Emerges as a Novel Regulator of Smooth Muscle Cell Phenotypic Modulation during Intimal Hyperplasia.

Neointimal hyperplasia is characterized by a loss of the contractile phenotype of vascular smooth muscle cells (VSMCs). Our group has recently shown that VSMC proliferation and migration are mediated by lysophosphatidic acid (LPA) during restenosis, but the role of autotaxin (ATX; lysophospholipase D), which produces LPA, remains unclear. Endothelial denudation of the mouse carotid artery was performed to induce neointimal hyperplasia, and the extent of damage caused by the ATX-LPA axis was assessed in VSMCs. We observed the upregulation of ATX activity (p < 0.0002) in the injured carotid artery using an AR2 probe fluorescence assay. Further, the tissue carotid LPA levels were elevated 2.7-fold in carotid vessels, augmenting neointimal hyperplasia. We used an electrical cell-substrate impedance sensor (ECIS) to measure VSMC proliferation and migration. Treatment with an ATX inhibitor (PF8380) or LPA receptor inhibitor (Ki16425) attenuated VSMC proliferation (extracellular signal-regulated kinases) activity and migration in response to recombinant ATX. Indeed, PF8380 treatment rescued the aggravated post-wire injury neointima formation of carotid arteries. The upregulation of ATX following vessel injury leads to LPA production in VSMCs, favoring restenosis. Our observations suggest that inhibition of the ATX-LPA axis could be therapeutically targeted in restenosis to minimize VSMC phenotypic modulation and inflammation after vascular injury.

Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes.

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX-LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX-/-) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with the endothelial deletion of ATX. Permeability and infarct volume were reduced in ERT2 ATX-/- mice compared to ischemia-reperfusion (I/R)-only mice. In addition, the cerebral blood flow was retained in ERT2 ATX-/- compared to I/R mice. The outcomes in the stroke model are alleviated due to the limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX-/- mice. This study suggests that endothelial-specific ATX leads to increased LPA in the brain vasculature following ischemic-reperfusion and ultimately disrupts vascular permeability, resulting in adverse stroke outcomes.

Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice.

Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression.

Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer.

Lysophosphatidic acid (LPA), a multifunctional endogenous phospholipid, plays a vital role in cellular homeostasis and the malignant behavior of cancer cells through G-protein-coupled receptors. However, the role of LPA in ß-catenin-mediated gastric cancer is unknown. Here, we have noted the high expression of LPAR2 in human gastric cancer tissues, and that LPA treatment significantly increased the proliferation, migration, and invasion of human gastric cancer cells. Results from our biochemical experiments showed that an LPA exposure increased the expression of ß-catenin and its nuclear localization, increased the phosphorylation of glycogen synthase kinase 3ß (GSK-3ß), decreased the expression of Axin2, and increased the expression of the target genes of the ß-catenin signaling pathway. The LPA2 receptor (LPAR2) antagonist significantly reduced the LPA-induced nuclear localization of ß-catenin, the primary signaling event. The knockdown of LPAR2 in the gastric cancer cell lines robustly reduced the LPA-induced ß-catenin activity. An LPA exposure increased the ATP production by both oxidative phosphorylation and glycolysis, and this effect was abrogated with the addition of an LPAR2 antagonist and XAV393, which stabilizes the Axin and inhibits the ß-catenin signaling pathway. Based on our findings, the possibility that LPA contributes to gastric cancer initiation and progression through the ß-catenin signaling pathway as well as by the dysregulation of the energy metabolism via the LPAR2 receptor and Axin2, respectively, provides a novel insight into the mechanism of and possible therapeutic targets of gastric cancer.

Electrophilic Aldehyde 4-Hydroxy-2-Nonenal Mediated Signaling and Mitochondrial Dysfunction.

