Diastolic dysfunction in hypertension.

PubMed

Nazário Leão, R; Marques da Silva, P

Hypertension and coronary heart disease, often coexisting, are the most common risk factors for heart failure. The progression of hypertensive heart disease involves myocardial fibrosis and alterations in the left ventricular geometry that precede the functional change, initially asymptomatic. The left ventricular diastolic dysfunction is part of this continuum being defined by the presence of left ventricular diastolic dysfunction without signs or symptoms of heart failure or poor left ventricular systolic function. It is highly prevalent in hypertensive patients and is associated with increased cardiovascular morbidity and mortality. Despite its growing importance in clinical practice it remains poorly understood. This review aims to present the epidemiological fundamentals and the latest developments in the pathophysiology, diagnosis and treatment of left ventricular diastolic dysfunction. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Hypertensive Emergencies in Pregnancy.

PubMed

Olson-Chen, Courtney; Seligman, Neil S

2016-01-01

The prevalence of hypertensive disorders in pregnancy is increasing. The etiology and pathophysiology of hypertensive disorders in pregnancy remain poorly understood. Hypertensive disorders are a major cause of maternal and perinatal morbidity and mortality. Treatment of hypertension decreases the incidence of severe hypertension, but it does not impact rates of preeclampsia or other pregnancy complications. Several antihypertensive medications are commonly used in pregnancy, although there is a lack of randomized controlled trials. Severe hypertension should be treated immediately to prevent maternal end-organ damage. Appropriate antepartum, intrapartum, and postpartum management is important in caring for patients with hypertensive disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunological mechanisms behind the cystic fibrosis-ABPA link.

PubMed

Hartl, Dominik

2009-01-01

Allergic bronchopulmonary aspergillosis (ABPA), a pulmonary hypersensitivity disease mediated by an allergic response to Aspergillus fumigatus (A. fumigatus), occurs preferentially in disease conditions with an impaired pulmonary immunity, especially in cystic fibrosis (CF) and allergic asthma. The pathophysiological mechanisms underlying the link between CF and ABPA are poorly understood. Animal and human data support a critical role for chemokines, especially CCL17 and its receptor CCR4, in ABPA. A summary and discussion of the immunological mechanism involved in the pathogenesis of ABPA with a focus on CF lung disease and the role of chemokines is presented here.

Spasmodic Dysphonia: A Review. Part 2: Characterization of Pathophysiology.

PubMed

Hintze, Justin M; Ludlow, Christy L; Bansberg, Stephen F; Adler, Charles H; Lott, David G

2017-10-01

Objective The purpose of this review is to describe the recent advances in characterizing spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. The pathophysiology is poorly understood, and there are diagnostic difficulties. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusion The diagnosis of spasmodic dysphonia can be difficult due to the lack of a scientific consensus on diagnostic criteria and the fact that other voice disorders may present similarly. Confusion can arise between spasmodic dysphonia and muscle tension dysphonia. Spasmodic dysphonia symptoms are tied to particular speech sounds, whereas muscle tension dysphonia is not. With the advent of more widespread use of high-speed laryngoscopy and videokymography, measures of the disruptions in phonation and delays in the onset of vocal fold vibration after vocal fold closure can be quantified. Recent technological developments have expanded our understanding of the pathophysiology of spasmodic dysphonia. Implications for Practice A 3-tiered approach, involving a questionnaire, followed by speech assessment and nasolaryngoscopy is the most widely accepted method for making the diagnosis in most cases. More experimental and invasive techniques such as electromyography and neuroimaging have been explored to further characterize spasmodic dysphonia and aid in diagnosing difficult cases.

Do arterial stiffness and wave reflection underlie cardiovascular risk in ethnic minorities?

PubMed

Faconti, Luca; Nanino, Elisa; Mills, Charlotte E; Cruickshank, Kennedy J

2016-01-01

Increasing evidence indicates that remarkable differences in cardiovascular risk between ethnic groups cannot be fully explained by traditional risk factors such as hypertension, diabetes or dislipidemia measured in midlife. Therefore, the underlying pathophysiology leading to this "excess risk" in ethnic minority groups is still poorly understood, and one way to address this issue is to shift the focus from "risk" to examine target organs, particularly blood vessels and their arterial properties more directly. In fact, structural and functional changes of the vascular system may be identifiable at very early stages of life when traditional factors are not yet developed. Arterial stiffening, measured as aortic pulse wave velocity, and wave reflection parameters, especially augmentation index, seem to be an important pathophysiological mechanism for the development of cardiovascular disease and predict mortality independent of other risk factors. However, data regarding these arterial indices in ethnic minorities are relatively rare and the heterogeneity between populations, techniques and statistical methods make it difficult to fully understand their role.

Integration of sensory force feedback is disturbed in CRPS-related dystonia.

PubMed

Mugge, Winfred; van der Helm, Frans C T; Schouten, Alfred C

2013-01-01

Complex regional pain syndrome (CRPS) is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. The origin of this movement disorder is poorly understood, although recent insights suggest involvement of disturbed force feedback. Assessment of sensorimotor integration may provide insight into the pathophysiology of fixed dystonia. Sensory weighting is the process of integrating and weighting sensory feedback channels in the central nervous system to improve the state estimate. It was hypothesized that patients with CRPS-related dystonia bias sensory weighting of force and position toward position due to the unreliability of force feedback. The current study provides experimental evidence for dysfunctional sensory integration in fixed dystonia, showing that CRPS-patients with fixed dystonia weight force and position feedback differently than controls do. The study shows reduced force feedback weights in CRPS-patients with fixed dystonia, making it the first to demonstrate disturbed integration of force feedback in fixed dystonia, an important step towards understanding the pathophysiology of fixed dystonia.

Cardiovascular Impact in Patients Undergoing Maintenance Hemodialysis: Clinical Management Considerations

PubMed Central

Chirakarnjanakorn, Srisakul; Navaneethan, Sankar D.; Francis, Gary S.; Tang, W.H. Wilson

2017-01-01

Patients undergoing maintenance hemodialysis develop both structural and functional cardiovascular abnormalities. Despite improvement of dialysis technology, cardiovascular mortality of this population remains high. The pathophysiological mechanisms of these changes are complex and not well understood. It has been postulated that several non-traditional, uremic-related risk factors, especially the long-term uremic state, which may affect the cardiovascular system. There are many cardiovascular changes that occur in chronic kidney disease including left ventricular hypertrophy, myocardial fibrosis, microvascular disease, accelerated atherosclerosis and arteriosclerosis. These structural and functional changes in patients receiving chronic dialysis make them more susceptible to myocardial ischemia. Hemodialysis itself may adversely affect the cardiovascular system due to non-physiologic fluid removal, leading to hemodynamic instability and initiation of systemic inflammation. In the past decade there has been growing awareness that pathophysiological mechanisms cause cardiovascular dysfunction in patients on chronic dialysis, and there are now pharmacological and non-pharmacological therapies that may improve the poor quality of life and high mortality rate that these patients experience. PMID:28108129

Childhood functional abdominal pain: mechanisms and management.

PubMed

Korterink, Judith; Devanarayana, Niranga Manjuri; Rajindrajith, Shaman; Vlieger, Arine; Benninga, Marc A

2015-03-01

Chronic abdominal pain is one of the most common clinical syndromes encountered in day to day clinical paediatric practice. Although common, its definition is confusing, predisposing factors are poorly understood and the pathophysiological mechanisms are not clear. The prevailing viewpoint in the pathogenesis involves the inter-relationship between changes in hypersensitivity and altered motility, to which several risk factors have been linked. Making a diagnosis of functional abdominal pain can be a challenge, as it is unclear which further diagnostic tests are necessary to exclude an organic cause. Moreover, large, well-performed, high-quality clinical trials for effective agents are lacking, which undermines evidence-based treatment. This Review summarizes current knowledge regarding the epidemiology, pathophysiology, risk factors and diagnostic work-up of functional abdominal pain. Finally, management options for children with functional abdominal pain are discussed including medications, dietary interventions, probiotics and psychological and complementary therapies, to improve understanding and to maximize the quality of care for children with this condition.

Mechanism of Sleep Disturbance in Children with Atopic Dermatitis and the Role of the Circadian Rhythm and Melatonin

PubMed Central

Chang, Yung-Sen; Chiang, Bor-Luen

2016-01-01

Sleep disturbance is common in children with atopic dermatitis (AD). It is a major factor leading to impaired quality of life in these patients and could have negative effects on neurocognitive function and behavior. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. Pruritus and scratching could lead to sleep disruption but is unlikely the sole etiology. The circadian rhythm of cytokines, the immune system, and skin physiology such as transcutaneous water loss and skin blood flow might also play a role. Recent studies have suggested that melatonin could also be involved due to its multiple effects on sleep, immunomodulation, and anti-oxidant ability. Environmental factors should also be considered. In this review, we summarize the current understanding of the pathophysiology of sleep disturbance in children with AD, and discuss possible therapeutic implications. PMID:27043528

[Exercise-induced oedema due to hormone-containing intrauterine device].

PubMed

Franssen, Laurens E; Bos, Willem-Jan W

2012-01-01

Oedema is a known adverse effect of the levonorgestrel-containing intrauterine device (Mirena IUD). However, exercise-induced oedema has not been described before. A 38-year-old woman presented with symptoms of diffuse, exercise-induced oedema and dyspnoea. Tests for heart failure and other causes of oedema showed no abnormalities. All symptoms resolved spontaneously after the patient initiated removal of the IUD. The pathophysiology of exercise-induced oedema is still poorly understood. When confronted with a patient with oedema (induced by exercise or other cause), the most common causes must first be excluded. If no explanation can be found, then the effects of medication must not be overlooked.

Hypersomnia: Evaluation, Treatment, and Social and Economic Aspects.

PubMed

Saini, Prabhjyot; Rye, David B

2017-03-01

Most central disorders of hypersomnolence are conditions with poorly understood pathophysiologies, making their identification, treatment, and management challenging for sleep clinicians. The most challenging to diagnose and treat is idiopathic hypersomnia. There are no FDA-approved treatments, and off-label usage of narcolepsy treatments seldom provide benefit. Patients are largely left on their own to alleviate the compound effects of this disorder on their quality of life. This review covers the major points regarding clinical features and diagnosis of idiopathic hypersomnia, reviews current evidence supporting the available treatment options, and discusses the psychosocial impact and effects of idiopathic hypersomnia. Copyright © 2016 Elsevier Inc. All rights reserved.

Adhesive capsulitis: An age related symptom of metabolic syndrome and chronic low-grade inflammation?

PubMed

Pietrzak, Max

2016-03-01

Adhesive capsulitis (AC) is very poorly understood, particularly it's underlying etiology. Obesity and metabolic syndrome, which are strongly associated with chronic low grade inflammation, are becoming increasingly understood to underlie a raft of morbid states including upper limb pain syndromes, diabetes (DM), cardiovascular disease (CVD), cancer and central nervous system dysfunction and degeneration. Notwithstanding age, two of the strongest established risk factors for AC are DM and CVD. The hypothesis argues that similar to DM and CVD, the inflammation and capsular fibrosis seen in AC is precipitated by metabolic syndrome and chronic low grade inflammation. These pathophysiological mechanisms are highly likely to be perpetuated by upregulation of pro-inflammatory cytokine production, sympathetic dominance of autonomic balance, and neuro-immune activation. The hypothesis predicts and describes how these processes may etiologically underpin and induce each sub-classification of AC. An improved understanding of the etiology of AC may lead to more accurate diagnosis, improved management, treatment outcomes, and reduce or prevent pain, disability and suffering associated with the disease. The paper follows on with a discussion of similarities between the pathophysiology of AC to general systemic inflammatory control mechanisms whereby connective tissue (CT) fibrosis is induced as a storage depot for leukocytes and chronic inflammatory cells. The potential role of hyaluronic acid (HA), the primary component of the extracellular matrix (ECM) and CT, in the pathophysiology of AC is also discussed with potential treatment implications. Lastly, a biochemical link between physical and mental health through the ECM is described and the concept of a periventricular-limbic central driver of CT dysfunction is introduced. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coronary artery disease in Bangladesh: A review

PubMed Central

Islam, A.K.M. Monwarul; Majumder, A.A.S.

2013-01-01

Coronary artery disease (CAD) is an increasingly important medical and public health problem, and is the leading cause of mortality in Bangladesh. Like other South Asians, Bangladeshis are unduly prone to develop CAD, which is often premature in onset, follows a rapidly progressive course and angiographically more severe. The underlying pathophysiology is poorly understood. Genetic predisposition, high prevalence of metabolic syndrome and conventional risk factors play important role. Lifestyle related factors, including poor dietary habits, excess saturated and trans fat, high salt intake, and low-level physical activity may be important as well. Some novel risk factors, including hypovitaminosis D, arsenic contamination in water and food-stuff, particulate matter air pollution may play unique role. At the advent of the new millennium, we know little about our real situation. Largescale epidemiological, genetic and clinical researches are needed to explore the different aspects of CAD in Bangladesh. PMID:23993003

Type 4 cardiorenal syndrome.

PubMed

Pinheiro da Silva, Ana Luísa; Vaz da Silva, Manuel Joaquim

2016-11-01

The Acute Dialysis Quality Initiative consensus conference proposed a classification of cardiorenal syndrome (CRS), aiming for a better delineation of each subtype. Although the exact pathophysiology of type 4 CRS is not completely understood, the mechanisms involved are probably multifactorial. There is growing evidence that oxidative stress is a major connector in the development and progression of type 4 CRS. Giving its complexity, poor prognosis and increasing incidence, type 4 CRS is becoming a significant public health problem. Patients with chronic kidney disease are particularly predisposed to cardiac dysfunction, due to the high prevalence of traditional cardiovascular risk factors in this population, but the contribution of risk factors specific to chronic kidney disease should also be taken into account. Much remains to be elucidated about type 4 CRS: despite progress over the last decade, there are still significant questions regarding its pathophysiology and there is as yet no specific therapy. A better understanding of the mechanisms involved may provide potential targets for intervention. The present review will provide a brief description of the definition, epidemiology, diagnosis, prognosis, biomarkers and management strategies of type 4 CRS, and the pathophysiological mechanisms and risk factors presumably involved in its development will be particularly highlighted. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

A clinical comparison of penetrating and blunt traumatic brain injuries.

PubMed

Santiago, Luis A; Oh, Bryan C; Dash, Pramod K; Holcomb, John B; Wade, Charles E

2012-01-01

Traumatic brain injury (TBI) is a leading cause of injury death and long-term disability in the USA. It commonly results from blunt (closed) or penetrating trauma. The majority of civilian TBI is caused by falls or motor vehicle collisions, whereas military TBI mainly results from explosions. Although penetrating injuries are less common than closed injuries in the civilian population, they are far more lethal. Unfortunately, the pathophysiologic differences between penetrating and closed TBI remain poorly understood due to the lack of studies on the subject. Many studies on the prognostic factors of mortality and functional outcome after TBI exclude penetrating brain injuries from their series because they are believed to have a different pathophysiology. 125 Articles regarding brain injury were reviewed and summarized for this report. Despite the absence of a clear delineation between penetrating and blunt TBI, the current guidelines for penetrating TBI suggest defaulting to management strategies used for closed TBI with limited supportive evidence. Thus, injuries that appear to have different pathophysiologies and outcomes are managed equally and perhaps not optimally. In view of the incomplete understanding of the impact of mechanism of injury on TBI outcomes, as demonstrated in the current review, new research studies are required to improve evidence-based TBI guidelines tailored especially for penetrating injuries.

Motor and somatosensory conversion disorder: a functional unawareness syndrome?

PubMed

Perez, David L; Barsky, Arthur J; Daffner, Kirk; Silbersweig, David A

2012-01-01

Although conversion disorder is closely connected to the origins of neurology and psychiatry, it remains poorly understood. In this article, the authors discuss neural and clinical parallels between lesional unawareness disorders and unilateral motor and somatosensory conversion disorder, emphasizing functional neuroimaging/disease correlates. Authors suggest that a functional-unawareness neurobiological framework, mediated by right hemisphere-lateralized, large-scale brain network dysfunction, may play a significant role in the neurobiology of conversion disorder. The perigenual anterior cingulate and the posterior parietal cortices are detailed as important in disease pathophysiology. Further investigations will refine the functional-unawareness concept, clarify the role of affective circuits, and delineate the process through which functional neurologic symptoms emerge.

Cardiovascular impact in patients undergoing maintenance hemodialysis: Clinical management considerations.

PubMed

Chirakarnjanakorn, Srisakul; Navaneethan, Sankar D; Francis, Gary S; Tang, W H Wilson

2017-04-01

Patients undergoing maintenance hemodialysis develop both structural and functional cardiovascular abnormalities. Despite improvement of dialysis technology, cardiovascular mortality of this population remains high. The pathophysiological mechanisms of these changes are complex and not well understood. It has been postulated that several non-traditional, uremic-related risk factors, especially the long-term uremic state, which may affect the cardiovascular system. There are many cardiovascular changes that occur in chronic kidney disease including left ventricular hypertrophy, myocardial fibrosis, microvascular disease, accelerated atherosclerosis and arteriosclerosis. These structural and functional changes in patients receiving chronic dialysis make them more susceptible to myocardial ischemia. Hemodialysis itself may adversely affect the cardiovascular system due to non-physiologic fluid removal, leading to hemodynamic instability and initiation of systemic inflammation. In the past decade there has been growing awareness that pathophysiological mechanisms cause cardiovascular dysfunction in patients on chronic dialysis, and there are now pharmacological and non-pharmacological therapies that may improve the poor quality of life and high mortality rate that these patients experience. Copyright © 2017 Elsevier B.V. All rights reserved.

Understanding the complete pathophysiology of chronic mild to moderate neck pain: Implications for the inclusion of a comprehensive sensorimotor evaluation.

PubMed

Cheever, Kelly M; Myrer, J William; Johnson, A Wayne; Fellingham, Gilbert W

2017-09-22

Inconsistencies in the literature concerning the effect of neck pain have led to a lack of understanding concerning the complete pathophysiology of neck pain. While the effect of neck pain on motor function as measured by active range of motion and isometric neck strength is well documented the effect of neck pain on sensory measures such as tactical acuity and neck reposition error (NRE) remain poorly understood. The purpose of this study was to evaluate a combined sensorimotor evaluation to explore the potential benefits of incorporating both sensory and motor task into a physical evaluation of neck pain suffers to gain an added knowledge of the complete pathophysiology of their health status. A cross-sectional study that measured neck joint reposition error, tactical acuity, neck isometric strength and range of motion in 40 volunteer participants (22 pain, 18 control). A statistically significant increase in NRE in flexion (2.75∘± 1.52∘ vs. 4.53∘± 1.74∘ and in extension (3.78∘± 1.95∘ vs 5.77∘± 2.73∘ in participants suffering from neck pain was observed. Additionally, the dermatome C5 was found to be the most affected. No differences were found in neck strength or neck range of motion between healthy controls and patients with chronic moderate neck pain.

A 27-year-old woman with a diagnosis of polycystic ovary syndrome.

PubMed

Legro, Richard S

2007-02-07

Ms R, a 27-year-old woman with polycystic ovary syndrome (PCOS) diagnosed after irregular menses, hirsutism, and polycystic ovaries, is concerned about weight gain despite regular exercise and watching her diet. Prescribed oral contraceptives to regulate her menses and help reduce her androgen levels, she wants to know the alternatives for treatment of PCOS. The varying definitions of PCOS and its heterogeneity confound the interpretation of studies on PCOS. Specific diagnostic criteria have been established based on expert opinion but have not been validated. Several commonly performed laboratory tests are generally unhelpful and the pathophysiology is poorly understood. Treatment options for Ms R, including those that may affect her weight gain, are reviewed and implications for future fertility are discussed.

Electrical storm and calcium signaling: a review.

PubMed

Tsuji, Yukiomi

2011-01-01

Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, is a serious condition, adversely affecting prognosis in patients with implantable cardioverter/defibrillators. Electrical storm patients often die of progressive heart failure, but the underlying molecular basis is poorly understood. We have recently created an animal model of ES that features repetitive implantable cardioverter/defibrillator firing for recurrent ventricular fibrillation and found that ES events cause striking activation of Ca(2+)/calmodulin-dependent protein kinase II and prominent alteration of Ca(2+)-handling protein phosphorylation, possibly explaining mechanical dysfunction and arrhythmia promotion that characterize ES. Here, the pathophysiology and potential therapeutic strategies for ES, based on experimental and clinical studies by us and others, are described. Copyright © 2011 Elsevier Inc. All rights reserved.

Pathophysiology of migraine

PubMed Central

Goadsby, Peter J.

2012-01-01

Migraine is a common disabling brain disorder whose pathophysiology is now being better understood. The study of anatomy and physiology of pain producing structures in the cranium and the central nervous system modulation of the input have led to the conclusion that migraine involves alterations in the sub-cortical aminergic sensory modulatory systems that influence the brain widely. PMID:23024559

Addressing the Complexity of Tourette's Syndrome through the Use of Animal Models

PubMed Central

Nespoli, Ester; Rizzo, Francesca; Boeckers, Tobias M.; Hengerer, Bastian; Ludolph, Andrea G.

2016-01-01

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority—up to 90%—of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms. PMID:27092043

Physiology of breathlessness associated with pleural effusions

PubMed Central

Thomas, Rajesh; Jenkins, Susan; Eastwood, Peter R.; Lee, Y.C. Gary; Singh, Bhajan

2015-01-01

Purpose of review Pleural effusions have a major impact on the cardiorespiratory system. This article reviews the pathophysiological effects of pleural effusions and pleural drainage, their relationship with breathlessness, and highlights key knowledge gaps. Recent findings The basis for breathlessness in pleural effusions and relief following thoracentesis is not well understood. Many existing studies on the pathophysiology of breathlessness in pleural effusions are limited by small sample sizes, heterogeneous design and a lack of direct measurements of respiratory muscle function. Gas exchange worsens with pleural effusions and improves after thoracentesis. Improvements in ventilatory capacity and lung volumes following pleural drainage are small, and correlate poorly with the volume of fluid drained and the severity of breathlessness. Rather than lung compression, expansion of the chest wall, including displacement of the diaphragm, appears to be the principle mechanism by which the effusion is accommodated. Deflation of the thoracic cage and restoration of diaphragmatic function after thoracentesis may improve diaphragm effectiveness and efficiency, and this may be an important mechanism by which breathlessness improves. Effusions do not usually lead to major hemodynamic changes, but large effusions may cause cardiac tamponade and ventricular diastolic collapse. Patients with effusions can have impaired exercise capacity and poor sleep quality and efficiency. Summary Pleural effusions are associated with abnormalities in gas exchange, respiratory mechanics, respiratory muscle function and hemodynamics, but the association between these abnormalities and breathlessness remains unclear. Prospective studies should aim to identify the key mechanisms of effusion-related breathlessness and predictors of improvement following pleural drainage. PMID:25978627

Physiology of breathlessness associated with pleural effusions.

PubMed

Thomas, Rajesh; Jenkins, Susan; Eastwood, Peter R; Lee, Y C Gary; Singh, Bhajan

2015-07-01

Pleural effusions have a major impact on the cardiorespiratory system. This article reviews the pathophysiological effects of pleural effusions and pleural drainage, their relationship with breathlessness, and highlights key knowledge gaps. The basis for breathlessness in pleural effusions and relief following thoracentesis is not well understood. Many existing studies on the pathophysiology of breathlessness in pleural effusions are limited by small sample sizes, heterogeneous design and a lack of direct measurements of respiratory muscle function. Gas exchange worsens with pleural effusions and improves after thoracentesis. Improvements in ventilatory capacity and lung volumes following pleural drainage are small, and correlate poorly with the volume of fluid drained and the severity of breathlessness. Rather than lung compression, expansion of the chest wall, including displacement of the diaphragm, appears to be the principle mechanism by which the effusion is accommodated. Deflation of the thoracic cage and restoration of diaphragmatic function after thoracentesis may improve diaphragm effectiveness and efficiency, and this may be an important mechanism by which breathlessness improves. Effusions do not usually lead to major hemodynamic changes, but large effusions may cause cardiac tamponade and ventricular diastolic collapse. Patients with effusions can have impaired exercise capacity and poor sleep quality and efficiency. Pleural effusions are associated with abnormalities in gas exchange, respiratory mechanics, respiratory muscle function and hemodynamics, but the association between these abnormalities and breathlessness remains unclear. Prospective studies should aim to identify the key mechanisms of effusion-related breathlessness and predictors of improvement following pleural drainage.

[Dysphagia in Parkinson's Disease: Pathophysiology, Diagnosis and Therapy].

PubMed

Suttrup, I; Warnecke, T

2016-07-01

Oropharyngeal and esophageal dysphagia are a frequent, but seldom diagnosed symptom of Parkinson's disease (PD). More than 80 % of patients with PD develop dysphagia during the course of their disease leading to a reduced quality of life, complicated medication intake, malnutrition and aspiration pneumonia, which is a major cause of death in PD. The underlying pathophysiology is poorly understood. Impaired dopaminergic and non-dopaminergic mechanisms of the cortical swallowing network as well as peripheral neuromuscular involvement have been suggested to contribute to its multifactorial genesis. Diagnostic screening methods include PD-specific questionnaires and a modified water test. Fiber optic endoscopic evaluation of swallowing (FEES) and videofluoroscopic swallowing study (VFSS), which complement each other, are the gold standard for evaluation of PD-related dysphagia. For evaluation of esophageal dysphagia, the high-resolution manometry (HRM) may be a helpful tool. In addition to dysphagia-specific treatment by speech and language therapists (SLTs), optimized dopaminergic medication is a meaningful therapeutic option. A promising novel method is intensive training of expiratory muscle strength (EMST). Deep brain stimulation does not seem to have a clinically relevant effect on swallowing function in PD. © Georg Thieme Verlag KG Stuttgart · New York.

Gasotransmitter Heterocellular Signaling

PubMed Central

Kolluru, Gopi K.; Shen, Xinggui; Yuan, Shuai; Kevil, Christopher G.

2017-01-01

Abstract Significance: The family of gasotransmitter molecules, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), has emerged as an important mediator of numerous cellular signal transduction and pathophysiological responses. As such, these molecules have been reported to influence a diverse array of biochemical, molecular, and cell biology events often impacting one another. Recent Advances: Discrete regulation of gasotransmitter molecule formation, movement, and reaction is critical to their biological function. Due to the chemical nature of these molecules, they can move rapidly throughout cells and tissues acting on targets through reactions with metal groups, reactive chemical species, and protein amino acids. Critical Issues: Given the breadth and complexity of gasotransmitter reactions, this field of research is expanding into exciting, yet sometimes confusing, areas of study with significant promise for understanding health and disease. The precise amounts of tissue and cellular gasotransmitter levels and where they are formed, as well as how they react with molecular targets or themselves, all remain poorly understood. Future Directions: Elucidation of specific molecular targets, characteristics of gasotransmitter molecule heterotypic interactions, and spatiotemporal formation and metabolism are all important to better understand their true pathophysiological importance in various organ systems. Antioxid. Redox Signal. 26, 936–960. PMID:28068782

The disturbance of antioxidant/oxidant balance in fish experimentally infected by Aeromonas caviae: Relationship with disease pathophysiology.

PubMed

Baldissera, Matheus D; Souza, Carine F; Parmeggiani, Belisa; Leipnitz, Guilhian; Verdi, Camila Marina; Santos, RobertoC V; Stefani, Lenita M; Baldisserotto, Bernardo

2018-06-07

Aeromonas caviae is a Gram-negative bacterium rarely found in fish but it can be associated to high mortality of infected animals. The disease pathogenesis in fish associated to liver and kidney lesions directly linked to the initiation and progression of the disease remains poorly understood. Thus, the aim of this study was to evaluate whether A. caviae infection causes oxidative stress in liver and kidney of silver catfish Rhamdia quelen, and its involvement in disease pathogenesis. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels increased in liver and kidney of fish experimentally infected by A. caviae compared to the control uninfected group. On the other hand, non-protein sulfhydryl (NPSH) levels decreased in both tissues of infected animals, while the glutathione S-transferase (GST) activity decreased only in the hepatic tissue. No difference was observed between groups in both tissues regarding superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) activities and glutathione (GSH) levels. In summary, the disturbance of hepatic and renal antioxidant/oxidant equilibrium contributes to the pathophysiology of the disease in fish experimentally infected by A. caviae. Copyright © 2018 Elsevier Ltd. All rights reserved.

Fatigue in Parkinson's disease: concepts and clinical approach.

PubMed

Nassif, Daniel V; Pereira, João S

2018-03-01

Parkinson's disease (PD) is a progressive neurological disorder characterized by a large number of motor and non-motor features. Fatigue is one of the most common and most disabling symptoms among patients with PD, and it has a significant impact on their quality of life. Although fatigue has been recognized for a long time, its pathophysiology remains poorly understood, and there is no evidence to support any therapeutic approach in PD patients. Expert consensus on case definition and diagnostic criteria for PD-related fatigue have been recently published, and although they still need to be adequately validated, they provide a great step forward in the study of fatigue. The goal of this article is to provide relevant information for the identification and management of patients with fatigue. © 2018 Japanese Psychogeriatric Society.

Quantitative optical coherence tomography imaging of intermediate flow defect phenotypes in ciliary physiology and pathophysiology

NASA Astrophysics Data System (ADS)

Huang, Brendan K.; Gamm, Ute A.; Jonas, Stephan; Khokha, Mustafa K.; Choma, Michael A.

2015-03-01

Cilia-driven fluid flow is a critical yet poorly understood aspect of pulmonary physiology. Here, we demonstrate that optical coherence tomography-based particle tracking velocimetry can be used to quantify subtle variability in cilia-driven flow performance in Xenopus, an important animal model of ciliary biology. Changes in flow performance were quantified in the setting of normal development, as well as in response to three types of perturbations: mechanical (increased fluid viscosity), pharmacological (disrupted serotonin signaling), and genetic (diminished ciliary motor protein expression). Of note, we demonstrate decreased flow secondary to gene knockdown of kif3a, a protein involved in ciliogenesis, as well as a dose-response decrease in flow secondary to knockdown of dnah9, an important ciliary motor protein.

Optical metabolic imaging for monitoring tracheal health

NASA Astrophysics Data System (ADS)

Sharick, Joe T.; Gil, Daniel A.; Choma, Michael A.; Skala, Melissa C.

2016-04-01

The health of the tracheal mucosa and submucosa is a vital yet poorly understood component of critical care medicine, and a minimally-invasive method is needed to monitor tracheal health in patients. Of particular interest are the ciliated cells of the tracheal epithelium that move mucus away from the lungs and prevent respiratory infection. Optical metabolic imaging (OMI) allows cellular-level measurement of metabolism, and is a compelling method for assessing tracheal health because ciliary motor proteins require ATP to function. In this pilot study, we apply multiphoton imaging of the fluorescence intensities and lifetimes of metabolic co-enzymes NAD(P)H and FAD to the mucosa and submucosa of ex vivo mouse trachea. We demonstrate the feasibility and potential diagnostic utility of these measurements for assessing tracheal health and pathophysiology at the single-cell level.

Neurogenic Causes of Detrusor Underactivity

PubMed Central

Kadow, Brian T.; Tyagi, Pradeep; Chermansky, Christopher J.

2015-01-01

Detrusor underactivity (DU) is a poorly understood dysfunction of the lower urinary tract which arises from multiple etiologies. Symptoms of DU are non-specific, and a pressure-flow urodynamic study is necessary to differentiate DU from other conditions such as overactive bladder (OAB) or bladder outlet obstruction (BOO). The prevalence of DU ranges from 10–48%, and DU is most prevalent in elderly males. The pathophysiology underlying DU can be from both neurogenic and non-neurogenic causes. In this article, we review the neurogenic causes of detrusor underactivity, including diabetic bladder dysfunction, spinal cord injury, multiple sclerosis, Parkinson’s disease, cerebrovascular accident, traumatic brain injury, and Fowler’s syndrome. As knowledge about the underlying causes of DU advances, there have been several potential therapeutic approaches proposed to help those who suffer from this condition. PMID:26715948

Genes, molecules and patients—Emerging topics to guide clinical pain research

PubMed Central

Sikandar, Shafaq; Patel, Ryan; Patel, Sital; Sikander, Sanam; Bennett, David L.H.; Dickenson, Anthony H.

2013-01-01

This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain. PMID:23500200

Postconcussion Syndrome: A Review.

PubMed

Barlow, Karen M

2016-01-01

Postconcussion syndrome is a symptom complex with a wide range of somatic, cognitive, sleep, and affective features, and is the most common consequence of traumatic brain injury. Between 14% and 29% of children with mild traumatic brain injury will continue to have postconcussion symptoms at 3 months, but the pathophysiological mechanisms driving this is poorly understood. The relative contribution of injury factors to postconcussion syndrome decreases over time and, instead, premorbid factors become important predictors of symptom persistence by 3 to 6 months postinjury. The differential diagnoses include headache disorder, cervical injury, anxiety, depression, somatization, vestibular dysfunction, and visual dysfunction. The long-term outcome for most children is good, although there is significant morbidity in the short term. Management strategies target problematic symptoms such as headaches, sleep and mood disturbances, and cognitive complaints. © The Author(s) 2014.

PERIPARTUM DEPRESSION AND ANXIETY AS AN INTEGRATIVE CROSS DOMAIN TARGET FOR PSYCHIATRIC PREVENTATIVE MEASURES

PubMed Central

Babb, Jessica A.; Deligiannidis, Kristina M.; Murgatroyd, Christopher A.

2014-01-01

Exposure to high levels of early life stress has been identified as a potent risk factor for neurodevelopmental delays in infants, behavioral problems and autism in children, but also for several psychiatric illnesses in adulthood, such as depression, anxiety, autism, and posttraumatic stress disorder. Despite having robust adverse effects on both mother and infant, the pathophysiology of peripartum depression and anxiety are poorly understood. The objective of this review is to highlight the advantages of using an integrated approach addressing several behavioral domains in both animal and clinical studies of peripartum depression and anxiety. It is postulated that a greater focus on integrated cross domain studies will lead to advances in treatments and preventative measures for several disorders associated with peripartum depression and anxiety. PMID:24709228

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

Pruritus: Management Algorithms and Experimental Therapies

PubMed Central

Steinhoff, Martin; Cevikbas, Ferda; Ikoma, Akihiko; Berger, Timothy G.

2013-01-01

Pruritus (itch) is a major symptom in many dermatologic as well as systemic diseases and has a dramatic impact on the quality of life in these patients. The symptom of itch has to be treated on the basis of its pathophysiology and its underlying disease. In daily practice, a “quick” diagnosis of the underlying disease is often difficult, although a rapid relief of the itch is desired. We often treat patients on the basis of the symptomatology. A rational therapeutic ladder for a symptomatic therapy is useful until the final diagnosis has been confirmed. There are probably many subtypes of pruritus, just as there are many diseases that cause itch. The pathophysiology in many subtypes of pruritus is still poorly understood, hindering a rapid and targeted treatment strategy. An extensive diagnostic workup is often required to determine the final cause(s) of the itch. Thus, in daily life, physicians often start with a more or less rational therapeutic strategy to combat the debilitating itch. We present possible therapeutic ladders that form the basis for effective therapeutic itch strategies in various diseases. On the basis of our current knowledge about the different pathophysiologies of itch, on clinical trials or case reports, and our own clinical experience, we aim to present therapeutic ladders for the rapid as well as long-term management of itch. Finally, we summarize current exciting developments of experimental strategies in itch research and in clinical development for itch therapy. PMID:21767775

Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

PubMed Central

Suls, Arvid; Dedeken, Peter; Goffin, Karolien; Van Esch, Hilde; Dupont, Patrick; Cassiman, David; Kempfle, Judith; Wuttke, Thomas V.; Weber, Yvonne; Lerche, Holger; Afawi, Zaid; Vandenberghe, Wim; Korczyn, Amos D.; Berkovic, Samuel F.; Ekstein, Dana; Kivity, Sara; Ryvlin, Philippe; Claes, Lieve R. F.; Deprez, Liesbet; Maljevic, Snezana; Vargas, Alberto; Van Dyck, Tine; Goossens, Dirk; Del-Favero, Jurgen; Van Laere, Koen; De Jonghe, Peter

2008-01-01

Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome. PMID:18577546

Chronic Diffuse Pain and Functional Gastrointestinal Disorders After Traumatic Stress: Pathophysiology Through a Polyvagal Perspective

PubMed Central

Kolacz, Jacek; Porges, Stephen W.

2018-01-01

Chronic diffuse pain disorders, such as fibromyalgia, and functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, place substantial burden on those affected and on the medical system. Despite their sizable impact, their pathophysiology is poorly understood. In contrast to an approach that focuses on the correlation between heart rate variability (HRV) and a specific organ or symptom, we propose that a bio-evolutionary threat-related autonomic response—as outlined in the Polyvagal Theory—may serve as a plausible explanation of how HRV, particularly respiratory sinus arrhythmia (RSA), would index the pathophysiology of these disorders. Evidence comes from: (1) the well-documented atypical autonomic regulation of the heart common to fibromyalgia and irritable bowel syndrome reflected in dampened RSA, (2) the neural architecture that integrates the heart, pain pathways, and the gastrointestinal tract, (3) the common physical co-morbidities shared by chronic diffuse pain and FGIDs, many of which are functionally regulated by the autonomic nervous system, (4) the elevated risk of chronic diffuse pain and FGIDs following traumatic stress or abuse, (5) and the elevated risk of chronic diffuse pain and FGIDs in individuals with anxiety and panic disorders. This novel conceptualization points to a pathogenesis rooted in changes to brain-body autonomic feedback loops in response to evolutionarily-salient threat cues, providing an integrated biopsychosocial model of chronic diffuse pain and FGIDs and suggesting new, non-pharmacological treatment strategies. PMID:29904631

Recent advances in the pathophysiology of arterial hypertension: potential implications for clinical practice.

PubMed

Hering, Dagmara; Trzebski, Andrzej; Narkiewicz, Krzysztof

2017-03-01

Hypertension remains a major and growing public health problem associated with the greatest global rate of cardiovascular morbidity and mortality. Although numerous factors contribute to poor control of blood pressure (BP) and to pseudoresistance (eg, unawareness, lifestyle habits, nonadherence to medication, insufficient treatment, drug‑induced hypertension, undiagnosed secondary causes), true resistant hypertension (RH) is reported in 10.1% of patients treated for elevated BP. While the mechanisms underlying RH remain complex and not entirely understood, sympathetic activation involved in the pathophysiology of hypertension, disease progression, and adverse complications is further augmented in patients with drug‑resistant hypertension. The well‑established contribution of neurogenic component of hypertension has led to the introduction of new alternative therapies aimed specifically at modulating central and neural reflexes mechanisms involved in BP control. Although clinical benefits of lowering BP with renal denervation, baroreflex activation therapy, carotid body denervation, central arteriovenous anastomosis, and deep brain stimulation have advanced our knowledge on uncontrolled hypertension, the variable BP response has prompted extensive ongoing research to define predictors of treatment effectiveness and further investigation of pathophysiology of RH. Very recently, research on the role of vasopressinergic neurons, masked tachycardia, and impaired brain neural activity has provided novel insights into hypertension. This review briefly summarizes the role of the centrally mediated sympathetic nervous system in hypertension, the therapeutic strategies that distinctively target impaired neural reflex mechanisms, and potential implications for future clinical research and therapies.

Phenotype- and Genotype-Specific Structural Alterations in Spasmodic Dysphonia

PubMed Central

Bianchi, Serena; Battistella, Giovanni; Huddleston, Hailey; Scharf, Rebecca; Fleysher, Lazar; Rumbach, Anna F.; Frucht, Steven J.; Blitzer, Andrew; Ozelius, Laurie J.; Simonyan, Kristina

2017-01-01

Background Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. Methods Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). Results Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. Conclusions Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. PMID:28186656

Anatomy, function, and pathophysiology of the posterior tibial tendon.

PubMed

Smith, C F

1999-07-01

The posterior tibial tendon is vital for the structure and function of the foot and ankle. Dysfunction of the tendon can be debilitating and devastating. In recent years, much attention had been directed toward the diagnosis and treatment of PTTD. To properly diagnose and devise an appropriate treatment regimen, the anatomy, function, and pathophysiology associated with PTTD need to be thoroughly understood.

Swallowing Disorders in Schizophrenia.

PubMed

Kulkarni, Deepika P; Kamath, Vandan D; Stewart, Jonathan T

2017-08-01

Disorders of swallowing are poorly characterized but quite common in schizophrenia. They are a source of considerable morbidity and mortality in this population, generally as a result of either acute asphyxia from airway obstruction or more insidious aspiration and pneumonia. The death rate from acute asphyxia may be as high as one hundred times that of the general population. Most swallowing disorders in schizophrenia seem to fall into one of two categories, changes in eating and swallowing due to the illness itself and changes related to psychotropic medications. Behavioral changes related to the illness are poorly understood and often involve eating too quickly or taking inappropriately large boluses of food. Iatrogenic problems are mostly related to drug-induced extrapyramidal side effects, including drug-induced parkinsonism, dystonia, and tardive dyskinesia, but may also include xerostomia, sialorrhea, and changes related to sedation. This paper will provide an overview of common swallowing problems encountered in patients with schizophrenia, their pathophysiology, and management. While there is a scarcity of quality evidence in the literature, a thorough history and examination will generally elucidate the predominant problem or problems, often leading to effective management strategies.

Advances in IBS 2016: A Review of Current and Emerging Data.

PubMed

Schoenfeld, Philip S

2016-08-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide.

Advances in IBS 2016: A Review of Current and Emerging Data

PubMed Central

Schoenfeld, Philip S.

2016-01-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide. PMID:28070176

Emerging roles for hemostatic dysfunction in malaria pathogenesis.

PubMed

O'Sullivan, Jamie M; Preston, Roger J S; O'Regan, Niamh; O'Donnell, James S

2016-05-12

Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance. © 2016 by The American Society of Hematology.

Spectrum of MRI findings in clinical athletic pubalgia.

PubMed

Zajick, Donald C; Zoga, Adam C; Omar, Imran M; Meyers, William C

2008-03-01

Athletic pubalgia is a frequently encountered syndrome for clinicians who treat active patients participating in a wide variety of athletic endeavors worldwide. Pathologies associated with this clinical scenario span anatomically from the pubic symphysis to the hip and include a myriad of poorly understood and incompletely described musculoskeletal entities, many of which are centered about the pubic symphysis and its tendinous attachments. In this article, we discuss the relevant anatomy and pathophysiology for the most frequently encountered of these disorders, using magnetic resonance (MR) images as a guide. We describe an MR imaging protocol tailored to clinical athletic pubalgia. We then review reproducible MRI patterns of pathology about the pubic symphysis, the rectus abdominis/adductor aponeurosis and the inguinal ring, as well as a group of clinically confounding entities remote from the symphysis but visible by MRI.

Treatment of Chagas Cardiomyopathy

PubMed Central

Botoni, Fernando A.; Ribeiro, Antonio Luiz P.; Marinho, Carolina Coimbra; Lima, Marcia Maria Oliveira; Nunes, Maria do Carmo Pereira; Rocha, Manoel Otávio C.

2013-01-01

Chagas' disease (ChD), caused by the protozoa Trypanosoma cruzi (T. cruzi), was discovered and described by the Brazilian physician Carlos Chagas in 1909. After a century of original description, trypanosomiasis still brings much misery to humanity and is classified as a neglected tropical disease prevalent in underdeveloped countries, particularly in South America. It is an increasing worldwide problem due to the number of cases in endemic areas and the migration of infected subjects to more developed regions, mainly North America and Europe. Despite its importance, chronic chagas cardiomyopathy (CCC) pathophysiology is yet poorly understood, and independently of its social, clinical, and epidemiological importance, the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Therefore, the objective of this review is to describe the treatment of Chagas cardiomyopathy with emphasis on its peculiarities. PMID:24350293

Revealing the role of phospholipase Cβ3 in the regulation of VEGF-induced vascular permeability

PubMed Central

Hoeppner, Luke H.; Phoenix, Kathryn N.; Clark, Karl J.; Bhattacharya, Resham; Gong, Xun; Sciuto, Tracey E.; Vohra, Pawan; Suresh, Sandip; Bhattacharya, Santanu; Dvorak, Ann M.; Ekker, Stephen C.; Dvorak, Harold F.; Claffey, Kevin P.

2012-01-01

VEGF induces vascular permeability (VP) in ischemic diseases and cancer, leading to many pathophysiological consequences. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of VP do not exist. In the present study, we report a heat-inducible VEGF transgenic zebrafish (Danio rerio) model through which VP can be monitored in real time. Using this approach with morpholino-mediated gene knock-down and knockout mice, we describe a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated VP by regulating intracellular Ca2+ release. Our results suggest an important effect of PLCβ3 on VP and provide a new model with which to identify genetic regulators of VP crucial to several disease processes. PMID:22674805

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

PubMed

Pohl, Calvin S; Medland, Julia E; Moeser, Adam J

2015-12-15

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. Copyright © 2015 the American Physiological Society.

