Better Understanding Of Pathophysiological Processes Research Articles

Better Comprehension of Primary Pyogenic Spinal Infections.

To the Editor: Some years ago, childhood spondylodiscitis was used to describe a continuum of primary pyogenic spinal infections (PPSIs), from discitis to vertebral osteomyelitis, including spondylodiscitis with its occasional associated soft-tissue abscesses. The pathophysiology of PPSIs has, nevertheless, become clearer and less controversial. The theory suggesting that spondylodiscitis was a self-limiting inflammatory condition is now considered completely obsolete. A better understanding of pathophysiological processes has made it possible to differentiate forms of childhood PPSI according to patients’ ages, their immune system development, better knowledge of their bacterial etiology, and the vascularization of their vertebrae and disks. The different clinical forms of PPSI have now been categorized in various ways that physicians and pediatricians should know. The first classification is based on the child’s age and the development of their immune system, and it distinguishes three main clinical forms of childhood PPSI. The neonate form of spondylodiscitis generally affects infants under 6 months old and is recognized as the most severe manifestation of the disease: patients often present with septicemia and multiple infectious foci. Fortunately, this is the rarest form of the disease. The infantile form concerns children from 6 to 48 months old (a period during which maternally derived immunity decreases and stops), the age group representing 60%–80% of cases of childhood spondylodiscitis. Finally, in the third form, affecting children above 4 years old, patients are more prone to being febrile and appearing very ill. The second classification can be superimposed on the first and assigns each age group a bacterial probability of spondylodiscitis. Approximately 80% of spondylodiscitis cases in children younger than 6 months are due to S. aureus. For children from 6 to 48 months old, there are now robust arguments supporting the hypothesis that K. kingae should be considered the primary etiological pathogen for spondylodiscitis. The third form affects children older than 4 years of age, and S. aureus is the predominant pathogen. Finally, a third classification is based on the anatomical characteristics of the patient’s vertebral endplate and disk vascularization. Many studies have demonstrated that the vertebral endplates and the superficial portion of the disks share a common blood supply at birth that gradually regresses during infancy. In children, the metaphysis of the vertebral body has a rich blood flow, with an incomplete vascular ring ending at the pedicle’s base. Otherwise, it has been shown that several fine anastomotic branches exist between the upper and lower metaphyseal rings of two adjacent vertebrae, mostly present around the disk’s posterolateral region, providing its blood flow. It is also commonly accepted that infection starts under the vertebral endplates, that it subsequently and successively crosses both the vertebral endplate and the disk’s surface via those fine anastomotic branches, reaching the adjacent vertebral body and, lastly, the disk space between the two affected vertebral bodies. Interestingly, the blood vessels which cross the vertebral endplates evolve at around 7 or 8 years old. These anatomical observations lead to two conclusions. First, it becomes reasonable to think that pure discitis, as some authors have suggested, cannot occur. Secondly, it seems highly likely that children will tend to have spondylodiscitis before the age of 7 to 8 years old and, afterwards, that older children and adolescents are more likely to develop vertebral osteomyelitis, providing that the infection is not neglected. Unfortunately, these concepts do not yet appear in textbooks or university curricula, thus perpetuating enormous confusion about these infections.

Non-medicalization of medical science: Rationalization for future.

As we delve into the intricacies of human disease, millions of people continue to be diagnosed as having what are labelled as pre-conditions or sub-clinical entities and may receive treatments designed to prevent further progression to clinical disease, but with debatable impact and consequences. Endocrinology is no different, with almost every organ system and associated diseases having subclinical entities. Although the expansion of these “grey” pre-conditions and their treatments come with a better understanding of pathophysiologic processes, they also entail financial costs and drug adverse-effects, and lack true prevention, thus refuting the very foundation of Medicine laid by Hippocrates “Primum non nocere” (Latin), i.e., do no harm. Subclinical hypothyroidism, prediabetes, osteopenia, and minimal autonomous cortisol excess are some of the endocrine pre-clinical conditions which do not require active pharmacological management in the vast majority. In fact, progression to clinical disease is seen in only a small minority with reversal to normality in most. Giving drugs also does not lead to true prevention by changing the course of future disease. The goal of the medical fraternity thus as a whole should be to bring this large chunk of humanity out of the hospitals towards leading a healthy lifestyle and away from the label of a medical disease condition.