Reactive oxygen species (ROS), a by-product of aerobic life, are highly reactive molecules with unpaired electrons. The excess of ROS leads to oxidative stress, instigating the peroxidation of polyunsaturated fatty acids (PUFA) in the lipid membrane through a free radical chain reaction and the formation of the most bioactive aldehyde, known as 4-hydroxynonenal (4-HNE). 4-HNE functions as a signaling molecule and toxic product and acts mainly by forming covalent adducts with nucleophilic functional groups in proteins, nucleic acids, and lipids. The mitochondria have been implicated as a site for 4-HNE generation and adduction. Several studies clarified how 4-HNE affects the mitochondria's functions, including bioenergetics, calcium homeostasis, and mitochondrial dynamics. Our research group has shown that 4-HNE activates mitochondria apoptosis-inducing factor (AIFM2) translocation and facilitates apoptosis in mice and human heart tissue during anti-cancer treatment. Recently, we demonstrated that a deficiency of SOD2 in the conditional-specific cardiac knockout mouse increases ROS, and subsequent production of 4-HNE inside mitochondria leads to the adduction of several mitochondrial respiratory chain complex proteins. Moreover, we highlighted the physiological functions of HNE and discussed their relevance in human pathophysiology and current discoveries concerning 4-HNE effects on mitochondria.

Monitoring Mitochondrial Morphology and Respiration in Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (DOX)-induced cardiomyopathy constitutes dose-dependent cardiac toxicity, culminating in fatal heart failure progression. Cardiac toxicity limits effective and subsequent use of DOX in chemotherapy regimens in pediatric, adult, and recurrent cancer patients. DOX-induced profound alterations in mitochondrial morphology, dynamics, and defects in mitochondrial energy metabolism in the heart comprise key stressors in DOX-induced cardiotoxicity. Hence, the discovery of novel molecular targets and therapeutics to mitigate DOX-induced mitochondrial dysfunctions are imperative. Herein, we provided two laboratory protocols to monitor DOX-induced alterations in mitochondrial morphology and respiration in isolated primary neonatal rat cardiomyocytes. Neonatal rat cardiomyocytes are extensively used to monitor signaling mechanisms regulating cardiomyopathy in vitro. Therefore, these protocols will help researchers study the effects of novel pharmacological and genetic manipulations against DOX-induced alterations in mitochondrial morphology and energy metabolism in cardiomyocytes.

Rotenone-Induced 4-HNE Aggresome Formation and Degradation in HL-1 Cardiomyocytes: Role of Autophagy Flux.

Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction; however, little is known about the degradation mechanism of 4-HNE-adducted proteins. Autophagy is a dynamic process that maintains cellular homeostasis by removing damaged organelles and proteins. In this study, we determined the role of a superoxide dismutase (SOD) mimetic MnTnBuOE-2-PyP5+ (MnP, BMX-001) on rotenone-induced 4-HNE aggresome degradation in HL-1 cardiomyocytes. A rotenone treatment (500 nM) given for 24 h demonstrated both increased ROS and 4-HNE aggresome accumulation in HL-1 cardiomyocytes. In addition, cardiomyocytes treated with rotenone displayed an increase in the autophagy marker LC3-II, as shown by immunoblotting and immunofluorescence. A pre-treatment with MnP (20 µM) for 24 h attenuated rotenone-induced ROS formation. An MnP pre-treatment showed decreased 4-HNE aggresomes and LC3-II formation. A rotenone-induced increase in autophagosomes was attenuated by a pre-treatment with MnP, as shown by fluorescent-tagged LC3 (tfLC3). Rotenone increased tubulin hyperacetylation through the ROS-mediated pathway, which was attenuated by MnP. The disruption of autophagy caused HL-1 cell death because a 3-methyladenine inhibitor of autophagosomes caused reduced cell death. Yet, rapamycin, an inducer of autophagy, increased cell death. These results indicated that a pre-treatment with MnP decreased rotenone-induced 4-HNE aggresomes by enhancing the degradation process.

The Influence of Analgesic Modalities on Postoperative Cancer Recurrence.