Case Report of a Patient With Idiopathic Hypersomnia and a Family History of Malignant Hyperthermia Undergoing General Anesthesia: An Overview of the Anesthetic Considerations.

PubMed

Aflaki, Sena; Hu, Sally; Kamel, Rami A; Chung, Frances; Singh, Mandeep

2017-05-01

The pathophysiologic underpinnings of idiopathic hypersomnia and its interactions with anesthetic medications remain poorly understood. There is a scarcity of literature describing this patient population in the surgical setting. This case report outlines the anesthetic considerations and management plan for a 55-year-old female patient with a known history of idiopathic hypersomnia undergoing an elective shoulder arthroscopy in the ambulatory setting. In addition, this case offers a unique set of considerations and conflicts related to the patient having a family history of malignant hyperthermia. A combined technique of general and regional anesthesia was used. Anesthesia was maintained with total intravenous anesthesia via the use of propofol and remifentanil. The depth of anesthesia was monitored with entropy. There were no perioperative complications.

Peripartum depression and anxiety as an integrative cross domain target for psychiatric preventative measures.

PubMed

Babb, Jessica A; Deligiannidis, Kristina M; Murgatroyd, Christopher A; Nephew, Benjamin C

2015-01-01

Exposure to high levels of early life stress has been identified as a potent risk factor for neurodevelopmental delays in infants, behavioral problems and autism in children, but also for several psychiatric illnesses in adulthood, such as depression, anxiety, autism, and posttraumatic stress disorder. Despite having robust adverse effects on both mother and infant, the pathophysiology of peripartum depression and anxiety are poorly understood. The objective of this review is to highlight the advantages of using an integrated approach addressing several behavioral domains in both animal and clinical studies of peripartum depression and anxiety. It is postulated that a greater focus on integrated cross domain studies will lead to advances in treatments and preventative measures for several disorders associated with peripartum depression and anxiety. Copyright © 2014 Elsevier B.V. All rights reserved.

Pathophysiology, Evaluation, and Treatment of Bloating

PubMed Central

Gabbard, Scott L.; Crowell, Michael D.

2011-01-01

Abdominal bloating is commonly reported by men and women of all ages. Bloating occurs in nearly all patients with irritable bowel syndrome, and it also occurs in patients with other functional and organic disorders. Bloating is frequently disturbing to patients and frustrating to clinicians, as effective treatments are limited and are not universally successful. Although the terms bloating and abdominal distention are often used interchangeably, these symptoms likely involve different pathophysiologic processes, both of which are still not completely understood. The goal of this paper is to review the pathophysiology, evaluation, and treatment of bloating and abdominal distention. PMID:22298969

Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice.

PubMed

Sava, Ruxandra I; March, Keith L; Pepine, Carl J

2018-02-01

Pregnancy-related hypertension (PHTN) syndromes are a frequent and potentially deadly complication of pregnancy, while also negatively impacting the lifelong health of the mother and child. PHTN appears in women likely to develop hypertension later in life, with the stress of pregnancy unmasking a subclinical hypertensive phenotype. However, distinguishing between PHTN and chronic hypertension is essential for optimal management. Preeclampsia (PE) is linked to potentially severe outcomes and lacks effective treatments due to poorly understood mechanisms. Inadequate remodeling of spiral uterine arteries (SUAs), the cornerstone of PE pathophysiology, leads to hypoperfusion of the developing placenta. In normal pregnancies, extravillous trophoblast (EVT) cells assume an invasive phenotype and invade SUAs, transforming them into large conduits. Decidual natural killer cells play an essential role, mediating materno-fetal immune tolerance, inducing early SUA remodeling and regulating EVT invasiveness. Notch signaling is important in EVT phenotypic switch and is dysregulated in PE. The hypoxic placenta releases antiangiogenic and proinflammatory factors that converge upon maternal endothelium, inducing endothelial dysfunction, hypertension, and organ damage. Hypoxia-inducible factor 1-α is upstream of such molecules, whereas endothelin-1 is a major effector. We also describe important genetic links and evidence of incomplete materno-fetal immune tolerance, with PE patients presenting with autoantibodies, lower T reg , and higher T h 17 cells. Thus, PE manifestations arise as a consequence of mal-placentation or/and because of a predisposition of the maternal vascular bed to excessively react to pathogenic molecules. From this pathophysiological basis, we provide current and propose future therapeutic directions for PE. © 2018 Wiley Periodicals, Inc.

Using human brain imaging studies as a guide towards animal models of schizophrenia

PubMed Central

BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

2015-01-01

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

Phenotype- and genotype-specific structural alterations in spasmodic dysphonia.

PubMed

Bianchi, Serena; Battistella, Giovanni; Huddleston, Hailey; Scharf, Rebecca; Fleysher, Lazar; Rumbach, Anna F; Frucht, Steven J; Blitzer, Andrew; Ozelius, Laurie J; Simonyan, Kristina

2017-04-01

Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS.

PubMed

Kuttikat, Anoop; Noreika, Valdas; Shenker, Nicholas; Chennu, Srivas; Bekinschtein, Tristan; Brown, Christopher Andrew

2016-01-01

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits.

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS

PubMed Central

Kuttikat, Anoop; Noreika, Valdas; Shenker, Nicholas; Chennu, Srivas; Bekinschtein, Tristan; Brown, Christopher Andrew

2016-01-01

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits. PMID:26858626

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

PubMed

Cahill, Lindsay S; Gazdzinski, Lisa M; Tsui, Albert Ky; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory Mt; Kassner, Andrea; Sled, John G

2017-03-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

PubMed Central

Gazdzinski, Lisa M; Tsui, Albert KY; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory MT; Kassner, Andrea; Sled, John G

2016-01-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia. PMID:27165012

White-Nose Syndrome Disease Severity and a Comparison of Diagnostic Methods.

PubMed

McGuire, Liam P; Turner, James M; Warnecke, Lisa; McGregor, Glenna; Bollinger, Trent K; Misra, Vikram; Foster, Jeffrey T; Frick, Winifred F; Kilpatrick, A Marm; Willis, Craig K R

2016-03-01

White-nose syndrome is caused by the fungus Pseudogymnoascus destructans and has killed millions of hibernating bats in North America but the pathophysiology of the disease remains poorly understood. Our objectives were to (1) assess non-destructive diagnostic methods for P. destructans infection compared to histopathology, the current gold-standard, and (2) to evaluate potential metrics of disease severity. We used data from three captive inoculation experiments involving 181 little brown bats (Myotis lucifugus) to compare histopathology, quantitative PCR (qPCR), and ultraviolet fluorescence as diagnostic methods of P. destructans infection. To assess disease severity, we considered two histology metrics (wing area with fungal hyphae, area of dermal necrosis), P. destructans fungal load (qPCR), ultraviolet fluorescence, and blood chemistry (hematocrit, sodium, glucose, pCO2, and bicarbonate). Quantitative PCR was most effective for early detection of P. destructans, while all three methods were comparable in severe infections. Correlations among hyphae and necrosis scores, qPCR, ultraviolet fluorescence, blood chemistry, and hibernation duration indicate a multi-stage pattern of disease. Disruptions of homeostasis occurred rapidly in late hibernation. Our results provide valuable information about the use of non-destructive techniques for monitoring, and provide novel insight into the pathophysiology of white-nose syndrome, with implications for developing and implementing potential mitigation strategies.

Essential Tremor: What We Can Learn from Current Pharmacotherapy.

PubMed

Ondo, William

2016-01-01

The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design. We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor. Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta-adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration. To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials.

Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging.

PubMed

Wortinger, Laura Anne; Endestad, Tor; Melinder, Annika Maria D; Øie, Merete Glenne; Sulheim, Dag; Fagermoen, Even; Wyller, Vegard Bruun

2017-05-01

Studies of neurocognition suggest that abnormalities in cognitive control contribute to the pathophysiology of chronic fatigue syndrome (CFS) in adolescents, yet these abnormalities remain poorly understood at the neurobiological level. Reports indicate that adolescents with CFS are significantly impaired in conflict processing, a primary element of cognitive control. In this study, we examine whether emotional conflict processing is altered on behavioral and neural levels in adolescents with CFS and a healthy comparison group. Fifteen adolescent patients with CFS and 24 healthy adolescent participants underwent functional magnetic resonance imaging (fMRI) while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect labeled words. Adolescent CFS patients were less able to engage the left amygdala and left midposterior insula (mpINS) in response to conflict than the healthy comparison group. An association between accuracy interference and conflict-related reactivity in the amygdala was observed in CFS patients. A relationship between response time interference and conflict-related reactivity in the mpINS was also reported. Neural responses in the amygdala and mpINS were specific to fatigue severity. These data demonstrate that adolescent CFS patients displayed deficits in emotional conflict processing. Our results suggest abnormalities in affective and cognitive functioning of the salience network, which might underlie the pathophysiology of adolescent CFS.

Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review

PubMed Central

Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

2016-01-01

Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies. PMID:27187381

Drug Development and Biologics in Asthma. A New Era.

PubMed

Doyle, Ramona

2016-03-01

Considerable progress has been made toward developing targeted biological therapeutics for asthma, due in large part to a deeper understanding of asthma pathophysiology. This explosion of knowledge has revealed asthma to be a much more complex and heterogeneous entity than previously understood. The identification of particular asthma phenotypes with distinct pathophysiologic mechanisms has opened up a new era for patient populations not well served by current therapies, especially patients with severe asthma.

A Unified Pathophysiological Construct of Diabetes and its Complications.

PubMed

Schwartz, Stanley S; Epstein, Solomon; Corkey, Barbara E; Grant, Struan F A; Gavin Iii, James R; Aguilar, Richard B; Herman, Mary E

2017-09-01

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

A narrative review on the difficulties associated with fibromyalgia diagnosis

PubMed Central

Kumbhare, Dinesh; Ahmed, Sara; Watter, Scott

2017-01-01

Fibromyalgia presents a clinical enigma as its pathophysiology is not well understood and its symptoms are nonspecific and overlap with many disorders, making its diagnosis a challenge for clinicians and researchers. Efforts have been made to develop a set of diagnostic criteria for this disorder. However, these criteria rely heavily on expert clinician opinion and produce a large heterogeneity within the diagnosed population. With no present specific technique reflecting the underlying pathophysiology of fibromyalgia, a definitive diagnosis of fibromyalgia remains elusive. This review discusses some problems and challenges associated with fibromyalgia diagnosis and presents some novel findings on the pathophysiological nature of fibromyalgia. PMID:29290763

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

PubMed Central

Stowe, Irma B.; Mercado, Ellen L.; Stowe, Timothy R.; Bell, Erika L.; Oses-Prieto, Juan A.; Hernández, Hilda; Burlingame, Alma L.; McCormick, Frank

2012-01-01

The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome. PMID:22751498

Anti-resorptive osteonecrosis of the jaws: facts forgotten, questions answered, lessons learned.

PubMed

Carlson, Eric R; Schlott, Benjamin J

2014-05-01

Osteonecrosis of the jaws associated with bisphosphonate and other anti-resorptive medications (ARONJ) has historically been a poorly understood disease process in terms of its pathophysiology, prevention and treatment since it was originally described in 2003. In association with its original discovery 11 years ago, non-evidence based speculation of these issues have been published in the international literature and are currently being challenged. A critical analysis of cancer patients with ARONJ, for example, reveals that their osteonecrosis is nearly identical to that of cancer patients who are naive to anti-resorptive medications. In addition, osteonecrosis of the jaws is not unique to patients exposed to anti-resorptive medications, but is also seen in patients with osteomyelitis and other pathologic processes of the jaws. This article represents a review of facts forgotten, questions answered, and lessons learned in general regarding osteonecrosis of the jaws. Copyright © 2014 Elsevier Inc. All rights reserved.

The nature of the autonomic dysfunction in multiple system atrophy

NASA Technical Reports Server (NTRS)

Parikh, Samir M.; Diedrich, Andre; Biaggioni, Italo; Robertson, David

2002-01-01

The concept that multiple system atrophy (MSA, Shy-Drager syndrome) is a disorder of the autonomic nervous system is several decades old. While there has been renewed interest in the movement disorder associated with MSA, two recent consensus statements confirm the centrality of the autonomic disorder to the diagnosis. Here, we reexamine the autonomic pathophysiology in MSA. Whereas MSA is often thought of as "autonomic failure", new evidence indicates substantial persistence of functioning sympathetic and parasympathetic nerves even in clinically advanced disease. These findings help explain some of the previously poorly understood features of MSA. Recognition that MSA entails persistent, constitutive autonomic tone requires a significant revision of our concepts of its diagnosis and therapy. We will review recent evidence bearing on autonomic tone in MSA and discuss their therapeutic implications, particularly in terms of the possible development of a bionic baroreflex for better control of blood pressure.

PIGMENTED VILLONODULAR SYNOVITIS IN A RETICULATED GIRAFFE (GIRAFFA CAMELOPARDALIS).

PubMed

Ihms, Elizabeth A; Rivas, Anne; Bronson, Ellen; Mangus, Lisa M

2017-06-01

: A 17-yr-old, female, captive-born reticulated giraffe ( Giraffa camelopardalis ) presented with acute-onset lameness of the right metacarpophalangeal (fetlock) joint. Despite multiple courses of treatment, the lameness and swelling progressively worsened over a 3.5-yr period, and the giraffe was euthanized. At necropsy, gross and microscopic changes in the right, front fetlock and associated flexor tendon sheath included villous synovial hyperplasia and the formation of discrete pigmented nodules within synovial membranes. Histologically, the nodules were composed of abundant, fibrous connective tissue with heavy macrophage infiltration, hemosiderin deposition, and distinctive, multinucleated cells that resembled osteoclasts. These findings were consistent with pigmented villonodular synovitis (PVNS), a rare condition affecting both humans and animals. Although the pathophysiology of PVNS is poorly understood, lesions exhibit features of both neoplastic and reactive inflammatory processes. This case report represents, to the authors' knowledge, the first description of PVNS in a nondomestic ungulate.

[Clinical case of acute renal failure revealing an autoimmune hypothyroidism].

PubMed

Montasser, Dina Ibrahim; Hassani, Mohamed; Zajjari, Yassir; Bahadi, Abdelali; Alayoud, Ahmed; Hamzi, Amine; Hassani, Kawtar; Moujoud, Omar; Asseraji, Mohamed; Kadiri, Moncif; Aatif, Taoufik; El Kabbaj, Driss; Benyahia, Mohamed; Allam, Mustapha; Akhmouch, Ismail; Oualim, Zouhir

2010-04-01

Although the clinic picture is often indicative of muscle manifestations in patients with hypothyroidism, signs and symptoms of this condition are variable from simple elevation of serum muscle enzymes with myalgia, muscle weakness, cramps to rhabdomyolysis with acute renal failure which remains a rare event. Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Hypothyroidism is associated with significant effects on the kidney which the pathophysiology seems to be multifactorial, but the exact mechanisms remain poorly understood. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. The main objective of our observation is to report a case of acute renal failure revealing an autoimmune hypothyroidism in which thyroid hormone substitution led to a significant improvement in muscular, thyroid and renal disorders. Copyright 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Food protein-induced enterocolitis syndrome: a review of the new guidelines.

PubMed

Leonard, Stephanie A; Pecora, Valentina; Fiocchi, Alessandro Giovanni; Nowak-Wegrzyn, Anna

2018-01-01

Food protein-induced enterocolitis syndrome (FPIES) is a non IgE-mediated gastrointestinal food allergy that presents with delayed vomiting after ingestion primarily in infants. While the pathophysiology of FPIES is poorly understood, the clinical presentation of acute FPEIS reactions has been well characterized. The first International Consensus Guidelines for the Diagnosis and Management of Food Protein-induced Enterocolitis Syndrome were published in 2017 and reviewed epidemiology, clinical presentation, and prognosis of acute and chronic FPIES. The workgroup outlined clinical phenotypes, proposed diagnostic criteria, and made recommendations on management. This article summarizes the guidelines and adds recent updates. FPIES is gaining recognition, however there continues to be delays in diagnosis and misdiagnosis due to overlap of symptoms with over conditions, lack of a diagnostic test, and because some of the common trigger foods are not thought of as allergenic. More research into disease mechanisms and factors influencing differences between populations is needed.

A Review of MR Spectroscopy Studies of Pediatric Bipolar Disorder

PubMed Central

Kondo, D.G.; Hellem, T.L.; Shi, X.-F.; Sung, Y.H.; Prescot, A.P.; Kim, T.S.; Huber, R.S.; Forrest, L.N.; Renshaw, P.F.

2015-01-01

Pediatric bipolar disorder is a severe mental illness whose pathophysiology is poorly understood and for which there is an urgent need for improved diagnosis and treatment. MR spectroscopy is a neuroimaging method capable of in vivo measurement of neurochemicals relevant to bipolar disorder neurobiology. MR spectroscopy studies of adult bipolar disorder provide consistent evidence for alterations in the glutamate system and mitochondrial function. In bipolar disorder, these 2 phenomena may be linked because 85% of glucose in the brain is consumed by glutamatergic neurotransmission and the conversion of glutamate to glutamine. The purpose of this article is to review the MR spectroscopic imaging literature in pediatric bipolar disorder, at-risk samples, and severe mood dysregulation, with a focus on the published findings that are relevant to glutamatergic and mitochondrial functioning. Potential directions for future MR spectroscopy studies of the glutamate system and mitochondrial dysfunction in pediatric bipolar disorder are discussed. PMID:24557702

Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model

PubMed Central

Pizzagalli, Diego A.

2014-01-01

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (1) anhedonia, (2) dopamine, and (3) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affect mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research. PMID:24471371

Causes of learning disability and epilepsy: a review.

PubMed

Prince, Elizabeth; Ring, Howard

2011-04-01

Although the association between learning disability and epilepsy is well known, until relatively recently specific processes underlying this association were relatively poorly understood. However, scientific advances in molecular biology are starting to guide researchers towards descriptions of genetic and pathophysiological processes that may explain why syndromes of epilepsy and learning disability often co-exist. This article will focus largely on three areas of advancing knowledge: insights gained from wider use of genome-wide array comparative genomic hybridization (aCGH), specific insights gained from detailed study of Rett syndrome and the role of abnormalities of astrocytic function in predisposing to both epilepsy and learning disability. The enormous complexity of the biological underpinnings of the co-occurrence of epilepsy and learning disability are becoming apparent. In the future it is likely that research into therapeutic approaches will include, amongst other approaches, investigations of gene structure and expression, the role of astrocytes and the stability of dendritic spines.

Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma.

PubMed

Luczkowska, K; Litwinska, Z; Paczkowska, E; Machalinski, B

2018-04-01

Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.

The pathophysiology of delayed ejaculation

PubMed Central

2016-01-01

Delayed ejaculation (DE) is probably least studied, and least understood of male sexual dysfunctions, with an estimated prevalence of 1–4% of the male population. Pathophysiology of DE is multifactorial and including psychosexual-behavioral and cultural factors, disruption of ejaculatory apparatus, central and peripheral neurotransmitters, hormonal or neurochemical ejaculatory control and psychosocial factors. Although knowledge of the physiology of the DE has increased in the last two decade, our understanding of the different pathophysiological process of the causes of DE remains limited. To provide a systematic update on the pathophysiology of DE. A systematic review of Medline and PubMed for relevant publications on ejaculatory dysfunction (EjD), DE, retarded ejaculation, inhibited ejaculation, and climax was performed. The search was limited to the articles published between the January 1960 and December 2015 in English. Of 178 articles, 105 were selected for this review. Only those publications relevant to the pathophysiology, epidemiology and prevalence of DE were included. The pathophysiology of DE involves cerebral sensory areas, motor centers, and several spinal nuclei that are tightly interconnected. The biogenic, psychogenic and other factors strongly affect the pathophysiology of DE. Despite the many publications on this disorder, there still is a paucity of publications dedicated to the subject. PMID:27652227

Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements

PubMed Central

Levitt, David G; Levitt, Michael D

2016-01-01

Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. This review provides a summary that is not previously available in the literature, concerning how synthesis, catabolism, and renal and gastrointestinal clearance of albumin interact to bring about albumin homeostasis, with a focus on the clinical factors that influence this homeostasis. In normal humans, the albumin turnover time of about 25 days reflects a liver albumin synthesis rate of about 10.5 g/day balanced by renal (≈6%), gastrointestinal (≈10%), and catabolic (≈84%) clearances. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space. The best understood mechanism of chronic hypoalbuminemia is the decreased albumin synthesis observed in liver disease. Decreased albumin production also accounts for hypoalbuminemia observed with a low-protein and normal caloric diet. However, a calorie- and protein-deficient diet does not reduce albumin synthesis and is not associated with hypoalbuminemia, and CP is not a useful marker of malnutrition. In most disease states other than liver disease, albumin synthesis is normal or increased, and hypoalbuminemia reflects an enhanced rate of albumin turnover resulting either from an increased rate of catabolism (a poorly understood phenomenon) or enhanced loss of albumin into the urine (nephrosis) or intestine (protein-losing enteropathy). The latter may occur with subtle intestinal pathology and hence may be more prevalent than commonly appreciated. Clinically, reduced CP appears to be a result rather than a cause of ill-health, and therapy designed to increase CP has limited benefit. The ubiquitous occurrence of hypoalbuminemia in disease states limits the diagnostic utility of the CP measurement. PMID:27486341

Neurovascular contributions to migraine: Moving beyond vasodilation.

PubMed

Jacobs, Blaine; Dussor, Gregory

2016-12-03

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine are still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

The cerebral basis of Parkinsonian tremor: A network perspective.

PubMed

Helmich, Rick C

2018-02-01

Tremor in Parkinson's disease is a poorly understood sign. Although it is one of the clinical hallmarks of the disease, its pathophysiology remains unclear. It is clear that tremor involves different neural mechanisms than bradykinesia and rigidity, the other core motor signs of Parkinson's disease. In particular, the role of dopamine in tremor has been heavily debated given clinical observations that tremor has a variable response to dopaminergic medication. From a neuroscience perspective, tremor is also a special sign; unlike other motor signs, it has a clear electrophysiological signature (frequency, phase, and power). These unique features of tremor, and newly available neuroimaging methods, have sparked investigations into the pathophysiology of tremor. In this review, evidence will be discussed for the idea that parkinsonian tremor results from increased interactions between the basal ganglia and the cerebello-thalamo-cortical circuit, driven by altered dopaminergic projections to nodes within both circuits, and modulated by context-dependent factors, such as psychological stress. Models that incorporate all of these features may help our understanding of the pathophysiology of tremor and interindividual differences between patients. One example that will be discussed in this article is the "dimmer-switch" model. According to this model, cerebral activity related to parkinsonian tremor first arises in the basal ganglia and is then propagated to the cerebello-thalamo-cortical circuit, where the tremor rhythm is maintained and amplified. In the future, detailed knowledge about the architecture of the tremor circuitry in individual patients ("tremor fingerprints") may provide new, mechanism-based treatments for this debilitating motor sign. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Atrial Arrhythmia in Ageing Spontaneously Hypertensive Rats: Unraveling the Substrate in Hypertension and Ageing

PubMed Central

Lau, Dennis H.; Shipp, Nicholas J.; Kelly, Darren J.; Thanigaimani, Shivshankar; Neo, Melissa; Kuklik, Pawel; Lim, Han S.; Zhang, Yuan; Drury, Karen; Wong, Christopher X.; Chia, Nicholas H.; Brooks, Anthony G.; Dimitri, Hany; Saint, David A.; Brown, Lindsay; Sanders, Prashanthan

2013-01-01

Background Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR). Methods SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis. Results Compared to WKY controls, the SHR demonstrated: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages. Conclusions Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria. PMID:24013508

Neurovascular contributions to migraine: moving beyond vasodilation

PubMed Central

Jacobs, Blaine; Dussor, Gregory

2016-01-01

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine is still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder. PMID:27312704

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.

PubMed

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E; Seidman, J G; Pu, William T; Wang, Da-Zhi

2015-11-02

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

PubMed Central

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E.; Seidman, J.G.; Pu, William T.; Wang, Da-Zhi

2015-01-01

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression. PMID:26436652

Pharmacological and Physiological Characterization of the Tremulous Jaw Movement Model of Parkinsonian Tremor: Potential Insights into the Pathophysiology of Tremor

PubMed Central

Collins-Praino, Lyndsey E.; Paul, Nicholas E.; Rychalsky, Kristen L.; Hinman, James R.; Chrobak, James J.; Senatus, Patrick B.; Salamone, John D.

2011-01-01

Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor. PMID:21772815

Essential Tremor: What We Can Learn from Current Pharmacotherapy

PubMed Central

Ondo, William

2016-01-01

Background The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design. Methods We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor. Results Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta-adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration. Discussion To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials. PMID:26989572

Acute Exacerbation in Interstitial Lung Disease

PubMed Central

Leuschner, Gabriela; Behr, Jürgen

2017-01-01

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has been defined as an acute, clinically significant deterioration that develops within less than 1 month without obvious clinical cause like fluid overload, left heart failure, or pulmonary embolism. Pathophysiologically, damage of the alveoli is the predominant feature of AE-IPF which manifests histopathologically as diffuse alveolar damage and radiologically as diffuse, bilateral ground-glass opacification on high-resolution computed tomography. A growing body of literature now focuses on acute exacerbations of interstitial lung disease (AE-ILD) other than idiopathic pulmonary fibrosis. Based on a shared pathophysiology it is generally accepted that AE-ILD can affect all patients with interstitial lung disease (ILD) but apparently occurs more frequently in patients with an underlying usual interstitial pneumonia pattern. The etiology of AE-ILD is not fully understood, but there are distinct risk factors and triggers like infection, mechanical stress, and microaspiration. In general, AE-ILD has a poor prognosis and is associated with a high mortality within 6–12 months. Although there is a lack of evidence based data, in clinical practice, AE-ILD is often treated with a high dose corticosteroid therapy and antibiotics. This article aims to provide a summary of the clinical features, diagnosis, management, and prognosis of AE-ILD as well as an update on the current developments in the field. PMID:29109947

Non-ischemic diabetic cardiomyopathy may initially exhibit a transient subclinical phase of hyperdynamic myocardial performance.

PubMed

Hensel, Kai O

2016-09-01

Cardiovascular complications are the key cause for mortality in diabetes mellitus. Besides ischemia-related cardiac malfunction there is growing evidence for non-ischemic diabetes-associated heart failure in both type 1 and type 2 diabetes mellitus. The underlying pathophysiology of non-ischemic diabetic cardiomyopathy (NIDC) is poorly understood and data on myocardial mechanics in early stages of the disease are rare. However, several studies in both human and experimental animal settings have reported prima facie unexplained features indicating myocardial hyperdynamics early in the course of the disease. The new hypothesis is that - other than previously thought - NIDC may be non-linear and initially feature an asymptomatic subclinical phase of myocardial hypercontractility that precedes the long-term development of diabetes-associated cardiac dysfunction and ultimately heart failure. Diabetes-induced metabolic imbalances may lead to a paradoxic inotropic increase and inefficient myocardial mechanics that finally result in a gradual deterioration of myocardial performance. In conclusion, diabetic patients should be screened regularly and early in the course of the disease utilizing ultra-sensitive myocardial deformation imaging in order to identify patients at risk for diabetes-associated heart failure. Moreover, hyperdynamic myocardial deformation might help distinguish non-ischemic from ischemic diabetic cardiomyopathy. Further studies are needed to illuminate the underlying pathophysiological mechanisms, the exact spatiotemporal evolvement of diabetic cardiomyopathy and its long-term relation to clinical outcome parameters. Copyright © 2016 Elsevier Ltd. All rights reserved.

Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

PubMed Central

Cabrera-Mora, Monica; Garcia, AnaPatricia; Orkin, Jack; Strobert, Elizabeth; Barnwell, John W.; Galinski, Mary R.

2013-01-01

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies. PMID:23509137

Constipation: Pathophysiology and Current Therapeutic Approaches.

PubMed

Sharma, Amol; Rao, Satish

2017-01-01

Chronic constipation is a common, persistent condition affecting many patients worldwide, presenting significant economic burden and resulting in substantial healthcare utilization. In addition to infrequent bowel movements, the definition of constipation includes excessive straining, a sense of incomplete evacuation, failed or lengthy attempts to defecate, use of digital manoeuvres for evacuation of stool, abdominal bloating, and hard consistency of stools. After excluding secondary causes of constipation, chronic idiopathic or primary constipation can be classified as functional defecation disorder, slow-transit constipation (STC), and constipation-predominant irritable bowel syndrome (IBS-C). These classifications are not mutually exclusive and significant overlap exists. Initial therapeutic approach to primary constipation, regardless of aetiology, consists of diet and lifestyle changes such as encouraging adequate fluid and fibre intake, regular exercise, and dietary modification. Laxatives are the mainstay of pharmacologic treatment for potential long-term therapy in patients who do not respond to lifestyle or dietary modification. After a failed empiric trial of laxatives, diagnostic testing is necessary to understand underlying anorectal and/or colonic pathophysiology. No single test provides a comprehensive assessment for primary constipation; therefore, multiple tests are used to provide complementary information to one another. Dyssynergic defecation, a functional defecation disorder, is an acquired behavioural disorder of defecation present in two-thirds of adult patients, where an inability to coordinate the abdominal, recto-anal, and pelvic floor muscles during attempted defecation exists. Biofeedback therapy is the mainstay treatment for dyssynergic defecation aimed at improving coordination of abdominal and anorectal muscles. A large percentage of patients with dyssynergic defecation also exhibit rectal hyposensitivity and may benefit from the addition of sensory retraining. Our understanding of the pathophysiology of STC is evolving. The advent of high-resolution colonic manometry allows for the improved identification of colonic motor patterns and may provide further insight into pathophysiological mechanisms. In a minority of cases of STC, identification of colonic neuropathy suggests a medically refractory condition, warranting consideration of colectomy. The pathophysiology of IBS-C is poorly understood with multiple etiological factors implicated. Pharmacological advances in the treatment of primary constipation have added therapeutic options to the armamentarium of this disorder. Drug development in the secretagogue, serotonergic prokinetic, and ileal bile acid transporter inhibition pathways has yielded current and future medical treatment options for primary chronic constipation.

Color discrimination deficits in Parkinson's disease are related to cognitive impairment and white-matter alterations.

PubMed

Bertrand, Josie-Anne; Bedetti, Christophe; Postuma, Ronald B; Monchi, Oury; Génier Marchand, Daphné; Jubault, Thomas; Gagnon, Jean-François

2012-12-01

Color discrimination deficit is a common nonmotor manifestation of Parkinson's disease (PD). However, the pathophysiology of this dysfunction remains poorly understood. Although retinal structure changes found in PD have been suggested to cause color discrimination deficits, the impact of cognitive impairment and cortical alterations remains to be determined. We investigated the contribution of cognitive impairment to color discrimination deficits in PD and correlated them with cortical anomalies. Sixty-six PD patients without dementia and 20 healthy controls performed the Farnsworth-Munsell 100 hue test and underwent a comprehensive neuropsychological assessment for mild cognitive impairment diagnosis. In a subgroup of 26 PD patients, we also used high-definition neuroanatomical magnetic resonance imaging for cortical thickness and diffusion tensor analysis. PD patients with mild cognitive impairment performed poorly on the Farnsworth-Munsell 100 hue test compared with PD patients without mild cognitive impairment and controls. In PD patients, performance on the Farnsworth-Munsell 100 hue test was correlated with measures of visuospatial abilities and executive functions. Neuroimaging analysis revealed higher mean and radial diffusivity values in right posterior white-matter structures that correlated with poor performance on the Farnsworth-Munsell 100 hue test. No cortical thickness correlation reached significance. This study showed that cognitive impairment makes a major contribution to the color discrimination deficits reported in PD. Thus, performance on the Farnsworth-Munsell 100 hue test may reflect cognitive impairment more than color discrimination deficits in PD. Poor performance on the Farnsworth-Munsell 100 hue test was also associated with white-matter alterations in right posterior brain regions. Copyright © 2012 Movement Disorder Society.

The pathophysiology of chronic noncommunicating hydrocephalus: lessons from continuous intracranial pressure monitoring and ventricular infusion testing.

PubMed

Eide, Per Kristian

2017-08-11

OBJECTIVE The pathophysiology of chronic noncommunicating hydrocephalus (ncHC) is poorly understood. This present study explored whether lessons about the pathophysiology of this clinical entity might be retrieved from results of overnight monitoring of pulsatile and static intracranial pressure (ICP) and ventricular infusion testing. METHODS The study cohort included adult patients (> 20 years of age) with chronic ncHC due to aqueductal stenosis in whom symptoms had lasted a minimum of 6 months. A reference cohort consisted of age- and sex-matched patients managed for communicating HC (cHC). Information about symptoms and clinical improvement following surgery was retrieved from a quality register, and results of overnight ICP recordings and ventricular infusion testing were retrieved from the hospital ICP database. RESULTS The cohort with ncHC consisted of 61 patients of whom 6 (10%) were managed conservatively, 34 (56%) by endoscopic third ventriculostomy (ETV), and 21 (34%) using ETV and subsequent shunt surgery. In patients responding to surgery, pulsatile ICP (mean ICP wave amplitude) was significantly increased to a similar magnitude in patients with ncHC and the reference cohort (cHC). Furthermore, intracranial compliance (ICC) was reduced in clinical responders. The results of ventricular infusion testing provided evidence that patients responding to ETV have impaired ventricular CSF absorption, while those requiring shunt placement after ETV present with impaired CSF absorption both in the intraventricular and extraventricular compartments. CONCLUSIONS The study may provide some lessons about the pathophysiology of chronic ncHC. First, increased pulsatile ICP and impaired ICC characterize patients with chronic ncHC who respond clinically to CSF diversion surgery, even though static ICP is not increased. Second, in patients responding clinically to ETV, impaired ventricular CSF absorption may be a key factor. Patients requiring shunt placement for clinical response appear to have both intraventricular and extraventricular CSF absorption failure. A subgroup of patients with ncHC due to aqueductal stenosis has normal ventricular CSF absorption and normal ICC and may not be in need of surgical CSF diversion.

Review article: the pathophysiology, differential diagnosis and management of rumination syndrome.

PubMed

Tack, J; Blondeau, K; Boecxstaens, V; Rommel, N

2011-04-01

Rumination syndrome, characterised by the effortless, often repetitive, regurgitation of recently ingested food into the mouth, was originally described in children and in the developmentally disabled. It is now well-recognised that rumination syndrome occurs in patients of all ages and cognitive abilities. To review a scholarly review on our current understanding of the rumination syndrome. The review was conducted on the basis of a medline search to identify relevant publications pertaining to the pathophysiology, clinical diagnosis and management of rumination syndrome. The Rome III consensus established diagnostic criteria for rumination syndrome in adults, children and infants. A typical history can be highly suggestive but oesophageal (high resolution) manometry/impedance with ingestion of a meal may help to distinguish rumination syndrome from other belching/regurgitation disorders. The pathophysiology is incompletely understood, but involves a rise in intra-gastric pressure, generated by a voluntary, but often unintentional, contraction of the abdominal wall musculature, at a time of low pressure in the lower oesophageal sphincter, causing retrograde movement of gastric contents into the oesophagus. To date, controlled trials in the treatment rumination syndrome are lacking. The mainstay of treatment for rumination syndrome is explanation and behavioural treatment which consists of habit reversal techniques that compete with the urge to regurgitate. Chewing gum, prokinetics, baclofen and even antireflux surgery have been proposed as adjunctive therapies, but high quality studies are generally lacking. Rumination is an under-recognised condition with incompletely understood pathophysiology. Behavioural therapy seems effective, but controlled treatment trials are lacking. © 2011 Blackwell Publishing Ltd.

Etiology of ejaculation and pathophysiology of premature ejaculation.

PubMed

Donatucci, Craig F

2006-09-01

Ejaculation is comprised of three stages of the male sexual response cycle, namely emission, ejection, and orgasm; however, in comparison with erection, which is a well-understood component of male sexual response, the pathophysiology of ejaculation has yet to be fully delineated. Premature ejaculation (PE), the most common sexual disorder in men, while believed to have a multifactorial etiology, is even less well understood. This article reviews the physiology of ejaculation, and the multifactorial pathophysiology of PE. The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24-26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE. There were 16 invited presenters and discussants; the group focused on several educational objectives. Data were obtained by extensive examination of published peer-reviewed literature. Evidence supports that biologic mechanisms associated with neurotransmitters such as norepinephrine, serotonin, oxytocin, Gamma-amino-butyric acid, and nitric oxide (NO) as well as the hormone estrogen play central roles in ejaculation, and subsequently may mediate PE. There is also emerging evidence to show that hyperthyroidism may be a causal factor in PE. Recent data also suggest that psychogenic factors include high level of any experience by some men with PE. The pathophysiology of both lifelong and acquired PE appears to be both neurobiogenic and psychogenic. While psychogenic factors appear to be contributory to PE, pharmacologic intervention of PE can modify intravaginal ejaculatory latency time (IELT), which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones.

[Grave's ophthalmopathy: therapeutic strategy. Review of 30 patients].

PubMed

Boulétreau, P; Ordonnez, I; Orgiazzi, J; Breton, P; Freidel, M

2005-04-01

Graves' ophthalmopathy is the primary etiology for exophthalmos in adults. It is a complex orbital disease whose pathophysiology remains controversial. Since its initial description more than 150 years ago, its heterogeneous clinical manifestations and poorly understood links with thyroid pathology remain unresolved issues. Disease activity is the main determinant for the management of Graves' ophthalmopathy, but treatments are often symptomatic, aiming at decreasing orbital inflammation. We report a retrospective analysis of 30 patients diagnosed with Graves' ophthalmopathy followed in our department between 1991 and 2002. Following a phase of medical management of their disease, all patients underwent surgical orbital decompression. Medical and surgical care provided as well as results are presented with a mean follow-up of 23 months. Based on our clinical experience, new concepts in the field of Graves' ophthalmopathy are discussed. Disease activity, evaluated through various means, appears to be the primary guide for therapeutic management. Moreover, the importance of a multidisciplinary approach is highlighted, in order to improve the management of this difficult disorder.

Human photosensitivity: from pathophysiology to treatment.

PubMed

Verrotti, A; Tocco, A M; Salladini, C; Latini, G; Chiarelli, F

2005-11-01

Photosensitivity is a condition detected on the electroencephalography (EEG) as a paroxysmal reaction to Intermittent Photic Stimulation (IPS). This EEG response, elicited by IPS or by other visual stimuli of daily life, is called Photo Paroxysmal Response (PPR). PPRs are well documented in epileptic and non-epileptic subjects. Photosensitivity rarely in normal individuals evolves into epilepsy. Photosensitive epilepsy is a rare refex epilepsy characterized by seizures in photosensitive individuals. The development of modern technology has increased the exposition to potential seizure precipitants in people of all ages, but especially in children and adolescents. Actually, videogames, computers and televisions are the most common triggers in daily life of susceptible persons. The mechanisms of generation of PPR are poorly understood, but genetic factors play an important rule. The control of visually induced seizures has, generally a good prognosis. In patients known to be visually sensitive, avoidance of obvious source and stimulus modifications are very important and useful to seizure prevention, but in the large majority of patients with epilepsy and photosensitivity antiepileptic drugs are needed.

What makes you tic? Translational approaches to study the role of stress and contextual triggers in Tourette syndrome

PubMed Central

Godar, Sean C; Bortolato, Marco

2016-01-01

Tourette syndrome (TS) is a neurodevelopmental condition characterized by multiple, recurring motor and phonic tics. Rich empirical evidence shows that the severity of tics and associated manifestations is increased by several stressors and contextual triggers; however, the neurobiological mechanisms responsible for symptom exacerbation in TS remain poorly understood. This conceptual gap partially reflects the high phenotypic variability in tics, as well as the existing difficulties in operationalizing and standardizing stress and its effects in a clinical setting. Animal models of TS may be highly informative tools to overcome some of these limitations; these experimental preparations have already provided critical insights on key aspects of TS pathophysiology, and may prove useful to identify the neurochemical alterations induced by different stressful contingencies. In particular, emerging knowledge on the role of contextual triggers in animal models of TS may inform the development of novel pharmacological interventions to reduce tic fluctuations in this disorder. PMID:27939782

MSK1 downregulation is associated with neuronal and astrocytic apoptosis following subarachnoid hemorrhage in rats.

PubMed

Ning, Bo; Guo, Geng; Liu, Hong; Ning, Lei; Sun, Bao-Liang; Li, Zhen; Wang, Shuo; Lv, Zheng-Wen; Fan, Cun-Dong

2017-09-01

MSK (mitogen- and stress-activated protein kinase) proteins are a family of mitogen-activated protein kinases. MSKs represent a novel type of pro-survival genes, potentially enhancing the phosphorylation of Bcl2-associated agonist of cell death. However, MSK's function and expression are poorly understood in the central nervous system. In the present study, a subarachnoid hemorrhage (SAH) model was established in SD rats and the expression of MSK1 in the brain subsequent to experimental SAH was investigated. In response to SAH, MSK1 mRNA and protein levels gradually declined, reaching the lowest point at 3 days, and increased thereafter. The expression of active caspase-3 was negatively correlated with MSK1 level. Colocalization and correlating changes in expression of MSK1 and active caspase-3 at neurons and astrocytes indicated that MSK1 downregulation may contribute to SAH-induced apoptosis, validating that MSK1 may be involved in the pathophysiology of the brain cortex subsequent to SAH.

Spinal cord infarction as a rare complication of fat embolism syndrome following bilateral intramedullary nailing of femur fractures.

PubMed

Kearsley, RoseMarie; Galbraith, John; Dalton, David; Motherway, Catherine

2016-09-13

Fat embolism syndrome (FES) is a rare and potentially fatal complication occurring most often after long bone or pelvic fractures and orthopaedic procedures. It can consist of pulmonary, central nervous system and cutaneous manifestations. The exact pathophysiology of emboli reaching the arterial circulation is poorly understood.1 It is suggested that this may occur by either 'paradoxical' embolism or microembolism.2 3 Its true incidence is unknown but increases in the presence of multiple closed fractures. It can be a diagnostic dilemma for clinicians and if suspected diffusion-weighted MRI is the modality of choice for the investigation of the central nervous system.4 We present the case of a 22-year-old man who developed multifocal cerebral infarcts, a right-sided cerebellar infarct and an infarct in the anterior cord bilaterally at the level of C5-C6 as a result of FES. 2016 BMJ Publishing Group Ltd.

A Pilot Prospective Study of Fetomaternal Hemorrhage Identified by Anemia in Asymptomatic Neonates

PubMed Central

Stroustrup, Annemarie; Plafkin, Callie

2016-01-01

Background Fetomaternal hemorrhage (FMH) is a poorly understood condition in which fetal erythrocytes transfer to the maternal circulation via a faulty placental barrier. Little is known about the true incidence, epidemiology, or pathophysiology of FMH in the general pregnant population as existing studies are based on retrospective cohorts and manifest diagnosis and selection bias. Objective To evaluate the practicability of a prospective study of fetomaternal hemorrhage in the general population based on antepartum maternal blood testing and neonatal anemia. Study Design Prospective cohort study. Result Nineteen pregnant women were enrolled prior to the term delivery of twenty well infants. Five neonates were unexpectedly anemic on first postnatal testing. Antenatal maternal blood samples associated with 2 of 5 anemic newborns had positive Kleihauer-Betke testing while no newborn with a normal postnatal blood count had an associated abnormal Kleihauer-Betke test. Conclusion Clinically significant FMH may be more common than previously thought. Prospective epidemiological study of FMH is feasible. PMID:26765555

A pilot prospective study of fetomaternal hemorrhage identified by anemia in asymptomatic neonates.

PubMed

Stroustrup, A; Plafkin, C

2016-05-01

Fetomaternal hemorrhage (FMH) is a poorly understood condition in which fetal erythrocytes transfer to the maternal circulation via a faulty placental barrier. Little is known about the true incidence, epidemiology or pathophysiology of FMH in the general pregnant population as existing studies are based on retrospective cohorts and manifest diagnosis and selection bias. The objective of this study was to evaluate the practicability of a prospective study of FMH in the general population based on antepartum maternal blood testing and neonatal anemia. Prospective cohort study. Nineteen pregnant women were enrolled prior to the term delivery of 20 well infants. Five neonates were unexpectedly anemic on first postnatal testing. Antenatal maternal blood samples associated with two of the five anemic newborns had positive Kleihauer-Betke testing while no newborn with a normal postnatal blood count had an associated abnormal Kleihauer-Betke test. Clinically significant FMH may be more common than previously thought. Prospective epidemiological study of FMH is feasible.

MODELS OF INSULIN RESISTANCE AND HEART FAILURE

PubMed Central

Velez, Mauricio; Kohli, Smita; Sabbah, Hani N.

2013-01-01

The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID:23456447

Alternatives to animal testing in basic and preclinical research of atopic dermatitis.

