Pathophysiology Of Disturbances Research Articles

Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes.

Two general approaches to the treatment of type 2 diabetes mellitus (T2DM) have been advocated. 1 ) A “guideline” approach that advocates sequential addition of antidiabetes agents with “more established use” (1); this approach more appropriately should be called the “treat to failure” approach, and deficiencies with this approach have been discussed (2). And 2 ) a “pathophysiologic” approach using initial combination therapy with agents known to correct established pathophysiologic defects in T2DM (3). Within the pathophysiologic approach, choice of antidiabetes agents should take into account the patient’s general health status and associated medical disorders. This individualized approach, which we refer to as the ABCD(E) of diabetes treatment (4), has been incorporated into the updated American Diabetes Association (ADA) guidelines (5). Even though physicians must be cognizant of these associated conditions (ABCDE) when initiating therapy in newly diagnosed T2DM patients, we believe that the most important consideration is to select antidiabetes agents that correct specific pathophysiologic disturbances present in T2DM and that have complementary mechanisms of action. Although it has been argued that the pathogenesis of T2DM differs in different ethnic groups (6), evidence to support this is weak. Although the relative contributions of β-cell failure and insulin resistance to development of glucose intolerance may differ in different ethnic groups (6), the core defects of insulin resistance in muscle/liver/adipocytes and progressive β-cell failure (3) are present in virtually all T2DM patients and must be treated aggressively to prevent the relentless rise in HbA1c that is characteristic of T2DM. In subsequent sections, we provide a review of the natural history of T2DM, specific pathophysiologic abnormalities responsible for T2DM, currently …

An Insight into the Changes in Human Plasma Proteome on Adaptation to Hypobaric Hypoxia

Adaptation to hypobaric hypoxia is required by animals and human in several physiological and pathological situations. Hypobaric hypoxia is a pathophysiological condition triggering redox status disturbances of cell organization leading, via oxidative stress, to proteins, lipids, and DNA damage. Identifying the molecular variables playing key roles in this process would be of paramount importance to shed light on the mechanisms known to counteract the negative effects of oxygen lack. To obtain a molecular signature, changes in the plasma proteome were studied by using proteomic approach. To enrich the low-abundance proteins in human plasma, two highly abundant proteins, albumin and IgG, were first removed. By comparing the plasma proteins of high altitude natives with those of a normal control group, several proteins with a significant alteration were found. The up-regulated proteins were identified as vitamin D-binding protein, hemopexin, alpha-1–antitrypsin, haptoglobin β-chain, apolipoprotein A1, transthyretin and hemoglobin beta chain. The down-regulated proteins were transferrin, complement C3, serum amyloid, complement component 4A and plasma retinol binding protein. Among these proteins, the alterations of transthyretin and transferrin were further confirmed by ELISA and Western blotting analysis. Since all the up- and down- regulated proteins identified above are well-known inflammation inhibitors and play a positive anti-inflammatory role, these results show that there is some adaptive mechanism that sustains the inflammation balance in high altitude natives exposed to hypobaric hypoxia.

An update on non-epileptic seizures: Diagnosis and brief notes on treatment

Abstract Non-epileptic seizures (NES) are episodes that appear as epileptic seizures, but are not caused by epileptic discharges in the brain. The inclusion of NES in the differential diagnosis of epileptic seizures is important, as an accurate diagnosis is required for the administration of appropriate treatment. NES in the differential diagnosis may be classified as (1) physiologic or pathophysiologic NES, e.g. syncope, sleep disturbances, motor symptoms, migraine attacks, etc., and (2) psychogenic NES (PNES), e.g. affective disorders with anxiety or panic, dissociative disorders (somatoform or conversion) as well as depression or posttraumatic stress disorder (PTSD). PNES is the condition most frequently misdiagnosed as epilepsy. We report NES as experienced in our epilepsy monitoring unit (EMU) for adults in the neurology department of a university hospital in Norway. Our main emphasis is on PNES, highlighting the diagnostic procedures, currently recommended treatment options, and follow-up. A team approach with video-EEG monitoring and clinical observation by trained nurses, epileptologists and other personnel is preferred in the diagnosis and treatment of PNES. Evaluations are performed by a neuropsychologist and trained social worker. The EMU closely cooperates with cardiologists and sleep center specialists. They can also refer patients to psychosomatic medicine specialists. Components of the differential diagnosis addressed are syncope, motor symptoms, sleep disorders, migraine and other paroxysmal neurological symptoms.

