All Articles

Yongming Sang*

Department of Agricultural and Environmental Sciences, College of Agriculture, Tennessee State University, 3500 John A. Merritt Boulevard, Nashville, TN, USA

Obesity and its related comorbidities are prevailing globally. Multiple factors are etiological to cause obesity and relevant metabolic disorders. In this regard, some pathogenic infections including those by viruses have also been associated with obesity (termed as infectobesity). In this mini-review, I examined recent publications about primary or cofactorial role of viral infections to exacerbate the local and systemic immunometabolic cues that underlie most cofactorial obesity. Major immuno-metabolic pathways involved, including that mediated by interferon (IFN) signaling and peroxisome proliferator activated receptor-γ (PPAR-γ), are discussed.

Varsha Jain¹, Sriram Venigalla¹, Kevin T. Nead¹, Wei-Ting Hwang², John N. Lukens¹, Tara C. Mitchell³, Jacob E. Shabason¹*

¹Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

²Department of Biostatistics, Epidemiology and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

³Division of Medical Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Pre-clinical data from animal models suggest that the anti-tumor efficacy of immune checkpoint blockade agents may be influenced by gender specific sex hormones. However, recent meta-analyses of clinical data aimed at addressing the impact of gender on response to these agents have demonstrated conflicting results. Given the discordant evidence, we sought to evaluate the association of gender with the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. This retrospective cohort study used the National Cancer Database to identify patients who were ≥18 years old with Stage IV melanoma from 2011 to 2015. Patterns of utilization of immunotherapy, including by gender, were assessed using multivariable logistic regression. A multivariable Cox proportional hazards model, including an interaction term between the receipt of immunotherapy and gender, was used to evaluate whether gender modified the association of receipt of immunotherapy with hazards of death. 11,944 patients met study inclusion criteria. Of these, 8,093 (68%) were males and 3,851 (32%) were females. 2,930 (25%) patients received immunotherapy while 9,014 (75%) did not. There was no statistically significant difference in the receipt of immunotherapy between males and females. On multivariable analysis, receipt of immunotherapy was associated with a survival benefit in both males and females. However, a statistically significant difference in efficacy of immunotherapy based on gender was not observed (p_interaction =0.422). Utilizing a real world cohort of patients derived from a national cancer registry, gender was not associated with differences in immunotherapy survival outcomes in patients with metastatic melanoma.

Bai Li, Tangxin Gao, Jing Du *

School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, Yunnan, China

Masaharu Takamori*

Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Ishikawa, 920-0025, Japan

The neuromuscular junction (NMJ) is organized by a complex architecture and various signals orchestrated by sophisticated interactions. They include the presynaptic Ca²⁺ homeostasis for acetylcholine (ACh) release in the active zone organization, the post-synaptic ACh receptor (AChR) clustering at endplate membranes, the trans-synaptic communication from muscle to nerve, and the synaptic stabilization. The present data and discussions are concerned in an adaptive change of ACh release from the nerve terminal and its immunological impairment in the post-synaptic disease (myasthenia gravis, MG) and the presynaptic disease (Lambert-Eaton myasthenic syndrome, LEMS).?Discussions mainly focus the antibody-induced failure of the synaptic compensatory mechanisms that are brought about by the presynaptic autoreceptors (the M1-type muscarinic AChR [mAChR] cooperated with adenosine receptors), and the non-voltage-gated Ca²⁺-dominant influx channel (transient receptor potential canonical [TRPCs], particularly its phenotype TRPC3). Besides the synaptic transmission fatigue, the TRPC3 antibodies are discussed in terms of their implication in the muscle contraction fatigue that often occurs in the thymoma-associated MG and reflects a defect in the physiological association of TRPC3 with the ryanodine receptor-1 in the excitation-contraction coupling in which the sarcoplasmic Ca²⁺ release takes place. In addition to the modulating role in the NMJ functions, the mAChRs participate in the innate and adaptive inmmunity by MG thymus and in the lung cancer (often associated with LEMS) growth.