PubMed

Löwa, Anna; Jevtić, Marijana; Gorreja, Frida; Hedtrich, Sarah

2018-05-01

Atopic dermatitis (AD) is a chronic inflammatory skin disease of increasing prevalence, especially in industrialized countries. Roughly 25% of the children and 1%-3% of adults are affected. Although significant progress has been made in the understanding of the pathogenesis of AD, many aspects remain poorly understood. Moreover, there is a pressing need for improved therapeutic options. Studies to elucidate the pathophysiological pathways of AD and to identify novel therapeutic targets over the last few decades have been conducted almost exclusively in animal models. However, in vitro approaches such as 3D skin disease models have recently emerged due to an increasing awareness of distinct interspecies-related differences that hamper the effective translation of results from animal models to humans. In addition, there is growing political and social pressure to develop alternatives to animal models according to the 3Rs principle (reduction, refinement and replacement of animal models). © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pregnancy and Infants' Outcome: Nutritional and Metabolic Implications.

PubMed

Berti, C; Cetin, I; Agostoni, C; Desoye, G; Devlieger, R; Emmett, P M; Ensenauer, R; Hauner, H; Herrera, E; Hoesli, I; Krauss-Etschmann, S; Olsen, S F; Schaefer-Graf, U; Schiessl, B; Symonds, M E; Koletzko, B

2016-01-01

Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.

Acid–base dysregulation and chemosensory mechanisms in panic disorder: a translational update

PubMed Central

Vollmer, L L; Strawn, J R; Sah, R

2015-01-01

Panic disorder (PD), a complex anxiety disorder characterized by recurrent panic attacks, represents a poorly understood psychiatric condition which is associated with significant morbidity and an increased risk of suicide attempts and completed suicide. Recently however, neuroimaging and panic provocation challenge studies have provided insights into the pathoetiology of panic phenomena and have begun to elucidate potential neural mechanisms that may underlie panic attacks. In this regard, accumulating evidence suggests that acidosis may be a contributing factor in induction of panic. Challenge studies in patients with PD reveal that panic attacks may be reliably provoked by agents that lead to acid–base dysbalance such as CO2 inhalation and sodium lactate infusion. Chemosensory mechanisms that translate pH into panic-relevant fear, autonomic, and respiratory responses are therefore of high relevance to the understanding of panic pathophysiology. Herein, we provide a current update on clinical and preclinical studies supporting how acid–base imbalance and diverse chemosensory mechanisms may be associated with PD and discuss future implications of these findings. PMID:26080089

Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration

PubMed Central

Lin, Benjamin; Yin, Taofei; Wu, Yi I.; Inoue, Takanari; Levchenko, Andre

2015-01-01

Directed cell migration in native environments is influenced by multiple migratory cues. These cues may include simultaneously occurring attractive soluble growth factor gradients and repulsive effects arising from cell-cell contact, termed contact inhibition of locomotion (CIL). How single cells reconcile potentially conflicting cues remains poorly understood. Here we show that a dynamic crosstalk between epidermal growth factor (EGF) mediated chemotaxis and CIL guide metastatic breast cancer cell motility, whereby cells become progressively insensitive to CIL in a chemotactic input-dependent manner. This balance is determined via integration of protrusion-enhancing signaling from EGF gradients and protrusion-suppressing signaling induced by CIL, mediated in part through EphB. Our results further suggest that EphB and EGF signaling inputs control protrusion formation by converging onto regulation of phosphatidylinositol 3-kinase (PI3K). We propose that this intricate interplay may enhance the spread of loose cell ensembles in pathophysiological conditions such as cancer, and possibly other physiological settings. PMID:25851023

The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer

PubMed Central

Zabron, Abigail; Edwards, Robert J.; Khan, Shahid A.

2013-01-01

Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field. PMID:23520144

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

PubMed Central

Lee, Y Y; Moujalled, D; Doerflinger, M; Gangoda, L; Weston, R; Rahimi, A; de Alboran, I; Herold, M; Bouillet, P; Xu, Q; Gao, X; Du, X-J; Puthalakath, H

2013-01-01

Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. PMID:23579242

Cardiac Cachexia: Perspectives for Prevention and Treatment.

PubMed

Okoshi, Marina Politi; Capalbo, Rafael Verardino; Romeiro, Fernando G; Okoshi, Katashi

2017-01-01

Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides.

PubMed

Medina-Cleghorn, Daniel; Heslin, Ann; Morris, Patrick J; Mulvihill, Melinda M; Nomura, Daniel K

2014-02-21

We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Here, we have used functional chemoproteomic and metabolomic platforms to broadly identify direct enzyme targets that are inhibited by widely used organophosphorus (OP) pesticides in vivo in mice and to determine metabolic alterations that are caused by these chemicals. We find that these pesticides directly inhibit over 20 serine hydrolases in vivo leading to widespread disruptions in lipid metabolism. Through identifying direct biological targets of OP pesticides, we show heretofore unrecognized modes of toxicity that may be associated with these agents and underscore the utility of using multidimensional profiling approaches to obtain a more complete understanding of toxicities associated with environmental chemicals.

Serotonin modulates a depression-like state in Drosophila responsive to lithium treatment

PubMed Central

Ries, Ariane-Saskia; Hermanns, Tim; Poeck, Burkhard; Strauss, Roland

2017-01-01

Major depressive disorder (MDD) affects millions of patients; however, the pathophysiology is poorly understood. Rodent models have been developed using chronic mild stress or unavoidable punishment (learned helplessness) to induce features of depression, like general inactivity and anhedonia. Here we report a three-day vibration-stress protocol for Drosophila that reduces voluntary behavioural activity. As in many MDD patients, lithium-chloride treatment can suppress this depression-like state in flies. The behavioural changes correlate with reduced serotonin (5-HT) release at the mushroom body (MB) and can be relieved by feeding the antidepressant 5-hydroxy-L-tryptophan or sucrose, which results in elevated 5-HT levels in the brain. This relief is mediated by 5-HT-1A receptors in the α-/β-lobes of the MB, whereas 5-HT-1B receptors in the γ-lobes control behavioural inactivity. The central role of serotonin in modulating stress responses in flies and mammals indicates evolutionary conserved pathways that can provide targets for treatment and strategies to induce resilience. PMID:28585544

The prevalence and clinical characteristics of punding in Parkinson's disease.

PubMed

Spencer, Ashley H; Rickards, Hugh; Fasano, Alfonso; Cavanna, Andrea E

2011-03-01

Punding (the display of stereotyped, repetitive behaviors) is a relatively recently discovered feature of Parkinson's disease (PD). Little is known about the prevalence and clinical characteristics of punding in PD. In this review, four large scientific databases were comprehensively searched for literature in relation to punding prevalence and clinical correlates in the context of PD. Prevalence was found to vary greatly (between 0.34 to 14%), although there were large disparities in study populations, assessment methods, and criteria. We observed an association between punding, dopaminergic medications, and impulse control disorder. Other characteristics, which may be more common among punders, include a higher severity of dyskinesia, younger age of disease onset, longer disease duration, and male gender. More research in large clinical datasets is required in many areas before conclusions are drawn. The pathophysiology behind the punding phenomenon is also poorly understood at present, rendering it difficult to develop targeted therapy. The current mainstay of treatment is the reduction in the dose of dopaminergic medications, the evidence for other suggested therapies being purely empirical.

Deletion of aquaporin-4 is neuroprotective during the acute stage of micro traumatic brain injury in mice.

PubMed

Liang, Fengyin; Luo, Chuanming; Xu, Guangqing; Su, Fengjuan; He, Xiaofei; Long, Simei; Ren, Huixia; Liu, Yaning; Feng, Yanqing; Pei, Zhong

2015-06-26

Micro traumatic brain injury (TBI) is the most common type of brain injury, but the mechanisms underlying it are poorly understood. Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet, which plays an important role in brain edema. However, little is known about the role of AQP4 in micro TBI. Here, we examined the role of AQP4 in the pathogenesis of micro TBI in a closed-skull brain injury model, using two-photon microscopy. Our results indicate that AQP4 deletion reduced cell death, water content, astrocyte swelling and lesion volume during the acute stage of micro TBI. Our data revealed that astrocyte swelling is a decisive pathophysiological factor in the acute phase of this form of micro brain injury. Thus, treatments that inhibit AQP4 could be used as a neuroprotective strategy for micro TBI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A review of the clinical implications of bisphosphonates in dentistry.

PubMed

Borromeo, G L; Tsao, C E; Darby, I B; Ebeling, P R

2011-03-01

Bisphosphonates are drugs that suppress bone turnover and are commonly prescribed to prevent skeletal related events in malignancy and for benign bone diseases such as osteoporosis. Bisphosphonate associated jaw osteonecrosis (ONJ) is a potentially debilitating, yet poorly understood condition. A literature review was undertaken to review the dental clinical implications of bisphosphonates. The present paper briefly describes the postulated pathophysiology of ONJ and conditions with similar clinical presentations. The implications of bisphosphonates for implantology, periodontology, orthodontics and endodontics are reviewed. Whilst bisphosphonates have potential positive applications in some clinical settings, periodontology particularly, further clinical research is limited by the risk of ONJ. Prevention and management are reviewed, including guidelines for reducing cumulative intravenous bisphosphonate dose, cessation of bisphosphonates prior to invasive dental treatment or after ONJ development, and the use of serum beta-CTX-1 in assessing risk. In the context of substantial uncertainty, the implications of bisphosphonate use in the dental clinical setting are still being determined. © 2010 Australian Dental Association.

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

PubMed

Schaller, Fabienne; Watrin, Françoise; Sturny, Rachel; Massacrier, Annick; Szepetowski, Pierre; Muscatelli, Françoise

2010-12-15

The onset of feeding at birth is a vital step for the adaptation of the neonate to extra uterine life. Prader-Willi syndrome (PWS) is a complex neurogenetic disorder caused by the alteration of several imprinted contiguous genes including MAGEL2. PWS presents with various clinical manifestations, including poor suckling behaviour and feeding problems in neonates. Hypothalamic defects have been proposed, but the pathophysiological mechanisms remain poorly understood. Here, we report that a Magel2-deficient mouse with 50% neonatal mortality had an altered onset of suckling activity and subsequent impaired feeding, suggesting a role of MAGEL2 in the suckling deficit seen in PW newborns. The hypothalamus of Magel2 mutant neonates showed a significant reduction in oxytocin (OT). Furthermore, injection of a specific OT receptor antagonist in wild-type neonates recapitulated the feeding deficiency seen in Magel2 mutants, and a single injection of OT, 3-5 h after birth, rescued the phenotype of Magel2 mutant pups, allowing all of them to survive. Our study illustrates the crucial role of feeding onset behaviour after birth. We propose that OT supply might constitute a promising avenue for the treatment of feeding difficulties in PW neonates and potentially of other newborns with impaired feeding onset.

The Role of Interleukin-10 in the Pathophysiology of Preeclampsia.

PubMed

Cubro, Hajrunisa; Kashyap, Sonu; Nath, Meryl C; Ackerman, Allan W; Garovic, Vesna D

2018-04-30

The pathophysiology of preeclampsia is complex and not entirely understood. A key feature in preeclampsia development is an immunological imbalance that shifts the maternal immune response from one of tolerance towards one promoting chronic inflammation and endothelial dysfunction. As a key regulator of immunity, IL-10 not only has immunomodulatory activity, but also directly benefits vasculature and promotes successful cellular interactions at the maternal-fetal interface. Here we focus on the mechanisms by which the dysregulation of IL-10 may contribute to the pathophysiology of preeclampsia. Dysregulation of IL-10 has been demonstrated in various animal models of preeclampsia. Decreased IL-10 production in both placenta and peripheral blood mononuclear cells has been reported in human studies, but with inconsistent results. The significance of IL-10 in preeclampsia has shifted from a key biomarker to one with therapeutic potential. As such, a better understanding of the role of this cytokine in the pathophysiology of preeclampsia is of paramount importance.

In vivo and in vitro characteristic of HIF-1α and relative genes in ischemic femoral head necrosis

PubMed Central

Zhang, Wanglin; Yuan, Zhe; Pei, Xinhong; Ma, Ruixue

2015-01-01

Background: Legg-Calvé-Perthes Disease (Perthes’ disease) is a childhood hip disorder initiated by ischemic necrosis of the growing femoral head. So far, the etiology and pathogenesis of Perthes’ disease is poorly understood. Materials and methods: Avascular osteonecrosis rat model was established to mimic the pathophysiological changes of femoral head necrosis. The chondrocytes of newborn Sprague-Dawley rats were isolated and cultured in hypoxic and normoxic condition. The expression characteristic of the hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated both in vivo and in vitro models. Vascular endothelial growth factor (VEGF) and apoptotic genes in chondrocytes treated with normoxia and hypoxia were also studied. Results: HIF-1α expression increased greatly after ischemic operation and kept at relative high level in the arthromeningitis stage and declined in the stages of osteonecrosis and reconstruction. The HIF-1α mRNA levels of chondrocytes incubated at hypoxia were significantly higher than the cells treated with normoxia at 24 and 72 hours. Hypoxia inhibited VEGF expression; chondrocytes could oppose this inhibition manifested by the increasing of VEGF mRNA level after 72 hours hypoxia. The expression of apoptotic genes, Casp3, Casp8 and Casp9, elevated in chondrocytes after hypoxia with time differences. Conclusion: Hypoxia might be an etiological factor for femoral head necrosis, HIF-1α, VEGF as well as apoptotic genes participated the pathophysiological process of ischemic osteonecrosis. PMID:26261616

Immunohistochemical characterization of human olfactory tissue

PubMed Central

Holbrook, Eric H.; Wu, Enming; Curry, William T.; Lin, Derrick T.; Schwob, James E.

2011-01-01

Objectives/Hypothesis The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction. Study Design An immunohistochemical analysis of human olfactory tissue using a comprehensive battery of proven antibodies. Methods Human olfactory mucosa obtained from 21 autopsy specimens was analyzed with immunohistochemistry. The position and extent of olfactory mucosa was assayed by staining whole mounts with neuronal markers. Sections of the OE were analyzed with an extensive group of antibodies directed against cytoskeletal proteins and transcription factors, as were surgical specimens from an esthesioneuroblastoma. Results Neuron-rich epithelium is always found inferior to the cribriform plate, even at advanced age, despite the interruptions in the neuroepithelial sheet caused by patchy respiratory metaplasia. The pattern of immunostaining with our antibody panel identifies two distinct types of basal cell progenitors in human OE similar to rodents. The panel also clarifies the complex composition of the esthesioneuroblastoma. Conclusion The extent of human olfactory mucosa at autopsy can easily be delineated as a function of age and neurological disease. The similarities in human vs. rodent OE will enable us to translate knowledge from experimental animals to humans and will extend our understanding of human olfactory pathophysiology. PMID:21792956

A Review on the Role of Inflammation in Attention-Deficit/Hyperactivity Disorder.

PubMed

Leffa, Douglas Teixeira; Torres, Iraci L S; Rohde, Luis Augusto

2018-06-06

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition that impairs quality of life in social, academic, and occupational contexts for both children and adults. Although a strong neurobiological basis has been demonstrated, the pathophysiology of ADHD is still poorly understood. Among the proposed mechanisms are glial activation, neuronal damage and degeneration, increased oxidative stress, reduced neurotrophic support, altered neurotransmitter metabolism, and blood-brain barrier disruption. In this way, a potential role of inflammation has been increasingly researched. However, evidence for the involvement of inflammation in ADHD is still scarce and comes mainly from (1) observational studies showing a strong comorbidity of ADHD with inflammatory and autoimmune disorders; (2) studies evaluating serum inflammatory markers; and (3) genetic studies. A co-occurrence of ADHD with inflammatory disorders has been demonstrated in a large number of subjects, suggesting a range of underlying mechanisms such as an altered immune response, common genetics, and environmental links. The evaluation of serum inflammatory markers has provided mixed results, likely due to the small sample sizes and high heterogeneity between biomarkers. However, there is evidence that increased inflammation during the early development may be a risk factor for ADHD symptoms. Although genetic studies have demonstrated a potential role for inflammation in this disorder, there is no clear evidence. To sum up, inflammation may be an important mechanism in ADHD pathophysiology, but more studies are still needed for a more precise conclusion. © 2018 S. Karger AG, Basel.

Knowledge gaps and research recommendations for essential tremor.

PubMed

Hopfner, Franziska; Haubenberger, Dietrich; Galpern, Wendy R; Gwinn, Katrina; Van't Veer, Ashlee; White, Samantha; Bhatia, Kailash; Adler, Charles H; Eidelberg, David; Ondo, William; Stebbins, Glenn T; Tanner, Caroline M; Helmich, Rick C; Lenz, Fred A; Sillitoe, Roy V; Vaillancourt, David; Vitek, Jerrold L; Louis, Elan D; Shill, Holly A; Frosch, Matthew P; Foroud, Tatiana; Kuhlenbäumer, Gregor; Singleton, Andrew; Testa, Claudia M; Hallett, Mark; Elble, Rodger; Deuschl, Günther

2016-12-01

Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Rho-kinase inhibition on complexity of breathing pattern in a guinea pig model of asthma

PubMed Central

Pazhoohan, Saeed; Javan, Mohammad; Hajizadeh, Sohrab

2017-01-01

Asthma represents an episodic and fluctuating behavior characterized with decreased complexity of respiratory dynamics. Several evidence indicate that asthma severity or control is associated with alteration in variability of lung function. The pathophysiological basis of alteration in complexity of breathing pattern in asthma has remained poorly understood. Regarding the point that Rho-kinase is involved in pathophysiology of asthma, in present study we investigated the effect of Rho-kinase inhibition on complexity of respiratory dynamics in a guinea pig model of asthma. Male Dunkin Hartley guinea pigs were exposed to 12 series of inhalations with ovalbumin or saline. Animals were treated by the Rho-kinase inhibitor Y-27632 (1mM aerosols) prior to each allergen challenge. We recorded respiration of conscious animals using whole-body plethysmography. Exposure to ovalbumin induced lung inflammation, airway hyperresponsiveness and remodeling including goblet cell hyperplasia, increase in the thickness of airways smooth muscles and subepithelial collagen deposition. Complexity analysis of respiratory dynamics revealed a dramatic decrease in irregularity of respiratory rhythm representing less complexity in asthmatic guinea pigs. Inhibition of Rho-kinase reduced the airway remodeling and hyperreponsiveness, but had no significant effect on lung inflammation and complexity of respiratory dynamics in asthmatic animals. It seems that airway hyperresponsiveness and remodeling do not significantly affect the complexity of respiratory dynamics. Our results suggest that inflammation might be the probable cause of shift in the respiratory dynamics away from the normal fluctuation in asthma. PMID:29088265

Disruptions of Host Immunity and Inflammation by Giardia Duodenalis: Potential Consequences for Co-Infections in the Gastro-Intestinal Tract

PubMed Central

Cotton, James A.; Amat, Christina B.; Buret, Andre G.

2015-01-01

Giardia duodenalis (syn. G. intestinalis, or G. lamblia) is a leading cause of waterborne diarrheal disease that infects hundreds of millions of people annually. Research on Giardia has greatly expanded within the last few years, and our understanding of the pathophysiology and immunology on this parasite is ever increasing. At peak infection, Giardia trophozoites induce pathophysiological responses that culminate in the development of diarrheal disease. However, human data has suggested that the intestinal mucosa of Giardia-infected individuals is devoid of signs of overt intestinal inflammation, an observation that is reproduced in animal models. Thus, our understanding of host inflammatory responses to the parasite remain incompletely understood and human studies and experimental data have produced conflicting results. It is now also apparent that certain Giardia infections contain mechanisms capable of modulating their host’s immune responses. As the oral route of Giardia infection is shared with many other gastrointestinal (GI) pathogens, co-infections may often occur, especially in places with poor sanitation and/or improper treatment of drinking water. Moreover, Giardia infections may modulate host immune responses and have been found to protect against the development of diarrheal disease in developing countries. The following review summarizes our current understanding of the immunomodulatory mechanisms of Giardia infections and their consequences for the host, and highlights areas for future research. Potential implications of these immunomodulatory effects during GI co-infection are also discussed. PMID:26569316

Minireview: Genetic basis of heterogeneity and severity in sickle cell disease

PubMed Central

Habara, Alawi

2016-01-01

Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co-inheritance of α thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling. PMID:26936084

Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy.

PubMed

Mansilha, Armando; Sousa, Joel

2018-06-05

Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies.

Urinary pH as a Risk Factor for Stone Type

NASA Astrophysics Data System (ADS)

Sakhaee, Khashayar

2007-04-01

A high urinary pH is main risk factor for the calcium phosphate stone formation; however, its pathophysiologic mechanism has not been fully understood. The introduction of Topiramate in the treatment of various neurological disorders has been complicated by metabolic acidosis, significant hypocitraturia, elevated urinary pH, and calcium phosphate stone formation. This model provides a probe to investigate the pathophysiologic mechanism of calcium phosphate stone formation and perhaps to develop appropriate countermeasures in the future. On the other hand an unduly acidic urine predisposes one to uric acid nephrolithiasis. Our recent investigation linking low urinary pH, and defective renal ammoniagenesis to insulin resistance provides new knowledge to unfold the pathophysiology of uric acid nephrolithiasis. The metabolic profile leading to uric acid stone may emerge as one of the components of metabolic syndrome.

DAILY VARIATION OF PARTICULATE AIR POLLUTION AND POOR CARDIAC AUTONOMIC CONTROL IN THE ELDERLY

EPA Science Inventory

Particulate matter air pollution (PM) has been related to cardiovascular disease mortality in a number of recent studies. The pathophysiologic mechanisms for this association are under study. Low heart rate variability, a marker of poor cardiac autonomic control, is associated wi...

Effect of chronic continual- and intermittent hypoxia-induced systemic inflammation on the cardiovascular system in rats.

PubMed

Xu, Xiao-Mei; Yao, Dan; Cai, Xue-Ding; Ding, Cheng; Lin, Qian-Ding; Wang, Liang-Xing; Huang, Xiao-Ying

2015-05-01

Obstructive sleep apnea syndrome (OSAS) has been recognized as an important risk factor for cardiovascular morbidity and mortality. However, the underlying mechanisms are poorly understood. Present study aimed to investigate the role of NF-κB-dependent inflammation pathways in pathophysiological responses of cardiovascular system in OSAS. Thirty male specific pathogen-free (SPF) Sprague-Dawley rats were randomly assigned to normoxia (N) group, continual hypoxia (CH) group, and intermittent hypoxia (IH) group (n = 10) and were exposed to N (21% O2), CH (8% O2), or IH (6-11% O2 for 10 s and 21% O2 for 80 s in every 90 s) for 8 h/day for 35 days. The hemodynamic and pathomorphologic effects of IH and CH exposure were investigated as well as the expression of NF-κB-dependent inflammation factors. Chronic IH or CH significantly increased mean pulmonary arterial pressure (mPAP) in rats, while no significant changes occurred in mean carotid arterial pressure (mCAP). The ratio of right ventricle (RV) to left ventricle (LV) + septum (S) was significantly increased by both IH and CH, suggesting RV hypertrophy was induced by IH or CH. Elastic fiber staining showed an irregular pattern of elastic fiber distribution after hypoxia, and aortic tunica media thickness was increased. Both chronic IH and CH upregulated the expressions of transcription factor NF-κB and related pro-inflammatory cytokines and adhesion molecules. The current study expands our understanding that both IH and CH could activate the expression of NF-κB and related inflammatory factors as well as cause pathophysiologic damage to the cardiovascular system in OSAS. All these results provide further support to an emerging hypothesis that activation of NF-κB-dependent inflammation may play a central role in the pathophysiology of cardiovascular dysfunction in OSAS.

Cerebellar involvement in essential tremor with and without resting tremor: A Diffusion Tensor Imaging study.

PubMed

Novellino, Fabiana; Nicoletti, Giuseppe; Cherubini, Andrea; Caligiuri, Maria Eugenia; Nisticò, Rita; Salsone, Maria; Morelli, Maurizio; Arabia, Gennarina; Cavalli, Salvatore Maria; Vaccaro, Maria Grazia; Chiriaco, Carmelina; Quattrone, Aldo

2016-06-01

Essential Tremor with resting tremor (rET) is a debated and poorly understood clinical phenotype. Converging evidences show that neurodegeneration of the cerebellum underlies the pathophysiology of ET, but it is not known if cerebellar changes also occurs in patients with rET. The aim of our study was to evaluate cerebellar microstructure in patients with ET with- (rET) and without resting tremor (ETwr) in comparison to healthy controls by MR Diffusion Tensor Imaging (DTI). We studied 67 patients with ET (rET: 29 and ETwr: 38) and 39 age-matched healthy controls (HC). DTI was performed to measure fractional anisotropy (FA) and mean diffusivity (MD) of white and grey matter (WM, GM) in the entire cerebellum and in right and left cerebellar hemispheres. MD was significantly higher in the cerebellar GM of ET total group (10.39 ± 0.87) in comparison with HC (9.90 ± 0.71) (p = 0.0027). Interestingly, MD was significantly different when ETwr (10.48 ± 0.77) were compared with HC (p = 0.0017), whereas a trend toward significance were found between rET (10.29 ± 0.99) and HC (p = 0.067). No differences among groups were found in MD of cerebellar WM and in FA values neither in the WM nor in the GM. Our results demonstrate the presence of microstructural changes in the cerebellum of patients with ET. It is noteworthy that rET showed intermediate values compared to HC and ETwr, suggesting that rET shares part of the pathophysiological mechanisms of ETwr, but cerebellar involvement seems do not fully account for rET. In addition to the cerebellar loops, other networks may play a role in rET pathophysiology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of heat stress on carbohydrate and lipid metabolism in growing pigs

USDA-ARS?s Scientific Manuscript database

Heat stress (HS) jeopardizes human and animal health and reduces animal agriculture productivity; however, its pathophysiology is not well understood. Study objectives were to evaluate the effects of HS on basal and stimulated energetic metabolism. Crossbred female pigs (57±5 kg body weight) were ...

Understanding the cellular basis and pathophysiology of Peyronie’s disease to optimize treatment for erectile dysfunction

PubMed Central

Alzubaidi, Raidh

2017-01-01

Erectile dysfunction (ED) is a common condition that significantly impacts a man’s physical and psychological well-being. ED is often associated with Peyronie’s disease (PD), which is an abnormal curvature of the penis. Delayed treatment of or surgical invention for PD often results in ED and therefore unsatisfied patients. The pathophysiology of PD is incompletely understood, but has been studied extensively and based on our current understanding of PD physiology, many medical treatment options have been proposed. In this paper, we will review what is known about the pathophysiology of PD and the medical treatment options that have been trialed as a result. More investigations in regards to the basic science of PD need to be carried out in order to elucidate the exact mechanisms of the fibrosis, and propose new, more successful treatment options which should be implemented prior to the onset of ED. PMID:28217450

Improved understanding of the pathophysiology of atrial fibrillation through the lens of discrete pathological pathways

PubMed Central

Balouch, Muhammad A.; Kolek, Matthew J.; Darbar, Dawood

2014-01-01

Atrial fibrillation (AF) is a common disorder with a complex and incompletely understood pathophysiology. Genetic approaches to understanding the pathophysiology of AF have led to the identification of several biological pathways important in the pathogenesis of the arrhythmia. These include pathways important for cardiac development, generation and propagation of atrial electrical impulses, and atrial remodeling and fibrosis. While common and rare genetic variants in these pathways are associated with increased susceptibility to AF, they differ substantially among patients with lone versus typical AF. Furthermore, how these pathways converge to a final common clinical phenotype of AF is unclear and might also vary among different patient populations. Here, we review the contemporary knowledge of AF pathogenesis and discuss how derangement in cardiac development, ion channel dysfunction, and promotion of atrial fibrosis may contribute to this common and important clinical disorder. PMID:25054116

Serum Tryptophan Metabolite Levels During Sleep in Patients With and Without Irritable Bowel Syndrome (IBS).

PubMed

Heitkemper, Margaret M; Han, Claire Jungyoun; Jarrett, Monica E; Gu, Haiwei; Djukovic, Danijel; Shulman, Robert J; Raftery, Daniel; Henderson, Wendy A; Cain, Kevin C

2016-03-01

Poor sleep and stress are more frequently reported by women with irritable bowel syndrome (IBS) than by healthy control (HC) women. The pathophysiology linking poor sleep and stress to gastrointestinal symptoms remains poorly understood. We used a metabolomic approach to determine whether tryptophan (TRP) metabolites differ between women with and without IBS and whether the levels are associated with sleep indices and serum cortisol levels. This study sample included 38 women with IBS and 21 HCs. The women were studied in a sleep laboratory for three consecutive nights. On the third night of the study, a social stressor was introduced, then blood samples were drawn every 20 min and sleep indices were measured. Metabolites were determined by targeted liquid chromatography tandem mass spectrometry in a sample collected 1 hr after the onset of sleep. The ratios of each metabolite to TRP were used for analyses. Correlations were controlled for age and oral contraceptive use. Melatonin/TRP levels were lower (p = .005) in the IBS-diarrhea group versus the IBS-constipation and HC groups, and kynurenine/TRP ratios tended to be lower (p = .067) in the total IBS and IBS-diarrhea groups compared to HCs. Associations within the HC group included melatonin/TRP with polysomnography-sleep efficiency (r = .61, p = .006) and weaker positive correlations with the other ratios for either sleep efficiency or percentage time in rapid eye movement sleep (r > .40, p = .025-.091). This study suggests that reductions in early nighttime melatonin/TRP levels may be related to altered sleep quality in IBS, particularly those with diarrhea. © The Author(s) 2015.

Prevalence, Outcomes, and Management of Enteral Tube Feeding Intolerance: A Retrospective Cohort Study in a Tertiary Center.

PubMed

Wang, Kailun; McIlroy, Kerry; Plank, Lindsay D; Petrov, Max S; Windsor, John A

2017-08-01

Enteral tube feeding (ETF) is the most common form of artificial feeding in hospitalized patients, and the development of intolerance (ETFI) is the most common complication. This study aimed to determine the prevalence of ETFI, the clinical consequences, and the current management approach to ETFI in hospitalized adult patients. Adult patients receiving ETF were identified from a prospective database in the Nutrition Services at Auckland City Hospital. Further information was obtained by the review of clinical records for a 12-month period, up to December 2014. The prevalence of ETFI was 33% among 754 patients. ETFI more frequently occurred in the intensive care unit ( P < .05). Patients with ETFI were less likely to reach their feeding goal rate ( P < .01). Multivariate analysis showed that younger age, certain specialties, and acute mesenteric ischemia were independent predictors of ETFI ( P < .05). The management of ETFI was highly variable. Medication was the most common treatment, while changes in the feeding protocol such as reducing infusion rate and stopping and changing the route of ETF were also frequently attempted. ETFI is a frequent problem in adult hospitalized patients receiving ETF, and it is associated with poor clinical outcomes such as inadequate nutrition and complications of feeding. While the pathophysiology is poorly understood, there also appears to be no standard evidence-based treatment. Studies investigating the mechanisms and optimized management are therefore indicated.

Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment.

PubMed

Coss, K P; Doran, P P; Owoeye, C; Codd, M B; Hamid, N; Mayne, P D; Crushell, E; Knerr, I; Monavari, A A; Treacy, E P

2013-01-01

Newborn screening for the inborn error of metabolism, classical galactosaemia prevents life-threatening complications in the neonatal period. It does not however influence the development of long-term complications and the complex pathophysiology of this rare disease remains poorly understood. The objective of this study was to report the development of a healthcare database (using Distiller Version 2.1) to review the epidemiology of classical galactosaemia in Ireland since initiation of newborn screening in 1972 and the long-term clinical outcomes of all patients attending the National Centre for Inherited Metabolic Disorders (NCIMD). Since 1982, the average live birth incidence rate of classical galactosaemia in the total Irish population was approximately 1:16,476 births. This reflects a high incidence in the Irish 'Traveller' population, with an estimated birth incidence of 1:33,917 in the non-Traveller Irish population. Despite early initiation of treatment (dietary galactose restriction), the long-term outcomes of classical galactosaemia in the Irish patient population are poor; 30.6 % of patients ≥ 6 yrs have IQs <70, 49.6 % of patients ≥ 2.5 yrs have speech or language impairments and 91.2 % of females ≥ 13 yrs suffer from hypergonadotrophic hypogonadism (HH) possibly leading to decreased fertility. These findings are consistent with the international experience. This emphasizes the requirement for continued clinical research in this complex disorder.

Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study

PubMed Central

Rose, Shannon; Bennuri, Sirish C.; Murray, Katherine F.; Buie, Timothy; Winter, Harland

2017-01-01

Gastrointestinal (GI) symptoms are prevalent in autism spectrum disorder (ASD) but the pathophysiology is poorly understood. Imbalances in the enteric microbiome have been associated with ASD and can cause GI dysfunction potentially through disruption of mitochondrial function as microbiome metabolites modulate mitochondrial function and mitochondrial dysfunction is highly associated with GI symptoms. In this study, we compared mitochondrial function in rectal and cecum biopsies under the assumption that certain microbiome metabolites, such as butyrate and propionic acid, are more abundant in the cecum as compared to the rectum. Rectal and cecum mucosal biopsies were collected during elective diagnostic colonoscopy. Using a single-blind case-control design, complex I and IV and citrate synthase activities and complex I-V protein quantity from 10 children with ASD, 10 children with Crohn’s disease and 10 neurotypical children with nonspecific GI complaints were measured. The protein for all complexes, except complex II, in the cecum as compared to the rectum was significantly higher in ASD samples as compared to other groups. For both rectal and cecum biopsies, ASD samples demonstrated higher complex I activity, but not complex IV or citrate synthase activity, compared to other groups. Mitochondrial function in the gut mucosa from children with ASD was found to be significantly different than other groups who manifested similar GI symptomatology suggesting a unique pathophysiology for GI symptoms in children with ASD. Abnormalities localized to the cecum suggest a role for imbalances in the microbiome, potentially in the production of butyrate, in children with ASD. PMID:29028817

Cigarette Smoke Upregulates PDE3 and PDE4 to Decrease cAMP in Airway Cells.

PubMed

Zuo, Haoxiao; Han, Bing; Poppinga, Wilfred J; Ringnalda, Lennard; Kistemaker, Loes E M; Halayko, Andrew J; Gosens, Reinoud; Nikolaev, Viacheslav O; Schmidt, Martina

2018-05-03

3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling in airway cells, in particular regulation of endogenous PDEs are poorly understood. We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mouse in vivo, ex vivo precision cut lung slices (PCLS), and in human in vitro cell models to track the effects of CS exposure. Under fenoterol stimulated conditions, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein upregulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed downregulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. We show that CS upregulates expression and activity of both PDE3 and PDE4, which regulate real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology. This article is protected by copyright. All rights reserved.

Perspective: Update on Idiopathic Intracranial Hypertension

PubMed Central

Bruce, Beau B.; Biousse, Valérie; Newman, Nancy J.

2011-01-01

Purpose Provide an update on various features of idiopathic intracranial hypertension. Design Perspective. Methods Selected articles on the epidemiology, clinical and imaging features, natural history, pathophysiology, and treatment of idiopathic intracranial hypertension were reviewed and interpreted in the context of the authors’ clinical and research experience. Results Idiopathic intracranial hypertension is primarily a disease of obese women of childbearing age, but it can affect patients of any weight, sex, and age. Although a relatively rare disorder, idiopathic intracranial hypertension’s associated costs in the U.S. entail hundreds of millions of dollars. Even following treatment, headaches are frequently persistent and may require the continued involvement of a neurologist. Quality of life reductions and depression are common among idiopathic intracranial hypertension patients. However, visual dysfunction, especially visual field abnormalities, represents the major morbidity of this disorder, and serial automated perimetry remains the primary mode of patient monitoring. Patients who are men, black, very obese, or anemic are at higher risk of visual loss. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding idiopathic intracranial hypertension’s pathophysiology. Treatment studies show that lumbar puncture is a valuable treatment (in addition to its crucial diagnostic role) and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, CSF diversion procedures, and cerebral venous stenting. Conclusions Many questions remain unanswered about idiopathic intracranial hypertension. Ongoing studies, especially an ongoing NIH-funded clinical trial of acetazolamide, should provide more insight into this important, yet poorly understood syndrome of isolated intracranial hypertension. PMID:21696699

Sinus and adenoid inflammation in children with chronic rhinosinusitis and asthma.

PubMed

Anfuso, Antony; Ramadan, Hassan; Terrell, Andrew; Demirdag, Yesim; Walton, Cheryl; Skoner, David P; Piedimonte, Giovanni

2015-02-01

Chronic rhinosinusitis (CRS) and asthma frequently coexist in children and adults. However, the precise pathophysiologic mechanism of this interaction is still poorly understood, especially in children, owing to the lack of direct measurements of mucosal inflammation in the upper airways. To determine the pathophysiologic mechanism by analyzing the expression of a large array of inflammatory cytokines and chemokines in the sinus and adenoid tissues surgically removed from pediatric patients with CRS refractory to medical management. Twenty-eight children 2 to 12 years old diagnosed with CRS with or without asthma and 10 controls were included in this prospective, nonrandomized study. Mucosal expression of 40 inflammatory cytokines was measured with a multiplex assay and was normalized to total tissue protein. Compared with children with CRS and without asthma, children with CRS and asthma had significantly higher sinus levels of tumor necrosis factor-α and adenoid levels of epidermal growth factor, eotaxin, fibroblast growth factor-2, growth-related oncogene, and platelet-derived growth factor-AA. The inflammatory response in the upper airway mucosa of children with asthma and CRS was similar, but more severe, compared with children with CRS without asthma. This observation is consistent with the hypothesis that asthma in these patients is caused or exacerbated by severe upper airway disease and supports the concept that treating sinus disease is paramount in the management of chronic asthma in children using, for the first time, direct measurements of airway inflammation in children. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Stem cells for amyotrophic lateral sclerosis modeling and therapy: myth or fact?

PubMed

Coatti, G C; Beccari, M S; Olávio, T R; Mitne-Neto, M; Okamoto, O K; Zatz, M

2015-03-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy. © 2015 International Society for Advancement of Cytometry.

Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model.

PubMed

Bauer, C A; Brozoski, T J

2001-03-01

Subjective tinnitus is a common and often debilitating disorder that is difficult to study because it is a perceptual state without an objective stimulus correlate. Studying tinnitus in humans is further complicated by the heterogeneity of tinnitus quality, severity, and associated hearing loss. As a consequence, the pathophysiology of tinnitus is poorly understood and treatments are often unsuccessful. In the present study, an animal psychophysical model was developed to reflect several features of tinnitus observed in humans. Chronic tinnitus was induced in rats by a single intense unilateral exposure to noise. The tinnitus was measured using a psychophysical procedure, which required the animals to discriminate between auditory test stimuli consisting of tones, noise, and 0 dB. Tinnitus was indicated by a frequency-specific shift in discrimination functions with respect to control subjects not exposed to noise. The psychophysical consequences of the noise exposure were best explained by a tinnitus hypothesis and could not be explained easily by other consequences of noise exposure such as hearing loss. The qualitative features of the tinnitus were determined and related to the duration of noise exposure and the associated cochlear trauma. The tinnitus was found to persist and intensify over 17 months of testing. Finally, the tinnitus was reversibly attenuated by treatment with gabapentin, a GABA agonist. It was concluded that this model reflected several features of human tinnitus, such as its tonality and persistence, and could be useful as a screen for potential therapeutics as well as a tool to help unravel the pathophysiology of the disorder of phantom auditory perception.

Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes

PubMed Central

Shields, Emily J.; Lam, Carol J.; Cox, Aaron R.; Rankin, Matthew M.; Van Winkle, Thomas J.; Hess, Rebecka S.; Kushner, Jake A.

2015-01-01

The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated β-cell destruction. It remains unclear to what extent β-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in β-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of β-cells. Very few β-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme β-cell deficiency in both new and longstanding disease. The β-cell predominant composition of canine islets and the near-total absence of β-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, β-cell loss underlies the pathophysiology of canine diabetes. PMID:26057531

Acute colonic diverticulitis: modern understanding of pathomechanisms, risk factors, disease burden and severity.

PubMed

Søreide, Kjetil; Boermeester, Marja A; Humes, David J; Velmahos, George C

2016-12-01

Conservative, non-antibiotic and non-surgical management of acute diverticulitis is currently being investigated. To better inform clinical decisions, better understanding of disease mechanisms, disease burden and severity is needed. Literature search of risk factors, pathophysiology, epidemiology and disease burden/severity reported over the last decade. Acute diverticulitis is a common disease and has a high disease burden. Incidence of hospital admissions is reported around 71 per 100,000 population, with reported increase in several subpopulations over the last decades. The incidence is likely to increase further with the aging populations. Risk factors for left-sided acute diverticulitis include dietary, anthropometric and lifestyle factors. Disease mechanisms are still poorly understood, but a distinction between inflammation and infection is emerging. The integrative and complex role of the gut microbiota has become an interesting factor for both understanding the disease as well as a potential target for intervention using probiotics. Mild, self-limiting events are increasingly reported from studies of successful non-antibiotic management in a considerable number of cases. Risk markers of progression to or presence of severe, complicated disease are needed for better disease stratification. Current risk stratification by clinical, imaging or endoscopic means is imperfect and needs validation. Long-term results from minimal-invasive and comparative surgical trials may better help inform clinicians and patients. Over- and under-treatment as well as over- and under-diagnosis of severity is likely to continue in clinical practice due to lack of reliable, robust and universal severity and classification systems. Better understanding of pathophysiology is needed.

Impact of Diabetic Complications on Balance and Falls: Contribution of the Vestibular System

PubMed Central

Lin, James; Staecker, Hinrich; Whitney, Susan L.; Kluding, Patricia M.

2016-01-01

Diabetes causes many complications, including retinopathy and peripheral neuropathy, which are well understood as contributing to gait instability and falls. A less understood complication of diabetes is the effect on the vestibular system. The vestibular system contributes significantly to balance in static and dynamic conditions by providing spatially orienting information. It is noteworthy that diabetes has been reported to affect vestibular function in both animal and clinical studies. Pathophysiological changes in peripheral and central vestibular structures due to diabetes have been noted. Vestibular dysfunction is associated with impaired balance and a higher risk of falls. As the prevalence of diabetes increases, so does the potential for falls due to diabetic complications. The purpose of this perspective article is to present evidence on the pathophysiology of diabetes-related complications and their influence on balance and falls, with specific attention to emerging evidence of vestibular dysfunction due to diabetes. Understanding this relationship may be useful for screening (by physical therapists) for possible vestibular dysfunction in people with diabetes and for further developing and testing the efficacy of interventions to reduce falls in this population. PMID:26251477

Acupuncture for Visceral Pain: Neural Substrates and Potential Mechanisms

PubMed Central

Chen, Shuping; Wang, Shubin; Rong, Peijing; Wang, Junying; Qiao, Lina; Feng, Xiumei; Liu, Junling

2014-01-01

Visceral pain is the most common form of pain caused by varied diseases and a major reason for patients to seek medical consultation. Despite much advances, the pathophysiological mechanism is still poorly understood comparing with its somatic counterpart and, as a result, the therapeutic efficacy is usually unsatisfactory. Acupuncture has long been used for the management of numerous disorders in particular pain and visceral pain, characterized by the high therapeutic benefits and low adverse effects. Previous findings suggest that acupuncture depresses pain via activation of a number of neurotransmitters or modulators including opioid peptides, serotonin, norepinephrine, and adenosine centrally and peripherally. It endows us, by advancing the understanding of the role of ion channels and gut microbiota in pain process, with novel perspectives to probe the mechanisms underlying acupuncture analgesia. In this review, after describing the visceral innervation and the relevant afferent pathways, in particular the ion channels in visceral nociception, we propose three principal mechanisms responsible for acupuncture induced benefits on visceral pain. Finally, potential topics are highlighted regarding the future studies in this field. PMID:25614752

Murine Models of Heart Failure with Preserved Ejection Fraction: a “Fishing Expedition”

PubMed Central

Valero-Muñoz, Maria; Backman, Warren; Sam, Flora

2017-01-01

Summary Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of HF in the presence of a normal left ventricular (LV) ejection fraction (EF). Despite accounting for up to 50% of all clinical presentations of HF, the mechanisms implicated in HFpEF are poorly understood, thus precluding effective therapy. The pathophysiological heterogeneity in the HFpEF phenotype also contributes to this disease and likely to the absence of evidence-based therapies. Limited access to human samples and imperfect animal models that completely recapitulate the human HFpEF phenotype have impeded our understanding of the mechanistic underpinnings that exist in this disease. Aging and comorbidities such as atrial fibrillation, hypertension, diabetes and obesity, pulmonary hypertension and renal dysfunction are highly associated with HFpEF. Yet, the relationship and contribution between them remains ill-defined. This review discusses some of the distinctive clinical features of HFpEF in association with these comorbidities and highlights the advantages and disadvantage of commonly used murine models, used to study the HFpEF phenotype. PMID:29333506

Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding

PubMed Central

Cansell, Céline; Castel, Julien; Denis, Raphaël G. P.; Rouch, Claude; Delbes, Anne-Sophie; Martinez, Sarah; Mestivier, Denis; Finan, Brian; Maldonado-Aviles, Jaime G.; Rijnsburger, Merel; Tschöp, Matthias H.; DiLeone, Ralph J.; Eckel, Robert H.; la Fleur, Susanne E.; Magnan, Christophe; Hnasko, Thomas S.; Luquet, Serge

2014-01-01

Circulating triglycerides (TG) normally increase after a meal but are altered in pathophysiological conditions such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food, and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking. PMID:24732670

New insights into the pathophysiology of post-stroke spasticity.

