Open AccessReview
Diaphragm Dysfunction: Diagnostic Approaches and Management Strategies
J. Clin. Med. 2016, 5(12), 113; doi:10.3390/jcm5120113 (registering DOI) -
Abstract
The diaphragm is the main inspiratory muscle, and its dysfunction can lead to significant adverse clinical consequences. The aim of this review is to provide clinicians with an overview of the main causes of uni- and bi-lateral diaphragm dysfunction, explore the clinical and
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The diaphragm is the main inspiratory muscle, and its dysfunction can lead to significant adverse clinical consequences. The aim of this review is to provide clinicians with an overview of the main causes of uni- and bi-lateral diaphragm dysfunction, explore the clinical and physiological consequences of the disease on lung function, exercise physiology and sleep and review the available diagnostic tools used in the evaluation of diaphragm function. A particular emphasis is placed on the clinical significance of diaphragm weakness in the intensive care unit setting and the use of ultrasound to evaluate diaphragmatic action. Full article
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Open AccessReview
Switching Roles of TGF-β in Cancer Development: Implications for Therapeutic Target and Biomarker Studies
J. Clin. Med. 2016, 5(12), 109; doi:10.3390/jcm5120109 -
Abstract
TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes
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TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes have not been identified. Recently, however, several findings have provided new insights on the contextual determinants of Smads in TGF-β’s biological processes. These novel switches and their effectors may serve as prognostic biomarkers and therapeutic targets of TGF-β-mediated cancer progression. Full article
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Open AccessReview
Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer
J. Clin. Med. 2016, 5(12), 111; doi:10.3390/jcm5120111 -
Abstract
TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous
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TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia. Full article
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Open AccessCase Report
Burkholderia contaminans Colonization from Contaminated Liquid Docusate (Colace) in a Immunocompetent Adult with Legionnaire’s Disease: Infection Control Implications and the Potential Role of Candida pellucosa
J. Clin. Med. 2016, 5(12), 110; doi:10.3390/jcm5120110 -
Abstract
Objective:B. contaminans was cultured from respiratory secretions and liquid docusate (Colace) in a Neurosurgical Intensive Care Unit (NICU) patient with community-acquired Legionnaire’s disease but not from another bottle given to the patient. Unexpectedly, C. pelliculosa was cultured from two bottles, but not
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Objective:B. contaminans was cultured from respiratory secretions and liquid docusate (Colace) in a Neurosurgical Intensive Care Unit (NICU) patient with community-acquired Legionnaire’s disease but not from another bottle given to the patient. Unexpectedly, C. pelliculosa was cultured from two bottles, but not the B. contaminans bottle or respiratory secretions. Methods:B. cepacia, later identified as B. contaminans, was cultured from a bottle of liquid docusate (Colace) dispensed to a non-cystic fibrosis patient. His respiratory secretions were colonized with B. contaminans. Results: Eradication of B. contaminans colonization in the patient’s respiratory secretions was attempted. With levofloxacin, B. contaminans developed multidrug resistance (MDR). Subsequent TMP-SMX therapy did not result in further MDR. Nine other ICU patients were given docusate from the same lot, but there were no other B. contaminans isolates. Conclusion:B. contaminans colonization of respiratory secretion may be difficult to eliminate. The significance of C. pelliculosa cultured from liquid docusate (Colace) remains to be elucidated. In this case, it appeared that B. contaminans may have inhibited the growth of C. pelliculosa in the same bottle. Others should be alerted to the possibility that C. pelliculosa may be present in B. contaminans–contaminated lots of liquid docusate (Colace). Full article
Open AccessArticle
Hyaluronic Acid Gel-Based Scaffolds as Potential Carrier for Growth Factors: An In Vitro Bioassay on Its Osteogenic Potential
J. Clin. Med. 2016, 5(12), 112; doi:10.3390/jcm5120112 -
Abstract
Hyaluronic acid (HA) has been utilized for a variety of regenerative medical procedures due to its widespread presence in connective tissue and perceived biocompatibility. The aim of the present study was to investigate HA in combination with recombinant human bone morphogenetic protein 9
