Critical Update Research Articles

Exercise-induced ROS in heat shock proteins response

Cells have evolved multiple and sophisticated stress response mechanisms aiming to prevent macromolecular (including proteins, lipids, and nucleic acids) damage and to maintain or re-establish cellular homeostasis. Heat shock proteins (HSPs) are among the most highly conserved, ubiquitous, and abundant proteins in all organisms. Originally discovered more than 50 years ago through heat shock stress, they display multiple, remarkable roles inside and outside cells under a variety of stresses, including also oxidative stress and radiation, recognizing unfolded or misfolded proteins and facilitating their restructuring. Exercise consists in a combination of physiological stresses, such as metabolic disturbances, changes in circulating levels of hormones, increased temperature, induction of mild to severe inflammatory state, increased production of reactive oxygen and nitrogen species (ROS and RNS). As a consequence, exercise is one of the main stimuli associated with a robust increase in different HSPs in several tissues, which appears to be also fundamental in facilitating the cellular remodeling processes related to the training regime. Among all factors involved in the exercise-related modulation of HSPs level, the ROS production in the contracting muscle or in other tissues represents one of the most attracting, but still under discussion, mechanism. Following exhaustive or damaging muscle exercise, major oxidative damage to proteins and lipids is likely involved in HSP expression, together with mechanically induced damage to muscle proteins and the inflammatory response occurring several days into the recovery period. Instead, the transient and reversible oxidation of proteins by physiological concentrations of ROS seems to be involved in the activation of stress response following non-damaging muscle exercise. This review aims to provide a critical update on the role of HSPs response in exercise-induced adaptation or damage in humans, focusing on experimental results where the link between redox homeostasis and HSPs expression by exercise has been addressed. Further, with the support of in vivo and in vitro studies, we discuss the putative molecular mechanisms underlying the ROS-mediated modulation of HSP expression and/or activity during exercise.

Single-Chain Folding of Synthetic Polymers: A Critical Update.

The current contribution serves as a critical update to a previous feature article from us (Macromol. Rapid Commun. 2012, 33, 958-971), and highlights the latest advances in the preparation of single chain polymeric nanoparticles and initial-yet promising-attempts towards mimicking the structure of natural biomacromolecules via single-chain folding of well-defined linear polymers via so-called single chain selective point folding and repeat unit folding. The contribution covers selected examples from the literature published up to ca. September 2015. Our aim is not to provide an exhaustive review but rather highlight a selection of new and exciting examples for single-chain folding based on advanced macromolecular precision chemistry. Initially, the discussion focuses on the synthesis and characterization of single-chain folded structures via selective point folding. The second part of the feature article addresses the folding of well-defined single-chain polymers by means of repeat unit folding. The current state of the art in the field of single-chain folding indicates that repeat unit folding-driven nanoparticle preparation is well-advanced, while initial encouraging steps towards building selective point folding systems have been taken. In addition, a summary of the-in our view-open key questions is provided that may guide future biomimetic design efforts.

Synaptic activity and Alzheimer's disease: a critical update.

Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Aβ) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Aβ and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology.

Muscle-bone interactions: From experimental models to the clinic? A critical update

Bone is a biomechanical tissue shaped by forces from muscles and gravitation. Simultaneous bone and muscle decay and dysfunction (osteosarcopenia or sarco-osteoporosis) is seen in ageing, numerous clinical situations including after stroke or paralysis, in neuromuscular dystrophies, glucocorticoid excess, or in association with vitamin D, growth hormone/insulin like growth factor or sex steroid deficiency, as well as in spaceflight. Physical exercise may be beneficial in these situations, but further work is still needed to translate acceptable and effective biomechanical interventions like vibration therapy from animal models to humans. Novel antiresorptive and anabolic therapies are emerging for osteoporosis as well as drugs for sarcopenia, cancer cachexia or muscle wasting disorders, including antibodies against myostatin or activin receptor type IIA and IIB (e.g. bimagrumab). Ideally, increasing muscle mass would increase muscle strength and restore bone loss from disuse. However, the classical view that muscle is unidirectionally dominant over bone via mechanical loading is overly simplistic. Indeed, recent studies indicate a role for neuronal regulation of not only muscle but also bone metabolism, bone signaling pathways like receptor activator of nuclear factor kappa-B ligand (RANKL) implicated in muscle biology, myokines affecting bone and possible bone-to-muscle communication. Moreover, pharmacological strategies inducing isolated myocyte hypertrophy may not translate into increased muscle power because tendons, connective tissue, neurons and energy metabolism need to adapt as well. We aim here to critically review key musculoskeletal molecular pathways involved in mechanoregulation and their effect on the bone-muscle unit as a whole, as well as preclinical and emerging clinical evidence regarding the effects of sarcopenia therapies on osteoporosis and vice versa.