PubMed

Li, Sheng; Francisco, Gerard E

2015-01-01

Spasticity is one of many consequences after stroke. It is characterized by a velocity-dependent increase in resistance during passive stretch, resulting from hyperexcitability of the stretch reflex. The underlying mechanism of the hyperexcitable stretch reflex, however, remains poorly understood. Accumulated experimental evidence has supported supraspinal origins of spasticity, likely from an imbalance between descending inhibitory and facilitatory regulation of spinal stretch reflexes secondary to cortical disinhibition after stroke. The excitability of reticulospinal (RST) and vestibulospinal tracts (VSTs) has been assessed in stroke survivors with spasticity using non-invasive indirect measures. There are strong experimental findings that support the RST hyperexcitability as a prominent underlying mechanism of post-stroke spasticity. This mechanism can at least partly account for clinical features associated with spasticity and provide insightful guidance for clinical assessment and management of spasticity. However, the possible role of VST hyperexcitability cannot be ruled out from indirect measures. In vivo measure of individual brainstem nuclei in stroke survivors with spasticity using advanced fMRI techniques in the future is probably able to provide direct evidence of pathogenesis of post-stroke spasticity.

New insights into the pathophysiology of post-stroke spasticity

PubMed Central

Li, Sheng; Francisco, Gerard E.

2015-01-01

Spasticity is one of many consequences after stroke. It is characterized by a velocity-dependent increase in resistance during passive stretch, resulting from hyperexcitability of the stretch reflex. The underlying mechanism of the hyperexcitable stretch reflex, however, remains poorly understood. Accumulated experimental evidence has supported supraspinal origins of spasticity, likely from an imbalance between descending inhibitory and facilitatory regulation of spinal stretch reflexes secondary to cortical disinhibition after stroke. The excitability of reticulospinal (RST) and vestibulospinal tracts (VSTs) has been assessed in stroke survivors with spasticity using non-invasive indirect measures. There are strong experimental findings that support the RST hyperexcitability as a prominent underlying mechanism of post-stroke spasticity. This mechanism can at least partly account for clinical features associated with spasticity and provide insightful guidance for clinical assessment and management of spasticity. However, the possible role of VST hyperexcitability cannot be ruled out from indirect measures. In vivo measure of individual brainstem nuclei in stroke survivors with spasticity using advanced fMRI techniques in the future is probably able to provide direct evidence of pathogenesis of post-stroke spasticity. PMID:25914638

The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection.

PubMed

Jaillon, Sébastien; Moalli, Federica; Ragnarsdottir, Bryndis; Bonavita, Eduardo; Puthia, Manoj; Riva, Federica; Barbati, Elisa; Nebuloni, Manuela; Cvetko Krajinovic, Lidija; Markotic, Alemka; Valentino, Sonia; Doni, Andrea; Tartari, Silvia; Graziani, Giorgio; Montanelli, Alessandro; Delneste, Yves; Svanborg, Catharina; Garlanda, Cecilia; Mantovani, Alberto

2014-04-17

Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs. Copyright © 2014 Elsevier Inc. All rights reserved.

Role of Cytokines as a Double-edged Sword in Sepsis

PubMed Central

CHAUDHRY, HINA; ZHOU, JUHUA; ZHONG, YIN; ALI, MIR MUSTAFA; MCGUIRE, FRANKLIN; NAGARKATTI, PRAKASH S.; NAGARKATTI, MITZI

2014-01-01

Background Sepsis is a deadly immunological disorder and its pathophysiology is still poorly understood. We aimed to determine if specific pro-inflammatory and anti-inflammatory cytokines can be used as diagnostic and therapeutic targets for sepsis. Materials and Methods Recent publications in the MEDLINE database were searched for articles regarding the clinical significance of inflammatory cytokines in sepsis. Results In response to pathogen infection, pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, IL-18 and tumor necrosis factor-α (TNF-α)] and anti-inflammatory cytokine (IL-10) increased in patients with sepsis. Importantly, a decrease in IL-6 was associated with a better prognosis and overproduction of IL-10 was found to be the main predictor of severity and fatal outcome. Conclusion Both pro-inflammatory and anti-inflammatory cytokines constitute a double-edged sword in sepsis; on one hand they are critical to eliminate the infection while on the other, excessive production can cause tissue and organ damage. Increase in cytokines such as IL-6, Il-8, IL-10, IL-18 and TNF-α may have implications in diagnosis and treatment of sepsis. PMID:24292568

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I

PubMed Central

2014-01-01

Background Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Results Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood–brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Conclusion Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke. PMID:24468193

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I.

PubMed

Zinnanti, William J; Lazovic, Jelena; Housman, Cathy; Antonetti, David A; Koeller, David M; Connor, James R; Steinman, Lawrence

2014-01-27

Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

Excitation-transcription coupling in parvalbumin-positive interneurons employs a novel CaM Kinase-dependent pathway distinct from excitatory neurons

PubMed Central

Cohen, Samuel M.; Ma, Huan; Kuchibhotla, Kishore V.; Watson, Brendon O.; Buzsáki, György; Froemke, Robert C.; Tsien, Richard W.

2016-01-01

Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. Here, we report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease. PMID:27041500

Tremor in multiple sclerosis: The intriguing role of the cerebellum.

PubMed

Ayache, Samar S; Chalah, Moussa A; Al-Ani, Tarik; Farhat, Wassim H; Zouari, Hela G; Créange, Alain; Lefaucheur, Jean-Pascal

2015-11-15

Tremor is frequently encountered in multiple sclerosis (MS) patients. However, its underlying pathophysiological mechanisms remain poorly understood. Our aim was to assess the potential role of the cerebellum and brain stem structures in the generation of MS tremor.We performed accelerometric (ACC) and electromyographic(EMG) assessment of tremor in 32MS patients with manual clumsiness. In addition to clinical examination, patients underwent a neurophysiological exploration of the brainstem and cerebellar functions,which consisted of blink and masseter inhibitory reflexes, cerebello-thalamo-cortical inhibition (CTCi), and somatosensory evoked potentials. Tremor was clinically visible in 18 patients and absent in 14. Patients with visible tremor had more severe score of ataxia and clinical signs of cerebellar dysfunction, as well as a more reduced CTCi on neurophysiological investigation. However, ACC and EMG recordings confirmed the presence of a real rhythmic activity in only one patient. In most MS patients, the clinically visible tremor corresponded to a pseudorhythmic activity without coupling between ACC and EMG recordings. Cerebellar dysfunction may contribute to the occurrence of this pseudorhythmic activity mimicking tremor during posture and movement execution.

Pancreatogenic choledocholithiasis in common bile duct stump after Roux-en-Y hepaticojejunostomy

PubMed Central

Jiang, Yuan-Hui; Zhang, An-Hong; Zhou, Shao-Jun

2017-01-01

Abstract Rationale: Choledocholithiasis in common bile duct (CBD) stump after Roux-en-Y hepaticojejunostomy (RYHJ) is incredibly rare and its pathophysiology is poorly understood. Patient concerns: A 79-year-old woman was admitted to our hospital with upper abdominal pain radiating through to the back in November 2016. Diagnoses: Abdominal computed tomography (CT) scan and magnetic resonance cholangiopancreatography (MRCP) revealed filling defects in CBD stump, chronic pancreatitis, and dilatation of CBD stump and main pancreatic duct (MPD). Interventions: During the endoscopic retrograde cholangiopancreatography (ERCP), cannulation proceeded easily from MPD to CBD through a variant pancreatic duct, and then white crushed stones extracted from the CBD stump. Elemental analysis and infrared spectrophotometry demonstrated that the main constituent of the calculi was calcium carbonate. Outcomes: After a therapeutic ERCP, the patient's symptoms disappeared, and a 9-month follow-up indicated no remaining stones or lithiasis relapse. Lessons: This type of choledocholithiasis in CBD stump after RYHJ has never been reported before. We nominated it as “pancreatogenic choledocholithiasis,” and pancreatobiliary reflux caused by a variant pancreatic duct may be the main cause. PMID:29145338

Ocular side effects of biological agents in oncology: what should the clinician be aware of?

PubMed Central

Hager, Tobias; Seitz, B

2014-01-01

During the last 20 years, biologicals have become increasingly relevant in oncologic therapy. Depending on the medication used, there are different profiles of ocular side effects. Although these can be present in up to 70% of patients, they are generally underreported in the literature. Therefore, the pathophysiological details of their development are often poorly understood. Herein we attempt to identify groups of biologicals to which a specific side effect profile can be assigned. We also tried to capture all relevant side effects and therefore conducted several database investigation including Medline, Cochrane library, and the drugs section of the US Food and Drug Administration (FDA), using the following search strings: “name of biological agent (both generic and commercial names)” AND “eye” OR “ocular”. If we found a side effect that has been associated with a drug, we researched Medline using the following search string: “name of biological agent” (both generic and commercial names) AND “term for the specific side effect”. Due to the wealth of material we report only the drugs that are approved by the FDA. PMID:24391443

Regulation of lipogenesis by cyclin-dependent kinase 8–mediated control of SREBP-1

PubMed Central

Zhao, Xiaoping; Feng, Daorong; Wang, Qun; Abdulla, Arian; Xie, Xiao-Jun; Zhou, Jie; Sun, Yan; Yang, Ellen S.; Liu, Lu-Ping; Vaitheesvaran, Bhavapriya; Bridges, Lauren; Kurland, Irwin J.; Strich, Randy; Ni, Jian-Quan; Wang, Chenguang; Ericsson, Johan; Pessin, Jeffrey E.; Ji, Jun-Yuan; Yang, Fajun

2012-01-01

Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degradation. Importantly, consistent with the physiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by feeding and insulin, resulting in decreased SREBP-1c phosphorylation. Moreover, overexpression of CycC efficiently suppressed insulin and feeding–induced lipogenic gene expression. Taken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved components of the insulin signaling pathway in regulating lipid homeostasis. PMID:22684109

Old treatments for new insights and strategies: proposed management in adults and children with alkaptonuria.

PubMed

Arnoux, Jean-Baptiste; Le Quan Sang, Kim-Hanh; Brassier, Anais; Grisel, Coraline; Servais, Aude; Wippf, Julien; Dubois, Sandrine; Sireau, Nicolas; Job-Deslandre, Chantal; Ranganath, Lakshminarayan; de Lonlay, Pascale

2015-09-01

Alkaptonuria (AKU) is caused by deficiency of the enzyme homogentisate 1,2 dioxygenase. It results in an accumulation of homogentisate which oxidizes spontaneously to benzoquinone acetate, a highly oxidant compound, which polymerises to a melanin-like structure, in a process called ochronosis. Asymptomatic during childhood, this accumulation will lead from the second decade of life to a progressive and severe spondylo-arthopathy, associated with multisystem involvement: osteoporosis/fractures, stones (renal, prostatic, gall bladder, salivary glands), ruptures of tendons/muscle/ligaments, renal failure and aortic valve disease. The pathophysiological mechanisms of AKU remain poorly understood, but recent advances lead us to reconsider the treatment strategy in AKU patients. Besides the supporting therapies (pain killers, anti-inflammatory drugs, physiotherapy, joints replacements and others), specific therapies have been considered (anti-oxidant, low protein diet, nitisinone), but clinical studies have failed to prove efficiency on the rheumatological lesions of the disease. Here we propose a treatment strategy for children and adults with AKU, based on a review of the latest findings on AKU and lessons from other aminoacipathies, especially tyrosinemias.

Agonal sequences in four filmed hangings: analysis of respiratory and movement responses to asphyxia by hanging.

PubMed

Sauvageau, Anny

2009-01-01

The human pathophysiology of asphyxia by hanging is still poorly understood, despite great advances in forensic science. In that context, filmed hangings may hold the key to answer questions regarding the sequence of events leading to death in human asphyxia. Four filmed hangings were analyzed. Rapid loss of consciousness was observed between 13 sec and 18 sec after onset of hanging, closely followed by convulsions (at 14-19 sec). A complex pattern of decerebration rigidity (19-21 sec in most cases), followed by a quick phase of decortication rigidity (1 min 00 sec-1 min 08 sec in most cases), an extended phase of decortication rigidity (1 min 04 sec-1 min 32 sec) and loss of muscle tone (1 min 38 sec-2 min 47 sec) was revealed. Very deep respiratory attempts started between 20 and 22 sec, the last respiratory attempt being detected between 2 min 00 sec and 2 min 04 sec. Despite differences in the types of hanging, this unique study reveals similarities that are further discussed.

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model

PubMed Central

Mercher, Thomas; Raffel, Glen D.; Moore, Sandra A.; Cornejo, Melanie G.; Baudry-Bluteau, Dominique; Cagnard, Nicolas; Jesneck, Jonathan L.; Pikman, Yana; Cullen, Dana; Williams, Ifor R.; Akashi, Koichi; Shigematsu, Hirokazu; Bourquin, Jean-Pierre; Giovannini, Marco; Vainchenker, William; Levine, Ross L.; Lee, Benjamin H.; Bernard, Olivier A.; Gilliland, D. Gary

2009-01-01

Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two–megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin κ J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL. PMID:19287095

Snoring and obstructive sleep apnoea in children: why should we treat?

PubMed

Gozal, David; O'Brien, Louise M

2004-01-01

Frequent and loud snoring is a very frequent condition in prepubertal children affecting approximately 10% of all 2-8 year old children. If polysomnographical evaluations are performed in these snoring children, approximately 10% will be diagnosed with obstructive sleep apnoea (OSA). The pathophysiology of OSA in children is still poorly understood. Indeed, while adenotonsillar hypertrophy is certainly a major contributor to OSA, other factors need to be implicated for OSA to develop. In recent years, it has become apparent that OSA and snoring are not as innocuous as previously thought. Indeed, epidemiological and pre-post treatment analyses have identified substantial morbidities that primarily affect cardiovascular and neurobehavioural systems, namely pulmonary hypertension, systemic elevation of arterial blood pressure, nocturnal enuresis, reduced somatic growth, behavioural problems that resemble attention deficit-hyperactivity disorder, as well as learning and cognitive deficits. These problems are associated with marked increases in healthcare-related costs. More importantly, if timely diagnosis and intervention are not implemented, some of these morbid complications may not be completely reversible, leading to long-lasting residual consequences.

Work-associated irritable larynx syndrome.

PubMed

Anderson, Jennifer A

2015-04-01

The purpose of this study is to review the relevant literature concerning work-associated irritable larynx syndrome (WILS), a hyperkinetic laryngeal disorder associated with occupational irritant exposure. Clinical symptoms are variable and include dysphonia, cough, dyspnoea and globus pharyngeus. WILS is a clinical diagnosis and can be difficult to differentiate from asthma. Treatment options for WILS include medical and behavioural therapy. Laryngeal-centred upper airway symptoms secondary to airborne irritants have been documented in the literature under a variety of diagnostic labels, including WILS, vocal cord dysfunction (VCD), laryngeal hypersensitivity and laryngeal neuropathy and many others. The underlying pathophysiology is as yet poorly understood; however, the clinical scenario suggests a multifactorial nature to the disorder. More recent literature indicates that central neuronal plasticity, inflammatory processes and psychological factors are all likely contributors. Possible mechanisms for WILS include central neuronal network plasticity after noxious exposure and/or viral infection, inflammation (i.e. reflux disease) and intrinsic patient factors such a psychological state. Treatment is individualized and frequently includes one or more of the following: environmental changes in the workplace, GERD therapy, behavioural/speech therapy, psychotherapy counselling and neural modifiers.

Ebf2 is required for development of dopamine neurons in the midbrain periaqueductal gray matter of mouse.

PubMed

Yang, Qiaoqiao; Liu, Shuxi; Yin, Min; Yin, Yanqing; Zhou, Guomin; Zhou, Jiawei

2015-11-01

Dopaminergic (DA) neurons in the midbrain ventral periaqueductal gray matter (PAG) play critical roles in various physiological and pathophysiological processes including sleep-wake rhyme, antinociception, and drug addiction. However, the molecular mechanisms underlying their development are poorly understood. Here, we showed that PAG DA neurons arose as early as E15.5 in mouse embryos. During the prenatal period, the majority of PAG DA neurons was distributed in the intermediate and caudal regions of the PAG. In the postnatal brain, ∼50% of PAG DA neurons were preferentially located in the caudal portion of the PAG. Moreover, transcription factor early B-cell factor 2 (Ebf2) was transiently expressed in a subset of DA neurons in embryonic ventral mesencephalon. Functional analysis revealed that loss of Ebf2 in vivo caused a marked reduction in the number of DA neurons in the midbrain PAG but not in the substantia nigra and ventral tegmental area. Thus, Ebf2 is identified as a novel and important regulator selectively required for midbrain PAG DA neuron development. © 2015 Wiley Periodicals, Inc.

Survival, gene and metabolite responses of Litoria verreauxii alpina frogs to fungal disease chytridiomycosis

NASA Astrophysics Data System (ADS)

Grogan, Laura F.; Mulvenna, Jason; Gummer, Joel P. A.; Scheele, Ben C.; Berger, Lee; Cashins, Scott D.; McFadden, Michael S.; Harlow, Peter; Hunter, David A.; Trengove, Robert D.; Skerratt, Lee F.

2018-03-01

The fungal skin disease chytridiomycosis has caused the devastating decline and extinction of hundreds of amphibian species globally, yet the potential for evolving resistance, and the underlying pathophysiological mechanisms remain poorly understood. We exposed 406 naïve, captive-raised alpine tree frogs (Litoria verreauxii alpina) from multiple populations (one evolutionarily naïve to chytridiomycosis) to the aetiological agent Batrachochytrium dendrobatidis in two concurrent and controlled infection experiments. We investigated (A) survival outcomes and clinical pathogen burdens between populations and clutches, and (B) individual host tissue responses to chytridiomycosis. Here we present multiple interrelated datasets associated with these exposure experiments, including animal signalment, survival and pathogen burden of 355 animals from Experiment A, and the following datasets related to 61 animals from Experiment B: animal signalment and pathogen burden; raw RNA-Seq reads from skin, liver and spleen tissues; de novo assembled transcriptomes for each tissue type; raw gene expression data; annotation data for each gene; and raw metabolite expression data from skin and liver tissues. These data provide an extensive baseline for future analyses.

Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models

PubMed Central

Bernstein, Steven L.; Johnson, Mary A.; Miller, Neil R.

2011-01-01

Anterior ischemic optic neuropathy (AION) can be divided into nonarteritic (NAION) and arteritic (AAION) forms. NAION makes up ~85% of all cases of AION, and until recently was poorly understood. There is no treatment for NAION, and its initiating causes are poorly understood, in part because NAION is not lethal, making it difficult to obtain fresh, newly affected tissue for study. In-vivo electrophysiology and post-mortem studies reveal specific responses that are associated with NAION. New models of NAION have been developed which enable insights into the pathophysiological events surrounding this disease. These models include both rodent and primate species, and the power of a `vertically integrated' multi-species approach can help in understanding the common cellular mechanisms and physiological responses to clinical NAION, and to identify potential approaches to treatment. The models utilize laser light to activate intravascular photoactive dye to induce capillary vascular thrombosis, while sparing the larger vessels. The observable optic nerve changes associated with rodent models of AION (rAION) and primate NAION (pNAION) are indistinguishable from that seen in clinical disease, including sectoral axonal involvement, and in-vivo electrophysiological data from these models are consistent with clinical data. Early post-infarct events reveal an unexpected inflammatory response, and changes in intraretinal gene expression for both stress response, while sparing outer retinal function, which occurs in AAION models. Histologically, the NAION models reveal an isolated loss of retinal ganglion cells by apoptosis. There are changes detectable by immunohistochemistry suggesting that other retinal cells mount a brisk response to retinal ganglion cell distress without themselves dying. The optic nerve ultimately shows axonal loss and scarring. Inflammation is a prominent early histological feature. This suggests that clinically, specific modulation of inflammation may be a useful approach to NAION treatment early in the course of the disease. PMID:21376134

Female Pattern Hair Loss: a clinical and pathophysiological review*

PubMed Central

Ramos, Paulo Müller; Miot, Hélio Amante

2015-01-01

Female Pattern Hair Loss or female androgenetic alopecia is the main cause of hair loss in adult women and has a major impact on patients' quality of life. It evolves from the progressive miniaturization of follicles that lead to a subsequent decrease of the hair density, leading to a non-scarring diffuse alopecia, with characteristic clinical, dermoscopic and histological patterns. In spite of the high frequency of the disease and the relevance of its psychological impact, its pathogenesis is not yet fully understood, being influenced by genetic, hormonal and environmental factors. In addition, response to treatment is variable. In this article, authors discuss the main clinical, epidemiological and pathophysiological aspects of female pattern hair loss. PMID:26375223

Diabetes Mellitus and Ischemic Heart Disease: The Role of Ion Channels

PubMed Central

D’Amato, Andrea; Netti, Lucrezia; Pucci, Mariateresa; De Marchis, Marialaura; Volterrani, Maurizio; Mancone, Massimo; Fedele, Francesco

2018-01-01

Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients. In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IHD. PMID:29534462

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

PubMed Central

2016-01-01

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues. PMID:28053994

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS.

PubMed

Frick, Luciana; Pittenger, Christopher

2016-01-01

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

Noninflammatory Joint Contractures Arising from Immobility: Animal Models to Future Treatments

PubMed Central

Wong, Kayleigh; Trudel, Guy; Laneuville, Odette

2015-01-01

Joint contractures, defined as the limitation in the passive range of motion of a mobile joint, can be classified as noninflammatory diseases of the musculoskeletal system. The pathophysiology is not well understood; limited information is available on causal factors, progression, the pathophysiology involved, and prediction of response to treatment. The clinical heterogeneity of joint contractures combined with the heterogeneous contribution of joint connective tissues to joint mobility presents challenges to the study of joint contractures. Furthermore, contractures are often a symptom of a wide variety of heterogeneous disorders that are in many cases multifactorial. Extended immobility has been identified as a causal factor and evidence is provided from both experimental and epidemiology studies. Of interest is the involvement of the joint capsule in the pathophysiology of joint contractures and lack of response to remobilization. While molecular pathways involved in the development of joint contractures are being investigated, current treatments focus on physiotherapy, which is ineffective on irreversible contractures. Future treatments may include early diagnosis and prevention. PMID:26247029

Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: Insights from experimental studies.

PubMed

Guihaire, Julien; Noly, Pierre Emmanuel; Schrepfer, Sonja; Mercier, Olaf

2015-10-01

The right ventricle (RV) has to face major changes in loading conditions due to cardiovascular diseases and pulmonary vascular disorders. Clinical experience supports evidence that the RV better compensates for volume than for pressure overload, and for chronic than for acute changes. For a long time, right ventricular (RV) pathophysiology has been restricted to patterns extrapolated from left heart studies. However, the two ventricles are anatomically, haemodynamically and functionally distinct. RV metabolic properties may also result in a different behaviour in response to pathological conditions compared with the left ventricle. In this review, current knowledge of RV pathophysiology is reported in the setting of chronic pressure overload, including recent experimental findings and emerging concepts. After a time-varying compensated period with preserved cardiac output despite overload conditions, RV failure finally occurs, leading to death. The underlying mechanisms involved in the transition from compensatory hypertrophy to maladaptive remodelling are not completely understood. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD).

PubMed

Sharma, Alok; Couture, Justin

2014-02-01

To review the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). A literature search was conducted in PubMed and EMBASE using the terms attention deficit hyperactive disorder, ADHD, pathophysiology, etiology, and neurobiology. Limits applied were the following: published in the past 10 years (January 2003 to August 2013), humans, review, meta-analysis, and English language. These yielded 63 articles in PubMed and 74 in EMBASE. After removing duplicate/irrelevant articles, 86 articles and their relevant reference citations were reviewed. ADHD is a neurological disorder that affects children, but symptoms may persist into adulthood. Individuals suffering from this disorder exhibit hyperactivity, inattention, impulsivity, and problems in social interaction and academic performance. Medications used to treat ADHD such as methylphenidate, amphetamine, and atomoxetine indicate a dopamine/norepinephrine deficit as the neurochemical basis of ADHD, but the etiology is more complex. Moreover, these agents have poor adverse effect profiles and a multitude of drug interactions. Because these drugs are also dispensed to adults who may have concomitant conditions or medications, a pharmacist needs to be aware of these adverse events and drug interactions. This review, therefore, focuses on the pathophysiology, etiology, and treatment of ADHD and details the adverse effects and drug interaction profiles of the drugs used to treat it. Published research shows the benefit of drug therapy for ADHD in children, but given the poor adverse effect and drug interaction profiles, these must be dispensed with caution.

Motoneuron firing in amyotrophic lateral sclerosis (ALS)

PubMed Central

de Carvalho, Mamede; Eisen, Andrew; Krieger, Charles; Swash, Michael

2014-01-01

Amyotrophic lateral sclerosis is an inexorably progressive neurodegenerative disorder involving the classical motor system and the frontal effector brain, causing muscular weakness and atrophy, with variable upper motor neuron signs and often an associated fronto-temporal dementia. The physiological disturbance consequent on the motor system degeneration is beginning to be well understood. In this review we describe aspects of the motor cortical, neuronal, and lower motor neuron dysfunction. We show how studies of the changes in the pattern of motor unit firing help delineate the underlying pathophysiological disturbance as the disease progresses. Such studies are beginning to illuminate the underlying disordered pathophysiological processes in the disease, and are important in designing new approaches to therapy and especially for clinical trials. PMID:25294995

Asymmetric pallidal neuronal activity in patients with cervical dystonia

PubMed Central

Moll, Christian K. E.; Galindo-Leon, Edgar; Sharott, Andrew; Gulberti, Alessandro; Buhmann, Carsten; Koeppen, Johannes A.; Biermann, Maxine; Bäumer, Tobias; Zittel, Simone; Westphal, Manfred; Gerloff, Christian; Hamel, Wolfgang; Münchau, Alexander; Engel, Andreas K.

2014-01-01

The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD) is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct vs. indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP) activity from the external (GPe) and internal pallidal segment (GPi) of 13 CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA) with those obtained in CD patients operated under general anaesthesia (GA). In awake patients, mean GPe discharge rate (52 Hz) was lower than that of GPi (72 Hz). Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe– and GPi–LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology. PMID:24574981

The role of casein-specific IgA and TGF-β in children with Food Protein-Induced Enterocolitis Syndrome to milk

PubMed Central

Konstantinou, George N.; Bencharitiwong, Ramon; Grishin, Alexander; Caubet, Jean-Christoph; Bardina, Luda; Sicherer, Scott H.; Sampson, Hugh A.; Nowak-Węgrzyn, Anna

2014-01-01

Background Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis. Objective To investigate humoral and cellular responses to casein in children with milk-FPIES, including the role of casein-specific (cs) IgA and T-cell mediated TGF-β responses. Patients and methods Thirty-one children previously diagnosed with milk-FPIES were challenged with milk. Twelve age-matched children with FPIES to other foods and 6 milk-tolerant children without a history of FPIES were used as controls. Casein-specific IgE, IgG, IgG4 and IgA were measured in serum and TGF-β levels in supernatants of casein-stimulated PBMCs. Result Twenty-six children with milk-FPIES reacted (active milk-FPIES) and five tolerated milk (milk-FPIES-resolved) during food challenge. All of them had significantly lower levels of csIgG, csIgG4 and csIgA than control children (p-value<0.001). There were no TGF-β responses in supernatants of active milk-FPIES children. Conclusion Children with milk-FPIES have low levels of csIgG, csIgG4 and csIgA. In particular, children with active FPIES to cow’s milk have deficient T-cell mediated TGF-β responses to casein, rendering TGF-β a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology and establish the diagnostic utility of TGF-β in milk-induced FPIES. PMID:25283440

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction*

PubMed Central

Wang, Meng; Liu, Hao; Zheng, Jing; Chen, Bobei; Zhou, Mi; Fan, Wenlu; Wang, Hen; Liang, Xiaoyang; Zhou, Xiaolong; Eriani, Gilbert; Jiang, Pingping; Guan, Min-Xin

2016-01-01

Several mitochondrial tRNA mutations have been associated with maternally inherited diabetes and deafness. However, the pathophysiology of these tRNA mutations remains poorly understood. In this report, we identified the novel homoplasmic 14692A→G mutation in the mitochondrial tRNAGlu gene among three Han Chinese families with maternally inherited diabetes and deafness. The m.14692A→G mutation affected a highly conserved uridine at position 55 of the TΨC loop of tRNAGlu. The uridine is modified to pseudouridine (Ψ55), which plays an important role in the structure and function of this tRNA. Using lymphoblastoid cell lines derived from a Chinese family, we demonstrated that the m.14692A→G mutation caused loss of Ψ55 modification and increased angiogenin-mediated endonucleolytic cleavage in mutant tRNAGlu. The destabilization of base-pairing (18A-Ψ55) caused by the m.14692A→G mutation perturbed the conformation and stability of tRNAGlu. An approximately 65% decrease in the steady-state level of tRNAGlu was observed in mutant cells compared with control cells. A failure in tRNAGlu metabolism impaired mitochondrial translation, especially for polypeptides with a high proportion of glutamic acid codons such as ND1, ND6, and CO2 in mutant cells. An impairment of mitochondrial translation caused defective respiratory capacity, especially reducing the activities of complexes I and IV. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increasing production of reactive oxygen species in the mutant cells. Our findings may provide new insights into the pathophysiology of maternally inherited diabetes and deafness, which is primarily manifested by the deficient nucleotide modification of mitochondrial tRNAGlu. PMID:27519417

Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy

PubMed Central

Carroll, Jenna C.; Iba, Michiyo; Bangasser, Debbie A.; Valentino, Rita J.; James, Michael J.; Brunden, Kurt R.; Lee, Virginia M.-Y.; Trojanowski, John Q.

2011-01-01

Since over-activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer’s disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both Aβ and tau pathology remain unclear. Therefore, we first established a model of chronic stress which exacerbates Aβ accumulation in Tg2576 mice and then extended this stress paradigm to a tau transgenic mouse model with the P301S mutation (PS19) which displays tau hyperphosphorylation, insoluble tau inclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, one month of restraint/isolation (RI) stress increased Aβ levels, suppressed microglial activation, and worsened spatial and fear memory compared to non-stressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF1) antagonist. The role for a CRF1-dependent mechanism was further supported by the finding that mice over-expressing CRF had increased hyperphosphorylated tau compared to wildtype littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aβ and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD. PMID:21976528

The Association Between Clinical Characteristics of Migraine and Brain GABA Levels: An Exploratory Study.

PubMed

Aguila, Maria-Eliza R; Rebbeck, Trudy; Leaver, Andrew M; Lagopoulos, Jim; Brennan, Patrick C; Hübscher, Markus; Refshauge, Kathryn M

2016-10-01

Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker. Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Tissue Specific Dysregulated Protein Subnetworks in Type 2 Diabetic Bladder Urothelium and Detrusor Muscle*

PubMed Central

Tomechko, Sara E.; Liu, Guiming; Tao, Mingfang; Schlatzer, Daniela; Powell, C. Thomas; Gupta, Sanjay; Chance, Mark R.; Daneshgari, Firouz

2015-01-01

Diabetes mellitus is well known to cause bladder dysfunction; however, the molecular mechanisms governing this process and the effects on individual tissue elements within the bladder are poorly understood, particularly in type 2 diabetes. A shotgun proteomics approach was applied to identify proteins differentially expressed between type 2 diabetic (TallyHo) and control (SWR/J) mice in the bladder smooth muscle and urothelium, separately. We were able to identify 1760 nonredundant proteins from the detrusor smooth muscle and 3169 nonredundant proteins from urothelium. Pathway and network analysis of significantly dysregulated proteins was conducted to investigate the molecular processes associated with diabetes. This pinpointed ERK1/2 signaling as a key regulatory node in the diabetes-induced pathophysiology for both tissue types. The detrusor muscle samples showed diabetes-induced increased tissue remodeling-type events such as Actin Cytoskeleton Signaling and Signaling by Rho Family GTPases. The diabetic urothelium samples exhibited oxidative stress responses, as seen in the suppression of protein expression for key players in the NRF2-Mediated Oxidative Stress Response pathway. These results suggest that diabetes induced elevated inflammatory responses, oxidative stress, and tissue remodeling are involved in the development of tissue specific diabetic bladder dysfunctions. Validation of signaling dysregulation as a function of diabetes was performed using Western blotting. These data illustrated changes in ERK1/2 phosphorylation as a function of diabetes, with significant decreases in diabetes-associated phosphorylation in urothelium, but the opposite effect in detrusor muscle. These data highlight the importance of understanding tissue specific effects of disease process in understanding pathophysiology in complex disease and pave the way for future studies to better understand important molecular targets in reversing bladder dysfunction. PMID:25573746

Tissue specific dysregulated protein subnetworks in type 2 diabetic bladder urothelium and detrusor muscle.

PubMed

Tomechko, Sara E; Liu, Guiming; Tao, Mingfang; Schlatzer, Daniela; Powell, C Thomas; Gupta, Sanjay; Chance, Mark R; Daneshgari, Firouz

2015-03-01

Diabetes mellitus is well known to cause bladder dysfunction; however, the molecular mechanisms governing this process and the effects on individual tissue elements within the bladder are poorly understood, particularly in type 2 diabetes. A shotgun proteomics approach was applied to identify proteins differentially expressed between type 2 diabetic (TallyHo) and control (SWR/J) mice in the bladder smooth muscle and urothelium, separately. We were able to identify 1760 nonredundant proteins from the detrusor smooth muscle and 3169 nonredundant proteins from urothelium. Pathway and network analysis of significantly dysregulated proteins was conducted to investigate the molecular processes associated with diabetes. This pinpointed ERK1/2 signaling as a key regulatory node in the diabetes-induced pathophysiology for both tissue types. The detrusor muscle samples showed diabetes-induced increased tissue remodeling-type events such as Actin Cytoskeleton Signaling and Signaling by Rho Family GTPases. The diabetic urothelium samples exhibited oxidative stress responses, as seen in the suppression of protein expression for key players in the NRF2-Mediated Oxidative Stress Response pathway. These results suggest that diabetes induced elevated inflammatory responses, oxidative stress, and tissue remodeling are involved in the development of tissue specific diabetic bladder dysfunctions. Validation of signaling dysregulation as a function of diabetes was performed using Western blotting. These data illustrated changes in ERK1/2 phosphorylation as a function of diabetes, with significant decreases in diabetes-associated phosphorylation in urothelium, but the opposite effect in detrusor muscle. These data highlight the importance of understanding tissue specific effects of disease process in understanding pathophysiology in complex disease and pave the way for future studies to better understand important molecular targets in reversing bladder dysfunction. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.

PubMed

Andrade, Jason; Khairy, Paul; Dobrev, Dobromir; Nattel, Stanley

2014-04-25

Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%-26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca(2+)-handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca(2+)-handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.

Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome: new concepts in treatment.

PubMed

Gur, Ali; Oktayoglu, Pelin

2008-01-01

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic-pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration (FDA)-approved treatments except pregabalin. Recent pharmacological treatment studies about fibromyalgia have focused on selective serotonin and norepinephrine (NE) reuptake inhibitors, which enhance serotonin and NE neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.

The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome.

PubMed

Ren, Jun; Anversa, Piero

2015-02-15

Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

A novel murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) induced by immunization with a spermine binding protein (p25) peptide

PubMed Central

Altuntas, Cengiz Z.; Veizi, Elias; Izgi, Kenan; Bicer, Fuat; Ozer, Ahmet; Grimberg, Kerry O.; Bakhautdin, Bakytzhan; Sakalar, Cagri; Tasdemir, Cemal; Tuohy, Vincent K.

2013-01-01

The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poorly understood. Inflammatory and autoimmune mechanisms may play a role. We developed a murine model of experimental autoimmune prostatitis (EAP) that mimics the human phenotype of CP/CPPS. Eight-week-old mice were immunized subcutaneously with prostate-specific peptides in an emulsion of complete Freund's adjuvant. Mice were euthanized 10 days after immunization, and lymph node cells were isolated and assessed for recall proliferation to each peptide. P25 99–118 was the most immunogenic peptide. T-cell and B-cell immunity and serum levels of C-reactive protein and nitrate/nitrite levels were evaluated over a 9-wk period. Morphometric studies of prostate, 24-h micturition frequencies, and urine volume per void were evaluated. Tactile referred hyperalgesia was measured using von Frey filaments to the pelvic region. The unpaired Student's t-test was used to analyze differences between EAP and control groups. Prostates from p25 99–118-immunized mice demonstrated elevated gene expression levels of TNF-α, IL-17A, IFN-γ, and IL-1β, not observed in control mice. Compared with controls, p25 99–118-immunized mice had significantly higher micturition frequency and decreased urine output per void, and they demonstrated elevated pelvic pain response. p25 99–118 immunization of male SWXJ mice induced prostate-specific autoimmunity characterized by prostate-confined inflammation, increased micturition frequency, and pelvic pain. This autoimmune prostatitis model provides a useful tool for exploring the pathophysiology and new treatments. PMID:23344231

Preserved dichotomy but highly irregular and burst discharge in the basal ganglia in alert dystonic rats at rest.

PubMed

Kumbhare, Deepak; Chaniary, Kunal D; Baron, Mark S

2015-10-22

Despite its prevalence, the underlying pathophysiology of dystonia remains poorly understood. Using our novel tri-component classification algorithm, extracellular neuronal activity in the globus pallidus (GP), STN, and the entopeduncular nucleus (EP) was characterized in 34 normal and 25 jaundiced dystonic Gunn rats with their heads restrained while at rest. In normal rats, neurons in each nucleus were similarly characterized by two physiologically distinct types: regular tonic with moderate discharge frequencies (mean rates in GP, STN and EP ranging from 35-41 spikes/s) or irregular at slower frequencies (17-20 spikes/s), with a paucity of burst activity. In dystonic rats, these nuclei were also characterized by two distinct principal neuronal patterns. However, in marked difference, in the dystonic rats, neurons were primarily slow and highly irregular (12-15 spikes/s) or burst predominant (14-17 spikes/s), with maintained modest differences between nuclei. In GP and EP, with increasing severity of dystonia, burstiness was moderately further increased, irregularity mildly further increased, and discharge rates mildly further reduced. In contrast, these features did not appreciably change in STN with worsening dystonia. Findings of a lack of bursting in GP, STN and EP in normal rats in an alert resting state and prominent bursting in dystonic Gunn rats suggest that cortical or other external drive is normally required for bursting in these nuclei and that spontaneous bursting, as seen in dystonia and Parkinson's disease, is reflective of an underlying pathophysiological state. Moreover, the extent of burstiness appears to most closely correlate with the severity of the dystonia. Published by Elsevier B.V.

Brain structural changes in spasmodic dysphonia: A multimodal magnetic resonance imaging study.

PubMed

Kostic, Vladimir S; Agosta, Federica; Sarro, Lidia; Tomić, Aleksandra; Kresojević, Nikola; Galantucci, Sebastiano; Svetel, Marina; Valsasina, Paola; Filippi, Massimo

2016-04-01

The pathophysiology of spasmodic dysphonia is poorly understood. This study evaluated patterns of cortical morphology, basal ganglia, and white matter microstructural alterations in patients with spasmodic dysphonia relative to healthy controls. T1-weighted and diffusion tensor magnetic resonance imaging (MRI) scans were obtained from 13 spasmodic dysphonia patients and 30 controls. Tract-based spatial statistics was applied to compare diffusion tensor MRI indices (i.e., mean, radial and axial diffusivities, and fractional anisotropy) between groups on a voxel-by-voxel basis. Cortical measures were analyzed using surface-based morphometry. Basal ganglia were segmented on T1-weighted images, and volumes and diffusion tensor MRI metrics of nuclei were measured. Relative to controls, patients with spasmodic dysphonia showed increased cortical surface area of the primary somatosensory cortex bilaterally in a region consistent with the buccal sensory representation, as well as right primary motor cortex, left superior temporal, supramarginal and superior frontal gyri. A decreased cortical area was found in the rolandic operculum bilaterally, left superior/inferior parietal and lingual gyri, as well as in the right angular gyrus. Compared to controls, spasmodic dysphonia patients showed increased diffusivities and decreased fractional anisotropy of the corpus callosum and major white matter tracts, in the right hemisphere. Altered diffusion tensor MRI measures were found in the right caudate and putamen nuclei with no volumetric changes. Multi-level alterations in voice-controlling networks, that included regions devoted not only to sensorimotor integration, motor preparation and motor execution, but also processing of auditory and visual information during speech, might have a role in the pathophysiology of spasmodic dysphonia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Activity-based anorexia activates nesfatin-1 immunoreactive neurons in distinct brain nuclei of female rats.

PubMed

Scharner, Sophie; Prinz, Philip; Goebel-Stengel, Miriam; Lommel, Reinhard; Kobelt, Peter; Hofmann, Tobias; Rose, Matthias; Stengel, Andreas

2017-12-15

Activity-based anorexia (ABA) is an established animal model for the eating disorder anorexia nervosa (AN). The pathophysiology of AN and the involvement of food intake-regulatory peptides is still poorly understood. Nesfatin-1, an anorexigenic peptide also involved in the mediation of stress, anxiety and depression might be a likely candidate involved in the pathogenesis of AN. Therefore, activation of nesfatin-1 immunoreactive (ir) brain nuclei was investigated under conditions of ABA. Female Sprague-Dawley rats were used and divided into four groups (n=6/group): activity-based anorexia (ABA), restricted feeding (RF), activity (AC) and ad libitum fed (AL). After the 21-day experimental period and development of ABA, brains were processed for c-Fos/nesfatin-1 double labeling immunohistochemistry. ABA increased the number of nesfatin-1 immunopositive neurons in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, locus coeruleus and in the rostral part of the nucleus of the solitary tract compared to AL and AC groups (p<0.05) but not to RF rats (p>0.05). Moreover, we observed significantly more c-Fos and nesfatin-1 ir double-labeled cells in ABA rats compared to RF, AL and AC in the supraoptic nucleus (p<0.05) and compared to AL and AC in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, dorsal raphe nucleus and the rostral raphe pallidus (p<0.05). Since nesfatin-1 plays a role in the inhibition of food intake and the response to stress, we hypothesize that the observed changes of brain nesfatin-1 might play a role in the pathophysiology and symptomatology under conditions of ABA and potentially also in patients with AN. Copyright © 2017 Elsevier B.V. All rights reserved.

BMP4 and LGL1 are Down Regulated in an Ovine Model of Congenital Diaphragmatic Hernia

PubMed Central

Emmerton-Coughlin, Heather M. A.; Martin, K. Kathryn; Chiu, Jacky S. S.; Zhao, Lin; Scott, Leslie A.; Regnault, Timothy R. H.; Bütter, Andreana

2014-01-01

Background/Purpose: The molecular pathophysiology of lung hypoplasia in congenital diaphragmatic hernia (CDH) remains poorly understood. The Wnt signaling pathway and downstream targets, such as bone morphogenetic proteins (BMP) 4 and other factors such as late gestation lung protein 1 (LGL1), are essential to normal lung development. Nitrofen-induced hypoplastic CDH rodent lungs demonstrate down regulation of the Wnt pathway including BMP4 and reduced LGL1 expression. The aim of the current study was to examine the molecular pathophysiology associated with a surgically induced CDH in an ovine model. Methods: Left thoracotomy was performed at 80 days in 14 fetal sheep; CDH was created in seven experimental animals. Lungs were harvested at 136 days (term = 145 days). Lung weight (LW) and mean terminal bronchiole density (MTBD) were measured to determine the degree of pulmonary hypoplasia. Quantitative real time PCR was undertaken to analyze Wnt2, Wnt7b, BMP4, and LGL1 mRNA expression. Results: Total LW was decreased while MTBD was increased in the CDH group (p < 0.05), confirming pulmonary hypoplasia. BMP4 and LGL1 mRNA was significantly reduced in CDH lungs (p < 0.05). Wnt2 mRNA was decreased, although not significantly (p < 0.06). Conclusion: For the first time, down regulation of BMP4 and LGL1 are reported in an ovine CDH model. In contrast to other animal models, these changes are persistent to near term. These findings suggest that mechanical compression from herniated viscera may play a more important role in causing pulmonary hypoplasia in CDH, rather than a primary defect in lung organogenesis. PMID:25593968

Faecal soiling: pathophysiology of postdefaecatory incontinence.