Exploring New CGRP Family Peptides and their Receptors in Vertebrates

Vertebrates have expanded their habitats from aquatic to terrestrial environments, which has accompanied the evolution of cardiovascular and osmoregulatory hormones. Specifically, mammals have developed mechanisms to maintain high blood pressure and blood volume, while extant fishes have developed hypotensive and Na-extruding mechanisms to adapt to the marine environment where they underwent a vast diversification. The CGRP family is one of the hormone systems that decrease blood pressure and blood volume. Within the CGRP family of teleost fishes, we found that adrenomedullins (AMs) have diversified and five paralogs (AM1-5) form an independent subfamily. Based on this discovery in fishes, we found AM2 and AM5 in mammals. In mammalian species that have AM2 and/or AM5, the peptides assume greater importance in the case of pathophysiological disturbances in pressure and fluid balance such as hypertension and cardiac and renal failure. In addition, novel functions of AM peptides have been suggested by the discovery of AM2 and AM5 in mammals. Current research on the CGRP family is focused on the identification of new receptors for AM2/AM5 and the establishment of AM2 knockout mice, which will enable new developments in the basic and clinical research on this intriguing hormone family. Importantly, comparative fish studies can contribute to new developments in our understanding of the function of the AM peptides.

The origins of molecular psychiatry.

The origins of molecular psychiatry.

Gene expression in archived newborn blood spots distinguishes infants who will later develop cerebral palsy from matched controls

BackgroundGene expression in archived newborn blood spots remaining from newborn screening may reflect pathophysiological disturbances useful in understanding the etiology of cerebral palsy (CP).MethodsWe quantified the expression of gene sets representing four physiological pathways hypothesized to contribute to CP in archived unfrozen residual newborn blood spot specimens from 53 children with CP and 53 age, gender, and gestational-age–matched controls. We selected four empirical and three canonical gene sets representing inflammatory, hypoxic, coagulative, and thyroidal pathways, and examined mRNA expression using an 8×60K oligonucleotide microarray. The log2 fold change of gene expression between matched cases and controls were analyzed using the Generally Applicable Gene Set Enrichment (GAGE) method.ResultsThe empirical inflammatory and empirical hypoxic gene sets were significantly down-regulated in term-born CP cases (N = 33) as compared to matched controls (P = 0.0007 and 0.0009, respectively), while both gene sets were significantly up-regulated (P = 0.0055 and 0.0223, respectively) in preterm-born CP cases (N = 20). The empirical thyroidal gene set was significantly up-regulated in preterm-born CP (P = 0.0023).ConclusionThe newborn blood spot transcriptome can serve as a platform for investigating distinctive gene expression patterns in children who later develop CP.

Aqueous extract of Terminalia arjuna prevents cyclosporine-induced renal disorders