The potential for cancer cells to grow and to metastasize depends on complex interactions between inflammatory signals and pathways, immune cells, and elements of the stromal tissue in which they invade. Related to the nature of many cancers, the probability of recurrence can potentially be quite high for some patients. Immunology, lifestyle modifications, timing of disease, genetics, age, gender, and race are only a handful of ways the likelihood of cancer recurrence can be influenced. The quantity, or density, of certain immunological cells or factors, plays a role in the propagation of cancer cells. Opioids are often used in cancer patients for acute postoperative and chronic pain management. While they can produce significant pain relief, the type of analgesic utilized is important, as it may influence cancer propagation. In this regard, certain opioids have been found to increase T regulatory cells while suppressing NK cell function. Morphine may promote tumor neovascularization and expansion. Fentanyl administration significantly diminishes NK-cells and CD8+ cytotoxic T-cells. In a recent meta-analysis, propofol-based anesthesia improved both cancer-free survival and overall survival. COX inhibitors have also shown promise in persevering cancer immune function, as in literature involving ketorolac and celecoxib. In summary, inhaled anesthesia and opioids may contribute to a pro-tumor metastasis environment also known as cancer propagation; whereas propofol and COX inhibitors may provide a better alternative to reduce cancer recurrence and propagation.

The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion.

Endothelial permeability is a major complication that must be addressed during stroke treatment. Study of the mechanisms underlying blood−brain barrier (BBB) disruption and management of the hypoxic stress-induced permeability of the endothelium following reperfusion are both urgently needed for stroke management. Lysophosphatidic acid (LPA), a bioactive lipid essential for basic cellular functions, causes unfavorable outcomes during stroke progression. LPA-producing enzyme autotaxin (ATX) is regulated in ischemic stroke. We used an electrical cell-substrate impedance sensor (ECIS) to measure endothelial permeability. Mitochondrial bioenergetics were obtained using a Seahorse analyzer. AR-2 probe fluorescence assay was used to measure ATX activity. LPA increased endothelial permeability and reduced junctional protein expression in mouse brain microvascular endothelial cells (MBMEC). LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins. LPA significantly diminished mitochondrial function in MBMEC. ATX was upregulated (p < 0.05) in brain microvascular endothelial cells under hypoxic reperfusion. ATX activity and permeability were attenuated with the use of an ATX inhibitor in a mouse stroke model. The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX−LPA−LPAR axis could be therapeutically targeted in stroke to achieve better outcomes.

The molecular role of Sigmar1 in regulating mitochondrial function through mitochondrial localization in cardiomyocytes.

Sigmar1 is a widely expressed molecular chaperone protein in mammalian cell systems. Accumulating research demonstrated the cardioprotective roles of pharmacologic Sigmar1 activation by ligands in preclinical rodent models of cardiac injury. Extensive biochemical and immuno-electron microscopic research demonstrated Sigmar1's sub-cellular localization largely depends on cell and organ types. Despite comprehensive studies, Sigmar1's direct molecular role in cardiomyocytes remains elusive. In the present study, we determined Sigmar1's subcellular localization, transmembrane topology, and function using complementary microscopy, biochemical, and functional assays in cardiomyocytes. Quantum dots in transmission electron microscopy showed Sigmar1 labeled quantum dots on the mitochondrial membranes, lysosomes, and sarcoplasmic reticulum-mitochondrial interface. Subcellular fractionation of heart cell lysates confirmed Sigmar1's localization in purified mitochondria fraction and lysosome fraction. Immunocytochemistry confirmed Sigmar1 colocalization with mitochondrial proteins in isolated adult mouse cardiomyocytes. Sigmar1's mitochondrial localization was further confirmed by Sigmar1 colocalization with Mito-Tracker in isolated mouse heart mitochondria. A series of biochemical experiments, including alkaline extraction and proteinase K treatment of purified heart mitochondria, demonstrated Sigmar1 as an integral mitochondrial membrane protein. Sigmar1's structural requirement for mitochondrial localization was determined by expressing FLAG-tagged Sigmar1 fragments in cells. Full-length Sigmar1 and Sigmar1's C terminal-deletion fragments were able to localize to the mitochondrial membrane, whereas N-terminal deletion fragment was unable to incorporate into the mitochondria. Finally, functional assays using extracellular flux analyzer and high-resolution respirometry showed Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes. Overall, we found that Sigmar1 localizes to mitochondrial membranes and is indispensable for maintaining mitochondrial respiratory homeostasis in cardiomyocytes.