Anxiogenic Potential of Experimental Sleep Fragmentation Is Duration-Dependent and Mediated via Oxidative Stress State.

Sleep architecture alterations, among which sleep fragmentation is highly prevalent, represent risk factors for a variety of diseases, ranging from cardiovascular to brain disorders, including anxiety. What mediates anxiety occurrence upon sleep fragmentation is still a matter of debate. We hypothesized that the sleep fragmentation effects on anxiety are dependent on its duration and mediated by increased oxidative stress and alterations in the number of parvalbumin (PV+) interneurons in the hippocampus. Sleep was fragmented in rats by the treadmill method during a period of 14 days (SF group). Rats with undisturbed sleep in the treadmill (TC group) and those receiving equal amounts of treadmill belt motion (EC group) served as controls. To assess anxiety, we subjected rats to the open field, elevated plus maze, and light-dark tests on the 0, 7th, and 14th day. Upon the last test, brain structures were sampled for oxidative stress assessment and PV+ interneuron immunohistochemistry. The results of ethological tests of anxiety-linked behavior suggested duration-dependent anxiogenic potential of sleep fragmentation. Rats' anxiety-linked behavior upon sleep fragmentation significantly correlated with oxidative stress. The rats with fragmented sleep (SF) showed significantly higher oxidative stress in the hippocampus, thalamus, and cortex, compared to controls (TC and EC), while the antioxidant enzymes' activity was significantly decreased. No significant differences were observed in hippocampal PV+ interneurons among these groups. Our results showed that duration of sleep fragmentation is a significant determinant of anxiety-linked behavior, and these effects are mediated through oxidative distress in the brain. Herein, it is revealed that the sleep fragmentation-oxidative stress-anxiety axis contributes to our better understanding of pathophysiological processes, occurring due to disrupted sleep patterns.

Metabolic profiling of serum from dogs with pituitary-dependent hyperadrenocorticism

Hyperadrenocorticism (HAC) is one of the most common endocrine diseases in dogs characterized by excessive cortisol production caused by an adrenocorticotropic hormone (ACTH)-secreting tumor, namely pituitary-dependent HAC (PDH) or cortisol-secreting adrenal tumor. Metabolomics presents the ability to identify small molecule metabolites. Thus, the use of metabolomics techniques in canine PDH can provide information about the pathophysiology and metabolic changes in this disease. This study aimed to identify and compare differences in serum metabolites between dogs with PDH and healthy dogs. The metabolomic profile of 20 dogs diagnosed with PDH was compared with 20 healthy dogs using liquid chromatography/mass spectrometry (LC/MS), and metabolite discrimination was performed using partial least squares-discriminant analysis (PLS-DA), the variable important in projection (VIP) and fold changes (FC) group-wise comparisons. The hypergeometric test identified the significantly altered pathways. A total of 21 metabolites were found to be significantly different between the two groups. The major alterations were found in arachidonic and decanoic acid, and phospholipids related to phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI). These metabolites are related to insulin resistance and other complications (i.e. hypertension). Our results indicate that PDH produces changes in serum metabolites of dogs, and the knowledge of these changes can aid to better understanding of pathophysiological processes involved and contribute to potentially detect new biomarkers for this disease.

Phenotypic similarity for rare disease: Ciliopathy diagnoses and subtyping

Rare diseases are often hard and long to be diagnosed precisely, and most of them lack approved treatment. For some complex rare diseases, precision medicine approach is further required to stratify patients into homogeneous subgroups based on the clinical, biological or molecular features. In such situation, deep phenotyping of these patients and comparing their profiles based on subjacent similarities are thus essential to help fast and precise diagnoses and better understanding of pathophysiological processes in order to develop therapeutic solutions. In this article, we developed a new pipeline of using deep phenotyping to define patient similarity and applied it to ciliopathies, a group of rare and severe diseases caused by ciliary dysfunction. As a French national reference center for rare and undiagnosed diseases, the Necker-Enfants Malades Hospital (Necker Children's Hospital) hosts the Imagine Institute, a research institute focusing on genetic diseases. The clinical data warehouse contains on one hand EHR data, and on the other hand, clinical research data. The similarity metrics were computed on both data sources, and were evaluated with two tasks: diagnoses with EHRs and subtyping with ciliopathy specific research data. We obtained a precision of 0.767 in the top 30 most similar patients with diagnosed ciliopathies. Subtyping ciliopathy patients with phenotypic similarity showed concordances with expert knowledge. Similarity metrics applied to rare disease offer new perspectives in a translational context that may help to recruit patients for research, reduce the length of the diagnostic journey, and better understand the mechanisms of the disease.