Paolo Lissoni*, Giusy Messina, Franco Rovelli, Nicoletta Merli, Rosa Cusmai, Fernando Brivio, Arianna Lissoni, Giuseppe Di Fede

Institute of Biological Medicine, Milan, Italy

The future of laboratory analyses would require the identification of clinical parameters involving the main integrative biological functions including neuroendocrine, immune and cardiovascular systems, and capable of predicting the evidence of metabolic alterations and the possible occurrence of systemic diseases. According to the clinical data available up to now, the status of health may be identified by the following five major biomarkers, consisting of normal circadian rhythm of cortisol and the pineal hormone melatonin, normal blood concentrations of fatty acid amide hydrolase (FAAH), whose increase is associated with an endocannabinoid system deficiency, normal lymphocyte-to-monocyte ratio (LMR) values, normal blood levels of TGF-beta, the main immunosuppressive anti-inflammatory endogenous molecule, and normal values of ANP-to-ET-1 ratio. Since the evidence of alterations involving these five parameters may predispose to the onset of more severe metabolic disorders or systemic disease, the clinical evaluation of these five biomarkers could constitute the routinary laboratory analyses for realizing a real Preventive Medicine.

Richard White¹, Stephen Abel², Shaakir Hasan², Vivek Verma², Tulika Ranjan³, Stephen M. Karlovits², Rodney E Wegner²*

¹Allegheny Health Network, Department of Internal Medicine, Pittsburgh, PA, USA

²Allegheny Health Network Cancer Institute, Division of Radiation Oncology, Pittsburgh, PA, USA

³Allegheny Health Network Cancer Institute, Division of Neuro Oncology, Pittsburgh, PA, USA

Glioblastoma (GBM) carries an abysmal prognosis. Current standard of care involves an aggressive multimodality approach including surgical resection followed by adjuvant chemoradiation. Despite this approach, overall survival remains poor and treatment approaches continue to evolve. Given the successes of immunotherapy in other disease sites, implementation in GBM management may improve outcomes. We conducted this retrospective National Cancer Database (NCDB) study to analyze treatment trends and outcomes from 2004-2015 regarding immunotherapy for GBM and queried for patients diagnosed between 2004-2015 with GBM and excluded patients treated without surgery, extracranial radiation, or chemotherapy as well as those lost to follow up.

Of the 39,317 eligible patients in this study, 511 were treated with immunotherapy and 38,806 lack thereof. Median overall survival for all patients was 15 months with a 2 and 5 year survival rate of 29% and 8%, respectively. Factors positively influencing delivery of immunotherapy included younger age, higher income, facility location in a metropolitan location, greater distance to the treatment facility, treatment at an academic facility, treatment outside of the years 2007 to 2009, and Caucasian race. On propensity matched analysis, survival was 18 months and 17 months with and without immunotherapy, respectively (p=0.15). Higher comorbidity, lower income, and male gender predicted for worse survival.

The results of the NCDB analysis showed an initial decrease and then increase in the use of immunotherapy in the management of GBM. Propensity-matched analyses did not show an overall survival benefit.

Rodney E. Wegner¹*, Stephen Abel¹, Shaakir Hasan¹, Richard J. White¹, Gene Finley², Dulabh Monga², Athanasios Colonias¹, Vivek Verma¹