Chronic Low-Dose Alcohol Consumption Promotes Cerebral Angiogenesis in Mice.

Chronic alcohol consumption dose-dependently affects the incidence and prognosis of ischemic stroke. We determined the influence of chronic alcohol consumption on cerebral angiogenesis under physiological conditions and following ischemic stroke. In in vitro studies, acute exposure to low-concentration ethanol significantly increased angiogenic capability and upregulated vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) in C57BL/6J mouse brain microvascular endothelial cells (MBMVECs). The increased angiogenic capability was abolished in the presence of a VEGFR2 inhibitor. In addition, the increased angiogenic capability and upregulated VEGF-A and VEGFR2 remained in chronically low-concentration ethanol-exposed MBMVECs. In in vivo studies, 8-week gavage feeding with low-dose ethanol significantly increased vessel density and vessel branches and upregulated VEGF-A and VEGFR2 in the cerebral cortex under physiological conditions. Furthermore, vessel density, vessel branches, and expression of VEGF-A and VEGFR2 in the peri-infarct cortex were significantly greater in low-dose ethanol-fed mice at 72 h of reperfusion. Although low-dose ethanol did not alter cerebral vasoreactivity and regional cerebral blood flow (rCBF) either before or during ischemia, it significantly augmented post-ischemic hyperemia during reperfusion. In contrast, exposure to high-concentration ethanol and 8-week gavage feeding with high-dose ethanol only had a mild inhibitory effect on angiogenic capability and cerebral angiogenesis, respectively. We conclude that heavy alcohol consumption may not dramatically alter cerebral angiogenesis, whereas light alcohol consumption significantly promotes cerebral angiogenesis.

A Comprehensive Update of the Treatment and Management of Bertolotti's Syndrome: A Best Practices Review.

Bertolotti's Syndrome is defined as chronic back pain caused by transitional lumbosacral vertebra. The transitional vertebra may present with numerous clinical manifestations leading to a myriad of associated pain types. The most common is pain in the sacroiliac joint, groin, and hip region and may or may not be associated with radiculopathy. Diagnosis is made through a combination of clinical presentations and imaging studies and falls into one of four types. The incidence of transitional vertebra has a reported incidence between 4 and 36%; however, Bertolotti's Syndrome is only diagnosed when the cause of pain is attributed to this transitional anatomy. Therefore, the actual incidence is difficult to determine. Initial management with conservative treatment includes medical management and physical therapy. Injection therapy has been established as an effective second line. Epidural steroid injection at the level of the transitional articulation is effective, with either local anesthetics alone or in combination with steroids. Surgery carries higher risks and is reserved for patients failing previous lines of treatment. Options include surgical removal of the transitional segment, decompression of stenosed foramina, and spinal fusion. Recent evidence suggests that radiofrequency ablation (RFA) around the transitional segment may also provide relief. This manuscript is a comprehensive review of the literature related to Bertolotti's Syndrome. It describes the background, including epidemiology, pathophysiology, and etiology of the Syndrome, and presents the best evidence available regarding management options. Bertolotti's Syndrome is considered an uncommon cause of chronic back pain, though the actual incidence is unclear. Most evidence supporting these therapies is of lower-level evidence with small cohorts, and more extensive studies are required to provide strong evidence supporting best practices.

Disrupted Blood-Brain Barrier and Mitochondrial Impairment by Autotaxin-Lysophosphatidic Acid Axis in Postischemic Stroke.

Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood-brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood-brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24-hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood-brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7-fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4-fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P<0.01) basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity. Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP-LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin-LPA signaling blockade attenuates blood-brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke.

Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice.

