Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Advances in Wireless,Batteryless,Implantable Electronics for Real‑Time,Continuous Physiological Monitoring

This review summarizes recent progress in developing wireless,batteryless,fully implantable biomedical devices for real-time continuous physiological signal monitoring,focusing on advancing human health care.Design considerations,such as biological constraints,energy sourcing,and wireless communication,are discussed in achieving the desired performance of the devices and enhanced interface with human tissues.In addition,we review the recent achievements in materials used for developing implantable systems,emphasizing their importance in achieving multi-functionalities,biocompatibility,and hemocompatibility.The wireless,batteryless devices offer minimally invasive device insertion to the body,enabling portable health monitoring and advanced disease diagnosis.Lastly,we summarize the most recent practical applications of advanced implantable devices for human health care,highlighting their potential for immediate commercialization and clinical uses.

Krüppel-like factors 4 and 5:the yin and yang regulators of cellular proliferation

Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverseregulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closelyrelated members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFsoften exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-actingDNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemicalmechanisms of action of the two KLFs in the context of growth regulation.

Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke

Stroke is a leading cause of disability and death,yet effective treatments for acute stroke has been very limited.Thus far,tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients,yet its application is only applicable to less than 4–5% of stroke patients due to the narrow therapeutic window（〈 4.5 hours after the onset of stroke） and the high risk of hemorrhagic transformation.Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia,also known as targeted temperature management,can be a promising therapy for patients with different types of stroke.Moreover,the success in animal models using pharmacologically induced hypothermia（PIH） has gained increasing momentum for clinical translation of hypothermic therapy.This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia,as well as the recent development and findings behind PIH treatment.It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.

Clinical significance of main pancreatic duct dilation on computed tomography: Single and double duct dilation

AIM: To study the patients with main pancreatic duct dilation on computed tomography (CT) and thereby to provide the predictive criteria to identify patients at high risk of significant diseases, such as pancreatic cancer, and to avoid unnecessary work up for patients at low risk of such diseases. METHODS: Patients with dilation of the main pancreatic duct on CT at Emory University Hospital in 2002 were identified by computer search. Clinical course and ultimate diagnosis were obtained in all the identified patients by abstraction of their computer database records. RESULTS: Seventy-seven patients were identified in this study. Chronic pancreatitis and pancreatic cancer were the most common causes of the main pancreatic duct dilation on CT. Although the majority of patients with isolated dilation of the main pancreatic duct (single duct dilation) had chronic pancreatitis, one-third of patients with single duct dilation but without chronic pancreatitis had pancreatic malignancies, whereas most of patients with concomitant biliary duct dilation (double duct dilation) had pancreatic cancer. CONCLUSION: Patients with pancreatic double duct dilation need extensive work up and careful followup since a majority of these patients are ultimately diagnosed with pancreatic cancer. Patients with single duct dilation, especially such patients without any evidence of chronic pancreatitis, also need careful follow-up since the possibility of pancreatic malignancy, including adenocarcinoma and intraductal papillary mucinous tumors, is still high.

Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis

Systemic corticosteroids represent the standard treatment for autoimmune pancreatitis with IgG4-associated cholangitis.For steroid-dependent disease,azathioprine has been used for maintenance of remission.Mycophenolate mofetil has been used for transplant immunosuppression and more recently for autoimmune hepatitis;however,there are no case reports to date on the use of mycophenolate mofetil in adult patients with autoimmune pancreatitis.A patient with IgG4-mediated autoimmune pancreatitis and IgG4-associated cholangitis refractory to steroids and intolerant of azathioprine was treated with mycophenolate mofetil,which inhibits de novo guanosine synthesis and blockade of both B and T lymphocyte production.Introduction of mycophenolate mofetil and uptitration to 1000 mg by mouth twice daily over a treatment period of 4 mo was associated with improvement in the patient's energy level and blood glucose control and was not associated with any adverse events.The patient was managed without a biliary stent.However,there was a return of symptoms,jaundice,increase in transaminases,and hyperbilirubinemia when the prednisone dose reached 11 mg per day.In the first report of mycophenolate mofetil use in an adult patient with IgG4-associated autoimmune pancreatitis and IgG4-associated cholangitis,the introduction of mycophenolate mofetil was safe and well-tolerated without adverse events,but it did not enable discontinuation of the steroids.Mycophenolate mofetil and other immunomodulatory therapies should continue to be studied for maintenance of remission in the large subset of patients with refractory or recurrent autoimmune pancreatitis.