Compressive Pressure Versus Time in Cauda Equina Syndrome: A Systematic Review and Meta-Analysis of Experimental Studies.

Systematic review and meta-analysis. To examine the relationship between compressive pressure and its duration in cauda equina compression, and the effects of subsequent decompression, on neurophysiological function, and pathophysiology in animal studies. We further aim to investigate these relationships with systemic blood pressure to assess whether a vascular component in the underlying mechanism may contribute to the clinical heterogeneity of this disease. The complex relationship between preoperative factors and outcomes in cauda equina syndrome (CES) suggests heterogeneity within CES which may inform better understanding of pathophysiological process, their effect on neurological function, and prognosis. Systematic review identified 17 relevant studies including 422 animals and reporting electrophysiological measures (EP), histopathology, and blood flow. Modeling using meta-regression analyzed the relationship between compressive pressure, duration of compression, and electrophysiological function in both compression and decompression studies. Modeling suggested that electrophysiological dysfunction in acute cauda equina compression has a sigmoidal response, with particularly deterioration when mean arterial blood pressure is exceeded and, additionally, sustained for approximately 1 hour. Accounting for pressure and duration may help risk-stratify patients pre-decompression. Outcomes after decompression appeared to be related more to the degree of compression, where exceeding systolic blood pressure tended to result in an irreversible lesion, rather than duration of compression. Prognosis was most strongly associated with residual pre-decompression function. Compressive pressure influences effects and outcomes of cauda equina compression. We suggest the presence of two broad phenotypic groups within CES defined by the degree of ischaemia as a potential explanatory pathophysiological mechanism. 1.

The post thrombotic syndrome: Ignore it and it will come back to bite you

Post thrombotic syndrome (PTS) is a very common chronic complication of deep venous thrombosis (DVT), as three out of ten patients with lower extremity DVT will develop PTS. The possibility to identify patients at risk is limited. Diagnosis is challenging, because there is no gold standard diagnostic method. Progress in diagnostic options may therefore change future diagnostic strategies. The better understanding of pathophysiologic processes that underlie PTS may stimulate the development of treatment modalities and improve and diversify management options. The quest for adequate preventive strategies and treatment is important because PTS has a detrimental effect on patients' quality of life and is associated with increased healthcare as well as societal costs. [1,2]The problem of PTS prevention is therefore clearly relevant to patients, doctors as well as policy makers.

Monoclonal antibodies and Fc fragments for treating solid tumors

Advances in biotechnology, better understanding of pathophysiological processes, as well as the identification of an increasing number of molecular markers have facilitated the use of monoclonal antibodies and Fc fragments in various fields in medicine. In this context, a rapidly growing number of these substances have also emerged in the field of oncology. This review will summarize the currently approved monoclonal antibodies used for the treatment of solid tumors with a focus on their clinical application, biological background, and currently ongoing trials.

Gender Specific Influence of Fish Oil or Atorvastatin on Functional Properties of Renal Na,K-ATPase in Healthy Wistar and Hypertriglyceridemic Rats

For better understanding of pathophysiological processes leading to increased retention of sodium as a consequence of hyperlipidemia, the properties of renal Na,K-ATPase, a key enzyme involved in maintaining sodium homeostasis in the organism, were studied. Enzyme kinetics of renal Na,K-ATPase were used for characterization of ATP- and Na(+)-binding sites after administration of fish oil (FO) (30 mg·day(-1)) or atorvastatin (0.5 mg·100 g(-1)·day(-1)) to healthy Wistar rats and rats with hereditary hypertriglyceridemia of both genders. Untreated healthy Wistar and also hypertriglyceridemic female rats revealed higher Na,K-ATPase activity as compared to respective untreated male groups. Hypertriglyceridemia itself was accompanied with higher Na,K-ATPase activity in both genders. Fish oil improved the enzyme affinity to ATP and Na(+), as indicated by lowered values of K(m) and K(Na) in Wistar female rats. In Wistar male rats FO deteriorated the enzyme in the vicinity of the Na(+)-binding site as revealed from the increased K(Na) value. In hypertriglyceridemic rats FO induced a significant effect only in females in the vicinity of the sodium binding sites resulting in improved affinity as documented by the lower value of K(Na). Atorvastatin aggravated the properties of Na,K-ATPase in both genders of Wistar rats. In hypertriglyceridemic rats protection of Na,K-ATPase was observed, but this effect was bound to females only. Both treatments protected renal Na,K-ATPase in a gender specific mode, resulting probably in improved extrusion of excessive intracellular sodium out of the cell affecting thus the retention of sodium in hHTG females only.