Clinical epidemiology of human AE in Europe

This review gives a critical update of the situation regarding alveolar echinococcosis (AE) in Europe in humans, based on existing publications and on findings of national and European surveillance systems. All sources point to an increase in human cases of AE in the “historic endemic areas” of Europe, namely Germany, Switzerland, Austria and France and to the emergence of human cases in countries where the disease had never been recognised until the end of the 20th century, especially in central-eastern and Baltic countries. Both increase and emergence could be only due to methodological biases; this point is discussed in the review. One explanation may be given by changes in the animal reservoir of the parasite, Echinococcus multilocularis (increase in the global population of foxes in Europe and its urbanisation, as well as a possible increased involvement of pet animals as definitive infectious hosts). The review also focuses onto 2 more original approaches: (1) how changes in therapeutic attitudes toward malignant and chronic inflammatory diseases may affect the epidemiology of AE in the future in Europe, since a recent survey of such cases in France showed the emergence of AE in patients with immune suppression since the beginning of the 21st century; (2) how setting a network of referral centres in Europe based on common studies on the care management of patients might contribute to a better knowledge of AE epidemiology in the future.

Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes.

Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

THE ‘SOS’ AMPHORA: AN UPDATE

Research conducted and published over the last 35 years has brought to light much new information concerning the so-called ‘SOS’ amphora, produced primarily in Attica and Euboea in the Archaic period. However, little focused work has been undertaken in the study of these vessels since Johnston and Jones' seminal work in 1978. This paper therefore provides a critical update on the production and distribution of SOS amphorae using the current data available. Included in this update is a discussion of recent research on Early Iron Age amphorae that may help situate the SOS amphora within a broader ceramic milieu. A new distribution of SOS amphorae also necessitates a reappraisal of some previously held ideas concerning their chronological patterns and the specific actors involved in their shipment. Taking into consideration the multiple spatial and temporal varieties of SOS amphorae, it can be shown that these vessels were relatively evenly deposited across the Mediterranean, from Iberia to the Levant, very early in the Archaic period. In combination with other factors, this widespread distribution may support the hypothesis that non-Greek seafarers were involved with transporting Athenian and Euboean SOS amphorae. Ultimately, it is hoped that a fresh look at this ceramic shape, however brief, might contribute to existing scholarly debates on cultural interactions and mobility within the Mediterranean basin during the Archaic period.

Management of bronchiectasis in adults.

Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials.

How does TDCS shape neural brain networks? A critical up-date

How does TDCS shape neural brain networks? A critical up-date

A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: genetic association study, systematic review and meta-analyses.

A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women (148 IRSA and 149 control women), conduct a systematic review of literature on the association between NOS3 gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014. We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSA was significant for the +894 G/T SNP under the dominant genetic model (GT+TT versus GG) based on fixed (odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.28-1.86, P = <0.01) and random effects models (OR = 1.54, 95% CI = 1.03-2.31, P = 0.03). In conclusion, the GT and TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA.

Synchronous Primary Endometrial and Ovarian Cancers: A Critical Update

Synchronous primary cancers are relatively uncommon in general population. Only 0.5-1.7% of women with gynecological malignancies, have synchronous primary cancers of the female genital tract. In those patients, the most common combination is synchronous primary endometrial and ovarian cancers.