¹Allegheny Health Network Cancer Institute, Division of Radiation Oncology, USA

²Allegheny Health Network Cancer Institute, Division of Medical Oncology, USA

Immunotherapy (IMT) has revolutionized the treatment of stage IV non-small cell lung cancer (NSCLC). However, optimal timing of IMT in relation to stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) is unknown. Utilizing the National Cancer Database, we examined trends in IMT use in metastatic NSCLC patients and the potential survival implications of IMT timing in relation to SBRT/SRS. We queried the NCDB for patients with Stage IV NSCLC diagnosed between 2004-2015. Patients receiving IMT and SBRT/SRS to any site were included. Multivariate logistic regression identified predictors of IMT use. Receiver operator characteristic curve analysis determined an a priori timeframe between SBRT and IMT predictive of optimal overall survival (OS). Univariate and multivariate analyses identified factors predictive of OS. Propensity-adjusted Cox proportional hazard ratios were used to mitigate indication bias. Of 13,862 eligible patients, 371 received IMT. The majority (75%) received chemotherapy. IMT use was associated with improved median OS on univariate analysis (17 vs. 13 months, p<0.0001). Adenocarcinoma histology, chemotherapy use, and recent treatment year were associated with IMT. On multivariate propensity-adjusted Cox regression, predictors for improved OS included: younger age, lower comorbidity score, lower grade, private insurance, IMT use, and female sex. Patients treated ≥ 21 days (a priori threshold) after SBRT/SRS initiation had improved median OS (19 vs. 15 months, p=0.0335). In patients with Stage IV NSCLC, IMT use following SBRT/SRS has increased. OS improved when IMT was given ≥3 weeks after initiating SBRT/SRS; suggesting a potential optimal time-frame between RT and IMT.

Greg A. Kirchenbaum, Jodi Hanson, Diana R. Roen, Paul V. Lehmann*

Cellular Technology Limited (CTL) Shaker Heights, OH, 44122-5350, USA

T cells not only protect us from infectious diseases and cancer, but are also involved in transplant rejection, autoimmune diseases, and allergies. Each of these immunologic processes share a common link in which antigen-specific T cells undergo expansion, with some of the resulting progeny differentiating into memory cells. Memory T cells belong to several distinct lineages, and sub-lineages, that fundamentally differ in their effector functions and capacity to mediate a protective or pathological immune response. In this mini-review, we outline how such memory T cell subpopulations can readily be identified on the basis of their secretory signature using a multi-color ImmunoSpot® assay.

Hildegard M Schuller*

Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA

This mini-review summarizes current knowledge on similarities and synergism between smoking and psychological stress-induced modulations of growth stimulating and inhibiting regulatory networks in epithelial cells and epithelial cancers with emphasis on cancer stimulating neurotransmitters and their receptors as well as cancer inhibiting γ-aminobutyric acid (GABA) and opioids. Hyperactive cAMP signaling downstream of beta-adrenergic receptors (β-ARs) has been identified as the driving force of most smoking-associated cancers by numerous preclinical studies and psychological stress intensifies these effects while experimental stress reduction inhibits. The integration of cAMP reduction via stress reduction by pharmacological and psychological means such as psychotherapy, relaxation meditation and yoga into any cancer treatment strategy is recommended.

Alison Taylor¹*, Christopher E. Rudd^2,3

¹Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James’s University Hospital, LEEDS LS9 7TF, UK

²Division of Immunology-Oncology Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

³Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Kaity H. Tung, Marc S. Ernstoff, Cheryl Allen, Shin La Shu*

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

Tumor-derived exosomes (TEX) are important intercellular messengers that contribute to tumorigenesis and metastasis through a variety of mechanisms such as immunosuppression and metabolic reprogramming that generate a pre-metastatic niche favorable to tumor progression. Our lab has contributed further to the understanding of the miRNA payloads in TEX by demonstrating that human melanoma-derived exosome (HMEX) associated miRNAs contribute to the metabolic reprogramming of normal stroma. This mini-review highlights the role of TEX in the tumor microenvironment (TME) and the hypothesis that exosomes may also generate a host-tumor “macroenvironment” beyond the TME through their miRNA and protein payloads, so to speak “fertilizing the soil for cancer seeding.”

