Background: The role of different diets and nutrients in the pathogenesis of cardiac dysfunction is controversial. However, it is well known that the Western diet has pro-inflammatory systemic effects, whereas Mediterranean-style diets have anti-inflammatory effects in all body systems. This study aimed to examine the effects of functional foods, omega-3 fatty acids and flavonoid-rich diets in patients with a high risk of Cardiovascular Diseases (CVDs) with reference to Heart Failure (HF).
The present study aimed to evaluate the effect of a progressive load of physical activity on a musculoskeletal injury in rats.Sixty-four rates were divided into two groups: experimental group (EG), which underwent physical activity (swimming) with a progressive load, and the control group (CG), which was not submitted to this program.The training was carried out according to an adapted version of the Gonçalves (1999) swimming system.Injuries were caused to the gastrocnemic muscle by inducing 40% NaOH.On days 2, 7, 14, and 21 after inducing muscle injury, the animals from both EC and CG were sacrificed.The injured area was removed and processed.The neutrophils, macrophages, lymphocytes, and plasmocytes were quantified by hematoxylin and eosin (H&E) stain.The percentage of the area of type I and type III collagen were quantified by a histological cut stained with picrosirius red stain (PSR) and submitted to polarization.A greater number of macrophages (GE=19.98±4.39;GC=2.48±1.00;p=0.006) and lymphocytes (GE=2.12±0.82;GC=0.06±0.82;p=0.037) after 2 days, and of macrophages (GE=15.74±3.00;GC=6.02±1.95;p=0.007) and lymphocytes (GE=2.01±0.78;GC=0.14±0.09;p=0.044) after 7 days, could be observed in the EG when compared to the CG; however, the opposite was true for neutrophils (GE=48.12±17.04;GC=105.54±12.25;p=0.005).After 14 days, a smaller quantity of neutrophils (GE= 32.70±10.26;GC= 90.96±17.62;p= 0.044) and a larger quantity of plasmocytes (GE=9.06±3.84;GC=0.68±0.53;p=0.028) could be observed in the EG as compared to the CG.A greater area of type III collagen could be observed in the EG when compared to the CG over a 14-day period (GE=44.90±16.15;GC=0.74±0.40;p=0.000) and a 21-day period (GE=13.19±9.09;GC=1.02±0.94;p=0.029), whereas the opposite could be observed for type I collagen.The physical activity promoted an increase in the deposition of type III collagen in the muscle injury.This activity accelerated the repair process after 14 days, possibly moderated by the larger number of inflammatory cells, while after 21 days, the lesion presented a lesser resistance.
The first cases of mucocutaneous lymph node syndrome (MLNS) were reported by Dr Tomisaku Kawasaki in 1967.His surname was later assigned to this new disease entity, and I was fortunate to meet him at the 100 th Annual Conference of the German Paediatric Association in Berlin in 2004 [1].According to our current understanding Kawasaki disease (KD) is a systemic autoimmune vasculitis which occurs in genetically susceptible people following an acute infection.Outside Japan KD has a low incidence and is notoriously difficult to diagnose because of its similarity to common infective childhood illnesses and a lack of specific and sensitive laboratory tests.The case report of KD by Bangert et al. [2] illustrates these difficulties aptly and calls for prompt diagnosis and treatment of this condition to avoid serious cardiovascular complications.
A diagnosis of Kawasaki disease (KD) is mainly based on clinical criteria.We discuss the case of a young boy who presented at the ages of 7 months and 13 months with signs and symptoms suggestive of Kawasaki disease.At the first episode he was treated for Kawasaki disease and at the second episode for lymphadenitis and fever.A diagnosis of recurrent KD was only made retrospectively when he developed thrombocytosis and desquamation of the extremities.Subsequent echocardiograms revealed no abnormalities.It is important that a diagnosis of KD is considered in any child presenting with a fever of more than 5 days irrespective of the previous medical history.