Hospice Medical Director Update and Exam Prep (P01)

•Employ the clinical, regulatory, leadership, and administrative skills and ethical knowledge required in the role of hospice medical director.•Assess and manage pain and other symptoms based on the best available evidence.•Describe the hospice medical director’s role on the interdisciplinary care team and within the hospice organization.•Analyze regulatory issues affecting the hospice medical director and find strategies to fulfill these requirements. Join peers and national experts to explore and further develop the skills needed to successfully navigate today’s hospice environment. This intensive review will serve as part of your preparation for the Hospice Medical Director Certification Board exam and is based on the exam blueprint (www.hmdcb.org). The workshop also serves as a great orientation for those new to the hospice field or as a critical update for all hospice practitioners and managers.

Critical update on 2‐methacryloyloxyethyl phosphorylcholine (MPC) polymer science

ABSTRACT2‐Methacryloyloxyethyl phosphorylcholine (MPC) is a custom methacrylate with a zwitterionic phosphorylcholine moiety on the side chain. In the past 25 years, MPC has been used as a building block for a wide range of polymeric biomaterials because of its excellent resistance to nonspecific protein adsorption, cell adhesion, and blood coagulation. Recently, MPC polymers with specific features have been used in bioengineering and nanomedicine. This review focuses on three topics that highlight the latest findings on MPC polymers, that is, specific recognition of C‐reactive protein (CRP), cell‐membrane‐penetration abilities, and lubrication properties. These developments will extend the applications of this biomimetic material from bioinert polymers to biosensing, CRP inhibitors, prodrug carriers, subcellular bioimaging, cell manipulation, and joint replacement. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41766.

Treatment-related gastrointestinal toxicities and advanced colorectal or pancreatic cancer: A critical update

Gastrointestinal toxicities (GIT), including oral mucositis, nausea and vomiting, and diarrhea, are common side effects of chemotherapy and targeted agents in patients with advanced colorectal cancer and pancreatic cancer. Being often underreported, it is still difficult to precisely establish their burden in terms of both patient's quality of life and cancer care costs. Moreover, with the use of more intensive upfront combination regimens, the frequency of these toxicities is rapidly growing with a potential negative effect also on patient's outcome, as a result of dose reductions, delays or even discontinuation of active treatments. Thus, identifying patients at higher risk of developing GIT as well as an optimal management are paramount in order to improve patient's compliance and outcome. After the description of the main treatment-induced GIT, we discuss the current knowledge on the pathophysiology of these side effects and comment the scales commonly used to assess and grade them. We then provide a critical update on GIT incidence based on the results of key randomized trials conducted in patients with metastatic colorectal cancer and advanced pancreatic cancer.

Morbillivirus de los Delfines: Patógeno re-emergente en la población de cetáceos

Dolphin morbillivirus (DMV) is one of the most important pathogen of cetaceans. It was first described in the late 80s, since has been causing outbreaks that affects dolphin populations and also in other cetaceans in the U.S. and in the Mediterranean sea. We conducted a bibliographic search in MedLine, SciELO, Scopus® and Google Scholar without timeline limits using MeSH terms such as Cetacean morbillivirus, Pilot Whale morbillivirus, Dolphin morbillivirus, Strandings, etc., with the aim of provide a critical update on basic, clinical and epidemiological aspects of one of the most important emerging infections for cetacean wildlife, with particular emphasis on the current alternatives for diagnosis and control. Based on the information gathered we concluded that there is not only a need to study and quantify the strandings, but we need to develop awareness of the importance of this viral infection in cetaceans and to apply effective management plans that maintain those populations in biological balance.

Allergy immunotherapy: what is the evidence for cost saving?