Christian S Simoneti, Elcio O Vianna*

Department of Medicine; Medical School of Ribeirão Preto, University of São Paulo; Ribeirão Preto, Brazil

Karina M. Mata¹*, Cleverson R. Fernandes¹, Cristiane Tefé-Silva², Simone G. Ramos¹

¹Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

²University Center of Barão de Mauá, Ribeirão Preto, SP, Brazil

Abdominal aortic aneurysm (AAA) represents a complex pathophysiological process of weakening and dilatation of the aortic wall associated with atherosclerosis, chronic inflammatory response and hemodynamic alterations. Degradation of the extracellular matrix by the matrix metalloproteinases (MMPs) and an imbalance between MMPs and their tissue inhibitors (TIMPs), have fundamental roles in the development of AAA. However, the exact pathogenetic mechanisms remain incompletely elucidated. In addition to the previous results already published “Interference of doxycycline pretreatment in a model of abdominal aortic aneurysms”, in this commentary we have complementary results. Here we have included new findings of the TIMPs 1 and 2 expressions in animals submitted to AAA surgical induction associated with doxycycline pretreatment. In this study, we used a new experimental model, developed in our laboratory, to induce AAA by combining two potential causes of MMP secretion: inflammation and turbulent blood flow. Male Wistar rats were divided into Control (C), Control+ Doxycycline (C+D), Aneurysms (A) and Aneurysms+Doxycycline (A+D) groups. The rats were euthanized at 3, 7 or 15 days post-surgery (dps). The administrated doxycycline started 48 hours before the surgical induction of AAA until the end of the experiment. After 1, 3, 7, and 15 dps, the animals were euthanized under anesthesia and the vessels were collected to measurement of TIMPs 1 and 2 by western blot. Our results demonstrate an increased expression of TIMPs 1 and 2 in aneurysm group (A) probably in an attempt to counteract the increased activity of MMPs 2 and 9. In aneurysms groups submitted to doxycycline pretreatment (A+D) showed the regulation of expression of TIMP 1 and 2, remaining close to baseline levels from the third day, similar to expression found the control groups (C and C + D). This study suggests that the pretreatment with doxycycline balances the TIMPs 1 and 2 expressions with a protective effect on the progression of abdominal aortic aneurysms in experimental model.

José Perdomo

Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Gulhadiye Avcu¹, Deniz Yilmaz Karapinar^2*

¹Ege University Faculty of Medicine, Children’s Hospital, Department of Pediatric Infectious Disease, 35040 Bornova Izmir, Turkey

²Ege University Faculty of Medicine, Children’s Hospital, Pediatric Hematology, 35040 Bornova Izmir, Turkey

Invasive fungal infections, including invasive aspergillosis are associated with a high morbidity and mortality especially in immunocompromised patients. Diagnosis is often difficult due to several factors such as delay in clinical suspicion and the lack of spesific clinical findings. Galactomannan is a polysaccharide cell wall component of Aspergillus and galactomannan antigen detection has become widely used for diagnosis of invasive aspergillosis. Here, we tried to discuss the diagnostic value of the galactomannan test in the context of literature review.

Astrid Obermayer¹*, Walter Stoiber¹, Fikreta Grabcanovic-Musija², Michael Studnicka²

¹Department of Biosciences, Biomedical Ultrastructure Research, University of Salzburg, Salzburg, Austria

²University Clinic of Pneumology, Paracelsus Medical University, Salzburg, Austria

Since their discovery about fifteen years ago, neutrophil extracellular traps (NETs) have been recognized as an intrinsic part of vertebrate innate immunity and inflammatory response. Consisting of entangled strands of extracellular DNA decorated with histones, elastase, myeloperoxidase and other proteins, NETs entrap and kill pathogens, but are increasingly also found to contribute to acute and chronic inflammatory disease due to their toxicity to host cell and autoimmunity induction. Chronic obstructive pulmonary disease (COPD) turned out to be among the major disorders involving overshooting formation of NETs and associated adverse effect. In the present review, we summarize the progress in knowledge on the role of NETs in COPD pathology made since our first reports on this subject. We highlight recent substantial advances and discuss possible cause-and-effect relationships, connections with common comorbidities and interactions with drugs, also to illustrate the importance of NETs as a future diagnostic tool and target for new medication strategies.