Current definition of inflammation by its cardinal signs is obsolete and unsuitable for guiding adequate therapeutic strategies.Furthermore, present theory of the inflammatory process regarding vascular phenomena as essential for generation of cardinal signs is invalid and unable to explain well established empirical facts, particularly the extent of the osmotic pressure and temperature variations within the inflamed tissue.From five cardinal signs, there is actually just one specific macroscopic sign of inflammation, namely localized edema.Further, the driving force for tissue fluid accumulation is defined in biochemical terms and as such taken for the definition of the inflammatory process.Inflammation may be defined as a degenerative process which is intense enough to cause local accumulation of low molecular weight catabolic products, which in turn elevates tissue osmotic pressure that attracts extra fluid, with or without heat release sufficient for significant elevation of tissue temperature.This process is in a sharp contrast to the pathogenesis of burns, where externally applied heat causes a process that is in essence opposite to inflammation, bearing only some superficial similarities with the latter.The inflammatory process is itself a pathological process, whereas the natural anti-inflammatory response that ensues after acute inflammation tends to reverse tissue homeostasis towards normality and should therefore be regarded as a true defensive reaction of the affected tissue.Based on the therapeutic principle of reverse thermodynamics, heat application to the inflamed tissue is an obvious, yet non-exclusive therapeutic choice that follows from the given universal definition of inflammation.
Zinc status and infections are closely inter-related.For nearly half a century, the effects that zinc depletion has on the status of the immune system has been slowly elucidated.More recently, the effects that infection and sepsis have on an organism's zinc supplies have begun to be recognized and potential therapeutic intervention in this zinc/infection interplay are beginning to be explored.The literature related to these areas is reviewed, and possible future directions are discussed.
Heat shock proteins (HSPs) are molecular chaperones that facilitate the proper folding and assembly of nascent polypeptides and assist in the refolding and stabilization of damaged polypeptides. Through these largely intracellular functions, the HSPs maintain homeostasis and assure cell survival. However, a growing body of literature suggests that HSPs have important effects in the extracellular environment as well. Extracellular HSPs are released from damaged or stressed cells and appear to act as local "danger signals" that activate stress response programs in surrounding cells. Importantly, extracellular HSPs have been shown to activate the host innate and adaptive immune response. With this in mind, extracellular HSPs are commonly included in a growing list of a family of proteins known as danger-associated molecular patterns (DAMPs) or alarmins, which trigger an immune response to tissue injury, such as may occur with trauma, ischemia-reperfusion injury, oxidative stress, etc. Extracellular HSPs, including Hsp72 (HSPA), Hsp27 (HSPB1), Hsp90 (HSPC), Hsp60 (HSPD), and Chaperonin/Hsp10 (HSPE) are especially attractrive candidates for DAMPs or alarmins which may be particularly relevant in the pathophysiology of the sepsis syndrome.
The mortality of septic shock in the pediatric population has improved over the last 2 decades with better supportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shock have been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not well understood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which is important to pathogen containment. Elements of the innate immune system activate the adaptive immune system in an antigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequent infection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immune cells and are capable of responding to highly conserved components of pathogens called pathogen associated molecular patterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. These receptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomal plasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRs are present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 like receptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated in components of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, and carbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganisms such as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs and PAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment and amplification of the full repertoire of the immune response. There are developmental differences in the immune systems of infants and children compared to adults. The innate immune system matures much earlier than the adaptive immune response and as a result infants and young children may be more reliant on their innate immune system. For this reason it important to fully understand the key elements of the innate immune response including the many categories of PRRs and their cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targets for therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signaling pathways as well as the major classes of PAMPs that activate them.
Despite significant progress in the understanding and treatment of sepsis, it continues to be a major health problem in United States and around the world.Sepsis accounted for nearly 4,500 deaths (mortality rate 10%) and approximately $2 billion per year in healthcare expenditures in the U.S. alone.In this review, we will revisit the definitions of pediatric sepsis and discuss the epidemiology of sepsis in the United States.During inflammatory states, the vascular endothelium plays a crucial role in modulating the host immune response and regulates the levels of coagulation, pro-inflammatory and anti-inflammatory factors in the blood.We review the role of endothelium in nitric oxide generation and activation of the coagulation cascade.Studies in critically ill patients and animal models have shown that increased apoptosis or "programmed cell death" of lymphoid organs contributes to immune suppression, anergy, and organ system dysfunction.In this chapter, we outline both intrinsic and extrinsic pathways that lead to apoptosis.