Development, Cell Differentiation, Angiogenesis—Microparticles and Their Roles in Angiogenesis

Cells of various types release small membrane vesicles called microparticles (MP) on their activation, as well as during the process of apoptosis. The properties and roles of MP generated in different contexts are diverse and are determined by their parent cell and the pathway of their generation, which affects their content. MP are involved in multiple cellular functions, including immunomodulation, inflammation, coagulation, and intercellular communication. MP are able to deliver molecular signals in the form of lipids, proteins, nucleic acids, or functional transmembrane proteins from the parent cell to distantly located targets. In this review, we summarize some of the current knowledge regarding MP and their functional roles in transfer of proteins, nucleic acids, and signal transduction stimulators between cells of different origins in different settings. We will focus on the ability of MP to mediate angiogenesis-related signals and their effect on cell development. The investigation of MP could elucidate new cellular communication pathways and may lead to better understanding of pathophysiological processes. From a clinical point of view, MP may serve as biomarkers for disease status and may be found useful for developing novel therapeutic strategies targeting angiogenesis-related conditions.

Circulating monocytes and atherogenesis: From animal experiments to human studies

Despite significant improvements in the prevention and management of atherosclerosis, its consequences still remain a major cause of disability and mortality. Better understanding of pathophysiological processes implicated in the initial stages of atherogenesis is critical for the discovery of effective approaches to prevent ischaemic stage of the disease and to reduce huge economic and social burden currently associated with atherosclerosis (1). According to the current paradigm the atherosclerotic process is primarily initiated in the vascular wall itself where monocyte-derived macrophages transform to ‘foam’ cells by accumulating lipids (2). Consequent apoptosis or death of macrophages is largely responsible for necrotic core generation, progressive accumulation of free cholesterol and expansion of the necrotic core within plaques. Often, unbalanced generation of inflammatory cytokines by plaque monocyte-derived macrophages (e.g. via up-regulation of Toll-like receptors) as well as angiogenic promoting pathological plaque neovascularisation, and enzymes degrading extracellular matrix results in destabilisation of atherosclerotic plaques (3–5). Whilst a critical role of vascular wall monocyte-derived macrophages in atherosclerotic plaque formation is widely recognised, the impact of circulating monocytes on atherogenesis is less established. For example, accumulation of modified (mainly oxidised) lipids via scavenger receptors was, until recently, exclusively attributed to vascular wall resident macrophages rather than circulating monocytes (6). Oxidised low-density lipoproteins (LDL) taken up via scavenger receptors (e.g. CD36 and CD204) are delivered to lysosomes, where they undergo esterification by cholesterol esterase and are largely converted into free cholesterol and fatty acids (6). It has been reported that CD36 contributes 60–70% of cholesterol ester accumulation in macrophages exposed to oxidised LDL (7). Deletion of the genes encoding CD36 and CD204 retards the development of atherosclerotic lesions in animal models of atherosclerosis (6). However, circulating monocytes are equipped with these same scavenger receptors and may thus start accumulating lipids even prior to their migration to tissues and differentiation to macrophages (8). Exposure to modified LDL induces rapid ‘foam’ cell formation from freshly isolated peripheral blood monocytes, accompanied by upregulation of CD204 and CD36 (8). The clinical relevance of these findings is supported by the observation that an absence of CD36 on circulating monocytes in individuals from a Japanese population results in 40–50% reduction in oxidised LDL binding to monocyte-derived-macrophages compared to normal subjects (9). Certainly, monocyte counts are increased in patients with stenotic coronary artery disease and the Intermountain Heart Collaborative Study Group recently reported a population of 3,227 patients with or without coronary artery disease whereby high monocyte counts were independent predictors of future myocardial infarction and death (10). However, the impact of monocytes in atherogenesis may go far beyond direct lipid accumulation as they are also actively involved in inflammatory responses attributable to their principal function within the innate immune system. Indeed, Correspondence to: Dr. Eduard Shantsila University of Birmingham Centre for Cardiovascular Sciences, City Hospital Birmingham, B18 7QH, UK Tel: +44 121 554 3801, Fax: +44 121 554 4083 E-mail: e.shantsila@bham.ac.uk