Fani L. Moreira Neto^1,2,3*

¹Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal

²IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal

³Departamento de Biomedicina – Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal

Heat shock protein 90 (HSP90) belongs to a highly conserved family of molecular chaperones and is responsible for regulating the protein folding quality control of specific client proteins. In a recent study published in Molecular Neurobiology, HSP90mRNA levels were found significantly decreased after knock-down in vitro of activating transcription factor 3 (ATF3), indicating that this stress-inducible gene that mediates pro-apoptosis or cytoprotection might act as positive regulator of HSP90 expression. In the rodent model of Monoarthritis, characterized by being accompanied by chronic joint inflammatory pain, the mRNA and protein levels for HSP90 were significantly increased in dorsal root ganglia (DRG). Additionally, a reversal in the HSP90 mRNA upregulation and in the 70kDa protein isoform levels following intrathecal delivery of a HSP90 inhibitor, along with an attenuation of movement-induced mechanical allodynia, and reduced neuronal sensitization and satellite glial cells (SGC) activation in ipsilateral DRG of the arthritic animals were also observed. This suggests a putative role of HSP90 in chronic inflammatory pain pathophysiology at sensory ganglia level that is still unexplored. To date only a few studies demonstrated a link between pain and HSP90 modulation, but there are several evidences that HSP90 is involved in inflammation, tumorigenesis and neurodegeneration. Here, we discuss the status of the studies demonstrating a role for HSP90 in inflammation and comment on their possible involvement in neuronal/glial driven pain mechanisms.

Hideto Tamura¹*, Mariko Ishibashi², Mika Sunakawa¹, Hidemi Takahashi², Koiti Inokuchi¹

¹Department of Hematology, Nippon Medical School, Tokyo, Japan

²Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan

Programmed death ligand 1 (PD-L1) expression on myeloma cells is induced by JAK2, STAT3, and MEK1/2-mediated interleukin-6 signaling, a strong inducer of PD-L1 interferon-γ produced by T and natural killer cells, and APRIL produced by osteoclasts in the tumor microenvironment. The soluble form of PD-L1, derived from extracellular domains of PD-L1 molecules expressed in the tumor environment, may also contribute to tumor immune evasion. PD-L1-expressing myeloma cells not only have the ability to escape from the attack of tumor-specific T cells but also high proliferation potential. Furthermore, PD-L1 on myeloma cells delivers a reverse signal to tumor cells through PD-1 binding, resulting in the phosphorylation of Akt accompanied by the acquisition of resistance to anti-myeloma agents. Based on the function of PD-L1 in myeloma, the blockade of the PD-1–PD-L1 pathway is a reasonable treatment in refractory patients. Phase I/II clinical trials of anti-PD-1 antibody combined with immunomodulatory drugs demonstrated excellent effects in heavily pretreated multiple myeloma patients with acceptable tolerability. The timing and combination drug of anti-PD-1/PD-L1 antibodies should be considered to improve clinical effects with low mortality in refractory myeloma patients.

Yasemin Yuyucu Karabulut*

Mersin University Medical School, Department of Pathology, Mersin, Turkey

Intranodal palisaded myofibroblastoma, also known as “intranodal hemorrhagic spindle cell tumor with amianthoid fibers,” is a benign mesenchymal tumor of the lymph node originating from smooth muscle cells and myofibroblasts often with the presence of amianthoid fibers. Ninety-three cases of intranodal palisaded myofibroblastoma have been reported in the literatüre since its first description and most of them have the same clinical history “painless firm nodüle”. It is mostly seen in inguinal region there are few cases have been described in other locations. It’s large and important differential diagnostic spectrum makes this tumor special.