Effects of congenital ptosis on the refractive development of eye and vision in children

AIM:To investigate the influence of unilateral congenital ptosis on the development of the eye and vision in children.METHODS:In this prospective observational study,41 patients with unilateral congenital ptosis were enrolled(age range 3-15y).The blepharoptosis was divided into 3 subgroups according to the margin reflex distance-1(MRD-1),including mild group(MRD-1>2 mm),moderate group(0<MRD-1<2 mm),and severe group(MRD-1<0 mm).The fellow eyes served as controls.All subjects underwent ocular examinations,including axial length,keratometry,and refractive error.RESULTS:The incidence of astigmatism(ptotic eyes:58.5%vs fellow eyes:24.4%,P=0.002)and magnitude of cylindrical power(ptotic eyes:-0.86±0.79 D vs fellow eyes:-0.43±0.63 D,P=0.003)differed significantly between the ptotic eyes and the fellow eyes.The spherical equivalent refraction(P=0.006),spherical power(P=0.01),cylindrical power(P=0.011),axial length-corneal radius(AL/CR)ratio(P=0.009),frequency of hyperopia(P=0.002)and astigmatism(P=0.004)were significantly different among the ptotic eye subgroups and the fellow eye group.In addition,in patients with congenital ptosis,the incidence of amblyopia is 43.9%and the incidence of anisometropia is 24.4%.More importantly,the ratio of AL/CR showed significantly positive correlation with the severity of ptosis(P=0.002).CONCLUSION:Congenital ptosis may lead to a delayed eyeball development in the aspect of AL/CR.The risk of amblyopia is also increased due to visual deprivation and aggravated anisometropia,particularly in severe ptosis case.

Memory CD8+ T cell differentiation in viral infection: A cell for all seasons

Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virus- specific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.

The plasminogen activating system in the pathogenesis of Alzheimer’s disease

Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published to this date.

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics

This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.

The subcutaneous implantable cardioverter defibrillator—— review of the recent data

下的可植入的 cardioverter 使用高压脉冲来消减心脏(SICD ) 是为突然的心脏的死亡(SCD ) 的预防的 transvenous ICD 的一种选择。多重研究证明了 SICD 在对待室的心律不齐安全、有效。当更早的研究主要与 channelopathies 注册了更年轻的病人时，更最近的报告为 SCD 的预防为 ICD 治疗与典型指示包括了病人。在这评论，我们总结可得到的数据当加亮它的利弊时，在 SICD 上标明日期。

Geriatric cardiology and the Great Wall International Congress of Cardiology 2015

The burgeoning geriatric population worldwide has resuited in an unprecedented challenge to the cardiology community.Cardiovascular disease is the major cause of morbidity and mortality in the elderly population,but its recognition and management are characteristically confounded by substantial comorbidities,polypharmacy,and other complexities of care,not encountered in younger cardiac patients.

Down-regulation of Tissue Factor by siRNA Increased Doxorubi-cin-induced Apoptosis in Human Neuroblastoma

The effects of tissue factor （TF） on doxorubicin-induced apoptosis in human neuroblastoma were investigated. The expression of TF was examined by Western blotting. TFsiRNA-pSUPER plasmid was constructed by inserting specific 19-nt silencing sequence targeting TF gene into pSUPER vector. Transfection of TFsiRNA-pSUPER was performed using lipofectamine^2000. The cytotoxicity of doxorubicin was determined by WST assay. The activation of Caspase-3 and PARP induced by doxorubicin was tested by Western blotting. The apoptotic cells were stained by Hochest33342 and counted under fluorescence inverted microscope. It was found that human neuroblastoma cell line SK-N-MC expressed high level of TE Knockdown of the TF expression was achieved by transfection of TFsiRNA-pSUPER on SK-N-MC cells in a dose-dependent manner. Inhibition of TF significantly decreased the viability of transfected SK-N-MC cells treated with different concentrations of doxorubicin. Cleavage of Caspase-3 and PARP was enhanced in transfected SK-N-MC cells with down-regulation of TF. TFsiRNA treatment significantly increased the number of apoptotic cells in transfected SK-N-MC cells as compared with those control cells （P〈0.05） when these cells were exposed to 1 μg/mL doxorubicin for 8 h. These results suggested that knockdown of the TF expression by specific siRNA vector could increase the cytotoxicity of doxorubicin and enhance doxorubicin-induced apoptosis in human neuroblastoma cells. Over-expression of TF might contribute to chemotherapy resistance in human neuroblastoma and its progression, at lest in part, by regulating doxorubicin-induced apoptosis.

Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system

Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.

Complement activation kindles the transition of acute post-traumatic brain injury to a chronic inflammatory disease

Traumatic brain injury(TBI)remains a major cause of disability among young adults in both civilian and military settings contributing to a high burden on healthcare systems(Badhiwala et al.,2019).Sequel of TBI,even mild injuries,include motor and sensory dysfunction,neurocognitive decline,neuropsychiatric complications,as well as increased risk of neurodegenerative and neurovascular events such as Alzheimer’s disease and stroke(Breunig et al.,2013;Burke et al.,2013;Li et al.,2017).Despite the acute nature of the insult in TBI,pathological changes in the traumatized brain are better recognized as a chronic rather than an acute neurological disease,a phenomenon that remains under-investigated.