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Hyaluronic acid (HA) has been utilized for a variety of regenerative medical procedures due to its widespread presence in connective tissue and perceived biocompatibility. The aim of the present study was to investigate HA in combination with recombinant human bone morphogenetic protein 9 (rhBMP9), one of the most osteogenic growth factors of the BMP family. HA was first combined with rhBMP9 and assessed for the adsorption and release of rhBMP9 over 10 days by ELISA. Thereafter, ST2 pre-osteoblasts were investigated by comparing (1) control tissue culture plastic, (2) HA alone, and (3) HA with rhBMP9 (100 ng/mL). Cellular proliferation was investigated by a MTS assay at one, three and five days and osteoblast differentiation was investigated by alkaline phosphatase (ALP) activity at seven days, alizarin red staining at 14 days and real-time PCR for osteoblast differentiation markers. The results demonstrated that rhBMP9 adsorbed within HA scaffolds and was released over a 10-day period in a controlled manner. While HA and rhBMP9 had little effect on cell proliferation, a marked and pronounced effect was observed for cell differentiation. rhBMP9 significantly induced ALP activity, mRNA levels of collagen1α2, and ALP and osteocalcin (OCN) at three or 14 days. HA also demonstrated some ability to induce osteoblast differentiation by increasing mRNA levels of OCN and increasing alizarin red staining at 14 days. In conclusion, the results from the present study demonstrate that (1) HA may serve as a potential carrier for various growth factors, and (2) rhBMP9 is a potent and promising inducer of osteoblast differentiation. Future animal studies are now necessary to investigate this combination approach in vivo. Full article
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Open AccessArticle
Monitoring of Physiological Parameters to Predict Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review
J. Clin. Med. 2016, 5(12), 108; doi:10.3390/jcm5120108 -
Abstract
Introduction: The value of monitoring physiological parameters to predict chronic obstructive pulmonary disease (COPD) exacerbations is controversial. A few studies have suggested benefit from domiciliary monitoring of vital signs, and/or lung function but there is no existing systematic review. Objectives: To conduct a
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Introduction: The value of monitoring physiological parameters to predict chronic obstructive pulmonary disease (COPD) exacerbations is controversial. A few studies have suggested benefit from domiciliary monitoring of vital signs, and/or lung function but there is no existing systematic review. Objectives: To conduct a systematic review of the effectiveness of monitoring physiological parameters to predict COPD exacerbation. Methods: An electronic systematic search compliant with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. The search was updated to April 6, 2016. Five databases were examined: Medical Literature Analysis and Retrieval System Online, or MEDLARS Online (Medline), Excerpta Medica dataBASE (Embase), Allied and Complementary Medicine Database (AMED), Cumulative Index of Nursing and Allied Health Literature (CINAHL) and the Cochrane clinical trials database. Results: Sixteen articles met the pre-specified inclusion criteria. Fifteen of these articules reported positive results in predicting COPD exacerbation via monitoring of physiological parameters. Nine studies showed a reduction in peripheral oxygen saturation (SpO2%) prior to exacerbation onset. Three studies for peak flow, and two studies for respiratory rate reported a significant variation prior to or at exacerbation onset. A particular challenge is accounting for baseline heterogeneity in parameters between patients. Conclusion: There is currently insufficient information on how physiological parameters vary prior to exacerbation to support routine domiciliary monitoring for the prediction of exacerbations in COPD. However, the method remains promising. Full article
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Open AccessReview
Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies
J. Clin. Med. 2016, 5(12), 107; doi:10.3390/jcm5120107 -
Abstract
Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for
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Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients. Full article
Open AccessArticle
Case Formulation in Young People with Post-Traumatic Stress Disorder and First-Episode Psychosis
J. Clin. Med. 2016, 5(11), 106; doi:10.3390/jcm5110106 -
Abstract
Background: Evidence based treatment interventions for young people with first-episode psychosis (FEP) and trauma histories is lacking. Although case formulation (CF) has been widely regarded in cognitive behavioural therapy manuals as beneficial, there is limited empirical research examining how clients and therapists experience
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Background: Evidence based treatment interventions for young people with first-episode psychosis (FEP) and trauma histories is lacking. Although case formulation (CF) has been widely regarded in cognitive behavioural therapy manuals as beneficial, there is limited empirical research examining how clients and therapists experience the process. Aim: This study aimed to explore young people’s reactions to CF in treatment for PTSD (post-traumatic stress disorder) and FEP. Method: Semi-structured interviews were conducted with three participants (aged 19–20) with FEP and PTSD and their therapists, after they had completed a trauma-focused treatment program with a CF component. Transcripts were analysed using an interpretative phenomenological approach and themes were derived. Results: Two themes related to participants’ experiences were identified from the analysis: (1) Developing Insight; (2) A challenging experience; and two themes from the therapists: (1) Doing the case formulation; (2) Value of case formulation. Participants and therapists reported benefits in making connections between current symptoms and past trauma. Participants viewed the process as challenging. Conclusion: Results suggest a potential discrepancy between the experience of the case formulation process for clients and therapists. Full article