PubMed

Pucciani, F

2013-08-01

Passive postdefaecatory incontinence is poorly understood and yet is an important clinical problem. The aim of this study was to characterize the pathophysiology of postdefaecatory incontinence in patients affected by faecal soiling. Seventy-two patients (30 women, age range 49-79 years; 42 men, age range, 53-75 years) affected by faecal passive incontinence with faecal soiling were included in the study. Two patient groups were identified: Group 1 comprised 42 patients with postdefaecatory incontinence and Group 2 had 30 patients without incontinence after bowel movements. After a preliminary clinical evaluation, including the Faecal Incontinence Severity Index (FISI) score and the obstructed defaecation syndrome (ODS) score, all patients of Groups 1 and 2 were studied by means of endoanal ultrasound and anorectal manometry. The results were compared with those from 20 healthy control subjects. A significantly higher ODS score was found in Group 1 (P < 0.001). Endoanal ultrasound revealed a significantly diffuse thinning of the internal anal sphincter (IAS) in Group 2 (P < 0.02) with a linear relationship between signs of IAS atrophy and the FISI score (ρs 0.78; P < 0.03). Anal resting pressure (Pmax and Pm ) was significantly lower in Group 2 (P < 0.04). The straining test was considered positive in 30 (71.4%) patients in Group 1, significantly greater than in Group 2 (P < 0.01). A significantly higher conscious rectal sensitivity threshold (CRST) was found in Group 1 patients (P < 0.01). The ODS score, a positive straining test and high CRST values suggest that postdefaecatory incontinence is secondary to impaired defaecation. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.

Rationale, design and objectives of ARegPKD, a European ARPKD registry study.

PubMed

Ebner, Kathrin; Feldkoetter, Markus; Ariceta, Gema; Bergmann, Carsten; Buettner, Reinhard; Doyon, Anke; Duzova, Ali; Goebel, Heike; Haffner, Dieter; Hero, Barbara; Hoppe, Bernd; Illig, Thomas; Jankauskiene, Augustina; Klopp, Norman; König, Jens; Litwin, Mieczyslaw; Mekahli, Djalila; Ranchin, Bruno; Sander, Anja; Testa, Sara; Weber, Lutz Thorsten; Wicher, Dorota; Yuzbasioglu, Ayse; Zerres, Klaus; Dötsch, Jörg; Schaefer, Franz; Liebau, Max Christoph

2015-02-18

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but frequently severe disorder that is typically characterized by cystic kidneys and congenital hepatic fibrosis but displays pronounced phenotypic heterogeneity. ARPKD is among the most important causes for pediatric end stage renal disease and a leading reason for liver-, kidney- or combined liver kidney transplantation in childhood. The underlying pathophysiology, the mechanisms resulting in the observed clinical heterogeneity and the long-term clinical evolution of patients remain poorly understood. Current treatment approaches continue to be largely symptomatic and opinion-based even in most-advanced medical centers. While large clinical trials for the frequent and mostly adult onset autosomal dominant polycystic kidney diseases have recently been conducted, therapeutic initiatives for ARPKD are facing the challenge of small and clinically variable cohorts for which reliable end points are hard to establish. ARegPKD is an international, mostly European, observational study to deeply phenotype ARPKD patients in a pro- and retrospective fashion. This registry study is conducted with the support of the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients (ESCAPE Network). ARegPKD clinically characterizes long-term ARPKD courses by a web-based approach that uses detailed basic data questionnaires in combination with yearly follow-up visits. Clinical data collection is accompanied by associated biobanking and reference histology, thus setting roots for future translational research. The novel registry study ARegPKD aims to characterize miscellaneous subcohorts and to compare the applied treatment options in a large cohort of deeply characterized patients. ARegPKD will thus provide evidence base for clinical treatment decisions and contribute to the pathophysiological understanding of this severe inherited disorder.

Adenosine and preeclampsia.

PubMed

Salsoso, Rocío; Farías, Marcelo; Gutiérrez, Jaime; Pardo, Fabián; Chiarello, Delia I; Toledo, Fernando; Leiva, Andrea; Mate, Alfonso; Vázquez, Carmen M; Sobrevia, Luis

2017-06-01

Adenosine is an endogenous nucleoside with pleiotropic effects in different physiological processes including circulation, renal blood flow, immune function, or glucose homeostasis. Changes in adenosine membrane transporters, adenosine receptors, and corresponding intracellular signalling network associate with development of pathologies of pregnancy, including preeclampsia. Preeclampsia is a cause of maternal and perinatal morbidity and mortality affecting 3-5% of pregnancies. Since the proposed mechanisms of preeclampsia development include adenosine-dependent biological effects, adenosine membrane transporters and receptors, and the associated signalling mechanisms might play a role in the pathophysiology of preeclampsia. Preeclampsia associates with increased adenosine concentration in the maternal blood and placental tissue, likely due to local hypoxia and ischemia (although not directly demonstrated), microthrombosis, increased catecholamine release, and platelet activation. In addition, abnormal expression and function of equilibrative nucleoside transporters is described in foetoplacental tissues from preeclampsia; however, the role of adenosine receptors in the aetiology of this disease is not well understood. Adenosine receptors activation may be related to abnormal trophoblast invasion, angiogenesis, and ischemia/reperfusion mechanisms in the placenta from preeclampsia. These mechanisms may explain only a low fraction of the associated abnormal transformation of spiral arteries in preeclampsia, triggering cellular stress and inflammatory mediators release from the placenta to the maternal circulation. Although increased adenosine concentration in preeclampsia may be a compensatory or adaptive mechanism favouring placental angiogenesis, a poor angiogenic state is found in preeclampsia. Thus, preeclampsia-associated complications might affect the cell response to adenosine due to altered expression and activity of adenosine receptors, membrane transporters, or cell signalling mechanisms. This review summarizes the evidence available on the potential involvement of the adenosine in the clinical, pathophysiology, and therapeutic features of preeclampsia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multifocal small bowel stromal tumours presenting with peritonitis in an HIV positive patient.

PubMed

Mansoor, Ebrahim

2014-01-01

The most common mesenchymal tumour of the gastrointestinal tract is stromal tumours (GISTs). Symptomatic GISTs can present with complications such as haemorrhage, obstruction and perforation. Complete surgical resection with negative margins is the mainstay of treatment but may be imprudent on emergent occasion. Tyrosine-kinase inhibitors (TKIs) have been revolutionary in the treatment of GISTs and have resulted in improved outcomes. A 41 year old HIV positive male presented with an acute history of abdominal pain and obstructive symptoms. Clinical examination revealed sepsis and peritonitis. One of the several small bowel tumours discovered at exploratory laparotomy was necrotic and perforated. The perforated tumour alone was resected and a small bowel internal hernia reduced. The patient made an uneventful recovery and will be considered for TKI therapy with a view to later re-operation. GISTs very rarely perforate. The pathophysiology of stromal tumour necrosis is poorly understood. Multifocality and small bowel location are poor prognosticators and may occur in the setting of familial GISTs, specific syndromes and sporadic cases. There is no established association between HIV and GISTs. Perforation occurs infrequently in ≤8% of symptomatic cases and poses increased risk of local recurrence. The surgical management of perforation takes precedence in an emergency. The surgeon must however take cognisance of the adherence to ideal oncologic principles where feasible. TKI therapy is invaluable if a re-exploration is to be later considered. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation.

PubMed

Langer, Arielle L; Ginzburg, Yelena Z

2017-06-01

Anemia of chronic inflammation (ACI) is a frequently diagnosed anemia and portends an independently increased morbidity and poor outcome associated with multiple underlying diseases. The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines which both directly and indirectly suppress erythropoiesis. Recent advances in molecular understanding of iron metabolism provide strong evidence that immune mediators, such as IL-6, lead to hepcidin-induced hypoferremia, iron sequestration, and decreased iron availability for erythropoiesis. The role of hepcidin-ferroportin axis in the pathophysiology of ACI is stimulating the development of new diagnostics and targeted therapies. In this review, we present an overview of and rationale for inflammation-, iron-, and erythropoiesis-related strategies currently in development. © 2017 International Society for Hemodialysis.

Laboratory tests for mumps vaccines.

PubMed

Minor, P D

1997-03-01

The action of live attenuated vaccines against mumps is poorly understood although their clinical efficacy is beyond doubt. The attenuated character of the vaccine is assured by consistency of production related to clinical trials, and limited studies of vaccine seeds in primates. Potency is assessed by infectivity in vitro and is subject to poorly understood sources of variation. Molecular biological studies are at an early stage.

Contact variables for exposure to avian influenza H5N1 virus at the human-animal interface.

PubMed

Rabinowitz, P; Perdue, M; Mumford, E

2010-06-01

Although the highly pathogenic avian influenza H5N1 virus continues to cause infections in both avian and human populations, the specific zoonotic risk factors remain poorly understood. This review summarizes available evidence regarding types of contact associated with transmission of H5N1 virus at the human-animal interface. A systematic search of the published literature revealed five analytical studies and 15 case reports describing avian influenza transmission from animals to humans for further review. Risk factors identified in analytical studies were compared, and World Health Organization-confirmed cases, identified in case reports, were classified according to type of contact reported using a standardized algorithm. Although cases were primarily associated with direct contact with sick/unexpectedly dead birds, some cases reported only indirect contact with birds or contaminated environments or contact with apparently healthy birds. Specific types of contacts or activities leading to exposure could not be determined from data available in the publications reviewed. These results support previous reports that direct contact with sick birds is not the only means of human exposure to avian influenza H5N1 virus. To target public health measures and disease awareness messaging for reducing the risk of zoonotic infection with avian influenza H5N1 virus, the specific types of contacts and activities leading to transmission need to be further understood. The role of environmental virus persistence, shedding of virus by asymptomatic poultry and disease pathophysiology in different avian species relative to human zoonotic risk, as well as specific modes of zoonotic transmission, should be determined.

Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

PubMed

Deng, Linhong; Bosse, Ynuk; Brown, Nathan; Chin, Leslie Y M; Connolly, Sarah C; Fairbank, Nigel J; King, Greg G; Maksym, Geoffrey N; Paré, Peter D; Seow, Chun Y; Stephen, Newman L

2009-10-01

Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSK's dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

Dandy-Walker syndrome presenting as opisthotonus: proposed pathophysiology.

PubMed

Ondo, W G; Delong, G R

1996-02-01

A patient with radiographically confirmed Dandy-Walker syndrome who presented with opisthotonus, a rarely reported clinical manifestation, is reported. From four separate pharmacologic trials (baclofen, diazepam, levodopa/carbidopa, and trihexyphenidyl), combination baclofen and diazepam therapy was determined to be most efficacious. Opisthotonus and extensor posturing remain only rudimentarily understood. We review the subject and propose a specific mechanism relating our patient's anatomic and physiologic conditions.

Modified Graded Motor Imagery for Complex Regional Pain Syndrome Type 1 of the Upper Extremity in the Acute Phase: A Patient Series

ERIC Educational Resources Information Center

Lagueux, Emilie; Charest, Joelle; Lefrancois-Caron, Eve; Mauger, Marie-Eve; Mercier, Emilie; Savard, Kim; Tousignant-Laflamme, Yannick

2012-01-01

Complex regional pain syndrome (CRPS) is a pathologic condition in which the painful experience is disproportionate in time and intensity in comparison with the inciting event. At present, the pathophysiology of CRPS is not well understood. Several studies have indicated that cortical reorganization plays a role in the persistence of the symptoms.…

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

PubMed

Jabbi, M; Korf, J; Kema, I P; Hartman, C; van der Pompe, G; Minderaa, R B; Ormel, J; den Boer, J A

2007-05-01

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

PubMed Central

Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

2015-01-01

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

Pathological effect of homeostatic synaptic scaling on network dynamics in diseases of the cortex.

PubMed

Fröhlich, Flavio; Bazhenov, Maxim; Sejnowski, Terrence J

2008-02-13

Slow periodic EEG discharges are common in CNS disorders. The pathophysiology of this aberrant rhythmic activity is poorly understood. We used a computational model of a neocortical network with a dynamic homeostatic scaling rule to show that loss of input (partial deafferentation) can trigger network reorganization that results in pathological periodic discharges. The decrease in average firing rate in the network by deafferentation was compensated by homeostatic synaptic scaling of recurrent excitation among pyramidal cells. Synaptic scaling succeeded in recovering the network target firing rate for all degrees of deafferentation (fraction of deafferented cells), but there was a critical degree of deafferentation for pathological network reorganization. For deafferentation degrees below this value, homeostatic upregulation of recurrent excitation had minimal effect on the macroscopic network dynamics. For deafferentation above this threshold, however, a slow periodic oscillation appeared, patterns of activity were less sparse, and bursting occurred in individual neurons. Also, comparison of spike-triggered afferent and recurrent excitatory conductances revealed that information transmission was strongly impaired. These results suggest that homeostatic plasticity can lead to secondary functional impairment in case of cortical disorders associated with cell loss.

Management of established pressure ulcer infections in spinal cord injury patients.

PubMed

Dinh, A; Bouchand, F; Davido, B; Duran, C; Denys, P; Lortat-Jacob, A; Rottman, M; Salomon, J; Bernard, L

2018-06-21

Pressure ulcers are frequently observed in spinal cord injury (SCI) patients. They can be life-threatening and are a major medico-economic burden. Despite their frequency, their pathophysiology and optimal management are still poorly understood. Most available data comes from non-comparative studies, especially in terms of antimicrobial use. We performed a critical review of the literature and opinions of infectious disease specialists based in a French expert center for this disease. We mainly focused on antimicrobial treatments prescribed in this situation. These infections are usually clinically diagnosed. Microbiological samples are not the gold standard for this assessment. Furthermore, reliable microbiological identification is a major challenge but should help select antimicrobial treatment. Imaging technique could be helpful but cannot replace the physical examination. The choice of antimicrobials must consider the potential ecological collateral damages in this vulnerable population. Antimicrobial therapy should be as short as possible, adapted to the microbiological identification, and must have suitable bioavailability. Management of infected pressure ulcers is a major concern in disabled patients already highly exposed to antimicrobial treatment and multidrug-resistant organisms colonization. Extensive data is required. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.

PubMed

Feichtinger, René G; Neureiter, Daniel; Skaria, Tom; Wessler, Silja; Cover, Timothy L; Mayr, Johannes A; Zimmermann, Franz A; Posselt, Gernot; Sperl, Wolfgang; Kofler, Barbara

2017-01-01

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

Microfluidics for investigating vaso-occlusions in sickle cell disease.

PubMed

Horton, Renita E

2017-07-01

SCD stems from amutation in the beta globin gene. Upon deoxygenation, hemoglobin polymerizes and triggers RBC remodeling. This phenomenon is central to SCD pathogenesis as individuals suffering from the disease are plagued by painful vaso-occlusive crises episodes. These episodes are the result of a combination of processes including inflammation, thrombosis, and blood cell adhesion to the vascular wall which leads to blockages within the vasculature termed vaso-occlusions. Vaso-occlusive episodes deprive tissues of oxygen and are a major contributor to SCD-related complications; unfortunately, the complex mechanisms that contribute to vaso-occlusions are not well understood. Vaso-occlusions can occur in post-capillary venules; hence, the microvasculature is a prime target for SCD therapies. Traditional in vitro systems poorly recapitulate architectural and dynamic flow properties of in vivo systems. However, microfluidic devices can capture features of the native vasculature such as cellular composition, flow, geometry, and ECM presentation. This review, although not comprehensive, highlights microfluidic approaches that aim to improve our current understanding of the pathophysiological mechanisms surrounding SCD. Microfluidic platforms can aid in identifying factors that may contribute to disease severity and can serve as suitable test beds for novel treatment strategies which may improve patient outcomes. © 2017 John Wiley & Sons Ltd.

Autophagy in atherosclerosis: a cell survival and death phenomenon with therapeutic potential.

PubMed

Martinet, Wim; De Meyer, Guido R Y

2009-02-13

Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. A growing body of evidence suggests that autophagy is stimulated in advanced atherosclerotic plaques by oxidized lipids, inflammation, and metabolic stress conditions. However, despite the increasing interest in autophagy in various pathophysiological situations such as neurodegeneration, cancer, and cardiac myopathies, the process remains an underestimated and overlooked phenomenon in atherosclerosis. As a consequence, its role in plaque formation and stability is poorly understood. Most likely, autophagy safeguards plaque cells against cellular distress, in particular oxidative injury, by degrading damaged intracellular material. In this way, autophagy is antiapoptotic and contributes to cellular recovery in an adverse environment. An interesting observation is that basal autophagy can be intensified by specific drugs. Excessively stimulated autophagic activity is capable of destroying major proportions of the cytosol, leading finally to type II programmed cell death that lacks several hallmarks of apoptosis or necrosis. Because atherosclerosis is an inflammatory disorder of the arterial intima, pharmacological approaches could be developed to stabilize vulnerable, rupture-prone lesions through selective induction of macrophage autophagic death.

Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

PubMed Central

Dace, Dru S.; Khan, Aslam A.; Stark, Jennifer L.; Kelly, Jennifer; Cross, Anne H.; Apte, Rajendra S.

2009-01-01

Background Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. Principal Findings Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. Significance These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome. PMID:19771172

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor.

PubMed

Hinson, Shannon R; Clift, Ian C; Luo, Ningling; Kryzer, Thomas J; Lennon, Vanda A

2017-05-23

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease.

PubMed

Haas, Joel T; Francque, Sven; Staels, Bart

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation, and hepatocyte dysfunction. Importantly, it is also closely linked to obesity and the metabolic syndrome. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma, and cardiovascular disease. Although the precise signals remain poorly understood, NAFLD pathogenesis likely involves actions of the different hepatic cell types and multiple extrahepatic signals. The complexity of this disease has been a major impediment to the development of appropriate metrics of its progression and effective therapies. Recent clinical data place increasing importance on identifying fibrosis, as it is a strong indicator of hepatic disease-related mortality. Preclinical modeling of the fibrotic process remains challenging, particularly in the contexts of obesity and the metabolic syndrome. Future studies are needed to define the molecular pathways determining the natural progression of NAFLD, including key determinants of fibrosis and disease-related outcomes. This review covers the evolving concepts of NAFLD from both human and animal studies. We discuss recent clinical and diagnostic methods assessing NAFLD diagnosis, progression, and outcomes; compare the features of genetic and dietary animal models of NAFLD; and highlight pharmacological approaches for disease treatment.

Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis

PubMed Central

Skaria, Tom; Wessler, Silja; Cover, Timothy L.; Posselt, Gernot; Sperl, Wolfgang; Kofler, Barbara

2017-01-01

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection. PMID:28744336

Ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients.

PubMed

Foglia, Elizabeth; Meier, Mary Dawn; Elward, Alexis

2007-07-01

Ventilator-associated pneumonia (VAP) is the second most common hospital-acquired infection among pediatric intensive care unit (ICU) patients. Empiric therapy for VAP accounts for approximately 50% of antibiotic use in pediatric ICUs. VAP is associated with an excess of 3 days of mechanical ventilation among pediatric cardiothoracic surgery patients. The attributable mortality and excess length of ICU stay for patients with VAP have not been defined in matched case control studies. VAP is associated with an estimated $30,000 in attributable cost. Surveillance for VAP is complex and usually performed using clinical definitions established by the CDC. Invasive testing via bronchoalveolar lavage increases the sensitivity and specificity of the diagnosis. The pathogenesis in children is poorly understood, but several prospective cohort studies suggest that aspiration and immunodeficiency are risk factors. Educational interventions and efforts to improve adherence to hand hygiene for children have been associated with decreased VAP rates. Studies of antibiotic cycling in pediatric patients have not consistently shown this measure to prevent colonization with multidrug-resistant gram-negative rods. More consistent and precise approaches to the diagnosis of pediatric VAP are needed to better define the attributable morbidity and mortality, pathophysiology, and appropriate interventions to prevent this disease.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection.

PubMed

Gregson, Aric L; Hoji, Aki; Injean, Patil; Poynter, Steven T; Briones, Claudia; Palchevskiy, Vyacheslav; Weigt, S Sam; Shino, Michael Y; Derhovanessian, Ariss; Sayah, David; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P; Belperio, John A

2015-12-15

The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection

PubMed Central

Hoji, Aki; Injean, Patil; Poynter, Steven T.; Briones, Claudia; Palchevskiy, Vyacheslav; Sam Weigt, S.; Shino, Michael Y.; Derhovanessian, Ariss; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P.; Belperio, John A.

2015-01-01

Rationale: The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. Objectives: To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Methods: Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. Measurements and Main Results: AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Conclusions: Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation. PMID:26308930

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance

PubMed Central

Tan, Chin Lik; Alavi, Seyed Alireza; Baldeweg, Stephanie E; Belli, Antonio; Carson, Alan; Feeney, Claire; Goldstone, Anthony P; Greenwood, Richard; Menon, David K; Simpson, Helen L; Toogood, Andrew A; Gurnell, Mark; Hutchinson, Peter J

2017-01-01

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines. PMID:28860331

Chronic proctalgia and chronic pelvic pain syndromes: New etiologic insights and treatment options

PubMed Central

Chiarioni, Giuseppe; Asteria, Corrado; Whitehead, William E

2011-01-01

This systematic review addresses the pathophysiology, diagnostic evaluation, and treatment of several chronic pain syndromes affecting the pelvic organs: chronic proctalgia, coccygodynia, pudendal neuralgia, and chronic pelvic pain. Chronic or recurrent pain in the anal canal, rectum, or other pelvic organs occurs in 7% to 24% of the population and is associated with impaired quality of life and high health care costs. However, these pain syndromes are poorly understood, with little research evidence available to guide their diagnosis and treatment. This situation appears to be changing: A recently published large randomized, controlled trial by our group comparing biofeedback, electrogalvanic stimulation, and massage for the treatment of chronic proctalgia has shown success rates of 85% for biofeedback when patients are selected based on physical examination evidence of tenderness in response to traction on the levator ani muscle-a physical sign suggestive of striated muscle tension. Excessive tension (spasm) in the striated muscles of the pelvic floor appears to be common to most of the pelvic pain syndromes. This suggests the possibility that similar approaches to diagnostic assessment and treatment may improve outcomes in other pelvic pain disorders. PMID:22110274

Aerophagia and Intestinal Gas.

PubMed

Quigley, Eamonn M. M.

2002-08-01

Aerophagia refers to a rather rare disorder that may occur in both children and adults that features repetitive air swallowing and belching and that may result in abdominal distention. There are few, if any, controlled studies to guide therapy, which remains largely supportive but may include behavioral therapy and psychotherapy. Bloating, distention, and other gas-related symptoms are common in functional gastrointestinal disorders, including the irritable bowel syndrome; their pathophysiology remains, for the most part, poorly understood. Two separate phenomena need to be distinguished in these disorders: gas production and gas perception. Thus, whereas gas production, which relates most closely to flatus emissions, is probably within the normal range in most patients with irritable bowel syndrome, gas transport or transit through the gut may be impaired and may lead to the retention of gas within segments of the gut. Visceral hypersensitivity, a common phenomenon in all functional disorders, may exacerbate the sensation of distention and contribute to other "gas-related" symptoms. Few controlled studies have addressed any of these issues. Although, on an empiric basis, dietary therapy may be partially effective in some situations, there is at present no data to support the use of any form of pharmacologic, endoscopic, or surgical therapy for any of these symptoms.

The Potential Role of Senescence As a Modulator of Platelets and Tumorigenesis

PubMed Central

Valenzuela, Claudio A.; Quintanilla, Ricardo; Moore-Carrasco, Rodrigo; Brown, Nelson E.

2017-01-01

In addition to thrombus formation, alterations in platelet function are frequently observed in cancer patients. Importantly, both thrombus and tumor formation are influenced by age, although the mechanisms through which physiological aging modulates these processes remain poorly understood. In this context, the potential effects of senescent cells on platelet function represent pathophysiological mechanisms that deserve further exploration. Cellular senescence has traditionally been viewed as a barrier to tumorigenesis. However, far from being passive bystanders, senescent cells are metabolically active and able to secrete a variety of soluble and insoluble factors. This feature, known as the senescence-associated secretory phenotype (SASP), may provide senescent cells with the capacity to modify the tissue environment and, paradoxically, promote proliferation and neoplastic transformation of neighboring cells. In fact, the SASP-dependent ability of senescent cells to enhance tumorigenesis has been confirmed in cellular systems involving epithelial cells and fibroblasts, leaving open the question as to whether similar interactions can be extended to other cellular contexts. In this review, we discuss the diverse functions of platelets in tumorigenesis and suggest the possibility that senescent cells might also influence tumorigenesis through their ability to modulate the functional status of platelets through the SASP. PMID:28894697

Aspirin Increases Mitochondrial Fatty Acid Oxidation

PubMed Central

Uppala, Radha; Dudiak, Brianne; Beck, Megan E.; Bharathi, Sivakama S.; Zhang, Yuxun; Stolz, Donna B.; Goetzman, Eric S.

2016-01-01

The metabolic effects of salicylates are poorly understood. This study investigated the effects of aspirin on fatty acid oxidation. Aspirin increased mitochondrial long-chain fatty acid oxidation, but inhibited peroxisomal fatty acid oxidation, in two different cell lines. Aspirin increased mitochondrial protein acetylation and was found to be a stronger acetylating agent in vitro than acetyl-CoA. However, aspirin-induced acetylation did not alter the activity of fatty acid oxidation proteins, and knocking out the mitochondrial deacetylase SIRT3 did not affect the induction of long-chain fatty acid oxidation by aspirin. Aspirin did not change oxidation of medium-chain fatty acids, which can freely traverse the mitochondrial membrane. Together, these data indicate that aspirin does not directly alter mitochondrial matrix fatty acid oxidation enzymes, but most likely exerts its effects at the level of long-chain fatty acid transport into mitochondria. The drive on mitochondrial fatty acid oxidation may be a compensatory response to altered mitochondrial morphology and inhibited electron transport chain function, both of which were observed after 24 hr incubation of cells with aspirin. These studies provide insight into the pathophysiology of Reye Syndrome, which is known to be triggered by aspirin ingestion in patients with fatty acid oxidation disorders. PMID:27856258

Leptin confers protection against TNF-α-induced apoptosis in rat cardiomyocytes.

PubMed

Yu, Lu; Zhao, Yanbo; Xu, Shengjie; Jin, Chongying; Wang, Min; Fu, Guosheng

2014-12-05

Leptin, an important adipose-derived hormone, is recognized as a crucial protein in energy homeostasis. Recent studies indicated that leptin is associated with cardiac pathophysiology, however, the role and mechanisms of leptin in cardiomyocytes apoptosis are poorly understood. Here we investigated whether leptin exerted protective effect on cardiomyocytes exposed to tumor necrosis factor-alpha (TNF-α) and the possible mechanisms. Neonatal rat cardiomyocytes were subjected to TNF-α in the presence or absence of leptin. By FITC/Annexin V flow cytometry and Western blot, we noticed that TNF-α increased Annexin V binding and cleaved caspase-3/PARP, which were attenuated by leptin pretreatment. Moreover, leptin protected cardiomyocytes against mitochondrial apoptosis by inhibiting cytochrome C elevation and Bcl-2 decreasing. TNF-α-induced P38 MAPK and NF-κB activation were abolished by leptin addition, and the P38 and NF-κB inhibitor, SB203580 and Bay117082, also mitigated the apoptotic effect of TNF-α, indicating that their activation might be responsible for the apoptosis in TNF-α-treated cardiomyocytes. Therefore, leptin conferred anti-apoptotic effect in cardiomyocytes exposed to TNF-α possibly by inhibiting TNF-α-activated P38 MAPK and NF-κB pathways.

The Leu72Met polymorphism of the ghrelin gene is significantly associated with binge eating disorder.

PubMed

Monteleone, Palmiero; Tortorella, Alfonso; Castaldo, Eloisa; Di Filippo, Carmela; Maj, Mario

2007-02-01

The pathophysiological mechanisms underlying binge eating disorder are poorly understood. Evidence exists for the fact that abnormalities in peptides involved in the regulation of appetite, including ghrelin, may play a role in binge eating behavior. Genes involved in the ghrelin physiology may therefore contribute to the biological vulnerability to binge eating disorder. We examined whether two polymorphisms of the ghrelin gene, the G152A (Arg51Gln) and C214A (Leu72Met), were associated with binge eating disorder. Ninety obese or nonobese women with binge eating disorder and 119 normal weight women were genotyped at the ghrelin gene. Statistical analyses showed that the Leu72Met ghrelin gene variant was significantly more frequent in binge eating disorder patients (chi2=5.940; d.f.=1, P=0.01) and was associated with a moderate, but significant risk to develop binge eating disorder (odds ratio=2.725, 95% confidence interval: 1.168-6.350). Although these data should be regarded as preliminary because of the small sample size, they suggest that the Leu72Met ghrelin gene variant may contribute to the genetic susceptibility to binge eating disorder.

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

PubMed Central

Lisieski, Michael J.; Eagle, Andrew L.; Conti, Alana C.; Liberzon, Israel; Perrine, Shane A.

2018-01-01

Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD. PMID:29867615

Evaluation of a Murine Single-Blood-Injection SAH Model

PubMed Central

Sommer, Clemens; Steiger, Hans-Jakob; Schneider, Toni; Hänggi, Daniel

2014-01-01

The molecular pathways underlying the pathogenesis after subarachnoid haemorrhage (SAH) are poorly understood and continue to be a matter of debate. A valid murine SAH injection model is not yet available but would be the prerequisite for further transgenic studies assessing the mechanisms following SAH. Using the murine single injection model, we examined the effects of SAH on regional cerebral blood flow (rCBF) in the somatosensory (S1) and cerebellar cortex, neuro-behavioural and morphological integrity and changes in quantitative electrocorticographic and electrocardiographic parameters. Micro CT imaging verified successful blood delivery into the cisterna magna. An acute impairment of rCBF was observed immediately after injection in the SAH and after 6, 12 and 24 hours in the S1 and 6 and 12 hours after SAH in the cerebellum. Injection of blood into the foramen magnum reduced telemetric recorded total ECoG power by an average of 65%. Spectral analysis of ECoGs revealed significantly increased absolute delta power, i.e., slowing, cortical depolarisations and changes in ripples and fast ripple oscillations 12 hours and 24 hours after SAH. Therefore, murine single-blood-injection SAH model is suitable for pathophysiological and further molecular analysis following SAH. PMID:25545775

Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72.

PubMed

Ji, Yon Ju; Ugolino, Janet; Brady, Nathan Ryan; Hamacher-Brady, Anne; Wang, Jiou

2017-07-03

A genetic mutation in the C9orf72 gene causes the most common forms of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 protein, predicted to be a DENN-family protein, is reduced in ALS and FTD, but its functions remain poorly understood. Using a 3110043O21Rik/C9orf72 knockout mouse model, as well as cellular analysis, we have found that loss of C9orf72 causes alterations in the signaling states of central autophagy regulators. In particular, C9orf72 depletion leads to reduced activity of MTOR, a negative regulator of macroautophagy/autophagy, and concomitantly increased TFEB levels and nuclear translocation. Consistent with these alterations, cells exhibit enlarged lysosomal compartments and enhanced autophagic flux. Loss of the C9orf72 interaction partner SMCR8 results in similar phenotypes. Our findings suggest that C9orf72 functions as a potent negative regulator of autophagy, with a central role in coupling the cellular metabolic state with autophagy regulation. We thus propose C9orf72 as a fundamental component of autophagy signaling with implications in basic cell physiology and pathophysiology, including neurodegeneration.

Musical hallucinations in a patient with presbycusis: a case report.

PubMed

Brunner, Jacob P; Amedee, Ronald G

2015-01-01

Musical hallucinations are a rare subtype of auditory hallucination characterized by the perception of musical sounds, instrumental music, or songs. They are most commonly seen in older women with age-related hearing loss but are also associated with neurologic and psychiatric conditions. The underlying pathophysiology is poorly understood and likely multifactorial. A 74-year-old woman presented with subjective hearing loss 2-3 years in duration with a recent development of hearing continuous patriotic and children's songs playing in her head. After extensive interviewing and the documentation of a normal otologic/comprehensive head and neck examination, audiologic evaluation revealed evidence of a symmetric high-frequency sensorineural hearing loss consistent with presbycusis. She was counseled on the use of ambient noise and offered a trial of binaural hearing amplification. The diagnosis of musical hallucinations requires the consideration of numerous possible etiologies. Treatment varies widely, but many patients improve with the use of ambient noise and hearing amplification. Lack of response requires the consideration of pharmacologic treatments such as anticonvulsants, antipsychotics, and anticholinesterases. It is important to reassure patients with a nonpsychiatric etiology that use of these drugs does not imply psychiatric illness.

Insomnia of childhood.

PubMed

Lipton, Jonathan; Becker, Ronald E; Kothare, Sanjeev V

2008-12-01

Insomnia is a major public health problem and is the most common sleep disturbance in both adults and children. The causes of sleeplessness are age-dependent and have potentially enormous effects on cognitive development, behavior, family dynamics, and the metabolic health of children. Here we review the epidemiology, cause, pathophysiology, and clinical approach to pediatric insomnia. Normal sleep is crucial for brain function, behavior, and normal metabolism. Consistently, sleep loss has been linked to behavioral and attention problems, impaired learning and memory, obesity, and psychiatric disorders. The neurological mechanisms that govern sleep initiation and maintenance are poorly understood. The types of insomnia are age-dependent and can occur as primary disorders, or in the context of another primary sleep disorder such as restless legs syndrome, or secondary to another underlying medical condition. Children with chronic diseases and especially children with neurodevelopmental disorders are at particular risk of insomnia. Pediatric insomnia is common and is a source of potential psychophysiological stress to both children and their caregivers. The causes of insomnia are various. Pediatricians should have a working knowledge of the causes of sleeplessness in order to promptly curtail the chronic effects of sleep loss and effectively screen for underlying, potentially treatable disorders.

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes.

PubMed

O'Dwyer, David N; Norman, Katy C; Xia, Meng; Huang, Yong; Gurczynski, Stephen J; Ashley, Shanna L; White, Eric S; Flaherty, Kevin R; Martinez, Fernando J; Murray, Susan; Noth, Imre; Arnold, Kelly B; Moore, Bethany B

2017-04-25

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than 1100 proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology.

Sturge-Weber syndrome: ear, nose, and throat issues and neurologic status.

PubMed

Irving, Natasha D; Lim, Jae Hyung; Cohen, Bernard; Ferenc, Lisa M; Comi, Anne M

2010-10-01

The pathophysiology of Sturge-Weber syndrome is poorly understood, and ear, nose, and throat involvement is possible. These issues can result in frequent illnesses or airway obstruction, affecting patients' neurologic status. Patients with definite brain involvement who reported potential ear, nose, and throat issues on intake questionnaires underwent retrospective reviews of their medical records. We examined the relationships between these issues, secondary surgical interventions, and patients' neurologic status. The most common complaints involved the sinuses and frequent ear infections. Six patients underwent placement of ear tubes, leading to improvements in migraines and stroke-like episodes in one patient, and improved seizure control in four others. Obstructive sleep apnea was confirmed in three patients who underwent sleep studies. Tonsil or adenoid removal occurred in another three patients. Surgery resulted in marked improvements regarding excessive drooling, daytime sleepiness, and breathing problems. These findings suggest that ear, nose, and throat problems occur frequently in patients with Sturge-Weber Syndrome, and when repeated ear infections are associated with uncontrolled seizures, early placement of ear tubes may be beneficial. Furthermore, patients with facial tissue hypertrophy may be at risk for obstructive sleep apnea, and should be appropriately evaluated. Copyright © 2010 Elsevier Inc. All rights reserved.

Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

PubMed Central

Rebello, Tahilia J.; Yu, Qinghui; Goodfellow, Nathalie M.; Caffrey Cagliostro, Martha K.; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y.; Chemiakine, Alexei; Rosoklija, Gorazd B.; Dwork, Andrew J.; Lambe, Evelyn K.; Ansorge, Mark S.

2014-01-01

Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2–P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2–P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors. PMID:25209278

Proton magnetic resonance spectroscopy in adult cancer patients with delirium

PubMed Central

Yager, Jeffrey R.; Magnotta, Vincent A.; Mills, James A.; Vik, Stacie M.; Weckmann, Michelle T.; Capizzano, Aristides A.; Gingrich, Roger; Beglinger, Leigh J.

2010-01-01

Background Delirium is associated with a host of negative outcomes, including increased risk of mortality, longer hospital stay, and poor long-term cognitive function. The pathophysiology of delirium is not well understood. Cancer patients undergoing a bone marrow transplant (BMT) are at high risk for developing delirium and Proton Magnetic Resonance Spectroscopy (1H-MRS) could lead to better understanding of the delirium process. Methods Fourteen BMT patients and 10 controls completed 1H-MRS, positioned above the corpus callosum, shortly after delirium onset or at study end if no delirium occurred. Results In the BMT-delirium group, statistically significantly elevated tCho/tCr was found in contrast to the BMT-no delirium group (p<0.05). The BMT–delirium group also showed statistically significantly lesser NAA/tCho compared to both controls (p=0.01) and the BMT–no delirium group (p=0.04). Conclusions Elevated choline and reduced NAA indicate inflammatory processes and white matter damage as well as neuronal metabolic impairment. Further research is needed to separate the choline peaks, as well as more detailed collection of medication regimens to determine whether a higher choline concentration is a function of the delirium process or cancer treatment effects. PMID:21227658

Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms?

PubMed Central

KIM, S. E.; CHANG, L.

2013-01-01

Background Irritable bowel syndrome and other gastrointestinal (GI) and non-GI disorders such as functional dyspepsia, fibromyalgia, temporomandibular joint disorder, interstitial cystitis/painful bladder syndrome, and chronic fatigue syndrome are known as functional pain syndromes. They commonly coexist within the same individual. The pathophysiologic mechanisms of these disorders are not well understood, but it has been hypothesized that they share a common pathogenesis. Purpose The objective of this review is to discuss the proposed pathophysiologic mechanisms, which have been similarly studied in these conditions. These mechanisms include enhanced pain perception, altered regional brain activation, infectious etiologies, dysregulations in immune and neuroendocrine function, and genetic susceptibility. Studies suggest that these functional disorders are multifactorial, but factors which increase the vulnerability of developing these conditions are shared. PMID:22863120

Pediatric IBS: an overview on pathophysiology, diagnosis and treatment.

PubMed

Chogle, Ashish; Mintjens, Stijn; Saps, Miguel

2014-04-01

Irritable bowel syndrome (IBS) is a common disorder in children and adults. The pathogenesis and pathophysiology of IBS remains incompletely understood. The biopsychosocial model, which conceptualizes chronic pain as a dysregulation of the gut-brain-homeostasis with peripheral and central factors mutually influencing each other, is the most accepted framework to explain IBS. Twin and family aggregation studies suggest a genetic component that does not exclusively explain the higher prevalence of IBS in certain families. Social learning (environmental factors) and maladaptive coping predispose children to develop IBS with greater disability and more frequent medical consultations. Early-life events constitute an additional risk factor for the development of IBS and other functional gastrointestinal disorders (FGIDs). Children with a history of cow's milk protein hypersensitivity or abdominal surgeries have a higher prevalence of IBS and other FGIDs years later. IBS frequently follows an episode of acute gastrointestinal inflammation (infectious or non-infectious). This article discusses the importance, known pathophysiological mechanisms, clinical approach, and evidence-based therapeutic options for the management of IBS in children and adolescents. Copyright 2014, SLACK Incorporated.

Neurogenic stuttering: a review of the literature.

PubMed

Cruz, C; Amorim, H; Beca, G; Nunes, R

2018-01-16

Neurogenic stuttering is a disorder of neurologic origin in the rhythm of speech during which the patient knows exactly what he wants to say but is unable to because of an involuntary prolongation, cessation or repetition of a sound. To assemble new insights regarding the epidemiology, pathophysiology, diagnosis, evaluation and treatment of neurogenic stuttering. A review of all PubMed and Scopus published articles between January 2000 and September 2016 was performed. Thirty-three publications were analyzed. Neurogenic stuttering is a rare entity whose epidemiological incidence is yet not fully established. It is correlated with several neurological diseases and with several possible localizations within the nervous system. Notwithstanding the recent advances in the understanding of the underlying mechanism, it is not yet possible to establish a single pathophysiological mechanism of neurogenic stuttering. The differential diagnosis is complex and requires the detailed knowledge of other language disorders. The treatment is currently based on specific speech language therapy strategies. Neurogenic stuttering is a complex disorder which is not fully understood. Additional studies might help to better explain the underlying pathophysiological mechanism and to open doors to novel therapeutic methods.

Overview of proteomics studies in obstructive sleep apnea

PubMed Central

Feliciano, Amélia; Torres, Vukosava Milic; Vaz, Fátima; Carvalho, Ana Sofia; Matthiesen, Rune; Pinto, Paula; Malhotra, Atul; Bárbara, Cristina; Penque, Deborah

2015-01-01

Obstructive sleep apnea (OSA) is an underdiagnosed common public health concern causing deleterious effects on metabolic and cardiovascular health. Although much has been learned regarding the pathophysiology and consequences of OSA in the past decades, the molecular mechanisms associated with such processes remain poorly defined. The advanced high-throughput proteomics-based technologies have become a fundamental approach for identifying novel disease mediators as potential diagnostic and therapeutic targets for many diseases, including OSA. Here, we briefly review OSA pathophysiology and the technological advances in proteomics and the first results of its application to address critical issues in the OSA field. PMID:25770042

[Haemorrhoidal disease: from pathophysiology to clinical presentation].

PubMed

Zeitoun, Jean-David; de Parades, Vincent

2011-10-01

Hemorrhoidal disease is the first cause of proctological consultation although epidemiology is poorly documented. Pathophysiology is complex and involves a fragmentation of supporting tissues as well as vascular changes with hypervascularization and/or impaired venous return. The only complication of external hemorrhoids is thrombosis, which is responsible for acute anal pain irrespective of bowel movements. Internal hemorrhoids most frequently cause prolapse and/or bleeding which is easily recognizable. Physical examination always confirms the diagnosis and a colonoscopy is required after 40 or 45 in order to rule out colorectal cancer. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Postoperative Takotsubo cardiomyopathy triggered by intraoperative fluid overload and acute hypertensive crisis.

PubMed

Varutti, Rosanna; Setti, Tommaso; Ezri, Tiberiu; Nicolosi, Gianluigi; Rellini, Gianluigi; Cassin, Matteo; Leykin, Yigal

2015-04-01

The Takotsubo cardiomyopathy is a rare haemodynamic dysfunction, only recently reported perioperatively. While the diagnostic criteria have been established and the outcome is known as favorable, the pathophysiological mechanisms are not entirely understood. Here we present the case of a patient scheduled for laparoscopic hysterectomy and adnexectomy, who early postoperatively developed a Takotsubo cardiomyopathy supposedly triggered by an acute hypertensive crisis due to intraoperative fluid overload.

Assessment of muscle tissue oxygen saturation after out-of-hospital cardiac arrest.

PubMed

Orban, Jean-Christophe; Scarlatti, Audrey; Danin, Pierre-Eric; Dellamonica, Jean; Bernardin, Gilles; Ichai, Carole

2015-12-01

Pathophysiology of cardiac arrest corresponds to an ischemia-reperfusion syndrome with deep impairment of microcirculation. Muscular tissue oxygen saturation (StO2) is a noninvasive method of evaluation of microcirculation. Our study was aimed at assessing the prognosis value of muscular StO2 in patients admitted for out-of-hospital cardiac arrest (OHCA) and treated with hypothermia. We conducted a prospective bicentric observational study including OHCA patients treated with therapeutic hypothermia. Baseline StO2, derived variables (desaturation and resaturation slopes), and lactate levels were compared at different times between patients with good and poor outcomes. Prognosis was assessed by the Cerebral Performance Category (CPC) score at 6 months after admission (CPC 1-2, good outcome; CPC 3-5, poor outcome). Forty-four patients were included, 17 good and 27 poor outcomes at 6 months. At admission, StO2 and lactate levels were lower in good outcome patients. Desaturation and resaturation slopes did not differ between groups. After an OHCA treated with therapeutic hypothermia, StO2 was correlated with outcome. Further research is needed to better understand the pathophysiological process underlying our results. Copyright © 2015 Elsevier Inc. All rights reserved.

Drug-induced gynecomastia: an evidence-based review.

PubMed

Deepinder, Fnu; Braunstein, Glenn D

2012-09-01

Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.

Takotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment.

PubMed

Komamura, Kazuo; Fukui, Miho; Iwasaku, Toshihiro; Hirotani, Shinichi; Masuyama, Tohru

2014-07-26

In 1990, takotsubo cardiomyopathy (TCM) was first discovered and reported by a Japanese cardiovascular specialist. Since then, this heart disease has gained worldwide acceptance as an independent disease entity. TCM is an important entity that differs from acute myocardial infarction. It occurs more often in postmenopausal elderly women, is characterized by a transient hypokinesis of the left ventricular (LV) apex, and is associated with emotional or physical stress. Wall motion abnormality of the LV apex is generally transient and resolves within a few days to several weeks. Its prognosis is generally good. However, there are some reports of serious TCM complications, including hypotension, heart failure, ventricular rupture, thrombosis involving the LV apex, and torsade de pointes. It has been suggested that coronary spasm, coronary microvascular dysfunction, catecholamine toxicity and myocarditis might contribute to the pathogenesis of TCM. However, its pathophysiology is not clearly understood.