Cyclosporine (CsA), a powerful immunosuppressant, had a significant impact on transplantation medicine, and exposure to this chemical is known to induce oxidative stress and causes renal injury by the formation of free radicals. Acute and chronic renal damage are very common pathophysiologic disturbances caused by CsA. The present study has been conducted to evaluate the protective role of the aqueous extract of the bark of Terminalia arjuna (TA), an important Indian medicinal plant widely used in the preparation of ayurvedic formulations, on CsA-induced oxidative stress and resultant dysfunction in the rat kidney. Animals were treated with the aqueous extract of TA (100 mg/kg body weight (b.wt)) and then treated with CsA (25 mg/kg b.wt) in olive oil for 14 days. The level of urea, uric acid, and creatinine was determined from serum sample. The enzymes, namely, alkaline phosphatase (ALP), acid phosphatase (ACP), aspartate transaminase (AST), and alanine transaminase (ALT), and enzymic indices of membrane integrity such as Na+K+ATPase, Ca2+ATPase, and Mg2+ATPases were estimated in the tissue of all study groups. Antioxidant status in kidney tissues was estimated by determining the activities of the antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione transferase (GST) and the levels of reduced glutathione, vitamin E, and vitamin C. In addition, the kidney phospholipids, cholesterol, triglycerides, and free fatty acids were determined in the tissue. Results showed that CsA caused a marked increase in the levels of urea, uric acid, and creatinine in serum and decreases the levels of ALP, ACP, AST, ALT, Na+K+ATPase, Ca2+ATPase, Mg2+ATPases, SOD, CAT, glutathione reductase, GST, GPx, vitamin E, and vitamin C whereas cholesterol, triglycerides, free fatty acid, and phospholipid levels were found to be increased in the kidney tissue homogenates of CsA-treated rats. Aqueous extract of TA successfully prevented the alterations of these effects in the experimental animals. Data also showed that the extract possessed strong free radical scavenging activity comparable to that of vitamin C. Our study demonstrated that the aqueous extract of the bark of TA could protect the kidney tissues against CsA-induced oxidative stress probably by increasing antioxidative defense activities.

C.I.2 Congenital myopathies: Blurring the boundaries, sharpening the focus

Congenital myopathies are essentially defined as clinico-pathological entities by characteristic histopathological and ultrastructural findings on the muscle biopsy in patients with early-onset weakness. Nemaline myopathies, core myopathies and centro-nuclear myopathies constitute the three “classic” groups, each of which now show an increasing degree of genetic and clinical heterogeneity. In addition, emerging evidence of overlapping histological and clinical features amongst classically defined entities and the realization that mutations in the same gene may underly more then one clinico-pathological entity suggest that there may be pathomechanisms that are shared between various congenital myopathies. Animal models, especially mouse and zebrafish have also underscored pathophysiologic concepts that reach across the boundaries of previously defined entities. The shared pathophysiological concept with currently the most support from clinical and animal work concerns the regulation of excitation contraction coupling via the functional unit at the triad: T-tubule, DHPR voltage sensitive calcium channel, RYR1 calcium release channel and the sarcoplasmic reticulum. For example, mutations in genes associated with the classic centronuclear myopathies cause functional abnormalities in this setup, while mutations in RYR1 itself, while typically causing core myopathies can also underly the histological as well as clinical features of centronuclear myopathy. Abnormalities of regulation and function of the contractile (myofibrillar) apparatus constitute the other larger emerging area of common final pathophysiological disturbances.

Volumetric and topographic differences in hippocampal subdivisions in borderline personality and bipolar disorders

Hippocampal abnormalities may be implicated in the pathophysiology of mental disorders with affective symptoms such as borderline personality disorder (BPD) and bipolar disorder (BD). We aimed to investigate hippocampal morphology in BPD and BD patients, compared to 1:1 age- and sex-matched healthy controls (HC) using a three-dimensional mapping method. Manual tracing of the hippocampi on magnetic resonance imaging (MRI) images was performed on 26 patients with BPD (age: 38±11; sex (f): 16 (61%)) and 15 with BD (age: 44±9; sex (f): 5 (33%)) and their age- and sex-matched HC (for BPD: n=26; age: 38±11; sex (f): 16 (61%); for BD: n=15; age: 44±9; sex (f): 5 (33%)). Compared to their reference groups, BPD patients showed smaller hippocampal volume bilaterally. The BD group showed significantly smaller right hippocampal volumes. In the surface maps, alterations were localized to different hippocampal sectors for the two groups: the CA1 regions and subiculum, bilaterally, in BPD, and the right dentate gyrus in the BD group. These differences persisted after controlling for alcohol and substance abuse. BPD and BD groups may exhibit distinct patterns of volumetric MRI changes in hippocampal subdivisions that might be related to the clinical phenomenology of each disorder.