Hepatitis C virus infection and lymphoma

Apart from its well known role as an etiological agent for non-A and non-B viral hepatitis, there is growing evidence that hepatitis C virus is associated to B-cell non-Hodgkin lymphoma. The association between HCV and lymphoproliferative disorders has been recently postulated based on epidemiological data, biological studies and clinical observations. Although various subtypes of lymphomas appear to be associated to HCV, diffuse large B-cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia and marginal zone lymphoma appeared to be particularly represented among HCV-positive patients. The causative role of HCV in those disorders has been further supported by the response to antiviral therapy. Despite a better understanding of pathophysiological processes at stake leading from HCV infection to overt lymphoma, many issues still need to be further elucidated. Although HCV has been demonstrated to directly infect peripheral blood mononuclear cells both in vitro and, in some cases, in vivo, a strong body of evidence rather supports the hypothesis of an indirect transformation mechanism by which sustained antigenic stimulation leads from oligoclonal to monoclonal expansion and sometimes to lymphoma, probably through secondary oncogenic events. Here, we review epidemiological and biological studies, as well as clinical data on antiviral therapy, linking HCV-infection to B-cell non-Hodgkin lymphoma.

Sudden Cardiac Death and Coronary Artery Disease —Pathophysiology and Risk Stratification

Management of Sudden Cardiac Death (SCD) is undergoing a radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiological processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost‐effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large.

Determination of the side-separated pulmonary right-to-left shunt volume

With the present method of intrapulmonary right-to-left shunt volume calculation, no differentiation can be made between the shunt volume shares of the right and left lungs. For a better understanding of pathophysiological processes during thorax surgery with side-separated ventilation, a side-separated shunt volume determination would be useful. In 14 young female pigs, catheters were implanted into the left atrium after left thoracotomy. After transient clamping of the ipsilateral pulmonary veins, pulmonary venous blood was selectively obtained from the right lung. Cardiac output (CO) and side-separated pulmonary perfusion were determined with flowprobes at the pulmonary trunk and the left pulmonary artery. The shunt volumes were determined before and after thoracotomy during two-lung ventilation (Two-LV), after one-lung (right) ventilation (One-LV) with a continuous positive airway pressure (CPAP) of +7.5, +5.0 cm H(2)O, and under atelectasis of the non-dependent left lung (NDL). After thoracotomy in lateral decubitus position and Two-LV, the shunt volumes of the two lungs differ. The right lung holds the major share (11.0 +/- 1.7% CO) [mean +/- SD]. The share of the left NDL is only 3.3 +/- 1.4. Under One-LV (right) and CPAP in the NDL, the total pulmonary shunt volume rises. This is caused by the increase in the NDL shunt volume share to 8.8 +/- 5.2 under CPAP +7.5 (p<0.05) and to 9.7 +/- 2.5 under CPAP +5.0 (p < 0.05). The new intraoperative method of side-separated arterial blood gas analysis in conjunction with side-separated perfusion measurement makes side- separated right-to-left shunt volume determination possible and may lead to interesting new pathophysiological insights.

Gene expression profiling in human cardiovascular disease

Gene expression profiling studies in human diseases have allowed better understanding of pathophysiological processes. In addition, they may lead to the development of new clinical tools to improve diagnosis and prognosis of patients. Most of these studies have been successfully performed for human cancers. Inspired by these results, researchers in the cardiovascular field have also started using large-scale transcriptional analysis to better understand and classify human cardiovascular disease. Here we provide an overview of the literature revealing new cardiac disease markers and encouraging results for further development of the expression profiling strategy for future clinical applications in cardiology.

Risk stratification and management of sudden cardiac death: a new paradigm.

Risk Stratification and Management of SCD. Management of SCD is undergoing radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiologic processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large.