Prevention of DNA damage by L-carnitine induced by metabolites accumulated in maple syrup urine disease in human peripheral leukocytes in vitro.

PubMed

Mescka, Caroline Paula; Wayhs, Carlos Alberto Yasin; Guerreiro, Gilian; Manfredini, Vanusa; Dutra-Filho, Carlos Severo; Vargas, Carmen Regla

2014-09-15

Maple syrup urine disease (MSUD) is an inherited aminoacidopathy caused by a deficiency in branched-chain α-keto acid dehydrogenase complex activity that leads to the accumulation of the branched-chain amino acids (BCAAs) leucine (Leu), isoleucine, and valine and their respective α-keto-acids, α-ketoisocaproic acid (KIC), α keto-β-methylvaleric acid, and α-ketoisovaleric acid. The major clinical features presented by MSUD patients include ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay, and mental retardation; however, the pathophysiology of this disease is poorly understood. MSUD treatment consists of a low protein diet supplemented with a mixture containing micronutrients and essential amino acids but excluding BCAAs. Studies have shown that oxidative stress may be involved in the neuropathology of MSUD, with the existence of lipid and protein oxidative damage in affected patients. In recent years, studies have demonstrated the antioxidant role of L-carnitine (L-Car), which plays a central function in cellular energy metabolism and for which MSUD patients have a deficiency. In this work, we investigated the in vitro effect of Leu and KIC in the presence or absence of L-Car on DNA damage in peripheral whole blood leukocytes using the alkaline comet assay with silver staining and visual scoring. Leu and KIC resulted in a DNA damage index that was significantly higher than that of the control group, and L-Car was able to significantly prevent this damage, mainly that due to KIC. Copyright © 2014 Elsevier B.V. All rights reserved.

Colony collapse disorder (CCD) and bee age impact honey bee pathophysiology

USDA-ARS?s Scientific Manuscript database

Honey bee (Apis mellifera) colonies continue to experience high annual losses that remain poorly explained. Numerous interacting factors have been linked to colony declines. Understanding the pathways linking dysfunction with symptoms is an important step in understanding the mechanisms of disease. ...

Stuttering priapism associated with hereditary spherocytosis.

PubMed

Prabhakaran, Karti; Jacobs, Bruce L; Smaldone, Marc C; Franks, Michael E

2007-10-01

Stuttering priapism is a clinical phenomenon that occurs commonly in certain patient populations, including sickle cell anemia and other hematologic dyscrasias. Although the mechanism is still not completely understood, treatment is focused on prevention of recurrence in the outpatient setting, and immediate detumescence and minimizing corporal fibrosis in the acute setting. We present a case of stuttering priapism in a 44 year-old male with hereditary spherocytosis and discuss the pathophysiology and clinical management of this entity.

Postoperative Takotsubo cardiomyopathy triggered by intraoperative fluid overload and acute hypertensive crisis

PubMed Central

Varutti, Rosanna; Setti, Tommaso; Ezri, Tiberiu; Nicolosi, Gianluigi; Rellini, Gianluigi; Cassin, Matteo; Leykin, Yigal

2015-01-01

The Takotsubo cardiomyopathy is a rare haemodynamic dysfunction, only recently reported perioperatively. While the diagnostic criteria have been established and the outcome is known as favorable, the pathophysiological mechanisms are not entirely understood. Here we present the case of a patient scheduled for laparoscopic hysterectomy and adnexectomy, who early postoperatively developed a Takotsubo cardiomyopathy supposedly triggered by an acute hypertensive crisis due to intraoperative fluid overload. PMID:28913455

Boxing sparring complicated by an acute subdural haematoma and brainstem haemorrhage.

PubMed

Hart, Michael G; Trivedi, Rikin A; Hutchinson, Peter J

2012-10-01

A professional boxer developed an acute subdural haematoma after boxing sparring. Despite timely surgical decompression, he had a poor overall outcome predominantly from a delayed brainstem haematoma. Magnetic resonance imaging (MRI) was used to elucidate the pathophysiology of the patients' injury and clinical condition.

Inflammation: The Common Pathway of Stress-Related Diseases

PubMed Central

Liu, Yun-Zi; Wang, Yun-Xia; Jiang, Chun-Lei

2017-01-01

While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases. PMID:28676747

Heart Failure as an Aging-Related Phenotype.

PubMed

Morita, Hiroyuki; Komuro, Issei

2018-01-27

The molecular pathophysiology of heart failure, which is one of the leading causes of mortality, is not yet fully understood. Heart failure can be regarded as a systemic syndrome of aging-related phenotypes. Wnt/β-catenin signaling and the p53 pathway, both of which are key regulators of aging, have been demonstrated to play a critical role in the pathogenesis of heart failure. Circulating C1q was identified as a novel activator of Wnt/β-catenin signaling, promoting systemic aging-related phenotypes including sarcopenia and heart failure. On the other hand, p53 induces the apoptosis of cardiomyocytes in the failing heart. In these molecular mechanisms, the cross-talk between cardiomyocytes and non-cardiomyocytes (e,g,. endothelial cells, fibroblasts, smooth muscle cells, macrophages) deserves mentioning. In this review, we summarize recent advances in the understanding of the molecular pathophysiology underlying heart failure, focusing on Wnt/β-catenin signaling and the p53 pathway.

Time perception impairs sensory-motor integration in Parkinson’s disease

PubMed Central

2013-01-01

It is well known that perception and estimation of time are fundamental for the relationship between humans and their environment. However, this temporal information processing is inefficient in patients with Parkinson’ disease (PD), resulting in temporal judgment deficits. In general, the pathophysiology of PD has been described as a dysfunction in the basal ganglia, which is a multisensory integration station. Thus, a deficit in the sensorimotor integration process could explain many of the Parkinson symptoms, such as changes in time perception. This physiological distortion may be better understood if we analyze the neurobiological model of interval timing, expressed within the conceptual framework of a traditional information-processing model called “Scalar Expectancy Theory”. Therefore, in this review we discuss the pathophysiology and sensorimotor integration process in PD, the theories and neural basic mechanisms involved in temporal processing, and the main clinical findings about the impact of time perception in PD. PMID:24131660

Takotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment

PubMed Central

Komamura, Kazuo; Fukui, Miho; Iwasaku, Toshihiro; Hirotani, Shinichi; Masuyama, Tohru

2014-01-01

In 1990, takotsubo cardiomyopathy (TCM) was first discovered and reported by a Japanese cardiovascular specialist. Since then, this heart disease has gained worldwide acceptance as an independent disease entity. TCM is an important entity that differs from acute myocardial infarction. It occurs more often in postmenopausal elderly women, is characterized by a transient hypokinesis of the left ventricular (LV) apex, and is associated with emotional or physical stress. Wall motion abnormality of the LV apex is generally transient and resolves within a few days to several weeks. Its prognosis is generally good. However, there are some reports of serious TCM complications, including hypotension, heart failure, ventricular rupture, thrombosis involving the LV apex, and torsade de pointes. It has been suggested that coronary spasm, coronary microvascular dysfunction, catecholamine toxicity and myocarditis might contribute to the pathogenesis of TCM. However, its pathophysiology is not clearly understood. PMID:25068020

COEXISTENCE OF CONSTIPATION AND INCONTINENCE IN CHILDREN AND ADULTS

PubMed Central

Nurko, S; Scott, SM

2011-01-01

The coexistence of constipation and fecal incontinence has long been recognized in pediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behavior problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics. PMID:21382577

Loin pain hematuria syndrome

PubMed Central

Zubair, Adeel S.; Salameh, Hassan; Erickson, Stephen B.; Prieto, Mikel

2016-01-01

Loin pain hematuria syndrome (LPHS), first described in 1967, is a rare pain syndrome, which is not well understood. The syndrome is characterized by severe intermittent or persistent flank pain, either unilateral or bilateral, associated with gross or microscopic hematuria. LPHS is a diagnosis of exclusion as there still is not a consensus of validated diagnostic criteria, though several criteria have been proposed. The wide differential diagnosis would suggest a meticulous yet specific diagnostic work-up depending on the individual clinical features and natural history. Several mechanisms regarding the pathophysiology of LPHS have been proposed but without pinpointing the actual causative etiology, the treatment remains symptomatic. Treatment modalities for LPHS are diverse including simple analgesia, opioid analgesic and kidney autotransplantation. This review article summarizes the current understanding regarding the pathophysiology of LPHS along with the steps required for proper diagnosis and a discussion of the different therapeutic approaches for LPHS. PMID:26798473

Stomach Dysfunction in Diabetes Mellitus: Emerging Technology and Pharmacology

PubMed Central

Szarka, Lawrence A.; Camilleri, Michael

2010-01-01

Gastroparesis and other types of gastric dysfunction result in substantial morbidity in diabetes patients. The pathophysiology of these disorders is incompletely understood. This article reviews techniques applicable to the assessment of gastric function in diabetes patients, including the measurement of emptying, accommodation, and contractility. Available treatment options are also reviewed, including novel yet unapproved serotonin 5-HT4 agonist pharmacological treatments, as well as the role of endoscopic, surgical, and device treatments of gastroparesis. PMID:20167183

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage

PubMed Central

Leclerc, Jenna L.; Garcia, Joshua M.; Diller, Matthew A.; Carpenter, Anne-Marie; Kamat, Pradip K.; Hoh, Brian L.; Doré, Sylvain

2018-01-01

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research. PMID:29623028

Postnatal Weight Gain Modifies Severity and Functional Outcome of Oxygen-Induced Proliferative Retinopathy

PubMed Central

Stahl, Andreas; Chen, Jing; Sapieha, Przemyslaw; Seaward, Molly R.; Krah, Nathan M.; Dennison, Roberta J.; Favazza, Tara; Bucher, Felicitas; Löfqvist, Chatarina; Ong, Huy; Hellström, Ann; Chemtob, Sylvain; Akula, James D.; Smith, Lois E.H.

2010-01-01

In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r2 = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome. PMID:21056995

Postnatal weight gain modifies severity and functional outcome of oxygen-induced proliferative retinopathy.

PubMed

Stahl, Andreas; Chen, Jing; Sapieha, Przemyslaw; Seaward, Molly R; Krah, Nathan M; Dennison, Roberta J; Favazza, Tara; Bucher, Felicitas; Löfqvist, Chatarina; Ong, Huy; Hellström, Ann; Chemtob, Sylvain; Akula, James D; Smith, Lois E H

2010-12-01

In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r(2) = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome.

Identification of MicroRNA-124-3p as a Putative Epigenetic Signature of Major Depressive Disorder

PubMed Central

Roy, Bhaskar; Dunbar, Michael; Shelton, Richard C; Dwivedi, Yogesh

2017-01-01

Major depressive disorder (MDD) is predicted to be the second leading cause of global disease burden by 2030. A large number of MDD patients do not respond to the currently available medication because of its poorly understood etiology. Recently, studies of microRNAs (miRNAs), which act as a molecular switch of gene expression, have shown promise in identifying a molecular network that could provide significant clues to various psychiatric illnesses. Using an in vitro system, a rodent depression model, and a human postmortem brain, we investigated the role of a brain-enriched, neuron-specific miRNA, miR-124-3p, whose expression is highly dysregulated in stressed rodents, and identified a set of target genes involved in stress response and neural plasticity. We also found that miR-124-3p is epigenetically regulated and its interaction with the RNA-induced silencing complex (RISC) is compromised in MDD. Using blood serum, we found similar dysregulation of miR-124-3p in antidepressant-free MDD subjects. Altogether, our study demonstrates potential contribution of miR-124-3p in the pathophysiology of MDD and suggests that this miRNA may serve as a novel target for drug development and a biomarker for MDD pathogenesis. PMID:27577603

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS.

PubMed

Silva, Mauro Sb; Prescott, Melanie; Campbell, Rebecca E

2018-04-05

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Protein Kinase Cα Modulates Estrogen-Receptor-Dependent Transcription and Proliferation in Endometrial Cancer Cells

PubMed Central

Thorne, Alicia M.; Jackson, Twila A.; Willis, Van C.; Bradford, Andrew P.

2013-01-01

Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The most prevalent endometrioid tumors are linked to excessive estrogen exposure and hyperplasia. However, molecular mechanisms and signaling pathways underlying their etiology and pathophysiology remain poorly understood. We have shown that protein kinase Cα (PKCα) is aberrantly expressed in endometrioid tumors and is an important mediator of endometrial cancer cell survival, proliferation, and invasion. In this study, we demonstrate that expression of active, myristoylated PKCα conferred ligand-independent activation of estrogen-receptor- (ER-) dependent promoters and enhanced responses to estrogen. Conversely, knockdown of PKCα reduced ER-dependent gene expression and inhibited estrogen-induced proliferation of endometrial cancer cells. The ability of PKCα to potentiate estrogen activation of ER-dependent transcription was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K) and Akt. Evidence suggests that PKCα and estrogen signal transduction pathways functionally interact, to modulate ER-dependent growth and transcription. Thus, PKCα signaling, via PI3K/Akt, may be a critical element of the hyperestrogenic environment and activation of ER that is thought to underlie the development of estrogen-dependent endometrial hyperplasia and malignancy. PKCα-dependent pathways may provide much needed prognostic markers of aggressive disease and novel therapeutic targets in ER positive tumors. PMID:23843797

Improving cognitive outcome in cerebral malaria: insights from clinical and experimental research.

PubMed

de Miranda, Aline Silva; Brant, Fátima; Machado, Fabiana Simão; Rachid, Milene Alvarenga; Teixeira, Antônio Lúcio

2011-12-01

Cerebral Malaria (CM) is a clinical syndrome defined by the World Health Organization (WHO) as a potentially reversible diffuse encephalopathy characterized mainly by coma and the presence of asexual forms of Plasmodium falciparum parasites in peripheral blood smears in the absence of other causes of encephalopathy. A wide range of clinical manifestations follows the disease including cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM pathogenesis remain incompletely understood although vascular, immunological and metabolic changes have been described. The classical treatment of CM is based on the administration of antimalarial drugs, especially chloroquine and artemisinin derivates as artesunate. Even with treatment, 15 to 20% of children with CM die and approximately 10 to 17% of those who survive remain with significant long-term cognitive impairment. In this context, neuroprotective and adjuvant therapies have been recently investigated in clinical and experimental studies of CM in an attempt to improve cognitive outcome. A poor understanding of pathophysiological mechanisms, properties of compounds used and patient selection have contributed to the lack of success of these interventions. This review discusses clinical aspects of cognitive sequelae, possible mechanisms involved in the brain injury, perspectives and limitations regarding the pharmacological strategies to improve cognitive outcome in CM.

Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

PubMed

Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

2014-03-01

Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

Regulation of cardiac excitation and contraction by p21 activated kinase-1.

PubMed

Ke, Yunbo; Lei, Ming; Solaro, R John

2008-01-01

Cardiac excitation and contraction are regulated by a variety of signaling molecules. Central to the regulatory scheme are protein kinases and phosphatases that carry out reversible phosphorylation of different effectors. The process of beta-adrenergic stimulation mediated by cAMP dependent protein kinase (PKA) forms a well-known pathway considered as the most significant control mechanism in excitation and contraction as well as many other regulatory mechanisms in cardiac function. However, although dephosphorylation pathways are critical to these regulatory processes, signaling to phosphatases is relatively poorly understood. Emerging evidence indicates that regulation of phosphatases, which dampen the effect of beta-adrenergic stimulation, is also important. We review here functional studies of p21 activated kinase-1 (Pak1) and its potential role as an upstream signal for protein phosphatase PP2A in the heart. Pak1 is a serine/threonine protein kinase directly activated by the small GTPases Cdc42 and Rac1. Pak1 is highly expressed in different regions of the heart and modulates the activities of ion channels, sarcomeric proteins, and other phosphoproteins through up-regulation of PP2A activity. Coordination of Pak1 and PP2A activities is not only potentially involved in regulation of normal cardiac function, but is likely to be important in patho-physiological conditions.

Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

PubMed

Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

2011-01-01

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.

Morphological and Molecular Descriptors of the Developmental Cycle of Babesia divergens Parasites in Human Erythrocytes.

PubMed

Rossouw, Ingrid; Maritz-Olivier, Christine; Niemand, Jandeli; van Biljon, Riette; Smit, Annel; Olivier, Nicholas A; Birkholtz, Lyn-Marie

2015-05-01

Human babesiosis, especially caused by the cattle derived Babesia divergens parasite, is on the increase, resulting in renewed attentiveness to this potentially life threatening emerging zoonotic disease. The molecular mechanisms underlying the pathophysiology and intra-erythrocytic development of these parasites are poorly understood. This impedes concerted efforts aimed at the discovery of novel anti-babesiacidal agents. By applying sensitive cell biological and molecular functional genomics tools, we describe the intra-erythrocytic development cycle of B. divergens parasites from immature, mono-nucleated ring forms to bi-nucleated paired piriforms and ultimately multi-nucleated tetrads that characterizes zoonotic Babesia spp. This is further correlated for the first time to nuclear content increases during intra-erythrocytic development progression, providing insight into the part of the life cycle that occurs during human infection. High-content temporal evaluation elucidated the contribution of the different stages to life cycle progression. Moreover, molecular descriptors indicate that B. divergens parasites employ physiological adaptation to in vitro cultivation. Additionally, differential expression is observed as the parasite equilibrates its developmental stages during its life cycle. Together, this information provides the first temporal evaluation of the functional transcriptome of B. divergens parasites, information that could be useful in identifying biological processes essential to parasite survival for future anti-babesiacidal discoveries.

Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo.

PubMed

Saint-Mezard, Pierre; Chavagnac, Cyril; Bosset, Sophie; Ionescu, Marius; Peyron, Eric; Kaiserlian, Dominique; Nicolas, Jean-Francois; Bérard, Frédéric

2003-10-15

Psychological stress affects the pathophysiology of infectious, inflammatory, and autoimmune diseases. However, the mechanisms by which stress could modulate immune responses in vivo are poorly understood. In this study, we report that application of a psychological stress before immunization exerts an adjuvant effect on dendritic cell (DC), resulting in increased primary and memory Ag-specific T cell immune responses. Acute stress dramatically enhanced the skin delayed-type hypersensitivity reaction to haptens, which is mediated by CD8(+) CTLs. This effect was due to increased migration of skin DCs, resulting in augmented CD8(+) T cell priming in draining lymph nodes and enhanced recruitment of CD8(+) T cell effectors in the skin upon challenge. This adjuvant effect of stress was mediated by norepinephrine (NE), but not corticosteroids, as demonstrated by normalization of the skin delayed-type hypersensitivity reaction and DC migratory properties following selective depletion of NE. These results suggest that release of NE by sympathetic nerve termini during a psychological stress exerts an adjuvant effect on DC by promoting enhanced migration to lymph nodes, resulting in increased Ag-specific T cell responses. Our findings may open new ways in the treatment of inflammatory diseases, e.g., psoriasis, allergic contact dermatitis, and atopic dermatitis.

Fatigue is not associated with impaired function of regulatory T cells in untreated patients with multiple sclerosis.

PubMed

Yaldizli, Ozguer; Kumar, Manoj; Vago, Susanne; Kreuzfelder, Erich; Limmroth, Volker; Putzki, Norman

2009-01-01

The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients. In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls. Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25- cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity. Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients.

Interactions between human osteoblasts and prostate cancer cells in a novel 3D in vitro model

PubMed Central

Sieh, Shirly; Lubik, Amy A; Clements, Judith A; Nelson, Colleen C

2010-01-01

Cell-cell and cell-matrix interactions play a major role in tumor morphogenesis and cancer metastasis. Therefore, it is crucial to create a model with a biomimetic microenvironment that allows such interactions to fully represent the pathophysiology of a disease for an in vitro study. This is achievable by using three-dimensional (3D) models instead of conventional two-dimensional (2D) cultures with the aid of tissue engineering technology. We are now able to better address the complex intercellular interactions underlying prostate cancer (CaP) bone metastasis through such models. In this study, we assessed the interaction of CaP cells and human osteoblasts (hOBs) within a tissue engineered bone (TEB) construct. Consistent with other in vivo studies, our findings show that intercellular and CaP cell-bone matrix interactions lead to elevated levels of matrix metalloproteinases, steroidogenic enzymes and the CaP biomarker, prostate specific antigen (PSA); all associated with CaP metastasis. Hence, it highlights the physiological relevance of this model. We believe that this model will provide new insights for understanding of the previously poorly understood molecular mechanisms of bone metastasis, which will foster further translational studies, and ultimately offer a potential tool for drug screening. PMID:21197221

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

PubMed Central

Hinson, Shannon R.; Clift, Ian C.; Luo, Ningling; Kryzer, Thomas J.; Lennon, Vanda A.

2017-01-01

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR’s gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG–AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO. PMID:28461494

Thermosensitive hydrogels deliver bioactive protein to the vaginal wall

PubMed Central

Good, Meadow M.; Montoya, T. Ignacio; Shi, Haolin; Zhou, Jun; Huang, YiHui; Tang, Liping; Acevedo, Jesus F.

2017-01-01

The pathophysiology and natural history of pelvic organ prolapse (POP) are poorly understood. Consequently, our approaches to treatment of POP are limited. Alterations in the extracellular matrix components of pelvic support ligaments and vaginal tissue, including collagen and elastin, have been associated with the development of POP in animals and women. Prior studies have shown the protease MMP-9, a key player of ECM degradation, is upregulated in vaginal tissues from both mice and women with POP. On the other hand, fibulin-5, an elastogenic organizer, has been found to inhibit MMP-9 in the vaginal wall. Hence, we hypothesized that prolonged release of fibulin-5 may delay progression of POP. To test the hypothesis, oligo (ethylene glycol)-based thermosensitive hydrogels were fabricated, characterized and then used to deliver fibulin-5 to the vaginal wall and inhibit MMP-9 activity. The results indicate that hydrogels are cell and tissue compatible. The hydrogels also prolong the ½ life of fibulin-5 in cultured vaginal fibroblasts and in the vaginal wall in vivo. Finally, fibulin-5-containing hydrogels resulted in incorporation of fibulin-5 into the vaginal matrix and inhibition of MMP-9 for several weeks after injection. These results support the idea of fibulin-5 releasing hydrogel being developed as a new treatment for POP. PMID:29073153

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: potential roles in GABAergic interneuron pathology.

PubMed

Schubert, Klaus Oliver; Föcking, Melanie; Cotter, David R

2015-09-01

Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus. Copyright © 2015 Elsevier B.V. All rights reserved.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

PubMed Central

Lequerré, Thierry; Bansard, Carine; Vittecoq, Olivier; Derambure, Céline; Hiron, Martine; Daveau, Maryvonne; Tron, François; Ayral, Xavier; Biga, Norman; Auquit-Auckbur, Isabelle; Chiocchia, Gilles; Le Loët, Xavier; Salier, Jean-Philippe

2009-01-01

Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment. PMID:19563633

Airway remodelling in the transplanted lung.

PubMed

Kuehnel, Mark; Maegel, Lavinia; Vogel-Claussen, Jens; Robertus, Jan Lukas; Jonigk, Danny

2017-03-01

Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

Paul Wittgenstein's right arm and his phantom: the saga of a famous concert pianist and his amputation.

PubMed

Boller, François; Bogousslavsky, Julien

2015-01-01

Reports of postamputation pain and problems linked to phantom limbs have increased in recent years, particularly in relation to war-related amputations. These problems are still poorly understood and are considered rather mysterious, and they are difficult to treat. In addition, they may shed light on brain physiology and neuropsychology. Functional neuroimaging techniques now enable us to better understand their pathophysiology and to consider new rehabilitation techniques. Several artists have suffered from postamputation complications and this has influenced not only their personal life but also their artistic work. Paul Wittgenstein (1887-1961), a pianist whose right arm was amputated during the First World War, became a famous left-handed concert performer. His case provides insight into Post-World War I musical and political history. More specifically, the impact on the artistic life of this pianist illustrates various postamputation complications, such as phantom limb, stump pain, and especially moving phantom. The phantom movements of his right hand helped him develop the dexterity of his left hand. Wittgenstein played piano works that were written especially for him (the most famous being Ravel's Concerto for the Left Hand) and composed some of his own. Additionally, several famous composers had previously written for the left hand. © 2015 Elsevier B.V. All rights reserved.

Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation.

PubMed

Dong, Hongquan; Zhang, Xiang; Wang, Yiming; Zhou, Xiqiao; Qian, Yanning; Zhang, Shu

2017-03-01

Brain inflammation has a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells are the "first responder" in the injury rather than microglia. Functional aspects of mast cell-microglia interactions remain poorly understood. Our results demonstrated that site-directed injection of the "mast cell degranulator" compound 48/80 (C48/80) in the hypothalamus induced mast cell degranulation, microglial activation, and inflammatory factor production, which initiated the acute brain inflammatory response. "Mast cell stabilizer" disodium cromoglycate (cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced microglial activation, inhibition of MAPK and AKT pathways, and repression of protein expression of histamine receptor 1 (H 1 R), histamine receptor 4 (H 4 R), protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. We also demonstrated that C48/80 had no effect on microglial activation in mast cell-deficient Kit W-sh/W-sh mice. These results implicate that activated brain mast cells trigger microglial activation and stabilization of mast cell inhibits microglial activation-induced central nervous system (CNS) inflammation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.

Utility of double-contrast multi-detector CT scans to assess cartilage thickness after tibial plafond fracture

PubMed Central

Thomas, Thaddeus P.; Van Hofwegen, Christopher J.; Anderson, Donald D.; Brown, Thomas D.; Marsh, J. Lawrence

2010-01-01

The pathophysiology of post-traumatic osteoarthritis (PTOA) after intra-articular fractures is poorly understood. Pursuit of a better understanding of this disease is complicated by inability to accurately monitor its onset, progression and severity. Common radiographic methods used to assess PTOA do not provide sufficient image quality for precise cartilage measurements. Double-contrast MDCT is an alternative method that may be useful, since it produces high-quality images in normal ankles. The purpose of this study was to assess this technique’s performance in assessing cartilage maintenance in ankles with an intra-articular fracture. Thirty-six tibial plafond fractures were followed over two years, with thirty-one MDCTs being obtained four months after injury, and twenty-two MDCTs after two years. Unfortunately, clinical results with this technique were unreliable due to pathology (presumed arthrofibrosis) and technical problems (pooling of contrast). The arthrofibrosis that developed in many patients inhibited proper joint access and contrast infiltration, although high-quality images were obtained in eleven patients. In this patient subset, in which focal regions of cartilage degeneration could be visualized, thickness could be measured with a high degree of fidelity. While thus useful in selected instances, double-contrast MDCT was too unreliable to be recommended to assess these particular types of injuries. PMID:20634971

Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

PubMed Central

Cardinal, R. N.; Rygula, R.; Hong, Y. T.; Fryer, T. D.; Sawiak, S. J.; Ferrari, V.; Cockcroft, G.; Aigbirhio, F. I.; Robbins, T. W.; Roberts, A. C.

2014-01-01

Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. PMID:24872570

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress.

PubMed

Kim, Kiyoon; Kim, Hunsung; Jeong, Kwon; Jung, Min Hyung; Hahn, Bum-Soo; Yoon, Kyung-Sik; Jin, Byung Kwan; Jahng, Geon-Ho; Kang, Insug; Ha, Joohun; Choe, Wonchae

2012-08-01

Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.

Motion sickness is linked to nystagmus-related trigeminal brain stem input: a new hypothesis.

PubMed

Gupta, Vinod Kumar

2005-01-01

Motion sickness is a common and distressing but poorly understood syndrome associated with nausea/vomiting and autonomic nervous system accompaniments that develops in the air or space as well as on sea or land. A bidirectional aetiologic link prevails between migraine and motion-sickness. Motion sickness provokes jerk nystagmus induced by both optokinetic and vestibular stimulation. Fixation of gaze or closure of eyes generally prevents motion sickness while vestibular otolithic function is eliminated in microgravity of space, indicating a predominant pathogenetic role for visuo-sensory input. Scopolamine, dimenhydrinate, and promethazine reduce motion-related nystagmus. Contraction of extraocular muscles generates proprioceptive neural traffic and can provoke an ocular hypertensive response. It is proposed that repetitive contractions of the extraocular muscles during motion-related jerk nystagmus rapidly augment brain stem afferent input by increasing proprioceptive neural traffic through connections of the oculomotor nerves with the ophthalmic nerve in the lateral wall of the cavernous sinus as well as by raising the intraocular pressure thereby stimulating anterior segment ocular trigeminal nerve fibers. This verifiable hypothesis defines the pathophysiological basis of individual susceptibility to motion sickness, elucidates the preventive mechanism of gaze fixation or ocular closure, advances the aetiologic link between MS and migraine, rationalizes the mechanism of known preventive drugs, and explores new therapeutic possibilities.

Effect of analgesic nerve block electrical stimulation in a patient with adhesive capsulitis.

PubMed

Gulick, Dawn T; Borger, Amy; McNamee, Lauren

2007-01-01

Although the pathophysiology of adhesive capsulitis is poorly understood, the primary goal of therapeutic intervention is to restore pain-free, functional range of motion (ROM) of the shoulder. Pain and muscle guarding, particularly of the subscapularis muscle, are common impairments that occur with adhesive capsulitis. The purpose of this case report is to describe a novel approach to help the pain-muscle guarding-pain cycle associated with pain and limited shoulder motion in a patient with a medical diagnosis of adhesive capsulitis. The patient was a 64-year-old female with adhesive capsulitis. Outcome variables were the Shoulder Pain and Disability Index (SPADI), internal rotation (IR) and external rotation (ER) ROM, and rotational lack. Twelve treatments of moist heat, analgesic nerve block electrical stimulation, contract/relax exercises for shoulder IR/ER, and Pendulum/Codman exercises were administered. After both 2 and 4 weeks of treatment, the patient demonstrated marked improvements in all areas. Overall, there was a 78-106% increase in ROM (IR and ER) and a 50-83% improvement in functional mobility (rotational lack & SPADI). It appears that analgesic electrical stimulation may have helped decrease the pain-muscle guarding cycle associated with adhesive capsulitis to enhance functional outcomes in a timely manner.

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

PubMed Central

Silva, Mauro S.B.; Prescott, Melanie; Campbell, Rebecca E.

2018-01-01

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP–transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype. PMID:29618656

The surface protein HvgA mediates group B streptococcus hypervirulence and meningeal tropism in neonates.

PubMed

Tazi, Asmaa; Disson, Olivier; Bellais, Samuel; Bouaboud, Abdelouhab; Dmytruk, Nicolas; Dramsi, Shaynoor; Mistou, Michel-Yves; Khun, Huot; Mechler, Charlotte; Tardieux, Isabelle; Trieu-Cuot, Patrick; Lecuit, Marc; Poyart, Claire

2010-10-25

Streptococcus agalactiae (group B streptococcus; GBS) is a normal constituent of the intestinal microflora and the major cause of human neonatal meningitis. A single clone, GBS ST-17, is strongly associated with a deadly form of the infection called late-onset disease (LOD), which is characterized by meningitis in infants after the first week of life. The pathophysiology of LOD remains poorly understood, but our epidemiological and histopathological results point to an oral route of infection. Here, we identify a novel ST-17-specific surface-anchored protein that we call hypervirulent GBS adhesin (HvgA), and demonstrate that its expression is required for GBS hypervirulence. GBS strains that express HvgA adhered more efficiently to intestinal epithelial cells, choroid plexus epithelial cells, and microvascular endothelial cells that constitute the blood-brain barrier (BBB), than did strains that do not express HvgA. Heterologous expression of HvgA in nonadhesive bacteria conferred the ability to adhere to intestinal barrier and BBB-constituting cells. In orally inoculated mice, HvgA was required for intestinal colonization and translocation across the intestinal barrier and the BBB, leading to meningitis. In conclusion, HvgA is a critical virulence trait of GBS in the neonatal context and stands as a promising target for the development of novel diagnostic and antibacterial strategies.

Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours.

PubMed

Makale, Milan T; McDonald, Carrie R; Hattangadi-Gluth, Jona A; Kesari, Santosh

2017-01-01

Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50-90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability.

Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse

PubMed Central

Scofield, Michael D.; Boger, Heather; Hensley, Megan; Kalivas, Peter W.

2014-01-01

Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration. PMID:24741055

Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy.

PubMed

Lacey, Cameron J; Doudney, Kit; Bridgman, Paul G; George, Peter M; Mulder, Roger T; Zarifeh, Julie J; Kimber, Bridget; Cadzow, Murray J; Black, Michael A; Merriman, Tony R; Lehnert, Klaus; Bickley, Vivienne M; Pearson, John F; Cameron, Vicky A; Kennedy, Martin A

2018-05-15

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Sykes, Catherine E; Shah, Mrudang M; Francescutti, Dina M; Rosenberg, David R; Thomas, David M; Kuhn, Donald M

2012-06-01

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.

PubMed

Planche, Vincent; Panatier, Aude; Hiba, Bassem; Ducourneau, Eva-Gunnel; Raffard, Gerard; Dubourdieu, Nadège; Maitre, Marlène; Lesté-Lasserre, Thierry; Brochet, Bruno; Dousset, Vincent; Desmedt, Aline; Oliet, Stéphane H; Tourdias, Thomas

2017-02-01

Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

A chronic animal model of migraine, induced by repeated meningeal nociception, characterized by a behavioral and pharmacological approach.

PubMed

Melo-Carrillo, Agustin; Lopez-Avila, Alberto

2013-10-01

Migraine is a chronic neurovascular disease characterized by recurrent unilateral headache, which induces incapacity. Despite all the progress that migraine research has provided, the neural mechanisms underlying the onset and maintenance of migraine attacks are poorly understood. Due to the complex characteristics of the disorder, it is difficult to develop a proper animal model that mimics all the clinical manifestations in humans. Taking into account the principal characteristics of the disease, the aim of this study is to develop a chronic animal model of migraine in which we can reproduce behavioral and pharmacological phenomena similar to those displayed by migraineurs. Our animal model displayed behavioral and pharmacological results similar to those experienced by migraineurs. Specifically, there was a decrease in routine physical activity and an increase in resting behavior. Also, the animals exhibited a novel behavior that we called ipsilateral facial grooming behavior provoked by the meningeal nociception. Moreover, one of the drugs used as treatment for migraine reduced the manifestations previously described. Our results determine that the model mimics many of the clinical features that patients exhibit during migraine attacks. This model can contribute to further understanding of the pathophysiology and the study of novel therapeutic approaches.

Atmospheric Research at BNL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peter Daum

2008-10-06

Brookhaven researcher Peter Daum discusses an international field experiment designed to make observations of critical components of the climate system of the southeastern Pacific. Because elements of this system are poorly understood and poorly represent

Atmospheric Research at BNL

ScienceCinema

Peter Daum

2017-12-09

Brookhaven researcher Peter Daum discusses an international field experiment designed to make observations of critical components of the climate system of the southeastern Pacific. Because elements of this system are poorly understood and poorly represent

Potential Role of the Gut Microbiome in ALS: A Systematic Review.

PubMed

Wright, Michelle L; Fournier, Christina; Houser, Madelyn C; Tansey, Malú; Glass, Jonathan; Hertzberg, Vicki Stover

2018-01-01

Amyotrophic lateral sclerosis (ALS) etiology and pathophysiology are not well understood. Recent data suggest that dysbiosis of gut microbiota may contribute to ALS etiology and progression. This review aims to explore evidence of associations between gut microbiota and ALS etiology and pathophysiology. Databases were searched for publications relevant to the gut microbiome in ALS. Three publications provided primary evidence of changes in microbiome profiles in ALS. An ALS mouse model revealed damaged tight junction structure and increased permeability in the intestine versus controls along with a shifted microbiome profile, including decreased levels of butyrate-producing bacteria. In a subsequent publication, again using an ALS mouse model, researchers showed that dietary supplementation with butyrate relieved symptoms and lengthened both time to onset of weight loss and survival time. In a small study of ALS patients and healthy controls, investigators also found decreased levels of butyrate-producing bacteria. Essential for maintaining gut barrier integrity, butyrate is the preferred energy source of intestinal epithelial cells. Ten other articles were reviews and commentaries providing indirect support for a role of gut microbiota in ALS pathophysiology. Thus, these studies provide a modicum of evidence implicating gut microbiota in ALS disease, although more research is needed to confirm the connection and determine pathophysiologic mechanisms. Nurses caring for these patients need to understand the gut microbiome and its potential role in ALS in order to effectively counsel patients and their families about emerging therapies (e.g., prebiotics, probiotics, and fecal microbial transplant) and their off-label uses.

Dysphagia in Parkinson's Disease.

PubMed

Suttrup, Inga; Warnecke, Tobias

2016-02-01

More than 80 % of patients with Parkinson's disease (PD) develop dysphagia during the course of their disease. Swallowing impairment reduces quality of life, complicates medication intake and leads to malnutrition and aspiration pneumonia, which is a major cause of death in PD. Although the underlying pathophysiology is poorly understood, it has been shown that dopaminergic and non-dopaminergic mechanisms are involved in the development of dysphagia in PD. Clinical assessment of dysphagia in PD patients is challenging and often delivers unreliable results. A modified water test assessing maximum swallowing volume is recommended to uncover oropharyngeal dysphagia in PD. PD-specific questionnaires may also be useful to identify patients at risk for swallowing impairment. Fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing study are both considered to be the gold standard for evaluation of PD-related dysphagia. In addition, high-resolution manometry may be a helpful tool. These instrumental methods allow a reliable detection of aspiration events. Furthermore, typical patterns of impairment during the oral, pharyngeal and/or esophageal swallowing phase of PD patients can be identified. Therapy of dysphagia in PD consists of pharmacological interventions and swallowing treatment by speech and language therapists (SLTs). Fluctuating dysphagia with deterioration during the off-state should be treated by optimizing dopaminergic medication. The methods used during swallowing treatment by SLTs shall be selected according to the individual dysphagia pattern of each PD patient. A promising novel method is an intensive training of expiratory muscle strength. Deep brain stimulation does not seem to have a clinical relevant effect on swallowing function in PD. The goal of this review is giving an overview on current stages of epidemiology, pathophysiology, diagnosis, and treatment of PD-associated dysphagia, which might be helpful for neurologists, speech-language therapists, and other clinicians in their daily work with PD patients and associated swallowing difficulties. Furthermore areas with an urgent need for future clinical research are identified.

Plasma cytokine expression in adolescent chronic fatigue syndrome.

PubMed

Wyller, Vegard Bruun; Sørensen, Øystein; Sulheim, Dag; Fagermoen, Even; Ueland, Thor; Mollnes, Tom Eirik

2015-05-01

Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescents. The pathophysiology is poorly understood, but low-grade systemic inflammation has been suggested as an important component. This study compared circulating levels of individual cytokines and parameters of cytokine networks in a large set of adolescent CFS patients and healthy controls, and explored associations between cytokines and symptoms in the CFS group. CFS patients (12-18years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Thus, the case definition was broader than the Fukuda-criteria of CFS. Healthy controls having comparable distribution of gender and age were recruited from local schools. Twenty-seven plasma cytokines, including interleukins, chemokines and growth factors were assayed using multiplex technology. The results were subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and patients were subgrouped according to the Fukuda-criteria. A total of 120 CFS patients and 68 healthy controls were included. CFS patients had higher scores for fatigue (p<0.001) and inflammatory symptoms (p<0.001) than healthy controls. All cytokine levels and cytokine network parameters were similar, and none of the differences were statistically different across the two groups, also when adjusting for adherence to the Fukuda criteria of CFS. Within the CFS group, there were no associations between aggregate cytokine network parameters and symptom scores. Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation, but plasma levels of individual cytokines as well as cytokine network measures were not different from healthy controls, and there were no associations between symptoms and cytokine expression in the CFS group. Low-grade systemic inflammation does not appear to be a central part of adolescent CFS pathophysiology. Copyright © 2014 Elsevier Inc. All rights reserved.

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

PubMed Central

Kerckhove, Nicolas; Collin, Aurore; Condé, Sakahlé; Chaleteix, Carine; Pezet, Denis; Balayssac, David

2017-01-01

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy. PMID:28286483

Leber's hereditary optic neuropathy (LHON)-associated ND5 12338T > C mutation altered the assembly and function of complex I, apoptosis and mitophagy.

PubMed

Zhang, Juanjuan; Ji, Yanchun; Lu, Yuanyuan; Fu, Runing; Xu, Man; Liu, Xiaoling; Guan, Min-Xin

2018-06-01

Mutations in mitochondrial DNA (mtDNA) have been associated with Leber's hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we demonstrated that a missense mutation (m.12338T>C, p.1M>T) in the ND5 gene contributed to the pathogenesis of LHON. The m.12338T>C mutation affected the first methionine (Met1) with a threonine and shortened two amino acids of ND5. We therefore hypothesized that the mutated ND5 perturbed the structure and function of complex I. Using the cybrid cell models, generated by fusing mtDNA-less (ρ°) cells with enucleated cells from LHON patients carrying the m.12338T>C mutation and a control subject belonging to the same mtDNA haplogroup, we demonstrated that the m.12338T>C mutation caused the reduction of ND5 polypeptide, perturbed assemble and activity of complex I. Furthermore, the m.12338T>C mutation caused respiratory deficiency, diminished mitochondrial adenosine triphosphate levels and membrane potential and increased the production of reactive oxygen species. The m.12338T>C mutation promoted apoptosis, evidenced by elevated release of cytochrome c into cytosol and increased levels of apoptosis-activated proteins: caspases 9, 3, 7 and Poly ADP ribose polymerase in the cybrids carrying the m.12338T>C mutation, as compared with control cybrids. Moreover, we also document the involvement of m.12338T>C mutation in decreased mitophagy, as showed by reduced levels of autophagy protein light chain 3 and accumulation of autophagic substrate p62 in the in mutant cybrids as compared with control cybrids. These data demonstrated the direct link between mitochondrial dysfunction caused by complex I mutation and apoptosis or mitophagy. Our findings may provide new insights into the pathophysiology of LHON.

Post-kala-azar dermal leishmaniasis in the Indian subcontinent: A threat to the South-East Asia Region Kala-azar Elimination Programme.

PubMed Central

Zijlstra, Eduard E.; Alves, Fabiana; Rijal, Suman; Arana, Byron; Alvar, Jorge

2017-01-01

Background The South-East Asia Region Kala-azar Elimination Programme (KAEP) is expected to enter the consolidation phase in 2017, which focuses on case detection, vector control, and identifying potential sources of infection. Post-kala-azar dermal leishmaniasis (PKDL) is thought to play a role in the recurrence of visceral leishmaniasis (VL)/kala-azar outbreaks, and control of PKDL is among the priorities of the KAEP. Methodology and principal finding We reviewed the literature with regard to PKDL in Asia and interpreted the findings in relation to current intervention methods in the KAEP in order to make recommendations. There is a considerable knowledge gap regarding the pathophysiology of VL and PKDL, especially the underlying immune responses. Risk factors (of which previous VL treatments may be most important) are poorly understood and need to be better defined. The role of PKDL patients in transmission is largely unknown, and there is insufficient information about the importance of duration, distribution and severity of the rash, time of onset, and self-healing. Current intervention methods focus on active case detection and treatment of all PKDL cases with miltefosine while there is increasing drug resistance. The prevention of PKDL by improved VL treatment currently receives insufficient attention. Conclusion and significance PKDL is a heterogeneous and dynamic condition, and patients differ with regard to time of onset after VL, chronicity, and distribution and appearance of the rash, as well as immune responses (including tendency to self-heal), all of which may vary over time. It is essential to fully describe the pathophysiology in order to make informed decisions on the most cost-effective approach. Emphasis should be on early detection of those who contribute to transmission and those who are in need of treatment, for whom short-course, effective, and safe drug regimens should be available. The prevention of PKDL should be emphasised by innovative and improved treatment for VL, which may include immunomodulation. PMID:29145397

Group 2 Pulmonary Hypertension: Pulmonary Venous Hypertension: Epidemiology and Pathophysiology.

PubMed

Clark, Craig B; Horn, Evelyn M

2016-08-01

Pulmonary hypertension from left heart disease (PH-LHD) is the most common form of PH, defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≥15 mm Hg. PH-LHD development is associated with more severe left-sided disease and its presence portends a poor prognosis, particularly once right ventricular failure develops. Treatment remains focused on the underlying LHD and despite initial enthusiasm for PH-specific therapies, most studies have been disappointing and their routine clinical use cannot be recommended. More work is urgently needed to better understand the pathophysiology underlying this disease and to develop effective therapeutic strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Inside the "fragile" infant: pathophysiology, molecular background, risk factors and investigation of neonatal osteopenia.

PubMed

Dokos, Charalampos; Tsakalidis, Christos; Tragiannidis, Athanasios; Rallis, Dimitrios

2013-05-01

Current research in bone mineral metabolism reveals many aspects of osteopenia occurred in premature infants. This review examines not only the pathophysiological and molecular mechanisms of newborn osteopenia but also the risk factors and investigation. Osteopenia of premature infants has increased incidence among other diseases of prematurity. Identification of risk factors is essential for monitoring of osteopenia. Some of the risk factors include low birth weight, prematurity, long term administration of drugs such as corticosteroids, methyloxanthines, furosemide, abnormalities in vitamin D metabolism, poor maternal nutritional and mineral uptake etc. Neonatologists, pediatricians and endocrinologists should investigate premature, low birth weight infants that have high serum alkaline phosphatase and have at least one risk factor.