Ischemic stroke is one of the leading causes of death and permanent disability in adults. Recently, we found that light alcohol consumption (LAC) suppresses post-ischemic inflammatory response, which plays an important role in ischemic brain damage. Our goal was to determine the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in the anti-inflammatory effect of LAC against transient focal cerebral ischemia. In in vivo study, male C57BL/6J wild type (WT) and endothelial-specific conditional PPARγ knockout mice were gavage fed with 0.7 g/kg/day ethanol or volume-matched water daily for 8 weeks. From the 7th week, 3 mg/kg/day GW9662 (a selective PPARγ antagonist) was intraperitoneally given for two weeks. Cerebral ischemia/reperfusion (I/R) injury and expression of manganese superoxide dismutase (MnSOD) and adhesion molecules, neutrophil infiltration, and microglial activation in the cerebral cortex before and following a 90 min unilateral middle cerebral artery occlusion (MCAO)/24 h reperfusion were evaluated. In in vitro study, the impact of chronic alcohol exposure on expression of PPARγ and MnSOD in C57BL/6J mouse brain microvascular endothelial cells (MBMVECs) was measured. PPARγ and MnSOD were significantly upregulated in the cerebral cortex of ethanol-fed WT mice and low-concentration ethanol-exposed C57BL/6J MBMVECs. GW9662 significantly inhibited alcohol-induced upregulation of MnSOD. Eight-week ethanol feeding significantly reduced cerebral I/R injury and alleviated the post-ischemic inflammatory response (upregulation of intercellular adhesion molecule-1 (ICAM-1) and E-selectin, microglial activation, and neutrophil infiltration). Treatment with GW9662 and endothelial-specific conditional knockout of PPARγ did not alter cerebral I/R injury and the inflammatory response in the control mice but abolish the neuroprotective effect in ethanol-fed mice. In addition, GW9662 and endothelial-specific conditional knockout of PPARγ diminished the inhibitory effect of LAC on the post-ischemic expression of adhesion molecules and neutrophil infiltration. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing the post-ischemic inflammation via activation of PPARγ.

A Comprehensive Review and Update of Post-surgical Cutaneous Nerve Entrapment.

PURPOSE OF REVIEW: This is a comprehensive review of the literature regarding post-surgical cutaneous nerve entrapment, epidemiology, pathophysiology, and clinical presentation. It focuses mainly on nerve entrapment leading to chronic pain and the available therapies. RECENT FINDINGS: Cutaneous nerve entrapment is not an uncommon result (up to 30% of patients) of surgery and could lead to significant, difficult to treat chronic pain. Untreated, entrapment can lead to neuropathy and damage to enervated structures and musculature, and significant morbidity and financial loss. Nerve entrapment is defined as pressure neuropathy from chronic compression. It causes changes to all layers of the nerve tissue. It is most significantly associated with hernia repair and other procedures employing a Pfannenstiel incision. The initial insult is usually incising of the nerve, followed by formation of a neuroma, incorporation of the nerve during closing, or constriction from adhesions. The three most commonly involved nerves are the iliohypogastric, ilioinguinal, and genitofemoral nerves. Cutaneous abdominal nerve entrapment could occur during thoracoabdominal surgery. The presentation of nerve entrapment usually involved post-surgical pain in the territory innervated by the trapped nerve, possibly with radiation that tracks the nerve course. Once a suspected neuropathy is identified, it can be diagnosed with relief in pain after a nerve block has been instilled. Treatment is usually started with pharmaceutical solutions, topical first and oral if those fail. Most patients require escalation to a second line of treatment and see good result with injection therapy. Those that require further escalation can choose between ablation and surgical therapies. Post-surgical nerve entrapment is not uncommon and causes serious morbidity and financial loss. It is underdiagnosed and thus undertreated. Preventing nerve entrapment is the best treatment; when it does occur, options include topical and oral analgesics, nerve blocks, ablation therapy, and repeat surgery.

Treatment and Management of Twelfth Rib Syndrome: A Best Practices Comprehensive Review.