Open AccessReview
Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment
J. Clin. Med. 2016, 5(11), 105; doi:10.3390/jcm5110105 -
Abstract
Posttraumatic stress disorder (PTSD) is a chronic psychological disorder that can develop after exposure to a traumatic event. This review summarizes the literature on the epidemiology, assessment, and treatment of PTSD. We provide a review of the characteristics of PTSD along with associated
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Posttraumatic stress disorder (PTSD) is a chronic psychological disorder that can develop after exposure to a traumatic event. This review summarizes the literature on the epidemiology, assessment, and treatment of PTSD. We provide a review of the characteristics of PTSD along with associated risk factors, and describe brief, evidence-based measures that can be used to screen for PTSD and monitor symptom changes over time. In regard to treatment, we highlight commonly used, evidence-based psychotherapies and pharmacotherapies for PTSD. Among psychotherapeutic approaches, evidence-based approaches include cognitive-behavioral therapies (e.g., Prolonged Exposure and Cognitive Processing Therapy) and Eye Movement Desensitization and Reprocessing. A wide variety of pharmacotherapies have received some level of research support for PTSD symptom alleviation, although selective serotonin reuptake inhibitors have the largest evidence base to date. However, relapse may occur after the discontinuation of pharmacotherapy, whereas PTSD symptoms typically remain stable or continue to improve after completion of evidence-based psychotherapy. After reviewing treatment recommendations, we conclude by describing critical areas for future research. Full article
Open AccessArticle
The Benefit of Conserving and Gaining Resources after Trauma: A Systematic Review
J. Clin. Med. 2016, 5(11), 104; doi:10.3390/jcm5110104 -
Abstract
Background: Traumatic events involve loss of resources, which has consistently been found to be associated with developing stress-related illness such as posttraumatic stress disorder (PTSD). Objective: The purpose of this systematic literature review was to determine if there is evidence for the salutatory
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Background: Traumatic events involve loss of resources, which has consistently been found to be associated with developing stress-related illness such as posttraumatic stress disorder (PTSD). Objective: The purpose of this systematic literature review was to determine if there is evidence for the salutatory effect of resource gain on PTSD, and if there are intervention models that utilize and assess gain in PTSD. Data Sources: All relevant online databases were systematically searched using key terms and a method, detailed in Figure 1. Results: Of 22 relevant articles, there were three intervention studies, one longitudinal naturalistic study, eleven non-intervention association studies focusing on PTSD, and eight non-intervention association studies not focusing on PTSD. The intervention and naturalistic studies showed a significant positive effect on PTSD by specifically targeting the gain of resources during an intervention. Other non-intervention research supports the notion that resource loss is pathogenic and resource gain is beneficial after traumatic exposure. Conclusions: Interventions that develop and assess effects of gain of various types of resources on stress-related illness should be encouraged. Interventions that already have proven efficacy for PTSD might include standardized assessment of resource loss and gain to further understand mechanisms of action. Full article
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Open AccessFeature PaperArticle
A Shared Decision-Making Approach to Telemedicine: Engaging Rural Patients in Glycemic Management
J. Clin. Med. 2016, 5(11), 103; doi:10.3390/jcm5110103 -
Abstract
Telemedicine can connect specialist health care providers with patients in remote and underserved areas. It is especially relevant in diabetes care, where a proliferation of treatment options has added further complexity to the care of an already complex, highly prevalent disease. Recent developments