The importance of the cortical subarachnoid space in understanding hydrocephalus.

PubMed

Rekate, Harold L; Nadkarni, Trimurti D; Wallace, Donna

2008-07-01

In this paper the authors define the role of the cortical subarachnoid space (CSAS) in poorly understood forms of hydrocephalus to cerebrospinal fluid (CSF) dynamics to improve understanding of the importance of the CSAS and its role in selecting patients for endoscopic third ventriculostomy (ETV). The secondary purpose of this work was to define testable hypotheses to explain enigmatic disorders of CSF dynamics and to suggest how these concepts could be tested. The magnitude of the contribution of the CSAS is explored using the solid geometry of concentric spheres. With this starting point, clinical conditions in which CSF dynamics are not easily understood are explored regarding the potential role of the CSAS. Overall, problems of CSF dynamics are easily understood. Insights may be gained when the results of a pathological process or its treatment vary from what has been expected. Acute changes in ventricular volume at the time that hydrocephalus develops, the failure of shunts, and the changes in ventricular volume with shunt repair may occur very rapidly. Changes in the volume of water in the brain, especially in the brain substance itself, are unlikely to occur at this rapid rate and may be interpreted as a simple redistribution of the CSF between the ventricle and CSAS with no initial change in the actual volume of brain parenchyma. Problems such as pseudotumor cerebri, shunt failure with nonresponsive ventricles, and negative-pressure hydrocephalus can be explained by assessing the ability of ventricular CSF to flow to the CSAS and the ability of this fluid to exit this compartment. Ventricular enlargement at the time of shunt failure implies a failure of flow between the ventricles and CSAS, implying that all patients who show this phenomenon are potential candidates for ETV. The important role of the CSAS in the pathophysiology of various forms of hydrocephalus has been largely ignored. Attention to the dynamics of the CSF in this compartment will improve understanding of enigmatic conditions of hydrocephalus and improve selection criteria for treatment paradigms such as ETV. These concepts lead to clearly defined problems that may be solved by the creation of a central database to address these issues.

Hydrocephalus in a patient with an unruptured pial arteriovenous fistula: hydrodynamic considerations, endovascular treatment, and clinical course.

PubMed

Morales-Gómez, Jesús A; Garza-Oyervides, Vicente V; Arenas-Ruiz, José A; Mercado-Flores, Mariana; Elizondo-Riojas, C Guillermo; Boop, Frederick A; de León, Ángel Martínez-Ponce

2017-03-01

Intracranial pial arteriovenous fistulas, also known as nongalenic fistulas, are rare vascular malformations affecting predominantly the pediatric population. Hydrocephalus is an unusual presentation in which the exact pathophysiology is not fully understood. The aim of treatment in these cases is occlusion of the fistula prior to considering ventricular shunting. Here, the authors describe the hydrodynamic considerations of the paravascular pathway and the resolution of hydrocephalus with endovascular treatment of the fistula.

Cronkhite- Canada syndrome; a case report and review of the literature

PubMed Central

Safari, Mohammad Taghi; Shahrokh, Shabnam; Ebadi, Shahram; Sadeghi, Amir

2016-01-01

Cronkhite- Canada syndrome (CCS) considered as a rare and non-hereditary disorder. Gastrointestinal polyposis and diarrhea along with some extra signs and symptoms such as hypoproteinemia, and epidermal manifestations are recognized in this syndrome. The pathophysiology of this syndrome is not completely understood and it seems that inflammatory processes may be involved. We present a 50 year-old man with hamartomatous polyps throughout the colon and long-lasting diarrhea not responding to typical therapies during three years. PMID:26744616

Ten years of a multidisciplinary diabetic foot team approach in Sao Paulo, Brazil

PubMed Central

Batista, Fábio; Augusto Magalhães, Antonio; Gamba, Mônica; Nery, Caio; Cardoso, Cristina

2010-01-01

Diabetes mellitus can cause devastating foot problems including loss of protective sensation with subsequent ulcerations and amputations. The natural history and pathophysiology of diabetic foot ulcers is best understood and managed by a multiprofessional team approach. The main factors for prevention and treatment of these devastating diabetic foot conditions are shown, with special attention to education of the patient. This approach decreases the morbidity of the disease, besides its economical and social feasibility. PMID:22396805

[Potential role of the angiogenic factor "EG-VEGF" in gestational trophoblastic diseases].

PubMed

Boufettal, H; Feige, J-J; Benharouga, M; Aboussaouira, T; Nadifi, S; Mahdaoui, S; Samouh, N; Alfaidy, N

2013-10-01

Gestational trophoblastic disease (MGT) includes a wide spectrum of pathologies of the placenta, ranging from benign precancerous lesions, with gestational trophoblastic tumors. Metastases are the leading causes of death as a result of this tumor. They represent a major problem for obstetrics and for the public health system. To date, there is no predictor of the progression of molar pregnancies to gestational trophoblastic tumor (GTT). Only an unfavorable plasma hCG monitoring after evacuation of hydatidiform mole is used to diagnose a TTG. The causes of the development of this cancer are still poorly understood. Increasing data in the literature suggests a close association between the development of this tumor and poor placental vascularization during the first trimester of pregnancy. The development of the human placenta depends on a coordination between the trophoblast and endothelial cells. A disruption in the expression of angiogenic factors could contribute to uterine or extra-uterine tissue invasion by extravillous trophoblast, contributing to the development of TTG. This review sheds lights on the phenomenon of angiogenesis during normal and abnormal placentation, especially during the MGT and reports preliminary finding concerning, the variability of expression of "Endocrine Gland-Derived Vascular Endothelial Growth Factor" (EG-VEGF), a specific placental angiogenic factor, in normal and molar placentas, and the potential role of differentiated expressions of the main placental angiogenic factors in the scalability of hydatidiform moles towards a recovery or towards the development of gestational trophoblastic tumor. Deciphering the mechanisms by which the angiogenic factor influences these processes will help understand the pathophysiology of MGT and to create opportunities for early diagnosis and treatment of the latter. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

GLUTAMATE ABNORMALITIES IN OBSESSIVE COMPULSIVE DISORDER: NEUROBIOLOGY, PATHOPHYSIOLOGY, AND TREATMENT

PubMed Central

Pittenger, Christopher; Bloch, Michael H.; Williams, Kyle

2011-01-01

Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. PMID:21963369

[Factitious disorders in dermatology: Value of the dissociative state concept].

PubMed

Fekih-Romdhane, F; Homri, W; Labbane, R

2016-03-01

Factitious disorders in dermatology consist of intentionally self-inflicted skin lesions that vary in morphology and distribution and occur on surfaces readily accessible to the patient's hands. They tend to be a chronic condition that waxes and wanes according to the circumstances of the patient's life. Patient management poses a particular challenge to the clinician and the prognosis is considered poor. The aetiopathogenesis of factitious disorders in dermatology is not completely understood. We present a case in which we suggested the occurrence of factitious behaviour during a dissociative state, and we briefly describe our diagnostic and therapeutic approach. A 48-year-old unemployed woman was referred to our department of psychiatry by her dermatologist for suspected factitious disorder. The patient was diagnosed with diabetes mellitus type 1 and had been hospitalized repeatedly for confirmed diabetic ketoacidosis. The onset of the disease was related to marital discord with her spouse. Numerous skin lesions had appeared on her face, arms, legs, neck and back. These lesions resulted in multiple hospital admissions and in amputation of her left leg. The condition had worsened considerably after her separation from her husband. During the initial conversation, the patient was unable to provide a clear history of the disease. She denied any knowledge of the circumstances in which these skin lesions appeared, and she did not admit self-infliction. Her mood was depressed and her speech was slow. We suspected that our patient was herself causing her skin lesions while in a dissociative state. Several arguments militate in favour of our hypothesis, particularly her history of childhood maltreatment and the association of traumatic life events with simultaneous deterioration of the skin. The explanation of the dissociative mechanism helped us to strengthen the therapeutic relationship. Within a few days, we noted a slow regression of the lesions, but the patient was still unable to explain how the lesions had occurred. The pathophysiology of factitious disorders in dermatology is poorly understood. It has strong ties with other psychiatric disorders, and according to several authors, skin lesions occur in dissociative states, after which patients do not remember how the skin change started. Management of this disease is challenging. An improved understanding of its mechanisms may enhance the prognosis for this particular group of patients. Copyright © 2015. Published by Elsevier Masson SAS.

Identification of the Upward Movement of Human CSF In Vivo and its Relation to the Brain Venous System.

PubMed

Dreha-Kulaczewski, Steffi; Joseph, Arun A; Merboldt, Klaus-Dietmar; Ludwig, Hans-Christoph; Gärtner, Jutta; Frahm, Jens

2017-03-01

CSF flux is involved in the pathophysiology of neurodegenerative diseases and cognitive impairment after traumatic brain injury, all hallmarked by the accumulation of cellular metabolic waste. Its effective disposal via various CSF routes has been demonstrated in animal models. In contrast, the CSF dynamics in humans are still poorly understood. Using novel real-time MRI, forced inspiration has been identified recently as a main driving force of CSF flow in the human brain. Exploiting technical advances toward real-time phase-contrast MRI, the current work analyzed directions, velocities, and volumes of human CSF flow within the brain aqueduct as part of the internal ventricular system and in the spinal canal during respiratory cycles. A consistent upward CSF movement toward the brain in response to forced inspiration was seen in all subjects at the aqueduct, in 11/12 subjects at thoracic level 2, and in 4/12 subjects at thoracic level 5. Concomitant analyses of CSF dynamics and cerebral venous blood flow, that is, in epidural veins at cervical level 3, uniquely demonstrated CSF and venous flow to be closely communicating cerebral fluid systems in which inspiration-induced downward flow of venous blood due to reduced intrathoracic pressure is counterbalanced by an upward movement of CSF. The results extend our understanding of human CSF flux and open important clinical implications, including concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and idiopathic intracranial hypertension. SIGNIFICANCE STATEMENT Effective disposal of brain cellular waste products via CSF has been demonstrated repeatedly in animal models. However, CSF dynamics in humans are still poorly understood. A novel quantitative real-time MRI technique yielded in vivo CSF flow directions, velocities, and volumes in the human brain and upper spinal canal. CSF moved upward toward the head in response to forced inspiration. Concomitant analysis of brain venous blood flow indicated that CSF and venous flux act as closely communicating systems. The finding of a human CSF-venous network with upward CSF net movement opens new clinical concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and ideopathic intracranial hypertension. Copyright © 2017 the authors 0270-6474/17/372395-08$15.00/0.

[Refeeding syndrome : Pathophysiology, risk factors, prevention, and treatment].

PubMed

Wirth, R; Diekmann, R; Janssen, G; Fleiter, O; Fricke, L; Kreilkamp, A; Modreker, M K; Marburger, C; Nels, S; Pourhassan, M; Schaefer, R; Willschrei, H-P; Volkert, D

2018-04-01

Refeeding syndrome is a life-threatening complication that may occur after initiation of nutritional therapy in malnourished patients, as well as after periods of fasting and hunger. Refeeding syndrome can be effectively prevented and treated if its risk factors and pathophysiology are known. The initial measurement of thiamine level and serum electrolytes, including phosphate and magnesium, their supplementation if necessary, and a slow increase in nutritional intake along with close monitoring of serum electrolytes play an important role. Since refeeding syndrome is not well known and the symptoms can be extremely heterogeneous, this complication is poorly recognized, especially against the background of severe disease and multimorbidity. This overview aims to summarize the current knowledge and increase awareness about refeeding syndrome.

Inside the “fragile” infant: pathophysiology, molecular background, risk factors and investigation of neonatal osteopenia

PubMed Central

Dokos, Charalampos; Tsakalidis, Christos; Tragiannidis, Athanasios; Rallis, Dimitrios

2013-01-01

Summary Current research in bone mineral metabolism reveals many aspects of osteopenia occurred in premature infants. This review examines not only the pathophysiological and molecular mechanisms of newborn osteopenia but also the risk factors and investigation. Osteopenia of premature infants has increased incidence among other diseases of prematurity. Identification of risk factors is essential for monitoring of osteopenia. Some of the risk factors include low birth weight, prematurity, long term administration of drugs such as corticosteroids, methyloxanthines, furosemide, abnormalities in vitamin D metabolism, poor maternal nutritional and mineral uptake etc. Neonatologists, pediatricians and endocrinologists should investigate premature, low birth weight infants that have high serum alkaline phosphatase and have at least one risk factor. PMID:24133523

Social Media Interruption Affects the Acquisition of Visually, Not Aurally, Acquired Information during a Pathophysiology Lecture

ERIC Educational Resources Information Center

Marone, Jane R.; Thakkar, Shivam C.; Suliman, Neveen; O'Neill, Shannon I.; Doubleday, Alison F.

2018-01-01

Poor academic performance from extensive social media usage appears to be due to students' inability to multitask between distractions and academic work. However, the degree to which visually distracted students can acquire lecture information presented aurally is unknown. This study examined the ability of students visually distracted by social…

Role of mitochondrial oxidative stress in hypertension

PubMed Central

Ungvari, Zoltan

2013-01-01

Based on mosaic theory, hypertension is a multifactorial disorder that develops because of genetic, environmental, anatomical, adaptive neural, endocrine, humoral, and hemodynamic factors. It has been recently proposed that oxidative stress may contribute to all of these factors and production of reactive oxygen species (ROS) play an important role in the development of hypertension. Previous studies focusing on the role of vascular NADPH oxidases provided strong support of this concept. Although mitochondria represent one of the most significant sources of cellular ROS generation, the regulation of mitochondrial ROS generation in the cardiovascular system and its pathophysiological role in hypertension are much less understood. In this review, the role of mitochondrial oxidative stress in the pathophysiology of hypertension and cross talk between angiotensin II signaling, pathways involved in mechanotransduction, NADPH oxidases, and mitochondria-derived ROS are considered. The possible benefits of therapeutic strategies that have the potential to attenuate mitochondrial oxidative stress for the prevention/treatment of hypertension are also discussed. PMID:24043248

Diagnosis and management of headache attributed to airplane travel.

PubMed

Mainardi, Federico; Maggioni, Ferdinando; Lisotto, Carlo; Zanchin, Giorgio

2013-03-01

The headache attributed to airplane travel, also named "airplane headache", is characterized by the sudden onset of a severe head pain exclusively in relation to airplane flights, mainly during the landing phase. Secondary causes, such as upper respiratory tract infections or acute sinusitis, must be ruled out. Although its cause is not thoroughly understood, sinus barotrauma should be reasonably involved in the pathophysiological mechanisms. Furthermore, in the current International Classification of Headache Disorders, rapid descent from high altitude is not considered as a possible cause of headache, although the onset of such pain in airplane travellers or aviators has been well known since the beginning of the aviation era. On the basis of a survey we conducted with the courteous cooperation of people who had experienced this type of headache, we proposed diagnostic criteria to be added to the forthcoming revision of the International Classification of Headache Disorders. Their formal validation would favour further studies aimed at improving knowledge of the pathophysiological mechanisms involved and at implementing preventative measures.

Anserine syndrome.

PubMed

Helfenstein, Milton; Kuromoto, Jorge

2010-01-01

Knee pain is a common complaint in clinical practice, and pes anserinus tendino-bursitis syndrome (PATB) has been frequently diagnosed based only on clinical features that may cause equivocal interpretations. Patients complain of characteristic spontaneous medial knee pain with tenderness in the inferomedial aspect of the joint. Studies with different imaging modalities have been undertaken during the last years to identify whether these patients suffer from bursitis, tendinitis, or both. Nevertheless, little is known regarding the structural defect responsible for this disturbance. Due to these problems and some controversies, we suggest the term "anserine syndrome" for this condition. Diabetes Mellitus is a known predisposing factor for this syndrome. Overweight and osteoarthritis seem to represent additional risk factors; however, their role in the pathophysiology of the disease is not yet understood. Treatment includes non-steroidal anti-inflammatory drugs, physiotherapy, and injections of corticosteroid, with highly variable responses, from 10 days to 36 months to achieve recovery. The lack of knowledge about its epidemiological, etiological, and pathophysiological aspects requires future studies for this common and intriguing disorder.

Post-Stroke Sleep-Disordered Breathing—Pathophysiology and Therapy Options

PubMed Central

Stevens, David; Martins, Rodrigo Tomazini; Mukherjee, Sutapa; Vakulin, Andrew

2018-01-01

Sleep-disordered breathing (SDB), encompassing both obstructive and central sleep apnea, is prevalent in at least 50% of stroke patients. Small studies have shown vast improvements in post-stroke functional recovery outcomes after the treatment of SDB by continuous positive airway pressure. However, compliance to this therapy is very poor in this complex patient group. There are alternative therapy options for SDB that may be more amenable for use in at least some post-stroke patients, including mandibular advancement, supine avoidance, and oxygen therapy. There are few studies, however, that demonstrate efficacy and compliance with these alternative therapies currently. Furthermore, novel SDB-phenotyping approaches may help to provide important clinical information to direct therapy selection in individual patients. Prior to realizing individualized therapy, we need a better understanding of the pathophysiology of SDB in post-stroke patients, including the role of inherent phenotypic traits, as well as the contribution of stroke size and location. This review summarizes the available literature on SDB pathophysiology and treatment in post-stroke patients, identifies gaps in the literature, and sets out areas for further research. PMID:29536012

Organ failure avoidance and mitigation strategies in surgery.

PubMed

McConnell, Kevin W; Coopersmith, Craig M

2012-04-01

Postoperative organ failure is a challenging disease process that is better prevented than treated. Providers should use close observation and clinical judgment, and checklists of best practices to minimize the risk of organ failure in their patients. The treatment of multiorgan dysfunction syndrome (MODS) generally remains supportive, outside of rapid initiation of source control (when appropriate) and targeted antibiotic therapy. More specific treatments may be developed as the complex pathophysiology of MODS is better understood and more homogenous patient populations are selected for study. Copyright © 2012 Elsevier Inc. All rights reserved.

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies.

PubMed

Skvarc, David R; Berk, Michael; Byrne, Linda K; Dean, Olivia M; Dodd, Seetal; Lewis, Matthew; Marriott, Andrew; Moore, Eileen M; Morris, Gerwyn; Page, Richard S; Gray, Laura

2018-01-01

Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Cervical myelitis presenting as occipital neuralgia.

PubMed

Noh, Sang-Mi; Kang, Hyun Goo

2018-07-01

Occipital neuralgia is a common form of headache that is characterized by paroxysmal severe lancinating pain in the occipital nerve distribution. The exact pathophysiology is still not fully understood and occipital neuralgia often develops spontaneously. There are no specific guidelines for evaluation of patients with occipital neuralgia. Cervical spine, spinal cord and posterior neck muscle lesions can induce occipital neuralgia. Brain and spine imaging may be necessary in some cases, according to the nature of the headache or response to treatment. We report a case of cervical myelitis presenting as occipital neuralgia.

Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

PubMed Central

Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

2011-01-01

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

PubMed Central

Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S.; Vaccarino, Flora M.; DiLeone, Ralph J.; Pittenger, Christopher

2015-01-01

Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS. PMID:25561540

Human rotavirus strain Wa downregulates NHE1 and NHE6 expressions in rotavirus-infected Caco-2 cells.

PubMed

Chen, Honglang; Song, Lijun; Li, Guixian; Chen, Wenfeng; Zhao, Shumin; Zhou, Ruoxia; Shi, Xiaoying; Peng, Zhenying; Zhao, Wenchang

2017-06-01

Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na + -coupled transport mechanisms at the luminal membrane, including Na + /H + exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs. Western blotting was employed for protein detection. Furthermore, immunocytochemistry was used to validate the NHE's protein expression. Finally, intracellular Ca 2+ concentration was detected by confocal laser scanning microscopy. The results demonstrated that the NHE6 mRNA and protein expressed in the human colon adenocarcinoma cell line (Caco-2). Furthermore, RV-Wa induced decreased expression of the NHE1 and NHE6 in Caco-2 cell in a time-dependent manner. In addition, intracellular Ca 2+ concentration in RV-Wa-infected Caco-2 cells was higher than that in the mock-infected cells. Furthermore, RV-Wa also can downregulate the expression of calmodulin (CaM) and calmodulin kinase II (CaMKII) in Caco-2 cells. These findings provides important insights into the mechanisms of rotavirus-induced diarrhea. Further studies on the underlying pathophysiological mechanisms that downregulate NHEs in RV-induced diarrhea are required.

Evaluation of bone microstructure in CRPS-affected upper limbs by HR-pQCT.

PubMed

Mussawy, Haider; Schmidt, Tobias; Rolvien, Tim; Rüther, Wolfgang; Amling, Michael

2017-01-01

Complex regional pain syndrome (CRPS) is a major complication after trauma, surgery, and/or immobilization of an extremity. The disease often starts with clinical signs of local inflammation and develops into a prolonged phase that is characterized by trophic changes and local osteoporosis and sometimes results in functional impairment of the affected limb. While the pathophysiology of CRPS remains poorly understood, increased local bone resorption plays an undisputed pivotal role. The aim of this retrospective clinical study was to assess the bone microstructure in patients with CRPS. Patients with CRPS type I of the upper limb whose affected and unaffected distal radii were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) were identified retrospectively. The osteology laboratory data and dual-energy X-ray absorptiometry (DXA) images of the left femoral neck and lumbar spine, which were obtained on the same day as HR-pQCT, were extracted from the medical records. Five patients were identified. The CRPS-affected upper limbs had significantly lower trabecular numbers and higher trabecular thicknesses than the unaffected upper limbs. However, the trabecular bone volume to total bone volume and cortical thickness values of the affected and unaffected sides were similar. Trabecular thickness tended to increase with time since disease diagnosis. CRPS associated with significant alterations in the bone microstructure of the affected upper limb that may amplify as the duration of disease increases.

Targeted Coagulation Management in Severe Trauma: The Controversies and the Evidence.

PubMed

Winearls, James; Reade, Michael; Miles, Helen; Bulmer, Andrew; Campbell, Don; Görlinger, Klaus; Fraser, John F

2016-10-01

Hemorrhage in the setting of severe trauma is a leading cause of death worldwide. The pathophysiology of hemorrhage and coagulopathy in severe trauma is complex and remains poorly understood. Most clinicians currently treating trauma patients acknowledge the presence of a coagulopathy unique to trauma patients-trauma-induced coagulopathy (TIC)-independently associated with increased mortality. The complexity and incomplete understanding of TIC has resulted in significant controversy regarding optimum management. Although the majority of trauma centers utilize fixed-ratio massive transfusion protocols in severe traumatic hemorrhage, a widely accepted "ideal" transfusion ratio of blood to blood products remains elusive. The recent use of viscoelastic hemostatic assays (VHAs) to guide blood product replacement has further provoked debate as to the optimum transfusion strategy. The use of VHA to quantify the functional contributions of individual components of the coagulation system may permit targeted treatment of TIC but remains controversial and is unlikely to demonstrate a mortality benefit in light of the heterogeneity of the trauma population. Thus, VHA-guided algorithms as an alternative to fixed product ratios in trauma are not universally accepted, and a hybrid strategy starting with fixed-ratio transfusion and incorporating VHA data as they become available is favored by some institutions. We review the current evidence for the management of coagulopathy in trauma, the rationale behind the use of targeted and fixed-ratio approaches and explore future directions.

Subclinical Disease Burden as Assessed by Whole-Body MRI in Subjects With Prediabetes, Subjects With Diabetes, and Normal Control Subjects From the General Population: The KORA-MRI Study.

PubMed

Bamberg, Fabian; Hetterich, Holger; Rospleszcz, Susanne; Lorbeer, Roberto; Auweter, Sigrid D; Schlett, Christopher L; Schafnitzel, Anina; Bayerl, Christian; Schindler, Andreas; Saam, Tobias; Müller-Peltzer, Katharina; Sommer, Wieland; Zitzelsberger, Tanja; Machann, Jürgen; Ingrisch, Michael; Selder, Sonja; Rathmann, Wolfgang; Heier, Margit; Linkohr, Birgit; Meisinger, Christa; Weber, Christian; Ertl-Wagner, Birgit; Massberg, Steffen; Reiser, Maximilian F; Peters, Annette

2017-01-01

Detailed pathophysiological manifestations of early disease in the context of prediabetes are poorly understood. This study aimed to evaluate the extent of early signs of metabolic and cardio-cerebrovascular complications affecting multiple organs in individuals with prediabetes. Subjects without a history of stroke, coronary artery disease, or peripheral artery disease were enrolled in a case-control study nested within the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and underwent comprehensive MRI assessment to characterize cerebral parameters (white matter lesions, microbleeds), cardiovascular parameters (carotid plaque, left ventricular function, and myocardial late gadolinium enhancement [LGE]), and metabolic parameters (hepatic proton-density fat fraction [PDFF] and subcutaneous and visceral abdominal fat). Among 400 subjects who underwent MRI, 103 subjects had prediabetes and 54 had established diabetes. Subjects with prediabetes had an increased risk for carotid plaque and adverse functional cardiac parameters, including reduced early diastolic filling rates as well as a higher prevalence of LGE compared with healthy control subjects. In addition, people with prediabetes had significantly elevated levels of PDFF and total and visceral fat. Thus, subjects with prediabetes show early signs of subclinical disease that include vascular, cardiac, and metabolic changes, as measured by whole-body MRI after adjusting for cardiometabolic risk factors. © 2017 by the American Diabetes Association.

Thoracic and abdominal aortas stiffen through unique extracellular matrix changes in intrauterine growth restricted fetal sheep.

PubMed

Dodson, R Blair; Rozance, Paul J; Petrash, Carson C; Hunter, Kendall S; Ferguson, Virginia L

2014-02-01

Intrauterine growth restriction (IUGR) is a fetal complication of pregnancy epidemiologically linked to cardiovascular disease in the newborn later in life. However, the mechanism is poorly understood with very little research on the vascular structure and function during development in healthy and IUGR neonates. Previously, we found vascular remodeling and increased stiffness in the carotid and umbilical arteries, but here we examine the remodeling and biomechanics in the larger vessels more proximal to the heart. To study this question, thoracic and abdominal aortas were collected from a sheep model of placental insufficiency IUGR (PI-IUGR) due to exposure to elevated ambient temperatures. Aortas from control (n = 12) and PI-IUGR fetuses (n = 10) were analyzed for functional biomechanics and structural remodeling. PI-IUGR aortas had a significant increase in stiffness (P < 0.05), increased collagen content (P < 0.05), and decreased sulfated glycosaminoglycan content (P < 0.05). Our derived constitutive model from experimental data related increased stiffness to reorganization changes of increased alignment angle of collagen fibers and increased elastin (P < 0.05) in the thoracic aorta and increased concentration of collagen fibers in the abdominal aorta toward the circumferential direction verified through use of histological techniques. This fetal vascular remodeling in PI-IUGR may set the stage for possible altered growth and development and help to explain the pathophysiology of adult cardiovascular disease in previously IUGR individuals.

Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease.

PubMed

Chou, Shih-Jie; Yu, Wen-Chung; Chang, Yuh-Lih; Chen, Wen-Yeh; Chang, Wei-Chao; Chien, Yueh; Yen, Jiin-Cherng; Liu, Yung-Yang; Chen, Shih-Jen; Wang, Chien-Ying; Chen, Yu-Han; Niu, Dau-Ming; Lin, Shing-Jong; Chen, Jaw-Wen; Chiou, Shih-Hwa; Leu, Hsin-Bang

2017-04-01

Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Asian consensus on irritable bowel syndrome.

PubMed

Gwee, Kok-Ann; Bak, Young-Tae; Ghoshal, Uday Chand; Gonlachanvit, Sutep; Lee, Oh Young; Fock, Kwong Ming; Chua, Andrew Seng Boon; Lu, Ching-Liang; Goh, Khean-Lee; Kositchaiwat, Chomsri; Makharia, Govind; Park, Hyo-Jin; Chang, Full-Young; Fukudo, Shin; Choi, Myung-Gyu; Bhatia, Shobna; Ke, Meiyun; Hou, Xiaohua; Hongo, Michio

2010-07-01

Many of the ideas on irritable bowel syndrome (IBS) are derived from studies conducted in Western societies. Their relevance to Asian societies has not been critically examined. Our objectives were to bring to attention important data from Asian studies, articulate the experience and views of our Asian experts, and provide a relevant guide on this poorly understood condition for doctors and scientists working in Asia. A multinational group of physicians from Asia with special interest in IBS raised statements on IBS pertaining to symptoms, diagnosis, epidemiology, infection, pathophysiology, motility, management, and diet. A modified Delphi approach was employed to present and grade the quality of evidence, and determine the level of agreement. We observed that bloating and symptoms associated with meals were prominent complaints among our IBS patients. In the majority of our countries, we did not observe a female predominance. In some Asian populations, the intestinal transit times in healthy and IBS patients appear to be faster than those reported in the West. High consultation rates were observed, particularly in the more affluent countries. There was only weak evidence to support the perception that psychological distress determines health-care seeking. Dietary factors, in particular, chili consumption and the high prevalence of lactose malabsorption, were perceived to be aggravating factors, but the evidence was weak. This detailed compilation of studies from different parts of Asia, draws attention to Asian patients' experiences of IBS.

Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration.

PubMed

Ouro, Alberto; Arana, Lide; Rivera, Io-Guané; Ordoñez, Marta; Gomez-Larrauri, Ana; Presa, Natalia; Simón, Jorge; Trueba, Miguel; Gangoiti, Patricia; Bittman, Robert; Gomez-Muñoz, Antonio

2014-12-15

Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis. Copyright © 2014 Elsevier Inc. All rights reserved.

Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis.

PubMed

Nikolic, Aleksandra

2018-05-12

Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF.

Bowel urgency in patients with irritable bowel syndrome.

PubMed

Basilisco, Guido; De Marco, Elisabetta; Tomba, Carolina; Cesana, Bruno Mario

2007-01-01

Bowel urgency is the most bothersome symptom in irritable bowel syndrome patients with diarrhea, but its pathophysiology is poorly understood. Our aim was to assess the relationships among reporting the symptom, the reservoir functions of the colon and rectum, and the patients' psychologic profile. The study involved 28 consecutive patients with irritable bowel syndrome and 17 healthy subjects. The presence or absence of bowel urgency was verified by means of a questionnaire during the 3 days required for the ingestion of radio-opaque markers. On the fourth day, an abdominal x-ray was taken to assess colonic transit time, and rectal sensory and motor responses were measured during rectal distention. The subjects' psychologic profiles were assessed using a psychologic symptoms checklist. Forty-six percent of the patients reported urgency associated with at least 1 defecation. The multivariate logistic regression analysis showed that colonic transit was the only variable independently associated with reported bowel urgency, but the threshold for the sensation of urgency was not removed from the model since its borderline significance level. Rectal compliance was closely associated with the threshold for the sensation of urgency during rectal distention but was not an independent factor for reporting the sensation. The patients with and without urgency showed altered psychologic profiles. The symptom of urgency is associated with objective alterations in the colonic and rectal reservoir of patients with irritable bowel syndrome.

HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.

PubMed

Salin-Cantegrel, Adèle; Shekarabi, Masoud; Holbert, Sébastien; Dion, Patrick; Rochefort, Daniel; Laganière, Janet; Dacal, Sandra; Hince, Pascale; Karemera, Liliane; Gaspar, Claudia; Lapointe, Jean-Yves; Rouleau, Guy A

2008-09-01

The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in the development of the nervous system remain poorly understood. The functional regulation of this transporter by protein partners is also largely unknown. Using a yeast two-hybrid approach, we discovered that the C-terminal domain (CTD) of KCC3, which is lost in most HMSN/ACC-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CK-B was further confirmed by in vitro glutathione S-transferase pull-down assay, followed by sequencing of the pulled-down complexes. In transfected cultured cells, immunofluorescence labeling showed that CK-B co-localizes with wild-type KCC3, whereas the kinase fails to interact with the inactive truncated KCC3. Finally, CK-B's inhibition by DNFB results in reduction of activity of KCC3 in functional assays using Xenopus laevis oocytes. This physical and functional association between the co-transporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of HMSN/ACC.

EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness

PubMed Central

Desjardins, Marie-Ève; Carrier, Julie; Lina, Jean-Marc; Fortin, Maxime; Gosselin, Nadia; Montplaisir, Jacques

2017-01-01

Abstract Study Objectives: Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. Methods: We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient’s episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results: Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes’ onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Conclusions: Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep. PMID:28204773

The surface protein HvgA mediates group B streptococcus hypervirulence and meningeal tropism in neonates

PubMed Central

Tazi, Asmaa; Disson, Olivier; Bellais, Samuel; Bouaboud, Abdelouhab; Dmytruk, Nicolas; Dramsi, Shaynoor; Mistou, Michel-Yves; Khun, Huot; Mechler, Charlotte; Tardieux, Isabelle; Trieu-Cuot, Patrick

2010-01-01

Streptococcus agalactiae (group B streptococcus; GBS) is a normal constituent of the intestinal microflora and the major cause of human neonatal meningitis. A single clone, GBS ST-17, is strongly associated with a deadly form of the infection called late-onset disease (LOD), which is characterized by meningitis in infants after the first week of life. The pathophysiology of LOD remains poorly understood, but our epidemiological and histopathological results point to an oral route of infection. Here, we identify a novel ST-17–specific surface-anchored protein that we call hypervirulent GBS adhesin (HvgA), and demonstrate that its expression is required for GBS hypervirulence. GBS strains that express HvgA adhered more efficiently to intestinal epithelial cells, choroid plexus epithelial cells, and microvascular endothelial cells that constitute the blood–brain barrier (BBB), than did strains that do not express HvgA. Heterologous expression of HvgA in nonadhesive bacteria conferred the ability to adhere to intestinal barrier and BBB-constituting cells. In orally inoculated mice, HvgA was required for intestinal colonization and translocation across the intestinal barrier and the BBB, leading to meningitis. In conclusion, HvgA is a critical virulence trait of GBS in the neonatal context and stands as a promising target for the development of novel diagnostic and antibacterial strategies. PMID:20956545

Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases.

PubMed

Müller-Deile, Janina; Dannenberg, Jan; Schroder, Patricia; Lin, Meei-Hua; Miner, Jeffrey H; Chen, Rongjun; Bräsen, Jan-Hinrich; Thum, Thomas; Nyström, Jenny; Staggs, Lynne Beverly; Haller, Hermann; Fiedler, Jan; Lorenzen, Johan M; Schiffer, Mario

2017-10-01

The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Characterization of mitochondrial proteome in a severe case of ETF-QO deficiency.

PubMed

Rocha, H; Ferreira, R; Carvalho, J; Vitorino, R; Santa, C; Lopes, L; Gregersen, N; Vilarinho, L; Amado, F

2011-12-10

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a mitochondrial fatty acid oxidation disorder caused by mutations that affect electron transfer flavoprotein (ETF) or ETF:ubiquinone oxidoreductase (ETF-QO) or even due to unidentified disturbances of riboflavin metabolism. Besides all the available data on the molecular basis of FAO disorders, including MADD, the pathophysiological mechanisms underlying clinical phenotype development, namely at the mitochondrial level, are poorly understood. In order to contribute to the elucidation of these mechanisms, we isolated mitochondria from cultured fibroblasts, from a patient with a severe MADD presentation due to ETF-QO deficiency, characterize its mitochondrial proteome and compare it with normal controls. The used approach (2-DE-MS/MS) allowed the positive identification of 287 proteins in both patient and controls, presenting 35 of the significant differences in their relative abundance. Among the differentially expressed are proteins associated to binding/folding functions, mitochondrial antioxidant enzymes as well as proteins associated to apoptotic events. The overexpression of chaperones like Hsp60 or mitochondrial Grp75, antioxidant enzymes and apoptotic proteins reflects the mitochondrial response to a complete absence of ETF-QO. Our study provides a global perspective of the mitochondrial proteome plasticity in a severe case of MADD and highlights the main molecular pathways involved in its pathogenesis. Copyright © 2011 Elsevier B.V. All rights reserved.

Catatonia: Our current understanding of its diagnosis, treatment and pathophysiology

PubMed Central

Rasmussen, Sean A; Mazurek, Michael F; Rosebush, Patricia I

2016-01-01

Catatonia is a psychomotor syndrome that has been reported to occur in more than 10% of patients with acute psychiatric illnesses. Two subtypes of the syndrome have been identified. Catatonia of the retarded type is characterized by immobility, mutism, staring, rigidity, and a host of other clinical signs. Excited catatonia is a less common presentation in which patients develop prolonged periods of psychomotor agitation. Once thought to be a subtype of schizophrenia, catatonia is now recognized to occur with a broad spectrum of medical and psychiatric illnesses, particularly affective disorders. In many cases, the catatonia must be treated before any underlying conditions can be accurately diagnosed. Most patients with the syndrome respond rapidly to low-dose benzodiazepines, but electroconvulsive therapy is occasionally required. Patients with longstanding catatonia or a diagnosis of schizophrenia may be less likely to respond. The pathobiology of catatonia is poorly understood, although abnormalities in gamma-aminobutyric acid and glutamate signaling have been suggested as causative factors. Because catatonia is common, highly treatable, and associated with significant morbidity and mortality if left untreated, physicians should maintain a high level of suspicion for this complex clinical syndrome. Since 1989, we have systematically assessed patients presenting to our psychiatry service with signs of retarded catatonia. In this paper, we present a review of the current literature on catatonia along with findings from the 220 cases we have assessed and treated. PMID:28078203

Quantitative Proteomic Profiling the Molecular Signatures of Annexin A5 in Lung Squamous Carcinoma Cells.

PubMed

Sun, Bing; Bai, Yuxin; Zhang, Liyuan; Gong, Linlin; Qi, Xiaoyu; Li, Huizhen; Wang, Faming; Chi, Xinming; Jiang, Yulin; Shao, Shujuan

Lung cancer remains the leading cancer killer around the world. It's crucial to identify newer mechanism-based targets to effectively manage lung cancer. Annexin A5 (ANXA5) is a protein kinase C inhibitory protein and calcium dependent phospholipid-binding protein, which may act as an endogenous regulator of various pathophysiological processes. However, its molecular mechanism in lung cancer remains poorly understood. This study was designed to determine the mechanism of ANXA5 in lung cancer with a hope to obtain useful information to provide a new therapeutic target. We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection. Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively. The IPA analysis revealed that glycolysis and gluconeogenesis were the predominant pathways modulated by ANXA5. Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation. Taken together, ANXA5 appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of ANXA5 as a potential target in lung cancer. This study might provide a new insight into the mechanism of ANXA5 in lung cancer.

Occupational vocal cord dysfunction due to exposure to wood dust and xerographic toner.

PubMed

Muñoz, Xavier; Roger, Alex; De la Rosa, David; Morell, Ferran; Cruz, Maria J

2007-04-01

Vocal cord dysfunction is a poorly understood entity that is often misdiagnosed as asthma. Both irritant and non-irritant vocal cord dysfunction have been described. This report presents two cases of irritant vocal cord dysfunction secondary to specific environmental exposure, the first to iroko and western red cedar wood (a carpenter) and the second to xerographic printing toner (a secretary). Several tests were performed, including chest radiographs, measurements of total serum immunoglobulin E, skin prick tests with common pneumoallergens (as well as iroko and western red cedar in the first case), pulmonary function studies, methacholine challenge testing, specific inhalation challenge performed with suspected agents in a single-blinded fashion, and peak expiratory flow testing and fiberoptic rhinolaryngoscopy (in case 1). During the specific inhalation challenge, the patients showed dysphonia, chest tightness, inspiratory stridor, and flattening of the inspiratory limb of the maximum flow-volume loop in spirometry, with no significant decreases in the level of forced expiratory volume in 1 second; fiberoptic rhinolaryngoscopy confirmed the diagnosis of vocal cord dysfunction in case 1. It is important to know that agents that can cause occupational asthma can also cause vocal cord dysfunction. The mechanisms by which these agents produce vocal cord dysfunction are unknown. The differences in the clinical presentation of the patients described relative to the reported cases suggest that more than one pathophysiological mechanism may be implicated in the genesis of this entity.

Complete Genome and Phylogeny of Puumala Hantavirus Isolates Circulating in France.

PubMed

Castel, Guillaume; Couteaudier, Mathilde; Sauvage, Frank; Pons, Jean-Baptiste; Murri, Séverine; Plyusnina, Angelina; Pontier, Dominique; Cosson, Jean-François; Plyusnin, Alexander; Marianneau, Philippe; Tordo, Noël

2015-10-22

Puumala virus (PUUV) is the agent of nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) in Europe. NE incidence presents a high spatial variation throughout France, while the geographical distribution of the wild reservoir of PUUV, the bank vole, is rather continuous. A missing piece of the puzzle is the current distribution and the genetic variation of PUUV in France, which has been overlooked until now and remains poorly understood. During a population survey, from 2008 to 2011, bank voles were trapped in eight different forests of France located in areas known to be endemic for NE or in area from where no NE case has been reported until now. Bank voles were tested for immunoglobulin (Ig)G ELISA serology and two seropositive animals for each of three different areas (Ardennes, Jura and Orleans) were then subjected to laboratory analyses in order to sequence the whole S, M and L segments of PUUV. Phylogenetic analyses revealed that French PUUV isolates globally belong to the central European (CE) lineage although isolates from Ardennes are clearly distinct from those in Jura and Orleans, suggesting a different evolutionary history and origin of PUUV introduction in France. Sequence analyses revealed specific amino acid signatures along the N protein, including in PUUV from the Orleans region from where NE in humans has never been reported. The relevance of these mutations in term of pathophysiology is discussed.

IPF: new insight on pathogenesis and treatment.

PubMed

Harari, S; Caminati, A

2010-05-01

Recent years have seen a robust influx of exciting new observations regarding the mechanisms that regulate the initiation and progression of pulmonary fibrosis but the pathogenesis remains poorly understood. The search for an alternative hypothesis to unremitting, chronic inflammation as the primary explanation for the pathophysiology of idiopathic pulmonary fibrosis (IPF) derives, in part, from the lack of therapeutic efficacy of high-dose immunosuppressive therapy in patients with IPF. The inflammatory hypothesis of IPF has since been challenged by the epithelial injury hypothesis, in which fibrosis is believed to result from epithelial injury, activation, and/or apoptosis with abnormal wound healing. This hypothesis suggests that recurrent unknown injury to distal pulmonary parenchyma causes repeated epithelial injury and apoptosis. The resultant loss of alveolar epithelium exposes the underlying basement membrane to oxidative damage and degradation. Emerging concepts suggest that IPF is the result of epithelial-mesenchymal interaction. The initiation of this fibrotic response may depend upon genetic factors and environmental triggers; the role of Th1 or Th2 cell-derived cytokines may also be important. This process appears to be unique to usual interstitial pneumonia/IPF. It is clear that IPF is a heterogeneous disease with variations in pathology, high-resolution computed tomography findings, and patterns of progression. Idiopathic pulmonary fibrosis is a complex disorder, and no unifying hypothesis has been identified at present that explains all the abnormalities.

Spasmodic Dysphonia: A Review. Part 1: Pathogenic Factors.

PubMed

Hintze, Justin M; Ludlow, Christy L; Bansberg, Stephen F; Adler, Charles H; Lott, David G

2017-10-01

Objective The purpose of this review is to describe the recent advances in identifying possible factors involved in the pathogenesis of spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. Pathogenesis of the disorder is poorly understood. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusions Several potential etiological factors have been proposed by epidemiological, genetic, and neuropathological studies. Spasmodic dysphonia is a rare disorder primarily affecting females beginning in their 40s. Vocal tremor co-occurs in 30% to 60%. Large cohort studies identified risk factors such as a family history of neurological disorders including dystonia and tremor, recent viral illness, and heavy voice use. As none are rare events, a complex interactive process may contribute to pathogenesis in a small proportion of those at risk. Consequences to pathogenesis are neurological processes found in spasmodic dysphonia: loss of cortical inhibition, sensory processing disturbances, and neuroanatomical and physiological differences in the laryngeal motor control system. Implications for Practice Diagnosis of spasmodic dysphonia usually includes speech and laryngoscopic assessment. However, as diagnosis is sometimes problematic, measurement of neurophysiological abnormalities may contribute useful adjuncts for the diagnosis of spasmodic dysphonia in the future.

Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

PubMed

Ladepeche, Laurent; Yang, Luting; Bouchet, Delphine; Groc, Laurent

2013-01-01

Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR) have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R) laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation.

PubMed

Di, Xiao-Jing; Wang, Ya-Juan; Han, Dong-Yun; Fu, Yan-Lin; Duerfeldt, Adam S; Blagg, Brian S J; Mu, Ting-Wei

2016-04-29

Proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABAA receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABAA receptors. Here, using the α1 subunits of GABAA receptors as a model substrate, we demonstrated that Grp94, a metazoan-specific Hsp90 in the ER lumen, uses its middle domain to interact with the α1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded α1 subunits in a glycan-dependent manner. This delivers misfolded α1 subunits to the Hrd1-mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone α1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABAA receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Stress model for research into preterm delivery among black women.