BACKGROUND: Twelfth rib syndrome, or slipping of the 12th rib, is an often overlooked cause for chronic chest, back, flank, and abdominal pain from irritation of the 12th intercostal nerve. Diagnosis is clinical and follows the exclusion of other causes of pain. This syndrome is usually accompanied by long-suffering, consequent psychiatric comorbidities, and increased health care costs, which are secondary to the delayed diagnosis. OBJECTIVES: This manuscript is a review of twelfth rib syndrome and its management options. The review provides etiology, pathophysiology, and epidemiology of twelfth rib syndrome. Additionally, diagnosis and current options for treatment and management are presented. STUDY DESIGN: This is a narrative review of twelfth rib syndrome. SETTING: A database review. METHODS: A PubMed search was conducted to ascertain seminal literature regarding twelfth rib syndrome. RESULTS: Conservative treatment is usually the first line, including local heat or ice packs, rest, and oral over-the-counter analgesics. Transcutaneous stimulation and 12th intercostal nerve cryotherapy have also been described with some success. Nerve blocks can additionally be tried and are usually effective in the immediate term; there is a paucity of evidence to suggest long-term efficacy. Surgical removal of all or part of the 12th rib and possibly the 11th rib, as well as the next line of therapy, may provide long-lasting relief of pain. LIMITATIONS: Further large scale clinical studies are needed to assess the most effective management of twelfth rib syndrome. CONCLUSIONS: Twelfth rib syndrome is usually diagnosed late and causes significant morbidity and suffering. The actual epidemiology is unclear given the difficulty of diagnosis. Nerve blocks and surgical rib resection appear to be effective in treating this syndrome, however, further evidence is required to properly evaluate them. Familiarity with this syndrome is crucial in reaching a prompter diagnosis.

Protective Effect of Low-Dose Alcohol Consumption against Post-Ischemic Neuronal Apoptosis: Role of L-PGDS.

Ischemic stroke is one of the leading causes of permanent disability and death in adults worldwide. Apoptosis is a major element contributing to post-ischemic neuronal death. We previously found that low-dose alcohol consumption (LAC) protects against neuronal apoptosis in the peri-infarct cortex following transient focal cerebral ischemia. Lipocalin-type prostaglandin D2 synthase (L-PGDS), which is mainly localized in the central nervous system (CNS), was previously shown to inhibit neuronal apoptosis. Therefore, we determined whether L-PGDS is involved in the protective effect of LAC against post-ischemic neuronal apoptosis. Wild-type (WT), CaMKIIαCreERT2/+/L-PGDS+/+, and CaMKIIαCreERT2/+/L-PGDSflox/flox mice on a C57BL/6J background were gavage fed with ethanol or volume-matched water once a day for 8 weeks. Tamoxifen (2 mg/day) was given intraperitoneally to CaMKIIαCreERT2/+/L-PGDS+/+ and CaMKIIαCreERT2/+/L-PGDSflox/flox mice for 5 days during the fourth week. AT-56 (30 mg/kg/day), a selective inhibitor of L-PGDS, was given orally to AT-56-treated WT mice from the fifth week for four weeks. Cerebral ischemia/reperfusion (I/R) injury, TUNEL-positive neurons, and cleaved caspase-3-positive neurons were measured at 24 h of reperfusion after a 90 min unilateral middle cerebral artery occlusion (MCAO). We found that 0.7 g/kg/day but not 2.8 g/kg/day ethanol significantly upregulated L-PGDS in the cerebral cortex. In addition, 0.7 g/kg/day ethanol diminished cerebral ischemia/reperfusion (I/R) injury and TUNEL-positive and cleaved caspase-3-positive neurons in the peri-infarct cortex in WT and CaMKIIαCreERT2/+/L-PGDS+/+ mice. Furthermore, the neuroprotective effect of 0.7 g/kg/day ethanol was alleviated in AT-56-treated WT and CaMKIIαCreERT2/+/L-PGDSflox/flox mice. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing post-ischemic neuronal apoptosis via an upregulated L-PGDS.