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Telemedicine can connect specialist health care providers with patients in remote and underserved areas. It is especially relevant in diabetes care, where a proliferation of treatment options has added further complexity to the care of an already complex, highly prevalent disease. Recent developments in health reform encourage delivery systems to use team-based models and engage patients in shared decision-making (SDM), where patients and providers together make health care decisions that are tailored to the specific characteristics and values of the patient. The goal of this project was to design, integrate, and evaluate a team-based, SDM approach delivered to patients with diabetes in a rural community, building upon the previously established telemedicine for reach, education, access, and treatment (TREAT) model. Patients in this feasibility study demonstrated improvement in hemoglobin A1c values, and reported better understanding of diabetes. Providers reported the SDM aids increased cohesion among team members (including patients) and facilitated patient education and behavioral goal setting. This project demonstrated that SDM could be integrated into the workflow of a telemedicine team visit with good provider and patient satisfaction. Full article
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Open AccessReview
Modulating the Gut Micro-Environment in the Treatment of Intestinal Parasites
J. Clin. Med. 2016, 5(11), 102; doi:10.3390/jcm5110102 -
Abstract
The interactions of micro-organisms cohabitating with Homo sapiens spans millennia, with microbial communities living in a symbiotic relationship with the host. Interacting to regulate and maintain physiological functions and immunological tolerance, the microbial community is able to exert an influence on host health.
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The interactions of micro-organisms cohabitating with Homo sapiens spans millennia, with microbial communities living in a symbiotic relationship with the host. Interacting to regulate and maintain physiological functions and immunological tolerance, the microbial community is able to exert an influence on host health. An example of micro-organisms contributing to an intestinal disease state is exhibited by a biodiverse range of protozoan and bacterial species that damage the intestinal epithelia and are therefore implicated in the symptoms of diarrhea. As a contentious exemplar, Blastocystis hominis is a ubiquitous enteric protist that can adversely affect the intestines. The symptoms experienced are a consequence of the responses of the innate immune system triggered by the disruption of the intestinal barrier. The infiltration of the intestinal epithelial barrier involves a host of immune receptors, including toll like receptors and IgM/IgG/IgA antibodies as well as CD8+ T cells, macrophages, and neutrophils. Whilst the mechanisms of interactions between the intestinal microbiome and protozoan parasites remain incompletely understood, it is acknowledged that the intestinal microbiota is a key factor in the pathophysiology of parasitic infections. Modulating the intestinal environment through the administration of probiotics has been postulated as a possible therapeutic agent to control the proliferation of intestinal microbes through their capacity to induce competition for occupation of a common biotype. The ultimate goal of this mechanism is to prevent infections of the like of giardiasis and eliminate its symptoms. The differing types of probiotics (i.e., bacteria and yeast) modulate immunity by stimulating the host immune system. Early animal studies support the potential benefits of probiotic administration to prevent intestinal infections, with human clinical studies showing probiotics can reduce the number of parasites and the severity of symptoms. The early clinical indications endorse probiotics as adjuncts in the pharmaceutical treatment of protozoan infections. Currently, the bar is set low for the conduct of well-designed clinical studies that will translate the use of probiotics to ameliorate protozoan infections, therefore the requisite is for further clinical research. Full article
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Open AccessArticle
Integrated Exposure-Based Therapy for Co-Occurring Post Traumatic Stress Disorder (PTSD) and Substance Dependence: Predictors of Change in PTSD Symptom Severity
J. Clin. Med. 2016, 5(11), 101; doi:10.3390/jcm5110101 -
Abstract
This paper examines factors associated with change in PTSD symptom severity among individuals randomised to receive an integrated exposure-based psychotherapy for PTSD and substance dependence–Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE). Outcomes examined include change in PTSD symptom
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This paper examines factors associated with change in PTSD symptom severity among individuals randomised to receive an integrated exposure-based psychotherapy for PTSD and substance dependence–Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE). Outcomes examined include change in PTSD symptom severity as measured by the Clinician Administered PTSD Scale (CAPS), and the reliability and clinical significance of change in PTSD symptom severity. Factors examined include patient baseline characteristics, treatment characteristics, and events over follow-up. The mean difference in CAPS score was 38.24 (SE 4.81). Approximately half (49.1%) demonstrated a reliable and clinically significant improvement in PTSD symptom severity. No one was classified as having demonstrated clinically significant worsening of symptoms. Three independent predictors of reductions in PTSD symptom severity were identified: baseline PTSD symptom severity (β 0.77, SE 0.23, p = 0.001), number of traumas experienced prior to baseline (β −0.30, SE 0.15, p = 0.049), and number of sessions attended (β 2.05, SE 0.87, p = 0.024). The present study provides further evidence regarding the safety of the COPE treatment and factors associated with improvement in PTSD symptom severity. The identification of only a small number of predictors of the outcome points to the broad applicability of the COPE treatment to PTSD and substance use disorder (SUD) patients. Full article