Given the widespread prevalence of allergic disease, its substantially associated clinical and economic burden, the unique disease-modifying benefits of allergy immunotherapy (AIT), and increased availability of sublingual immunotherapy (SLIT), a critical update of the evidence for AIT-related cost savings [for both subcutaneous immunotherapy (SCIT) and SLIT] is particularly relevant and timely. The present article reviews the evidence for SCIT-related and SLIT-related cost savings derived from a systematic review of the published literature. Examined were 24 publications pertaining to the health economics of AIT. Except for one early study comparing the costs of AIT to symptomatic drug treatment (SDT), the remainder provide compelling evidence for AIT cost savings (whether SCIT or SLIT) over SDT. Furthermore, of the six studies comparing cost outcomes of SLIT to SCIT, four reported cost savings favoring SLIT. This review, spanning research from Southern Europe, Scandinavia, Northern Europe, North America, and the Czech Republic, encompasses a range of perennial and seasonal allergic conditions, including allergic asthma, allergic rhinitis with or without asthma, and rhinoconjunctivitis with or without allergic rhinitis due to house dust mite, grass or ragweed pollen, or a mixture of various allergens. All but one study compellingly demonstrate cost savings conferred by AIT over SDT.

Epigenetics in esophageal cancers.

Esophageal cancers are a challenging upper gastrointestinal tract tumor entity for interdisciplinary oncology. For the two main histotypes, namely esophageal squamous cell carcinomas and Barrett's adenocarcinomas, several genetic aberrations have been shown to contribute to carcinogenesis and progression as well as to represent potential novel targets for therapeutic intervention. This is paralleled by growing insight into epigenetic alterations of esophageal cancers. Studies involving the analyses of human tissue specimens predominantly describe altered patterns of miRNA expression, DNA methylation patterns, and histone marks levels. This review provides a critical update on this increasing knowledge of epigenetic alteration in esophageal cancers by specifically focusing on the translational aspects of epigenetic analyses from human tissue specimens.

Prevention and Treatment of Cancer With Aspirin: Where Do We Stand?

Aspirin is arguably the synthesized drug that has been used most commonly in human history. Aspirin was originally developed and marketed for the treatment of inflammatory disorders at the end of the 19th century, but its mechanism of action remained unknown until the second half of the 20th century. Since the latter part of the 20th century aspirin also has been used for the primary and secondary prevention of cardiovascular diseases given its anti-thrombotic properties. An association between intake of aspirin and decreased cancer risk was identified in the past decades. Whether aspirin can be used as an anticancer agent in patients with a diagnosis of cancer was unknown until recently. Recent studies suggest that aspirin might provide therapeutic benefit in the adjuvant treatment of certain forms of cancer. This review provides a critical update on this topic, which has potential implications for oncologists and their patients.

Role of toll-like receptors in liver transplantation

Toll-like receptors (TLRs) are pathogen recognition receptors that orchestrate the innate immune response and the subsequent adaptive immune response. TLRs can be triggered by exogenous ligands expressed by invading pathogens or by the release of endogenous ligands, such as that occurring through cellular injury during the transplantation process. They are now recognized to play an important role in many facets of transplantation biology, including rejection and tolerance, ischemia/reperfusion injury (IRI), and infections after transplantation. The role of TLRs in liver transplantation is unique with respect to other organ transplants because the portal circulation is a continuous source of TLR2 and TLR4 ligands, and this influences TLR signaling pathways, which have a central role in transplantation immunity. This review provides a critical update on recent data outlining the important role of TLRs in liver transplantation, and there is a particular focus on emerging advances in our understanding of rejection and tolerance, IRI, and infections after transplantation and on the ways in which these events may influence the recurrence of diseases such as hepatitis C infection after liver transplantation.

Inflammation-induced lymphangiogenesis and lymphatic dysfunction

The lymphatic system is intimately linked to tissue fluid homeostasis and immune cell trafficking. These functions are paramount in the establishment and development of an inflammatory response. In the past decade, an increasing number of reports has revealed that marked changes, such as lymphangiogenesis and lymphatic contractile dysfunction occur in both vascular and nodal parts of the lymphatic system during inflammation, as well as other disease processes. This review provides a critical update on the role of the lymphatic system in disease process such as chronic inflammation and cancer and examines the changes in lymphatic functions the diseases cause and the influence these changes have on the progression of the diseases.