The influence of glucocorticoids on neuronal survival and synaptic function.

Abstract Glucocorticoids, recognized as stress-related steroid hormones secreted from adrenal glands, have multiple roles in brain function. The concentration of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and chronically elevated levels of glucocorticoids are putatively involved in the pathophysiology of mental disorders, such as depression. As corticosteroids are also widely used as medical drugs (e.g., for chronic lung disease in infants), the developmental influence of glucocorticoids on neuronal survival and synaptic plasticity is a critical concern. Although many reports suggest a biological effect of glucocorticoids on neuronal populations of the central nervous system (CNS), some reports suggest a possibility that glial responses (including regulation of neurotrophic factor expression) to glucocorticoids are different from that of neurons. In the present review, we show an overview of the current knowledge concerning the impact of glucocorticoids on behavior in animal models of depression, and on cell survival and function in the CNS.

Psychiatry and Clinical Neuroscience

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.For the past several decades, psychiatry has had a number of theories regarding the etiology and pathophysiology of mental disorders. These theories have largely been "chemical" in that alterations of neurotransmitter function and of the neurotransmitters themselves have provided the basis of these hypotheses.Zorumski and Rubin have written a delightful volume proposing a new and intriguing theory regarding the pathogenesis of mental disorders.J clin Psychiatry2012; 73(4):723© 2012 Physicians Postgraduate Press, Inc.†‹†‹†‹

Diabetes Mellitus and Acute Coronary Syndrome: Lessons From Randomized Clinical Trials

Diabetes mellitus is a major independent risk factor for acute coronary syndrome (ACS). In addition, diabetic patients with ACS suffer from increased mortality compared to their nondiabetic peers. Driven by multiple pathophysiological disturbances, such patients are predisposed to a proinflammatory, prothrombotic state, which may lead to plaque rupture. To counteract this more complex biology, several therapies and strategies have emerged, with some having unique preferential benefits in this population. Antiplatelet agents such as aspirin and clopidogrel have long been standard of care. Dose adjustment of these therapies remains the subject of continued research. Along with medical therapy, ACS diabetic patients preferentially benefit from primary percutaneous intervention compared to fibrinolysis. However, with advances in reperfusion techniques, the optimal strategy has yet to be determined. With these differences in ACS treatment responses, diabetic individuals may not just be a high-risk group, but may actually constitute a fundamentally different population, requiring dedicated clinical trials and individualized treatment regimens.

From system to organ to cell: oxygenation and perfusion measurement in anesthesia and critical care

Maintenance or restoration of adequate tissue oxygenation is a main goal of anesthesiologic and intensive care patient management. Pathophysiological disturbances which interfere with aerobic metabolism may occur at any stage in the oxygen cascade from atmospheric gas to the mitochondria, and there is no single monitoring modality that allows comprehensive determination of “the oxygenation”. To facilitate early detection of tissue hypoxia (or hyperoxia) and to allow a goal directed therapy targeted at the underlying problem, the anesthesiologist and intensive care physician require a thorough understanding of the numerous determinants that influence cellular oxygenation. This article reviews the basic physiology of oxygen uptake and delivery to tissues as well as the options to monitor determinants of oxygenation at different stages from the alveolus to the cell.