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Open AccessReview
The Future Prospects of Immune Therapy in Gastric and Esophageal Adenocarcinoma
J. Clin. Med. 2016, 5(11), 100; doi:10.3390/jcm5110100 -
Abstract
The prognosis of esophageal cancers is poor and novel approaches are urgently needed. Despite improvements in outcomes with transtuzumab and ramucirumab, these improvements added an average of only 2 to 3 months with a median overall survival reported to be around 1 year.
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The prognosis of esophageal cancers is poor and novel approaches are urgently needed. Despite improvements in outcomes with transtuzumab and ramucirumab, these improvements added an average of only 2 to 3 months with a median overall survival reported to be around 1 year. Comprehensive genomic sequencing has defined some molecular alterations with potential targets, but the majority of patients still do not benefit from druggable targets. Breakthroughs in immune checkpoint blockade have provided new therapeutic options in many cancers. Programmed death ligand 1 (PDL1) overexpression, a possible biomarker predicting response to immune checkpoint inhibitors, approaches forty percent in esophageal and gastric cancers. Translational and molecular studies have shown that esophageal cancers are possible candidate malignancies for immune checkpoint inhibition. In this review, we plan to highlight the mechanisms, preclinical, and early clinical data that provide insight on the role of immune therapeutics in esophageal cancers. Full article
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Open AccessArticle
An Admission-to-Discharge BNP Increase Is a Predictor of Six-Month All-Cause Death in ADHF Patients: Inferences from Multivariate Analysis Including Admission BNP and Various Clinical Measures of Congestion
J. Clin. Med. 2016, 5(11), 99; doi:10.3390/jcm5110099 -
Abstract
Background: According to some authors, a single isolated measurement of serum B-type natriuretic peptide (BNP) executed on hospital admission would not be a sufficiently accurate method to predict the outcome of patients with acute decompensated heart failure (ADHF). Aims: To verify this assumption,
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Background: According to some authors, a single isolated measurement of serum B-type natriuretic peptide (BNP) executed on hospital admission would not be a sufficiently accurate method to predict the outcome of patients with acute decompensated heart failure (ADHF). Aims: To verify this assumption, a retrospective study was conducted on patients hospitalized for ADHF. Our main objective was to ascertain whether there was any difference in midterm mortality among patients with increasing BNP at discharge as compared with those with decreasing BNP at discharge. Methods: Medical records were examined so as to make a partition of the ADHF patient population into two groups, the former characterized by a rise in BNP during hospitalization, and the latter exhibiting a decrease in BNP in the measurement taken at hospital discharge. Results: 177 patients were enrolled in a retrospective study. Among them, 53 patients (30%) had increased BNP at the time of discharge, whereas 124 (70%) showed decreases in serum BNP during their hospital stay. The group with patients who exhibited BNP increases at the time of discharge had a higher degree of congestion evident in the higher frequency of persistent jugular venous distention and persistent orthopnea at discharge. Moreover, patients with increased BNP at the time of discharge had a lower reduction in inferior vena cava maximum diameter (1.58 ± 2.2 mm vs. 6.32 ± 1.82 mm; p (one-way ANOVA) = 0.001). In contrast, there was no significant difference in weight loss when patients with increased BNP at discharge were compared with those with no such increase. A total of 14 patients (7.9%) died during the six-month follow-up period. Multivariable Cox proportional-hazards regression analysis revealed that a BNP increase at the time of discharge was an independent predictor of six-month all-cause mortality after adjustment for persistent jugular venous distention, persistent orthopnea, reduction in inferior vena cava maximum diameter at discharge, weight loss, serum urea, systolic blood pressure at admission, and BNP at admission (hazard ratio = 30.5424; 95% CI: 1.7409–535.8294, p = 0.0199). Conclusions: Among patients with a history of ADHF, more elevated BNP levels at the time of discharge from the hospital compared with those detected at admission identify a patient subset with a higher grade of congestion and higher six-month mortality. Full article
