Pain Management for the Sickle Cell Patient

Sickle cell disease (SCD) is a condition very common in the United States of America and its most common presenting symptom is pain related to vaso-occlusive events (VOE). The cost associated with healthcare for the sickle cell population exceeds 1 billion $USD yearly, and the majority of this cost is associated with admission related to vaso-occlusive events. With the increase longevity of patients with SCD, due to new therapies and vaccination against common infection related to SCD, the prevalence of older individuals experiencing VOE will likely increase. The psychological impact inflicted on patients with SCD can further complicate adequate care of patients experiencing acute or chronic pain and the latter must be taken into consideration when planning an optimal treatment regimen. This chapter reviews the short- and long-term management options of pain related to VOE, their limitations as well proposed regimen that could pave the way for the future of pain management of SCD

Survey of the relevance of mechanical engineering course curricula to the professional mechanical engineers

A number of mechanical engineering courses in the British Isles were reviewed and the literature was scanned for the different views and criticism of the available teaching systems. A survey of the opinions of engineers in Ireland about the academic engineering education which they had received was earned out by using a mail questionnaire formulated to obtain information about the industrial training component of the education process and the relevance of the ancillary and basic subjects 425 IEI members returned back the questionnaire, of which 282 member were mechanical engineers, and 70 I Mech E have also responded. This makes up 28% response rate. The respondents were from different age groups, courses backgrounds and occupying different jobs The majority of the respondents were satisfied with the education they received in general and they believe that it helped them in performing current duties. However, a large proportion of the respondents (49%) expressed their views on some weaknesses in the education process, among the important were 1) Some of the Subjects were not entirely relevant, 2) Absence of adequate industrial training schemes. The technical knowledge acquired by the engineers during their courses was the most important aspect they have gained from the university and decision making abilities and skills were of secondary importance in the courses of study. The responses of the sample population to the enquiries about the relevance and importance of the different subjects they learned at the university to their current duties indicated a significantly high degree of importance of computing, design and strength of materials among all of the groups surveyed However, other subjects were rated differently by the various generations of engineers. Those who graduated within last 25 years gave usually a slightly higher rating to all the subjects than other groups, the only significant exception was ergonomic subject which received a very low rating from the older generation. Though few respondents were graduated from sandwich courses, the sample population was strongly m favour of cooperative education

Regenerative Medicine

Chronic pain is a debilitating condition that affects millions of people world-wide, leading to physical incapacitation and financial strain. Common methods for treatment include physical therapy, oral medications, injections, surgery, and neuromodulation. Injectates with steroids and local anesthetics can be a temporizing measure with intolerable side effects. The use of autologous biologic injectates (e.g., platelet rich plasma, bone marrow aspirate concentrate, tissue grafts, and stem cells) is growing in therapeutic potential and enthusiasm, giving hope to a subset of patients that have either failed conventional therapy or are not candidates for traditional steroid injections. In this chapter, we will describe different cases in which regenerative medicine can help in painful conditions as well as neuro-degenerative conditions. Regenerative medicine can be the new frontier in providing long lasting relief through changes in cell-signaling cascades, however further trials are needed to validate their use

Methods for Analysis of Matrix Metalloproteinase Regulation of Neutrophil-Endothelial Cell Adhesion

Recent evidence indicates novel role for matrix metalloproteinases (MMPs), in particular gelatinase A (MMP-2), in the regulation of vascular biology that are unrelated to their well-known proteolytic breakdown of matrix proteins. We have previously reported that MMP-2 can modulate vascular reactivity by cleavage of the Gly32-Leu33 bound in big endothelin-1 (ET-1) yielding a novel vasoactive peptide ET-1[1-32]. These studies were conducted to investigate whether gelatinolytic MMPs could affect neutrophil-endothelial cell attachment. ET-1[1-32] produced by MMP-2 up-regulated CD11b/CD18 expression on human neutrophils, thereby promoted their adhesion to cultured endothelial cells. ET-1[1-32] evoked release of gelatinase B (MMP-9), which in turn cleaved big ET-1 to yield ET-1[1-32], thus revealing a self-amplifying loop for ET-1[1-32] generation. ET-1[1-32] was rather resistant to cleavage by neutrophil proteases and further metabolism of ET-1[1-32] was not a prerequisite for its biological actions on neutrophils. The neutrophil responses to ET-1[1-32] were mediated via activation of ET(A)receptors through activation of the Ras/Raf-1/MEK/ERK signaling pathway. These results suggest a novel role for gelatinase A and B in the regulation of neutrophil functions and their interactions with endothelial cells. Here we describe the methods in detail as they relate to our previously published work

Integrated cognitive behavioral intervention for functional tics (I-CBiT): case reports and treatment formulation