The inflammatory response to sepsis has classically been characterized by an overactive innate immune response.Recent adult and pediatric evidence suggests that the immune response is quite dynamic in this setting, often with endogenous innate and adaptive immunosuppression following the onset of sepsis.Sepsis-induced innate immune dysfunction can include reduction in antigen presenting capacity (as evidenced by decreased monocyte HLA-DR expression) and low pro-inflammatory cytokine production capacity (as evidenced by reduced ex vivo LPS-induced tumor necrosis factor-production).The term immunoparalysis describes a state of severe reduction in these parameters and has been associated with increased risks for the development of nosocomial infection and death in septic adults and children.Intriguing evidence suggests that immunoparalysis may be reversible with beneficial effects on outcomes.Adaptive immune dysfunction has also been reported following the onset of sepsis.Lymphopenia, lymphocyte apoptosis, and skewing toward anti-inflammatory T cell subtypes (such as regulatory T cells) have all been associated with adverse outcomes from sepsis.Without specific testing, most aspects of sepsis-related immune dysfunction are occult.Accordingly, the development of robust immune monitoring and modulation protocols should be a high priority in the battle to improve outcomes from sepsis in critically ill adults and children.
Susceptibility to, and outcome from, sepsis in children is highly variable due in part to genetic variation in genes coding for components of the innate immune response.This review article will discuss evidence for the influence of host genetic variability on the susceptibility to, and outcome from, sepsis in children and adults.Polymorphisms in genes coding for proteins involved in the recognition of bacterial pathogens (TLR4, CD-14, Fc RIIa, and mannose binding lectin) and the response to bacterial pathogens (TNF-, IL-1 , IL-1 , IL-1 RA , IL-6, IL-10, heat shock proteins, ACE, plasminogen activator inhibitor-1) can influence the amount or function of the protein produced in response to bacterial stimuli.Evidence is discussed suggesting that some of these genetic polymorphisms influence the susceptibility to, and outcome from, sepsis. Conclusion:Host genetic variability in the regulatory and coding regions of genes for components of the innate immune system may influence the susceptibility to and/or outcome from sepsis.The disparate results observed in many studies of polymorphisms in sepsis emphasize the need for future studies to be larger, to include the analysis of multiple polymorphisms, and to be better designed with respect to control populations in order to identify the degree of influence that genetic variability has on sepsis.
Heat shock proteins (HSPs) are molecular chaperones that facilitate the proper folding and assembly of nascent polypeptides and assist in the refolding and stabilization of damaged polypeptides.Through these largely intracellular functions, the HSPs maintain homeostasis and assure cell survival.However, a growing body of literature suggests that HSPs have important effects in the extracellular environment as well.Extracellular HSPs are released from damaged or stressed cells and appear to act as local "danger signals" that activate stress response programs in surrounding cells.Importantly, extracellular HSPs have been shown to activate the host innate and adaptive immune response.With this in mind, extracellular HSPs are commonly included in a growing list of a family of proteins known as danger-associated molecular patterns (DAMPs) or alarmins, which trigger an immune response to tissue injury, such as may occur with trauma, ischemia-reperfusion injury, oxidative stress, etc. Extracellular HSPs, including Hsp72 (HSPA), Hsp27 (HSPB1), Hsp90 (HSPC), Hsp60 (HSPD), and Chaperonin/Hsp10 (HSPE) are especially attractrive candidates for DAMPs or alarmins which may be particularly relevant in the pathophysiology of the sepsis syndrome.
The inflammatory response of the innate immune system to invading pathogen is complex and requires precise regulation in order to eradicate the organism while protecting the surrounding host tissues.Two main signal transduction pathways, the NF-B and mitogen activated protein kinase (MAPK) pathways, are activated by the invading pathogens requiring a set of negative regulatory processes once the pathogen is eradicated.In this review we focus on three key negative regulatory processes: intracellular inhibitors, regulatory phosphatases and epigenetic mechanisms.