Sabahat Abdullah, Sajjad Ur Rahman, Ahsan Naveed*, Qamar Majeed

Institute of Microbiology, University of Agriculture Faisalabad, 3840, Pakistan

Mosquito-borne diseases can be reduced drastically with the aid of vaccines which provoke mosquitocidal or mosquito-killing effect. The midgut of mosquito performs a fundamental role in the development and the transmission of ailment. Anti-midgut antibodies show the extensive variety of activity, blockading the development of pathogen in various species of mosquitoes. In addition to reducing the egg-laying ability of mosquitoes and survivorship also block the transmission activity of pathogen. Mitsuhashi and Maramorosch media was used to culture the mosquito midgut cells. The cells were formalin inactivated and injected into the rabbits in plain and adjuvanted form to raise hyperimmune serum. The serum was processed for IHA and serum showing high titre were selected for blood feeding assay. The blood from the rabbits was fed to the mosquitos to observe the mosquitocidal effect of the antigen. In blood feeding assay killing of mosquitoes was also observed after regular interval of time. The overall results proved that mosquito midgut contains antigenic peptides that may be able to induce the antibody response. These antigenic peptides somehow irritate digestive mucosa of the mosquitoes on blood feeding and have the potential to kill or reduce the mosquito population.

A Vossenkamper¹, G Warnes^2*

¹Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary London University, 4 Newark Street, London E1 2AT, UK

²Flow Cytometry Core Facility, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary London University, 4 Newark Street, London E1 2AT, UK

The use of the Western Blot technique has been the gold standard to determine protein expression and to semi-quantitate this expression in cell lysates. The recent publication of a flow cytometric immunophenotyping method employing fluorescently labelled antibodies to the intracellular labelling of antigens involved in Regulated Cell Death (RCD) processes has allowed the detection of three of these processes simultaneously which gave clarity to the interpretation of the relationship between apoptosis, RIP1 dependent apoptosis and necroptosis. Flow cytometry can now immunophenotype necroptosis by virtue of the up-regulation of RIP3 with simultaneous estimations of the degree of classic apoptosis (Caspase-3^+ve/RIP3^-ve) and of RIP1-dependent apoptosis (Caspase-3^+ve/RIP3^+ve) in live and dead cell populations. This approach for detecting multiple forms of cell death has been confirmed by the use of apoptosis and necroptosis blocking agents, zVAD and necrostatin-1 after treatment with etoposide or shikonin which induced apoptosis and necroptosis. The addition of anti-PARP and H2AX antibodies for the detection of parthanatos and DNA damage showed that double negative Caspase-3^-ve/RIP3^-ve cells detected in a previous study have undergone parthanatos or still display a negative phenotype for any cell death process.

Yusuke Masuishi*, Shota Endo, Hideaki Kasuga, Tomoo Hidaka, Takeyasu Kakamu, Tetsuhito Fukushima

Department of Hygiene and Preventive Medicine, Fukushima Medical University School of Medicine, 1Hikariga-oka, Fukushima City 960-1295, Japan

Unique and complex post-translational modifications are present in the outer leaflet of the plasma membrane. Glycosylphosphatidylinositol (GPI) anchoring is essential for the expression of several outer membrane proteins on the cell surface. A common GPI anchor structure is constituted by glycan moiety, lipid moiety, phosphate and ethanolamine. GPI-anchored proteins (GPI-APs) are observed among eukaryotic species. Abnormal GPI anchoring of proteins is thought to cause various diseases such as paroxysmal nocturnal hemoglobinuria. Recently, many inherited GPI deficiencies (IGDs) have been reported to cause epilepsy, mental retardation, coarse facial features, and multiple organ anomalies. Diseases caused by abnormal GPI anchoring will probably continue to increase, because it is still unknown how many causative genes of IGDs are present. Therefore, in order to study these diseases, the analytical methods of GPI-APs will become important in the future. To date, many methods have been developed for analysis of GPI- APs. In this review, we attempt to summarize the present knowledge about comprehensive analytical methods of GPI-APs and introduce briefly some GPI anchor-related diseases.