IntroductionThe onset of the COVID-19 pandemic saw a global surge in functional tic-like behaviors (FTLBs). FTLBs are unique from primary tic disorders. They are thought to manifest through a complex interplay between environmental and personal factors, including the stress-arousal system, and are characterized by their sudden and explosive onset. Accordingly, common interventions for tic disorders show limited efficacy in this population. We present an Integrated Cognitive Behavioral Intervention for Functional Tics (I-CBiT) that uses an urge acceptance model to manage tics and related stress and anxiety.MethodsWe describe the treatment outcomes of eight young people presenting with new and sudden onset FTLBs who underwent I-CBiT, which integrates traditional behavioral tic interventions with third-wave cognitive behavioral therapies. All cases completed the three-phase intervention involving core components of psychoeducation, exposure and response prevention with urge acceptance, sensory grounding strategies, and cognitive behavioral intervention targeting the stress-arousal system. Tic severity and impairment were assessed prior to treatment and at completion.ResultsAll cases showed a significant reduction in tic severity post I-CBiT and an improvement in overall daily living function. These cases highlight the role of urge acceptance in managing both tic urges and the underlying stress-arousal system to bring about long-term change.ConclusionWe demonstrated the efficacy of I-CBiT for managing FTLBs. Our findings illustrate the importance of treating underlying stress and anxiety in this population and, therefore, a need for greater interaction between multidisciplinary services in managing FTLBs to comprehensively cover the varied symptom presentations linked to thoughts, emotions, bodily sensations, and stress responses

Acetylcholine Inhibits Monomeric C-Reactive Protein Induced Inflammation, Endothelial Cell Adhesion, and Platelet Aggregation; A Potential Therapeutic?

Objectives: In this study, we examined the possibility of using targeted antibodies and the potential of small molecular therapeutics (acetylcholine, nicotine and tacrine) to block the pro-inflammatory and adhesion-related properties of monomeric C-reactive protein (mCRP). Methods: We used three established models (platelet aggregation assay, endothelial leucocyte binding assay and monocyte inflammation via ELISA and Western blotting) to assess the potential of these therapeutics. Results: The results of this study showed that monocyte induced inflammation (raised tumor necrosis factor-alpha-TNF-α) induced by mCRP was significantly blocked in the presence of acetylcholine and nicotine, whilst tacrine and targeted antibodies (clones 8C10 and 3H12) had less of or no significant effects. Western blotting confirmed the ability of acetylcholine to inhibit mCRP-induced cell signaling phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), p38 and nuclear factor-kappa B (NF-κB). There was no evidence of direct binding between small molecules and mCRP. mCRP also induced endothelial cell-monocyte adhesion in a dose dependent fashion, however, both acetylcholine and nicotine as well as targeting antibodies notably inhibited adhesion. Finally, we investigated their effects on mCRP-induced platelet aggregation. All three small molecules significantly attenuated platelet aggregation as did the antibody 8C10, although 3H12 had a weaker effect. Discussion: Acetylcholine and to a lesser extent nicotine show potential for therapeutic inhibition of mCRP-induced inflammation and cell and platelet adhesion. These results highlight the potential of targeted antibodies and small molecule therapeutics to inhibit the binding of mCRP by prevention of membrane interaction and subsequent activation of cellular cascade systems, which produce the pro-inflammatory effects associated with mCRP

Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice

Opposing effects of monomeric and pentameric C-reactive protein on endothelial progenitor cells

C-reactive protein (CRP) has been linked to the pathogenesis of atherosclerosis. The dissociation of native, pentameric (p)CRP to monomeric (m)CRP on the cell membrane of activated platelets has recently been demonstrated. The dissociation of pCRP to mCRP may explain local pro-inflammatory reactions at the site of developing atherosclerotic plaques. As a biomarker, pCRP predicts cardiovascular adverse events and so do reduced levels and function of circulating endothelial progenitor cells (EPCs). We hypothesised that mCRP and pCRP exert a differential effect on EPC function and differentiation. EPCs were treated with mCRP or pCRP for 72 h, respectively. Phenotypical characterisation was done by flow cytometry and immunofluorescence microscopy, while the effect of mCRP and pCRP on gene expression was examined by whole-genome gene expression analysis. The functional capacity of EPCs was determined by colony forming unit (CFU) assay and endothelial tube formation assay. Double staining for acetylated LDL and ulex lectin significantly decreased in cells treated with pCRP. The length of tubuli in a matrigel assay with HUVECs decreased significantly in response to pCRP, but not to mCRP. The number of CFUs increased after pCRP treatment. RNA expression profiling demonstrated that mCRP and pCRP cause highly contradictory gene regulation. Interferon-responsive genes (IFI44L, IFI44, IFI27, IFI 6, MX1, OAS2) were among the highly up-regulated genes after mCRP, but not after pCRP treatment. In conclusion, EPC phenotype, genotype and function were differentially affected by mCRP and pCRP, strongly arguing for differential roles of these two CRP conformations. The up-regulation of interferon-inducible genes in response to mCRP may constitute a mechanism for the local regulation of EPC function