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Open AccessArticle
B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes
J. Clin. Med. 2016, 5(11), 98; doi:10.3390/jcm5110098 -
Abstract
B cells have been strongly implicated in the development of human type 1 diabetes and are required for disease in the NOD mouse model. These functions are dependent on B cell antigen receptor (BCR) specificity and expression of MHC, implicating linked autoantigen recognition
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B cells have been strongly implicated in the development of human type 1 diabetes and are required for disease in the NOD mouse model. These functions are dependent on B cell antigen receptor (BCR) specificity and expression of MHC, implicating linked autoantigen recognition and presentation to effector T cells. BCR-antigen affinity requirements for participation in disease are unclear. We hypothesized that BCR affinity for the autoantigen insulin differentially affects lymphocyte functionality, including tolerance modality and the ability to acquire and become activated in the diabetogenic environment. Using combined transgenic and retrogenic heavy and light chain to create multiple insulin-binding BCRs, we demonstrate that affinity for insulin is a critical determinant of the function of these autoreactive cells. We show that both BCR affinity for insulin and genetic background affect tolerance induction in immature B cells. We also find new evidence that may explain the enigmatic ability of B cells expressing 125 anti-insulin BCR to support development of TID in NOD mice despite a reported affinity beneath requirements for binding insulin at in vivo concentrations. We report that when expressed as an antigen receptor the affinity of 125 is much higher than determined by measurements of the soluble form. Finally, we show that in vivo acquisition of insulin requires both sufficient BCR affinity and permissive host/tissue environment. We propose that a confluence of BCR affinity, pancreas environment, and B cell tolerance-regulating genes in the NOD animal allows acquisition of insulin and autoimmunity. Full article
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Open AccessCommunication
An Age-Related Morphometric Profile of Skeletal Muscle in Healthy Untrained Women
J. Clin. Med. 2016, 5(11), 97; doi:10.3390/jcm5110097 -
Abstract
There is a paucity of data on muscle biopsies in females of mixed ages in terms of age-related changes. Cross sections of autopsy material including the quadriceps femoris and biceps brachii muscles were obtained from 23 healthy women, aged 24–82 years, who had
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There is a paucity of data on muscle biopsies in females of mixed ages in terms of age-related changes. Cross sections of autopsy material including the quadriceps femoris and biceps brachii muscles were obtained from 23 healthy women, aged 24–82 years, who had suffered sudden death. We calculated the percentage of the number, and the mean diameter, of type I and type II muscle fibers within the fascicles as well as in their peripheral parts. The number of type II fibers were shown to reduce significantly with age (p < 0.005), especially in the fascicle periphery, but the percentage of type 1 fibers did not alter significantly. It was noted that type II fibers diminished in size with age, indicating a relationship between fiber size and age. This result became more apparent in the fascicle periphery (p < 0.05). In women, type II muscle fibers were seen to reduce in size and number with advancing age. We postulate that regular physical activity can increase the size of type II muscle fibers, thus helping to both prevent and treat age-related muscle loss. Full article
Open AccessReview
TGF-β Signaling in Bone Remodeling and Osteosarcoma Progression
J. Clin. Med. 2016, 5(11), 96; doi:10.3390/jcm5110096 -
Abstract
Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of
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Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of patients who present metastases will survive five years after initial diagnosis. Treating metastatic osteosarcoma thus remains a challenge. One of the main characteristics of osteosarcomas is their ability to deregulate bone remodelling. The invasion of bone tissue by tumor cells indeed affects the balance between bone resorption and bone formation. This deregulation induces the release of cytokines or growth factors initially trapped in the bone matrix, such as transforming growth factor-β (TGF-β), which in turn promote tumor progression. Over the past years, there has been considerable interest in the TGF-β pathway within the cancer research community. This review discusses the involvement of the TGF-β signalling pathway in osteosarcoma development and in their metastatic progression. Full article
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Open AccessArticle
Do Alcohol Misuse, Service Utilisation, and Demographic Characteristics Differ between UK Veterans and Members of the General Public Attending an NHS General Hospital?