Post-cardiac arrest syndrome: Mechanisms and evaluation of adrenal insufficiency

Cardiac arrest is one of the leading causes of death and represents maximal stress in humans. After restoration of spontaneous circulation, post-cardiac arrest syndrome is the predominant disorder in survivors. Besides the post-arrest brain injury, the post-resuscitation myocardial stunning, and the systemic ischemia/reperfusion response, this syndrome is characterized by adrenal insufficiency, a disorder that often remains undiagnosed. The pathophysiology of adrenal insufficiency has not been elucidated. We performed a comprehensive search of three medical databases in order to describe the major pathophysiological disturbances which are responsible for the occurrence of the disorder. Based on the available evidence, this article will help physicians to better evaluate and understand the hidden yet deadly post-cardiac arrest adrenal insufficiency.

Epilepsy in four genetically determined syndromes of intellectual disability

Epilepsy occurs with increased frequency in people with an intellectual disability (ID) compared to the rest of the population. A variety of research has in recent years shed light on genetic and biochemical aetiologies of epilepsy and, often in a different literature, on syndromes of ID. The aims of this annotation are to review developments in understanding of the pathophysiology of several ID syndromes in which epilepsy is a frequent co-occurrence and to relate these observations to recent advances in understanding of how these pathophysiological disturbances may lead to epilepsy. The ID syndromes selected for review were fragile X (FXS), Rett (RTT) and Angelman syndromes (AS) and tuberous sclerosis complex (TSC). Epilepsy is a significant aspect of these syndromes and relevant research into the genetic and biochemical pathophysiology of these four ID syndromes may be informative in establishing the association between epilepsy and ID. Employing a structured approach the authors initially searched the PubMed database for large case series describing the characteristics of epilepsy as manifested in these ID syndromes. The criteria for inclusion of the case series in the review were a sample size of greater than 50 and the description of several of the characteristic features of epilepsy, namely prevalence of seizures, age of seizure onset, seizure frequency, seizure semiology, severity and treatment. Following this, studies of the genetic and biochemical pathophysiology of these four ID syndromes were reviewed and the potential relevance of this research in understanding the association with epilepsy highlighted. Findings were considered in a focused manner in terms of effects on excitatory and inhibitory neurotransmitter systems and on glial function. Diverse genetic pathologies underlying several ID syndromes can lead to alterations in the functioning of the glutamatergic and GABAergic neurotransmitter systems. The mechanisms involved include transcriptional regulation in RTT, translational regulation in FXS and TSC, and UBE3A-mediated proteolysis in AS. Expression or functioning of receptor subunits, uptake sites and enzymes involved in neurotransmitter metabolism are often affected by these changes, and may lead to modifications in network excitability and neuronal plasticity that may contribute to epileptogenesis and ID. Dysfunction in astrocytes may also contribute to epileptogenesis and ID in FXS, RTT and TSC with potential mechanisms including failure of astrocytic support functions, glial inflammation and homeostatic disturbances that affect the excitability and architecture of neuronal networks. The annotation highlights research describing disturbances in excitatory and inhibitory neurotransmitter systems, neuronal ion channel and glial functions that provide possible explanations for the co-occurrence of seizures within several ID syndromes, in some cases suggesting possible avenues for research into novel therapeutic targets. Phenotypic overlaps between syndromes may also relate to roles for the implicated genes in different disturbances in linked biochemical pathways.

Measuring RNA editing of serotonin 2C receptor

Pre-mRNA of serotonin 2C receptor (HTR2C, 5-hydroxytryptamine (serotonin) receptor 2C) undergoes A-to-I type RNA editing, which is a post-transcriptional event leading to the change of genomically encoded information. RNA editing generates various HTR2C isoforms, each of which has distinctive receptor activity. Postmortem, animal, and pharmacological studies have suggested that the altered RNA editing of HTR2C is involved in the pathophysiology of mental disorders, although results remain inconsistent. Here we review the techniques used for estimation of RNA editing of HTR2C. Among the techniques reported so far, a high-throughput sequencing-based method would be the most powerful method of choice for the large-scale experiments. Several different methods that were previously developed, such as pyrosequencing and capillary electrophoresis, should be suitable for validation as well as for rapid screening or exploratory purposes.