Atsushi Anzai*, Motoaki Sano

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan

In-hospital outcomes are generally acceptable with the conservative treatment of uncomplicated type B aortic dissection, but some patients present with undesirable complications, such as aortic expansion and rupture. Beyond mechanical and shear forces of blood flow affecting the weakened aortic wall, excessive inflammatory response has been shown to be associated with aortic expansion and adverse clinical outcomes. We have previously demonstrated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. We propose that aortic dissection induces expression of the neutrophil chemoattractants CXCL1 and granulocyte-colony stimulating factor in the aortic tunica adventitia. These local environmental changes recruit neutrophils in combination with alteration of bone marrow milieu where reduced CXCL12 expression enhances neutrophil egress. Interleukin (IL)-6 production in the inflammatory adventitial neutrophils causes vascular inflammation, leading to vascular wall fragility. Targeting CXCR2 or IL-6 mitigates aortic expansion and prevents mice from aortic rupture. Collectively, adventitial neutrophil-mediated inflammation may be a potential therapeutic target to limit lethal complications after AAD.

Hillary W. Bedell^1,2 and Jeffrey R. Capadona^1,2*

¹Department of Biomedical Engineering, Case Western Reserve University, School of Engineering, 2071 MLK Jr. Drive, Wickenden Bldg, Cleveland OH 44106, USA

²Advanced Platform Technology Center, L. Stokes Cleveland VA Medical Center, Rehab. R&D, 10701 East Blvd. Mail Stop 151 AW/APT, Cleveland OH 44106, USA

Intracortical microelectrodes are used both in basic research to increase our understanding of the nervous system and for rehabilitation purposes through brain-computer interfaces. Yet, challenges exist preventing the widespread clinical use of this technology. A prime challenge is with the neuroinflammatory response to intracortical microelectrodes. This mini-review details immunomodulatory strategies employed to decrease the inflammatory response to these devices. Over time, broad-spectrum anti-inflammatory approaches, such as dexamethasone and minocycline, evolved into more targeted treatments since the underlying biology of the neuroinflammation was elucidated. This review also presents studies which examine novel prospective targets for future immunomodulatory targeting.

Eshetu Shibeshi Messeret^1*, Balcha Masresha², Ahmadu Yakubu³, Fussum Daniel¹, Mihigo R², Deo Nshimirimana⁴, Joseph Okeibunor⁵, Batholomew Akanmori²

¹Inter-country Support Team of East and Southern Africa, WHO African Region, Harare, Zimbabwe

²Immunization and Vaccines Development Programme, Family & Reproductive Health Cluster, WHO African Region, Brazzaville, Congo

³Immunization Vaccines and Biologicals Department, WHO Headquarters, Geneva, Switzerland

⁴WHO Country Office, Dakar, Senegal

⁵Polio Eradication Programme, WHO African Region, Brazzaville, Congo

Tetanus is a vaccine-preventable disease of significant public health importance especially in developing countries. The WHO strategy for the elimination of maternal and neonatal tetanus recommends the promotion of clean delivery practices, systematic immunization of pregnant women and those in the reproductive age (15-49 years) and surveillance for neonatal tetanus. Implementation of the recommended strategy with the support of WHO, UNICEF and other partners has led to significant decline in number of cases and deaths due to NT over the last decades. The coverage with the second or more dose of tetanus toxoid-containing vaccines (TT2+) a proxy for Protection at Birth (PAB) for the WHO African region has risen from 62% in 2000 to 77% by 2015 Reported cases of NT declined from 5175 in 2000 to 1289 in 2015.

The goal of eliminating maternal and neonatal tetanus by 2015 was missed, but some progress has been made. By the end of 2016, 37 out of 47 (79%) of the WHO AFR member states achieved elimination. The 10 member states remaining need additional support by all partners to achieve and maintain the goal of MNTE. Innovative ways of implementing the recommendations need to be urgently considered.