J. Clin. Med. 2016, 5(11), 95; doi:10.3390/jcm5110095 -
Abstract
The aim of this paper was to provide insights into alcohol misuse within UK veterans to inform as to whether their presentations differ from the general public. This was done by exploring differences in the severity of alcohol misuse between UK veterans and
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The aim of this paper was to provide insights into alcohol misuse within UK veterans to inform as to whether their presentations differ from the general public. This was done by exploring differences in the severity of alcohol misuse between UK veterans and the general public admitted to a general NHS hospital over an 18 month period using retrospective data. All patients admitted to the hospital were screened for alcohol misuse. Those deemed as experiencing problems were referred for specialist nurse-led support. A total of 2331 individuals were referred for this supported and administered with a standardised assessment that included measures of the severity of alcohol difficulties (AUDIT), dependency levels (LDQ), and assessed for the presence of withdrawal symptoms (CIWA-Ar). In addition, information was collected on service utilisation, referral category (medical or mental health), other substance misuse, and demographic characteristics. No differences were found between the severity of reported alcohol difficulties between veterans and non-veterans. Evidence was found to suggest that veterans were more likely to be referred for support with alcohol difficulties at an older age and to be admitted to hospital for longer periods of time. This could have considerable cost implications for the NHS. It was more common for veterans to present at hospital with physical health difficulties prior to being referred for support for alcohol. Full article
Open AccessReview
Ashamed and Afraid: A Scoping Review of the Role of Shame in Post-Traumatic Stress Disorder (PTSD)
J. Clin. Med. 2016, 5(11), 94; doi:10.3390/jcm5110094 -
Abstract
Background: Despite considerable progress in the treatment of post-traumatic stress disorder (PTSD), a large percentage of individuals remain symptomatic following gold-standard therapies. One route to improving care is examining affective disturbances that involve other emotions beyond fear and threat. A growing body of
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Background: Despite considerable progress in the treatment of post-traumatic stress disorder (PTSD), a large percentage of individuals remain symptomatic following gold-standard therapies. One route to improving care is examining affective disturbances that involve other emotions beyond fear and threat. A growing body of research has implicated shame in PTSD’s development and course, although to date no review of this specific literature exists. This scoping review investigated the link between shame and PTSD and sought to identify research gaps. Methods: A systematic database search of PubMed, PsycInfo, Embase, Cochrane, and CINAHL was conducted to find original quantitative research related to shame and PTSD. Results: Forty-seven studies met inclusion criteria. Review found substantial support for an association between shame and PTSD as well as preliminary evidence suggesting its utility as a treatment target. Several design limitations and under-investigated areas were recognized, including the need for a multimodal assessment of shame and more longitudinal and treatment-focused research. Conclusion: This review provides crucial synthesis of research to date, highlighting the prominence of shame in PTSD, and its likely relevance in successful treatment outcomes. The present review serves as a guide to future work into this critical area of study. Full article
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