Interactions of human truncated DISC1 proteins: implications for schizophrenia.

Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein–protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3β and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants LΔ78, LΔ3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3β. The temporal expression pattern of GSK3β in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function.

Assessment and Treatment of Cardiovascular Risk in Prediabetes: Impaired Glucose Tolerance and Impaired Fasting Glucose

Individuals with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are at high risk, not only to develop diabetes mellitus, but also to experience an adverse cardiovascular (CV) event (myocardial infarction, stroke, CV death) later in life. The underlying pathophysiologic disturbances (insulin resistance and impaired β-cell function) responsible for the development of type 2 diabetes are maximally/near maximally expressed in subjects with IGT/IFG. These individuals with so-called prediabetes manifest all of the same CV risk factors (dysglycemia, dyslipidemia, hypertension, obesity, physical inactivity, insulin resistance, procoagulant state, endothelial dysfunction, inflammation) that place patients with type 2 diabetes at high risk for macrovascular complications. The treatment of these CV risk factors should follow the same guidelines established for patients with type 2 diabetes, and should be aggressively followed to reduce future CV events.

Pathophysiology and pathogenesis of post-resuscitation myocardial stunning

The prognosis for cardiac arrest victims remains dismal, as only 17% survives to hospital discharge. Post-resuscitation myocardial stunning is the mechanical dysfunction that persists after the restoration of spontaneous circulation. Our knowledge regarding myocardial stunning has grown dramatically over the years, and several hypotheses have been proposed in order to explain its pathophysiology; however, the interrelationships among various mechanisms remain unclear. This review deals primarily with the basic aspects of the pathophysiology of post-resuscitation myocardial stunning. Given the large number of relevant studies and the fragmented information, an effort was made to summarize current knowledge in order to present a comprehensive pathophysiological mechanism. In this review, the pathophysiological disturbances occurring from the onset of cardiac arrest until the restoration of spontaneous circulation are addressed. Then, the pathophysiology of myocardial stunning during the post-resuscitation period is critically reviewed in 4 parts, the immediate, the early, the intermediate, and the recovery post-arrest phase. This article covers a huge gap in the existing literature regarding the pathophysiology of post-resuscitation period and provides a better understanding of the pathophysiology and pathogenesis of post-resuscitation myocardial stunning.

Self-Critical Perfectionism, Stress Generation, and Stress Sensitivity in Patients with Chronic Fatigue Syndrome: Relationship with Severity of Depression

Chronic Fatigue Syndrome (CFS) is a highly disabling disorder that is part of a broader spectrum of chronic pain and fatigue disorders. Although the etiology and pathogenesis of CFS largely remain unclear, there is increasing evidence that CFS shares important pathophysiological disturbances with mood disorders in terms of disturbances in the stress response and the stress system. From a psycho-dynamic perspective, self-critical perfectionism and related personality factors are hypothesized to explain in part impairments of the stress response in both depression and CFS. Yet, although there is ample evidence that high levels of self-critical perfectionism are associated with stress generation and increased stress sensitivity in depression, evidence supporting this hypothesis in CFS is currently lacking. This study therefore set out to investigate the relationship between self-critical perfectionism, the active generation of stress, stress sensitivity, and levels of depression in a sample of 57 patients diagnosed with CFS using an ecological momentary assessment approach. Results showed, congruent with theoretical assumptions, that self-critical perfectionism was associated with the generation of daily hassles, which in turn predicted higher levels of depression. Moreover, multilevel analyses showed that self-critical perfectionism was related to increased stress sensitivity in CFS patients over a 14-day period, and that increased stress sensitivity in turn was related to increased levels of depression. The implications of these findings for future research and particularly for the development of psychodynamic treatment approaches of CFS and related conditions are discussed.