Sepsis is a significant health problem in both critically ill children and adults. While the mortality rate from sepsis is much lower in children, sepsis is directly responsible for over 4,000 childhood deaths per year in the United States alone. At face value, this number suggests that more children die per year in the United States from sepsis as the primary cause than from cancer. Unfortunately, there are few studies on the epidemiology, pathophysiology, and management of sepsis in children. Moreover, extrapolation of adult data to critically ill children is probably not appropriate due to several key developmental differences in the host response to infection and response to therapy. Therefore, additional studies targeting sepsis in the pediatric population are urgently required.
The recognition, diagnosis, and management of sepsis remain among the greatest challenges in pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and underdeveloped countries and has an incidence that is predicted to increase each year. Unfortunately, promising therapies derived from preclinical models have universally failed to significantly reduce the substantial mortality and morbidity associated with sepsis. There are several key developmental differences in the host response to infection and therapy that clearly delineate pediatric sepsis as a separate, albeit related, entity from adult sepsis. Thus, there remains a critical need for well-designed epidemiologic and mechanistic studies of pediatric sepsis in order to gain a better understanding of these unique developmental differences so that we may provide the appropriate treatment. Herein, we will review the important differences in the pediatric host response to sepsis, highlighting key differences at the whole-organism level, organ system level, and cellular and molecular level.
Sepsis is one of the leading causes of death in critically ill patients in the intensive care unit. Sepsis accounts for significant morbidity and mortality in critically ill children as well. The pathophysiology of sepsis is characterized by a complex systemic inflammatory response, endothelial dysfunction, and alterations in the coagulation system, which lead to perturbations in the delivery of oxygen and metabolic substrates to the tissues, end-organ dysfunction, and ultimately death. Oxidative stress plays a crucial role as both a promoter and mediator of the systemic inflammatory response, suggesting potential targets for the treatment of critically ill children with the sepsis syndrome. Herein, we will provide a brief review of the role of oxidative and nitrosative stress in the pathophysiology of sepsis.
Sepsis remains one of the leading causes of morbidity and mortality in children despite improved understanding of the pathophysiology leading to better clinical management and survival. Recent studies have identified several areas that must be addressed by the clinician in order to continue to impact the morbidity and mortality associated with sepsis. In this review, we discuss the evidence in several of these areas including initial resuscitation, pathogen eradication, maintenance of oxygen delivery, and directed modifiers of the inflammatory response. Our overall goal is to provide the bedside clinician with an updated systematic approach to treat sepsis in children.
Sepsis is characterized by a systemic inflammatory response.Systemic physiologic changes can occur and lead to cellular damage and organ failure.The nuclear receptor, peroxisome proliferator-activated receptor-(PPAR ), is involved in the regulation of the inflammatory response and is altered in sepsis.Thiazolidinediones (TZDs), and the cyclopentenone prostaglandin, 15d-PGJ 2 , are specific PPAR agonists.Preclinical experimental in vitro and in vivo studies have demonstrated that pharmacological activation of PPAR provides potent anti-inflammatory effects.These agents may have effects at altering the inflammatory response in clinical sepsis.
Increasing evidence suggests that sphingosine-1-phosphate (S1P) is involved in the pathogenesis of allergic bronchial asthma. In the present study, the changes in the expression levels of enzymes associated with S1P turnover were determined in a mouse model of allergic bronchial asthma. Male BALB/c mice were actively sensitized with ovalbumin antigen, and were repeatedly challenged with aerosolized antigen. Twenty-four hours after the last antigen, total RNAs were extracted from lungs. The RT-PCR analyses revealed that mRNAs for the S1P-producing enzymes, sphingosine kinase 1 (SphK1) and SphK2, and for the S1P-breakdown enzymes, S1P phosphatase 1 (S1PP1), S1PP2, S1P lyase, and lipid phosphate phosphatase 1a, were expressed in the lungs of mice. Among them, the mRNA levels of SphK2 and S1PP1 were significantly increased in the lungs of the repeatedly antigen-challenged mice. It is thus possible that the S1P turnover is increased in the airways of allergic bronchial asthma.