Impact of gout on in-hospital outcomes of acute coronary syndrome-related hospitalizations and revascularizations: Insights from the national inpatient sample

BACKGROUND Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases. However, large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome (ACS)-related hospitalizations and post-revascularization is inadequate. AIM To evaluate the impact of gout on in-hospital outcomes of ACS hospitalizations, subsequent healthcare burden and predictors of post-revascularization inpatient mortality. METHODS We used the national inpatient sample (2010-2014) to identify the ACS and goutrelated hospitalizations, relevant comorbidities, revascularization and postrevascularization outcomes using the ICD-9 CM codes. A multivariable analysis was performed to evaluate the predictors of post-revascularization in-hospital mortality. RESULTS We identified 3144744 ACS-related hospitalizations, of which 105198 (3.35%) also had gout. The ACS-gout cohort were more often older white males with a higher prevalence of comorbidities. Coronary artery bypass grafting was required more often in the ACS-gout cohort. Post-revascularization complications including cardiac (3.2% vs 2.9%), respiratory (3.5% vs 2.9%), and hemorrhage (3.1% vs 2.7%) were higher whereas all-cause mortality was lower (2.2% vs 3.0%) in the ACSgout cohort (P < 0.001). An older age (OR 15.63, CI: 5.51-44.39), non-elective admissions (OR 2.00, CI: 1.44-2.79), lower household income (OR 1.44, CI: 1.17- 1.78), and comorbid conditions predicted higher mortality in ACS-gout cohort undergoing revascularization (P < 0.001). Odds of post-revascularization inhospital mortality were lower in Hispanics (OR 0.45, CI: 0.31-0.67) and Asians (OR 0.65, CI: 0.45-0.94) as compared to white (P < 0.001). However, postoperative complications significantly raised mortality odds. Mean length of stay, transfer to other facilities, and hospital charges were higher in the ACS-gout cohort. CONCLUSION Although gout was not independently associated with an increased risk of postrevascularization in-hospital mortality in ACS, it did increase postrevascularization complications.

Vision Screening in the Pediatrician’s Office

Objective: To assess current practices, attitudes, and perceived barriers toward pediatric vision screening. Patients and Methods: A link to a 9-question survey was electronically distributed to a national sample of 6000 pediatricians through Medical Marketing Services Inc. Data were collected using Survey Monkey. Results: Email open rate was 11%;37% of those who opened the email responded (225 respondents). Over ninety percent of respondents perform some type of vision screening at least yearly, although age at which screening began varied, with two thirds of respondents instituting formal vision screening after three years. Fifty eight percent of respondents were either extremely unsatisfied, unsatisfied or only somewhat satisfied with their current screening method. Preferred methods of screening and confidence of pediatricians in their ability to detect pathology varied for children under versus over age three. The least frequently used methods for all age groups were autorefraction and photoscreening. The most commonly reported barriers to screening were inadequate training (48%), time required for exam (42%), and inadequate reimbursement (32%). Conclusions: Perceived barriers to vision screening in the pediatrician office have been previously identified, and photoscreening and autorefraction have been identified as a possible means to circumvent them. In spite of the addition of new procedural codes, pediatricians continue to report similar barriers to screening.

Distal esophageal spasm:Update on diagnosis and management in the era of high-resolution manometry

Distal esophageal spasm(DES)is a rare major motility disorder in the Chicago classification of esophageal motility disorders(CC).DES is diagnosed by finding of≥20%premature contractions,with normal lower esophageal sphincter(LES)relaxation on high-resolution manometry(HRM)in the latest version of CCv3.0.This feature differentiates it from achalasia type 3,which has an elevated LES relaxation pressure.Like other spastic esophageal disorders,DES has been linked to conditions such as gastroesophageal reflux disease,psychiatric conditions,and narcotic use.In addition to HRM,ancillary tests such as endoscopy and barium esophagram can provide supplemental information to differentiate DES from other conditions.Functional lumen imaging probe(FLIP),a new cutting-edge diagnostic tool,is able to recognize abnormal LES dysfunction that can be missed by HRM and can further guide LES targeted treatment when esophagogastric junction outflow obstruction is diagnosed on FLIP.Medical treatment in DES mostly targets symptomatic relief and often fails.Botulinum toxin injection during endoscopy may provide a temporary therapy that wears off over time.Myotomy through peroral endoscopic myotomy or via surgical Heller myotomy can provide long term relief in cases with persistent symptoms.

Pulmonary artery catheterization in acute myocardial infarction complicated by cardiogenic shock:A review of contemporary literature

Acute myocardial infarction(AMI)with left ventricular(LV)dysfunction patients,the most common cause of cardiogenic shock(CS),have acutely deteriorating hemodynamic status.The frequent use of vasopressor and inotropic pharmacologic interventions along with mechanical circulatory support(MCS)in these patients necessitates invasive hemodynamic monitoring.After the pivotal Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial failed to show a significant improvement in clinical outcomes in shock patients managed with a pulmonary artery catheter(PAC),the use of PAC has become less popular in clinical practice.In this review,we summarize currently available literature to summarize the indications,clinical relevance,and recommendations for use of PAC in the setting of AMI-CS.