PubMed

Hogue, Carol J Rowland; Bremner, J Douglas

2005-05-01

The disparity between black and white infant mortality rates increased over the last decade, despite overall improvement in infant survival. Because most black infant deaths are related to preterm delivery, the discovery of the cause of premature birth in general and excess premature birth for black infants in particular is of paramount importance for reproductive health research. Substantial theoretic support exists for maternal stress as a risk factor for preterm birth. Traumatic events early in life may sensitize the adult to contemporary stresses and increase her vulnerability to stress-induced neuroendocrine or infection/inflammatory pathways to early parturition. In addition, an individual may prematurely age as a result of cumulative stress or a major traumatic event. This "stress age," which is synonymous with the concept of weathering and similar to the concept of allostatic load, may affect parturition through chronic conditions (such as hypertension) and in poorly understood pathophysiologic mechanisms that are related to increased chronologic age. One potential measure of stress age is maternal serum dehydroepiandrosterone sulfate. Maternal stress is a potential explanatory factor for excess preterm delivery among black women because of their exposure to racism-associated stress. However, few studies have addressed this question, and results are mixed. Future etiologic research must take into account the complexities of the measurement of stress age and past and current exposures to stress, which includes internalized racism and interpersonal racism.

Kidney disease in heart failure: the importance of novel biomarkers for type 1 cardio-renal syndrome detection.

PubMed

Palazzuoli, Alberto; McCullough, Peter A; Ronco, Claudio; Nuti, Ranuccio

2015-08-01

Chronic kidney disease (CKD) in heart failure (HF) has been recognized as an independent risk factor for adverse outcome, although the most important clinical trials tend to exclude patients with moderate and severe renal insufficiency. Despite this common association, the precise pathophysiological connection and liaison between heart and kidney is partially understood. Moreover, is it not enough considering how much cardio-renal syndrome type 1 is attributable to previous CKD, and how much to new-onset acute kidney injury (AKI). Neither development of AKI, its progression and time nor duration is related to an adverse outcome. An AKI definition is not universally recognized, and many confounding terms have been used in literature: "worsening renal function", "renal impairment", "renal dysfunction", etc., are all names that contribute to misunderstanding, and do not facilitate an universal classification. Therefore, AKI development should be the consequence of the basal clinical characteristics of patients, different primitive kidney disease and hemodynamic status. AKI could also be the mirror of several underlying associated diseases poorly controlled. Finally, it is not clear which is the optimal laboratory tool for identifying patients with an increased risk of AKI. In the current report, we review the different kidney diseases' impact in HF, and we analyze the modalities for AKI recognition during HF focusing our attention about some new biomarkers with potential application in the current setting.

[Late onset, non-infectious pulmonary complications after haematological stem cell transplantation].

PubMed

Bergeron, A; Feuillet, S; Meignin, V; Socie, G; Tazi, A

2008-02-01

Non infectious pulmonary complications which frequently occur in the late follow-up of haemopoietic stem cell transplant (HSCT) recipients account for an increase in mortality and morbidity. Different histological entities have been described among which bronchiolitis obliterans is the most common. Because of the absence of prospective epidemiological studies and the difficulties in obtaining surgical lung biopsies from these frail patients little is known about these conditions. Although their pathogenesis is poorly understood they probably result from a chronic pulmonary graft versus host disease (GVHD). The introduction of or increase in systemic immunosuppressive treatment, usually indicated for controlling extra-thoracic manifestations of GVHD, may lead to the resolution of an organising pneumonia but is usually ineffective in the treatment of bronchiolitis obliterans. Current prospective cohort studies together with randomised prospective studies evaluating more targeted treatments should help determine the frequency, the risk factors and the precise characteristics of the different entities of late non-infectious pulmonary diseases following HSCT and should also improve their management. Furthermore, the recent demonstration of lung abnormalities in animal models of chronic GVHD, similar to those observed in humans, should allow a better understanding of the pathogenesis. The prevalence of these diseases is increasing throughout the world. More precise analysis, the identification of risk factors and study of the pathophysiological mechanisms involved should allow better understanding and management than at present.

Factors related to outcome in heart failure with a preserved (or normal) left ventricular ejection fraction.

PubMed

Sanderson, John E

2016-07-01

Heart failure with a preserved ejection faction (HFpEF) is a growing and expensive cause of heart failure (HF) affecting particularly the elderly. It differs in substantial ways in addition to the normal left ventricular ejection fraction, from the more easily recognized form of heart failure with a reduced ejection fraction (HFrEF or 'systolic heart failure') and unlike HFrEF there have been little advances in treatment. In part, this relates to the complexity of the pathophysiology and identifying the correct targets. In HFpEF, there appears to be widespread stiffening of the vasculature and the myocardium affecting ventricular function (both systolic and diastolic), impeding ventricular suction, and thus early diastolic filling leading to breathlessness on exertion and later atrial failure and fibrillation. Left ventricular ejection fraction tends to gradually decline and some evolve into HFrEF. Most patients also have a mixture of several co-morbidities including hypertension, diabetes, obesity, poor renal function, lack of fitness, and often poor social conditions. Therefore, many factors may influence outcome in an individual patient. In this review, the epidemiology, possible causation, pathophysiology, the influence of co-morbidities and some of the many potential predictors of outcome will be considered.

Research Review: The Neurobiology and Genetics of Maltreatment and Adversity

ERIC Educational Resources Information Center

McCrory, Eamon; De Brito, Stephane A.; Viding, Essi

2010-01-01

The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individual's genetic make-up influence neurobiological development across infancy and childhood, which in…

New concept: cellular senescence in pathophysiology of cholangiocarcinoma.

PubMed

Sasaki, Motoko; Nakanuma, Yasuni

2016-01-01

Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.

Treatment of persistent post-concussion syndrome due to mild traumatic brain injury: current status and future directions.

PubMed

Hadanny, Amir; Efrati, Shai

2016-08-01

Persistent post-concussion syndrome caused by mild traumatic brain injury has become a major cause of morbidity and poor quality of life. Unlike the acute care of concussion, there is no consensus for treatment of chronic symptoms. Moreover, most of the pharmacologic and non-pharmacologic treatments have failed to demonstrate significant efficacy on both the clinical symptoms as well as the pathophysiologic cascade responsible for the permanent brain injury. This article reviews the pathophysiology of PCS, the diagnostic tools and criteria, the current available treatments including pharmacotherapy and different cognitive rehabilitation programs, and promising new treatment directions. A most promising new direction is the use of hyperbaric oxygen therapy, which targets the basic pathological processes responsible for post-concussion symptoms; it is discussed here in depth.

NASA Aims to Create First-Ever Space-Based Sodium Lidar to Study Poorly Understood Mesosphere

NASA Image and Video Library

2017-12-08

Caption: Mike Krainak (left) and Diego Janches recently won NASA follow-on funding to advance a spaceborne sodium lidar needed to probe Earth’s poorly understood mesosphere. Credits: NASA/W. Hrybyk More: A team of NASA scientists and engineers now believes it can leverage recent advances in a greenhouse-detecting instrument to build the world’s first space-based sodium lidar to study Earth’s poorly understood mesosphere. Scientist Diego Janches and laser experts Mike Krainak and Tony Yu, all of whom work at NASA’s Goddard Space Flight Center in Greenbelt, Maryland, are leading a research-and-development effort to further advance the sodium lidar, which the group plans to deploy on the International Space Station if it succeeds in proving its flightworthiness. Read more: go.nasa.gov/2rcGpSM NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.

PubMed

Baek, Jin Hyen; D'Agnillo, Felice; Vallelian, Florence; Pereira, Claudia P; Williams, Matthew C; Jia, Yiping; Schaer, Dominik J; Buehler, Paul W

2012-04-01

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

Nuclear medicine techniques in the assessment of alkaptonuria.

PubMed

Vinjamuri, Sobhan; Ramesh, Chandakacharla N; Jarvis, Jonathan; Gallagher, Jim A; Ranganath, Lakshminarayana L

2011-10-01

Alkaptonuria is a rare autosomal recessive disorder due to a lack of the enzyme homogentisate dioxygenase, leading to ochronosis, a process of accumulation of a melanin-like polymer of homogentisic acid in cartilage and other collagenous structures. Patients develop severe osteoarthropathy that resembles osteoarthritis. Although the diagnosis of alkaptonuria is not particularly challenging in view of the blue-black discolouration of visible connective tissue and the presence of homogentisic acid in urine, the natural history of alkaptonuria remains poorly understood. Patients would benefit immensely from an objective assessment of their disease status and from a clearer understanding of the pathophysiology and associated physical changes. Isotope bone scans, which are commonly used to identify the extent of involvement of bones in cancerous processes, have also been increasingly used for characterizing the extent of arthropathy in conditions such as osteoarthritis and rheumatoid arthritis. Semiquantitative scores based on the extent of involvement of joints have been used to describe the involvement of large joints in the context of symptomatic treatment for osteoarthritis. A similar semiquantitative isotope bone scan score depending on the involvement of the number of large joints in patients with alkaptonuria can be formulated and validated in a suitable cohort of patients. Bone densitometry measurement using dual-energy X-ray absorptiometry scanning is an internationally accepted tool to assess the risk and extent of osteoporosis, and is increasingly used to assess the additional fracture risk in patients with arthropathy. We believe that, currently, nuclear medicine techniques can provide useful information, which can be incorporated into disease severity scores for alkaptonuria. Once the biological basis for alkaptonuria is better understood, it is feasible that nuclear medicine techniques of even greater sensitivity and specificity can be developed, thereby taking advantage of the vast advances in the fields of radiochemistry, radiopharmacy, positron emission tomography-computed tomography and positron emission tomography-magnetic resonance imaging scanning.

National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction.

PubMed

Nieder, Michael L; McDonald, George B; Kida, Aiko; Hingorani, Sangeeta; Armenian, Saro H; Cooke, Kenneth R; Pulsipher, Michael A; Baker, K Scott

2011-11-01

Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Auditory Processing Disorders: Acquisition and Treatment

ERIC Educational Resources Information Center

Moore, David R.

2007-01-01

Auditory processing disorder (APD) describes a mixed and poorly understood listening problem characterised by poor speech perception, especially in challenging environments. APD may include an inherited component, and this may be major, but studies reviewed here of children with long-term otitis media with effusion (OME) provide strong evidence…

[Current concepts in pathophysiology of CRPS I].

PubMed

Nickel, F T; Maihöfner, C

2010-02-01

Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. Georg Thieme Verlag KG Stuttgart, New York.

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism.

PubMed

Hernández-Alvarez, María Isabel; Díaz-Ramos, Angels; Berdasco, María; Cobb, Jeff; Planet, Evarist; Cooper, Diane; Pazderska, Agnieszka; Wanic, Krzystof; O'Hanlon, Declan; Gomez, Antonio; de la Ballina, Laura R; Esteller, Manel; Palacin, Manuel; O'Gorman, Donal J; Nolan, John J; Zorzano, Antonio

2017-10-23

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.

Pathophysiology of gastro-esophageal reflux disease: a role for mucosa integrity?

PubMed

Farré, R

2013-10-01

Gastro-esophageal reflux disease (GERD) is very prevalent and has a high burden on health security system costs. Nevertheless, pathophysiology is complex and not well-understood. Several mechanisms have been proposed: decreased salivation, impaired esophageal clearance, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations (TLESRs), increased acid, and pepsin secretion, pyloric incompetence provoking duodeno-gastro-esophageal reflux of bile acids and trypsin. Independent of the relevance of each mechanism, the ultimate phenomenon is that mucosal epithelium is exposed for a longer time to agents as acid and pepsin or is in contact to luminal agents not commonly present in gastric refluxate as trypsin or bile acids. This leads to a visible damage of the epithelium (erosive esophagitis -EE) or impairing mucosal integrity without any sign of macroscopic alteration as occurs in non-erosive reflux disease (NERD). Luminal factors are not the only responsible for such impairment; more recent data indicate that endogenous factors may also play a role. This review will update the most recent findings on the putative pathophysiological mechanisms and specially will focus on the role of esophageal mucosal integrity in GERD. Methodologies used for the evaluation of mucosal integrity, its relevance in EE and NERD, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed. © 2013 John Wiley & Sons Ltd.

[Modeling of experimental hypertension by chronic salt loading combined with a low-protein diet in Wistar rats].

PubMed

Strekalova, V V; Khachirov, D G; Dedenkov, A N; Suvorov, Iu I; Shvatsabaia, I K

1989-01-01

Combination of chronic salt loading with protein-poor diet produces experimental hypertension with natrium consumption near to physiological. The present model is characterized, compared to the existing one, by stage development, moderate arterial blood pressure elevation and absence of "salt toxicosis" and may be thus considered more adequate for experimental investigation of primary arterial hypertension pathophysiology.

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice.

PubMed

Zhang, Cary; Chua, Berenice E; Yang, Annie; Shabanpoor, Fazel; Hossain, Mohammad Akhter; Wade, John D; Rosengren, K Johan; Smith, Craig M; Gundlach, Andrew L

2015-10-01

Anxiety disorders are among the most prevalent neuropsychiatric conditions, but their precise aetiology and underlying pathophysiological processes remain poorly understood. In light of putative anatomical and functional interactions of the relaxin-3/RXFP3 system with anxiety-related neural circuits, we assessed the ability of central administration of the RXFP3 agonist, RXFP3-A2, to alter anxiety-like behaviours in adult C57BL/6J mice. We assessed how RXFP3-A2 altered performance in tests measuring rodent anxiety-like behaviour (large open field (LOF), elevated plus maze (EPM), light/dark (L/D) box, social interaction). We examined effects of RXFP3-A2 on low 'basal' anxiety, and on elevated anxiety induced by the anxiogenic benzodiazepine, FG-7142; and explored endogenous relaxin-3/RXFP3 signalling modulation by testing effects of an RXFP3 antagonist, R3(B1-22)R, on these behaviours. Intracerebroventricular (icv) injection of RXFP3-A2 (1 nmol, 15 min pre-test) did not alter anxiety-like behaviour under 'basal' conditions in the LOF, EPM or L/D box, but reduced elevated indices of FG-7142-induced (30 mg/kg, ip) anxiety-like behaviour in the L/D box and a single-chamber social interaction test. Furthermore, R3(B1-22)R (4 nmol, icv, 15 min pre-test) increased anxiety-like behaviour in the EPM (reflected by reduced entries into the open arms), but not consistently in the LOF, L/D box or social interaction tests, suggesting endogenous signaling only weakly participates in regulating 'basal' anxiety-like behaviour, in line with previous studies of relaxin-3 and RXFP3 gene knockout mice. Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Subgroups of musculoskeletal pain patients and their psychobiological patterns - the LOGIN study protocol.

PubMed

Gerhardt, Andreas; Hartmann, Mechthild; Tesarz, Jonas; Janke, Susanne; Leisner, Sabine; Seidler, Günter; Eich, Wolfgang

2012-08-03

Pain conditions of the musculoskeletal system are very common and have tremendous socioeconomic impact. Despite its high prevalence, musculoskeletal pain remains poorly understood and predominantly non-specifically and insufficiently treated.The group of chronic musculoskeletal pain patients is supposed to be heterogeneous, due to a multitude of mechanisms involved in chronic pain. Psychological variables, psychophysiological processes, and neuroendocrine alterations are expected to be involved. Thus far, studies on musculoskeletal pain have predominantly focused on the general aspects of pain processing, thus neglecting the heterogeneity of patients with musculoskeletal pain. Consequently, there is a need for studies that comprise a multitude of mechanisms that are potentially involved in the chronicity and spread of pain. This need might foster research and facilitate a better pathophysiological understanding of the condition, thereby promoting the development of specific mechanism-based treatments for chronic pain. Therefore, the objectives of this study are as follows: 1) identify and describe subgroups of patients with musculoskeletal pain with regard to clinical manifestations (including mental co-morbidity) and 2) investigate whether distinct sensory profiles or 3) distinct plasma levels of pain-related parameters due to different underlying mechanisms can be distinguished in various subgroups of pain patients. We will examine a population-based chronic pain sample (n = 100), a clinical tertiary care sample (n = 100) and pain-free patients with depression or post-traumatic stress disorder and pain-free healthy controls (each n = 30, respectively). The samples will be pain localisation matched by sex and age to the population-based sample. Patients will undergo physical examination and thorough assessments of mental co-morbidity (including psychological trauma), perceptual and central sensitisation (quantitative sensory testing), descending inhibition (conditioned pain modulation, the diffuse noxious inhibitory control-like effect), as well as measurement of the plasma levels of nerve growth factor and endocannabinoids. The identification of the underlying pathophysiologic mechanisms in different subgroups of chronic musculoskeletal pain patients will contribute to a mechanism-based subgroup classification. This will foster the development of mechanism-based treatments and holds promise to treat patients more sufficient.

Relationship between Iron Accumulation and White Matter Injury in Multiple Sclerosis: A Case-Control Study

PubMed Central

Raz, Eytan; Branson, Brittany; Jensen, Jens H.; Bester, Maxim; Babb, James S.; Herbert, Joseph; Grossman, Robert I.; Inglese, Matilde

2015-01-01

PURPOSE Despite the increasing development and applications of iron imaging, the pathophysiology of iron accumulation in multiple sclerosis (MS), and its role in disease progression and development of clinical disability, is poorly understood. The aims of our study were to determine the presence and extent of iron in T2 visible lesions and gray and white matter using magnetic field correlation (MFC) MRI and correlate with microscopic white matter (WM) injury as measured by diffusion tensor imaging (DTI). MATERIALS AND METHODS This is a case-control study incuding a series of 31 patients with clinically definite MS. The mean age was 39 years [standard deviation (SD)=9.55], they were 11 males and 20 females, with a disease duration average of 3 years (range 0-13) and a median EDSS of 2 (0-4.5). Seventeen healthy volunteers (6 males and 11 females) with a mean age of 36 years (SD=11.4) were recruited. All subjects underwent MR imaging on a 3T scanner using T2-weighted sequence, 3D T1 MPRAGE, MFC, single-shot DTI and postcontrast T1. T2-lesion volumes, brain volumetry, DTI parameters and iron quantification were calculated and multiple correlations were exploited. RESULTS Increased MFC was found in the putamen (p=0.061), the thalamus (p=0.123), the centrum semiovale (p=0.053), globus pallidus (p=0.008) and gray matter (GM) (p=0.004) of MS patients compared to controls. The mean lesional MFC was 121 s−2 (SD=67), significantly lower compared to the GM MFC (<0.0001). The GM mean diffusivity (MD) was inversely correlated with the MFC in the centrum semiovale (p<0.001), and in the splenium of the corpus callosum (p<0.001). CONCLUSION Patients with MS have increased iron in the globus pallidus, putamen and centrum with a trend toward increased iron in all the brain structures. Quantitative iron evaluation of WM and GM may improve the understanding of MS pathophysiology, and might serve as a surrogate marker of disease progression. PMID:25416468

Biomechanics of subcellular structures by non-invasive Brillouin microscopy

NASA Astrophysics Data System (ADS)

Antonacci, Giuseppe; Braakman, Sietse

2016-11-01

Cellular biomechanics play a pivotal role in the pathophysiology of several diseases. Unfortunately, current methods to measure biomechanical properties are invasive and mostly limited to the surface of a cell. As a result, the mechanical behaviour of subcellular structures and organelles remains poorly characterised. Here, we show three-dimensional biomechanical images of single cells obtained with non-invasive, non-destructive Brillouin microscopy with an unprecedented spatial resolution. Our results quantify the longitudinal elastic modulus of subcellular structures. In particular, we found the nucleoli to be stiffer than both the nuclear envelope (p < 0.0001) and the surrounding cytoplasm (p < 0.0001). Moreover, we demonstrate the mechanical response of cells to Latrunculin-A, a drug that reduces cell stiffness by preventing cytoskeletal assembly. Our technique can therefore generate valuable insights into cellular biomechanics and its role in pathophysiology.

A Review of the Pathophysiology and Treatment of Psychosis in Parkinson’s Disease

PubMed Central

Zahodne, Laura B.; Fernandez, Hubert H.

2011-01-01

Psychotic symptoms in Parkinson’s disease (PD) are relatively common, and in addition to being a disturbance to patients’ daily lives, they have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past fifteen years, from an initial interpretation of symptoms as dopaminergic drug side effects to the current view of a complex interplay of extrinsic and disease-related factors. The present article reviews the unique clinical features of psychosis as expressed in PD, associated risk factors, and current theories behind its pathogenesis, including medications, visual processing deficits, sleep disturbances, genetics, and neurochemical and structural abnormalities. Finally, we review both traditional and emergent management strategies for PD psychosis, including antipsychotic agents, cholinesterase inhibitors, electroconvulsive therapy (ECT), and other pharmacological and psychological interventions. PMID:18665659

Isotopic signals of summer denitrification in a northern hardwood forested catchment

Treesearch

Sarah K. Wexler; Christine L. Goodale; Kevin J. McGuire; Scott W. Bailey; Peter M. Groffman

2014-01-01

Despite decades of measurements, the nitrogen balance of temperate forest catchments remains poorly understood. Atmospheric nitrogen deposition often greatly exceeds streamwater nitrogen losses; the fate of the remaining nitrogen is highly uncertain. Gaseous losses of nitrogen to denitrification are especially poorly documented and are often ignored. Here, we provide...

Punishment and Welfare: Paternal Incarceration and Families' Receipt of Public Assistance

ERIC Educational Resources Information Center

Sugie, Naomi F.

2012-01-01

The United States criminal justice and welfare systems are two important government institutions in the lives of the poor. Despite many theoretical discussions about their relationship, their operation at the level of offenders and families remains poorly understood. This paper utilizes Fragile Families and Child Wellbeing data to examine how…

The role of the amygdala in the pathophysiology of panic disorder: evidence from neuroimaging studies

PubMed Central

2012-01-01

Although the neurobiological mechanisms underlying panic disorder (PD) are not yet clearly understood, increasing amount of evidence from animal and human studies suggests that the amygdala, which plays a pivotal role in neural network of fear and anxiety, has an important role in the pathogenesis of PD. This article aims to (1) review the findings of structural, chemical, and functional neuroimaging studies on PD, (2) relate the amygdala to panic attacks and PD development, (3) discuss the possible causes of amygdalar abnormalities in PD, (4) and suggest directions for future research. PMID:23168129

Sex differences in abdominal aortic aneurysms.

PubMed

Boese, Austin C; Chang, Lin; Yin, Ke-Jie; Chen, Y Eugene; Lee, Jean-Pyo; Hamblin, Milton H

2018-06-01

Abdominal aortic aneurysm (AAA) is a vascular disorder with a high case fatality rate in the instance of rupture. AAA is a multifactorial disease, and the etiology is still not fully understood. AAA is more likely to occur in men, but women have a greater risk of rupture and worse prognosis. Women are reportedly protected against AAA possibly by premenopausal levels of estrogen and are, on average, diagnosed at older ages than men. Here, we review the present body of research on AAA pathophysiology in humans, animal models, and cultured cells, with an emphasis on sex differences and sex steroid hormone signaling.

Boxing-related head injuries.

PubMed

Jayarao, Mayur; Chin, Lawrence S; Cantu, Robert C

2010-10-01

Fatalities in boxing are most often due to traumatic brain injury that occurs in the ring. In the past 30 years, significant improvements in ringside and medical equipment, safety, and regulations have resulted in a dramatic reduction in the fatality rate. Nonetheless, the rate of boxing-related head injuries, particularly concussions, remains unknown, due in large part to its variability in clinical presentation. Furthermore, the significance of repeat concussions sustained when boxing is just now being understood. In this article, we identify the clinical manifestations, pathophysiology, and management of boxing-related head injuries, and discuss preventive strategies to reduce head injuries sustained by boxers.

Pain management in patients with chronic kidney disease

PubMed Central

Pham, Phuong-Chi T.; Toscano, Edgar; Pham, Phuong-Mai T.; Pham, Phuong-Anh T.; Pham, Son V.; Pham, Phuong-Thu T.

2009-01-01

Pain has been reported to be a common problem in the general population and end-stage renal disease (ESRD) patients. Although similar data for pre-ESRD patients are lacking, we recently reported that the prevalence of pain is also very high (>70%) among pre-ESRD patients at a Los Angeles County tertiary referral centre. The high prevalence of pain in the CKD population is particularly concerning because pain has been shown to be associated with poor quality of life. Of greater concern, poor quality of life, at least in dialysis patients, has been shown to be associated with poor survival. We herein discuss the pathophysiology of common pain conditions, review a commonly accepted approach to the management of pain in the general population, and discuss analgesic-induced renal complications and therapeutic issues specific for patients with reduced renal function. PMID:25949305

Polycystic Ovarian Syndrome: Is It Time to Rename PCOS to HA-PODS?

PubMed

Khadilkar, Suvarna Satish

2016-04-01

The term polycystic ovarian syndrome (PCOS) came into existence 80 years ago. Pathophysiology of PCOS remains ill understood despite extensive research in this field. It is now accepted that the manifestations of PCOS are not confined to the reproductive dysfunction, and there are endocrine-metabolic implications to PCOS with several consequences to female health. PCOS is a misnomer as ovaries do not contain epithelial cysts, but they are actually antral follicles. Moreover, the name PCOS neither reflects the hyperandrogenism which is essential for diagnosis nor the metabolic derangements. While various authors have expressed the need for change of the name, a suitable new option has not yet been established. This review aims to analyse the current understanding of pathophysiology of PCOS and addresses to the controversies associated with its diagnosis and nomenclature. The name "Hyperandrogenic Persistent Ovulatory Dysfunction Syndrome or HA-PODS" is proposed here to overcome diagnostic pitfalls of previous nomenclature. This new name will help formulate appropriate treatment and promote consistency in research as well. Further categorizations of HA-PODS are also discussed in the article.

Presence and Risk Factors for Glaucoma in Patients with Diabetes

PubMed Central

Song, Brian J.; Aiello, Lloyd Paul; Pasquale, Louis R.

2017-01-01

Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure – the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better-defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients. PMID:27766584

Leucine-Rich Repeat Kinase 2 in Parkinson's Disease: Updated from Pathogenesis to Potential Therapeutic Target.

PubMed

Chen, Jinhua; Chen, Ying; Pu, Jiali

2018-04-27

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment. © 2018 S. Karger AG, Basel.

Diagnosis and treatment of polycystic ovarian syndrome in adolescents.

PubMed

Nicandri, Katrina F; Hoeger, Kathleen

2012-12-01

To review what is understood about the pathophysiology of polycystic ovarian syndrome (PCOS), the diagnostic challenges of PCOS in adolescent women, associated risk factors, as well as the best evidence-based treatment options for adolescence. Diagnosing PCOS in adolescents requires a unique set of criteria for which no single marker currently exists. Adolescents at high risk for developing the syndrome are congenital virilization, low birth weight, premature pubarche, central precocious puberty, large for gestational age girls born to overweight mothers, obesity syndromes, insulin-resistant features, and girls born to parents with PCOS, central obesity, or diabetes in whom PCOS ought to be suspected when associated with irregular menses. Insulin, hyperandrogenemia, and adipocytokines are integral players in the pathophysiology of PCOS. PCOS may be an inheritable trait; however, no gene has yet been identified. Quality of life remains a concern for young women with PCOS. Lifestyle modifications geared to prevent long-term sequelae remain the first-line treatment in conjunction with oral contraceptive pills. Identifying PCOS in adolescents remains a diagnostic dilemma, but early intervention and treatment can improve long-term health.

Cardiovascular Consequences of Metabolic Syndrome

PubMed Central

Tune, Johnathan D.; Goodwill, Adam G.; Sassoon, Daniel J.; Mather, Kieren J.

2017-01-01

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiologic mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review we highlight current knowledge regarding the pathophysiologic consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiologic and molecular mechanisms that may contribute to these adverse outcomes. PMID:28130064

Cardiorenal Syndrome in Acute Heart Failure: Revisiting Paradigms.

PubMed

Núñez, Julio; Miñana, Gema; Santas, Enrique; Bertomeu-González, Vicente

2015-05-01

Cardiorenal syndrome has been defined as the simultaneous dysfunction of both the heart and the kidney. Worsening renal function that occurs in patients with acute heart failure has been classified as cardiorenal syndrome type 1. In this setting, worsening renal function is a common finding and is due to complex, multifactorial, and not fully understood processes involving hemodynamic (renal arterial hypoperfusion and renal venous congestion) and nonhemodynamic factors. Traditionally, worsening renal function has been associated with worse outcomes, but recent findings have revealed mixed and heterogeneous results, perhaps suggesting that the same phenotype represents a diversity of pathophysiological and clinical situations. Interpreting the magnitude and chronology of renal changes together with baseline renal function, fluid overload status, and clinical response to therapy might help clinicians to unravel the clinical meaning of renal function changes that occur during an episode of heart failure decompensation. In this article, we critically review the contemporary evidence on the pathophysiology and clinical aspects of worsening renal function in acute heart failure. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Motor automaticity in Parkinson’s disease

PubMed Central

Wu, Tao; Hallett, Mark; Chan, Piu

2017-01-01

Bradykinesia is the most important feature contributing to motor difficulties in Parkinson’s disease (PD). However, the pathophysiology underlying bradykinesia is not fully understood. One important aspect is that PD patients have difficulty in performing learned motor skills automatically, but this problem has been generally overlooked. Here we review motor automaticity associated motor deficits in PD, such as reduced arm swing, decreased stride length, freezing of gait, micrographia and reduced facial expression. Recent neuroimaging studies have revealed some neural mechanisms underlying impaired motor automaticity in PD, including less efficient neural coding of movement, failure to shift automated motor skills to the sensorimotor striatum, instability of the automatic mode within the striatum, and use of attentional control and/or compensatory efforts to execute movements usually performed automatically in healthy people. PD patients lose previously acquired automatic skills due to their impaired sensorimotor striatum, and have difficulty in acquiring new automatic skills or restoring lost motor skills. More investigations on the pathophysiology of motor automaticity, the effect of L-dopa or surgical treatments on automaticity, and the potential role of using measures of automaticity in early diagnosis of PD would be valuable. PMID:26102020

Low serotonin1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder.

PubMed

Tiger, Mikael; Farde, Lars; Rück, Christian; Varrone, Andrea; Forsberg, Anton; Lindefors, Nils; Halldin, Christer; Lundberg, Johan

2016-07-30

The pathophysiology of major depressive disorder (MDD) is not fully understood and the diagnosis is largely based on history and clinical examination. So far, several lines of preclinical data and a single imaging study implicate a role for the serotonin1B (5-HT1B) receptor subtype. We sought to study 5-HT1B receptor binding in brain regions of reported relevance in patients with MDD. Subjects were examined at the Karolinska Institutet PET centre using positron emission tomography (PET) and the 5-HT1B receptor selective radioligand [(11)C]AZ10419369. Ten drug-free patients with recurrent MDD and ten control subjects matched for age and sex were examined. The main outcome measure was [(11)C]AZ10419369 binding in brain regions of reported relevance in the pathophysiology of MDD. The [(11)C]AZ10419369 binding potential was significantly lower in the MDD group compared with the healthy control group in the anterior cingulate cortex (20% between-group difference), the subgenual prefrontal cortex (17% between-group difference), and in the hippocampus (32% between-group difference). The low anterior cingulate [(11)C]AZ10419369 binding potential in patients with recurrent MDD positions 5-HT1B receptor binding in this region as a putative biomarker for MDD and corroborate a role of the anterior cingulate cortex and associated areas in the pathophysiology of recurrent MDD. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Host- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients.

PubMed

Sousa, Rita de; França, Ana; Dória Nòbrega, Sónia; Belo, Adelaide; Amaro, Mario; Abreu, Tiago; Poças, José; Proença, Paula; Vaz, José; Torgal, Jorge; Bacellar, Fátima; Ismail, Nahed; Walker, David H

2008-08-15

The pathophysiologic mechanisms that determine the severity of Mediterranean spotted fever (MSF) and the host-related and microbe-related risk factors for a fatal outcome are incompletely understood. This prospective study used univariate and multivariate analyses to determine the risk factors for a fatal outcome for 140 patients with Rickettsia conorii infection admitted to 13 Portuguese hospitals during 1994-2006 with documented identification of the rickettsial strain causing their infection. A total of 71 patients (51%) were infected with the Malish strain of Rickettsia conorii, and 69 (49%) were infected with the Israeli spotted fever (ISF) strain. Patients were admitted to the intensive care unit (40 [29%]), hospitalized as routine inpatients (95[67%]), or managed as outpatients (5[4%]). Death occurred in 29 adults (21%). A fatal outcome was significantly more likely for patients infected with the ISF strain, and alcoholism was a risk factor. The pathophysiology of a fatal outcome involved significantly greater incidence of petechial rash, gastrointestinal symptoms, obtundation and/or confusion, dehydration, tachypnea, hepatomegaly, leukocytosis, coagulopathy, azotemia, hyperbilirubinemia, and elevated levels of hepatic enzymes and creatine kinase. Some, but not all, of these findings were observed more often in ISF strain-infected patients. Although fatalities and similar clinical manifestations occurred among both groups of patients, the ISF strain was more virulent than the Malish strain. Multivariate analysis revealed that acute renal failure and hyperbilirubinemia were most strongly associated with a fatal outcome.

Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success

PubMed Central

Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

2016-01-01

Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success. PMID:27621771

Catheter-based intervention for symptomatic patient with severe mitral regurgitation and very poor left ventricular systolic function - Safe but no room for complacency.

PubMed

Loh, Poay Huan; Bourantas, Christos V; Chan, Pak Hei; Ihlemann, Nikolaj; Gustafsson, Fin; Clark, Andrew L; Price, Susanna; Mario, Carlo Di; Moat, Neil; Alamgir, Farqad; Estevez-Loureiro, Rodrigo; Søndergaard, Lars; Franzen, Olaf

2015-11-26

Many patients with left ventricular systolic dysfunction have concomitant mitral regurgitation (MR). Their symptoms and prognosis worsen with increasing severity of MR. Percutaneous MitraClip(®) can be used safely to reduce the severity of MR even in patients with advanced heart failure and is associated with improved symptoms, quality of life and exercise tolerance. However, a few patients with very poor left ventricular systolic function may experience significant haemodynamic disturbance in the peri-procedural period. We present three such patients, highlighting some of the potential problems encountered and discuss their possible pathophysiological mechanisms and safety measures.

Catheter-based intervention for symptomatic patient with severe mitral regurgitation and very poor left ventricular systolic function - Safe but no room for complacency

PubMed Central

Loh, Poay Huan; Bourantas, Christos V; Chan, Pak Hei; Ihlemann, Nikolaj; Gustafsson, Fin; Clark, Andrew L; Price, Susanna; Mario, Carlo Di; Moat, Neil; Alamgir, Farqad; Estevez-Loureiro, Rodrigo; Søndergaard, Lars; Franzen, Olaf

2015-01-01

Many patients with left ventricular systolic dysfunction have concomitant mitral regurgitation (MR). Their symptoms and prognosis worsen with increasing severity of MR. Percutaneous MitraClip® can be used safely to reduce the severity of MR even in patients with advanced heart failure and is associated with improved symptoms, quality of life and exercise tolerance. However, a few patients with very poor left ventricular systolic function may experience significant haemodynamic disturbance in the peri-procedural period. We present three such patients, highlighting some of the potential problems encountered and discuss their possible pathophysiological mechanisms and safety measures. PMID:26635930

Evolution of a sediment wave in an experimental channel

Treesearch

Thomas E. Lisle; James E. Pizzuto; Hiroshi Ikeda; Fujiko Iseya; Yoshinori Kodama

1997-01-01

Abstract - The routing of bed material through channels is poorly understood. We approach the problem by observing and modeling the fate of a low-amplitude sediment wave of poorly sorted sand that we introduced into an experimental channel transporting sediment identical to that of the introduced wave. The wave essentially dispersed upstream and downstream without...

Independent Learning--What We Do When You're Not There

ERIC Educational Resources Information Center

Hockings, Christine; Thomas, Liz; Ottaway, Jim; Jones, Rob

2018-01-01

Independent learning is one of the cornerstones of UK higher education yet it is poorly understood by students and is seen by politicians as a poor substitute for face to face teaching. This paper explores students' understandings, approaches and experiences of independent learning and how they may become more effective independent learners. This…

The role of bedrock groundwater in rainfall-runoff response at hillslope and catchment scales

Treesearch

C. Gabrielli; J.J. McDonnell; W.T. Jarvis

2012-01-01

Bedrock groundwater dynamics in headwater catchments are poorly understood and poorly characterized. Direct hydrometric measurements have been limited due to the logistical challenges associated with drilling through hard rock in steep, remote and often roadless terrain. We used a new portable bedrock drilling system to explore bedrock groundwater dynamics aimed at...

Asian and Pacific Islander American Poverty: The Working Poor and the Jobless Poor.

ERIC Educational Resources Information Center

Toji, Dean S.; Johnson, James H.

1992-01-01

Assesses the incidence of Asian-American and Pacific Islander-American poverty, and offers a theoretical explanation for its existence. It is argued that poverty of Americans of Asian and Pacific Island descent is best understood in the context of the linkage of labor migration and U.S. labor market segmentation. (SLD)

Fox Den Disease: An Interesting Case Following Delayed Diagnosis.

PubMed

Stehr, Ryan C; Kim, Nicholas; LoGiudice, John A; Ludwig, Kirk

2015-06-01

Pyoderma fistulans sinifica, also known as fox den disease, is a rare and poorly understood inflammatory disorder of the skin and subcutaneous tissues. This disorder is often mistaken for other inflammatory skin disorders and treated inappropriately. The authors describe the case of a 53-year-old male who presented to the colorectal surgery service with a longstanding diagnosis of perirectal Crohn's disease. Despite aggressive immunosuppression and numerous surgical procedures, the patient continued to have unrelenting purulent drainage from the skin of his buttocks. Following wide excision of the affected skin and subcutaneous tissues by the colorectal surgeon, the plastic surgery team reconstructed the 30 cm x 55 cm wound using a combination of local flaps and skin grafts. The initial pathology report of the excised specimen confirmed the presence of nonspecific abscesses and inflammation. Upon special request by the plastic surgery team, the sample was resectioned with the specific intent of establishing a diagnosis of fox den disease. The additional slides met the criteria for an unequivocal diagnosis of fox den disease. Immunosuppression was discontinued and the patient healed his wounds without complication. Fox den disease is often overlooked because of the obscurity of the disease and the special histological sectioning needed to establish a diagnosis. In this case, the patient was unnecessarily treated with immunosuppressive drugs for more than 3 decades because of a misdiagnosis. With increased awareness of fox den disease, perhaps its pathophysiology can be better elucidated as more patients are appropriately diagnosed and treated.

Disrupted intrinsic and remote functional connectivity in heterotopia-related epilepsy.

PubMed

Liu, W; Hu, X; An, D; Gong, Q; Zhou, D

2018-01-01

Several neuroimaging studies have examined neural interactions in patients with periventricular nodular heterotopia (PNH). However, features of the underlying functional network remain poorly understood. In this study, we examined alterations in the local (regional) and remote (interregional) cerebral networks in this disorder. Twenty-eight subjects all having suffered from PNH with epilepsy, as well as 28 age- and sex- matched healthy controls, were enrolled in this study. Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were calculated to detect regional neural function and functional network integration, respectively. Compared with healthy controls, patients with PNH-related epilepsy showed decreased ALFF in the ventromedial prefrontal cortex (vmPFC) and precuneus areas. ALFF values in both areas were negative correlated with epilepsy duration (P < .05, Bonferroni-corrected). Furthermore, patients with PNH-related epilepsy had increased remote interregional FC mainly in bilateral prefrontal and parietal cortices, supramarginal gyrus, dorsal cingulate gyrus, and right insula; lower FC was found in posterior brain regions including bilateral parahippocampal gyrus and inferior temporal gyrus. Focal spontaneous hypofunction, as assessed by ALFF, correlates with epilepsy duration in patients with PNH-related epilepsy. Abnormalities existed both within the default-mode network and then across the whole brain, demonstrating that intrinsic brain dysfunction may be related to specific network interactions. Our findings provide novel understanding of the connectivity-based pathophysiological mechanisms of PNH. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Remote cerebellar hemorrhage following supratentorial craniotomy.

PubMed

Huang, Chih-Yuan; Lee, Po-Hsuan; Lin, Sheng-Hsiang; Chuang, Ming-Tsung; Sun, Yuan-Ting; Hung, Yu-Chang; Lee, E-Jian

2012-06-01

Cerebellar hemorrhage remote from the site of surgery may complicate neurosurgical procedure. The exact pathophysiology of this type of hemorrhage is poorly understood. We retrospectively compared 16 patients who had remote cerebellar hemorrhage (RCH) with a case-matched control cohort, to determine the significance of perisurgical and surgical factors that may predispose patients to such bleeding events. From 1 June 2005 to 31 December 2008, postoperative routine head computed tomographic (CT) scan was performed in our institution and 16 patients with RCH after supratentorial neurosurgical procedure were identified. The medical charts of these 16 cases and a control cohort of 64 patients were recorded. All parameters were analyzed with regards to various variables. The incidence RCH after supratentorial craniotomy increased after postoperative computed tomographic scan. The mechanism of cerebellar hemorrhage in this series of patients is most likely multifactorial. Several variables showed a significant association with the occurrence of RCH. Multivariate analysis indicated that the following two factors independently correlated with occurrence of RCH: (1) postoperative epidural drainage amount; and (2) history of previous cerebrovascular accident (CVA) with cerebral atrophy. All cases with RCH underwent medical treatment and no neurological sequelae associated with RCH. Postoperative epidural drainage amount and history of previous CVA with cerebral atrophy can reliably predict the occurrence of cerebellar hemorrhage after supratentorial craniotomy. One of the most important strategies to minimize hazardous complications is to be aware of these potential risk factors and to take action to prevent them.

Microparticles from splenectomized β-thalassemia/HbE patients play roles on procoagulant activities with thrombotic potential.

PubMed

Klaihmon, Phatchanat; Phongpao, Kunwadee; Kheansaard, Wasinee; Noulsri, Egarit; Khuhapinant, Archrob; Fucharoen, Suthat; Morales, Noppawan Phumala; Svasti, Saovaros; Pattanapanyasat, Kovit; Chaichompoo, Pornthip

2017-02-01

Thromboembolic events including cerebral thrombosis, deep vein thrombosis, and pulmonary embolism are major complications in β-thalassemia. Damaged red blood cells and chronic platelet activation in splenectomized β-thalassemia/HbE patients were associated with increased microparticles (MPs) releases into blood circulation. MPs are small membrane vesicles, which play important roles on coagulation. However, the role of MP in thalassemia is poorly understood. In this study, the effects of splenectomized-MPs on platelet activation and aggregation were investigated. The results showed that isolated MPs from fresh platelet-free plasma of patients and normal subjects directly induce platelet activation, platelet aggregation, and platelet-neutrophil aggregation in a dose-dependent manner. Interestingly, MPs obtained from splenectomized patients are more efficient in induction of platelet activation (P-selectin + ) when compared to MPs from normal subjects (P < 0.05), tenfold lower than pathophysiological level, at 1:0.1 platelet MP ratio. Co-incubation of splenectomized-MPs with either normal-, non-splenectomized- or splenectomized-platelets at 1:10 platelet MP ratio increased platelet activation up to 5.1 ± 2.2, 5.6 ± 3.7, and 9.5 ± 3.0%, respectively, when normalized with individual baseline. These findings suggest that splenectomized patients were proned to be activated by MPs, and splenectomized-MPs could play an important role on chronic platelet activation and aggregation, leading to thrombus formation in β-thalassemia/HbE patients.

Tumor necrosis factor-α, kidney function, and hypertension.

PubMed

Mehaffey, Eamonn; Majid, Dewan S A

2017-10-01

Hypertension is considered to be a low-grade inflammatory condition characterized by the presence of various proinflammatory cytokines. Tumor necrosis factor-α (TNF-α) is a constituent of the proinflammatory cytokines that is associated with salt-sensitive hypertension (SSH) and related renal injury. Elevated angiotensin II (ANG II) and other factors such as oxidative stress conditions promote TNF-α formation. Many recent studies have provided evidence that TNF-α exerts a direct renal action by regulating hemodynamic and excretory function in the kidney. The cytokine incites a strong natriuretic response and plays a part in regulation of the intrarenal renin-angiotensin system. The exact mechanistic role of TNF-α in the development of SSH is as yet poorly understood. While TNF-α antagonism has been shown to attenuate hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-α usually induces hypotensive as well as natriuretic responses, indicating a counterregulatory role of TNF-α in SSH. Differential activities of two cell surface receptors of TNF-α (receptor type 1 and type 2) may explain the contradictory functions of TNF-α in the setting of hypertension. This short review will evaluate ongoing research studies that investigate the action of TNF-α within the kidney and its role as an influential pathophysiological variable in the development of SSH and renal injury. This information may help to develop specific TNF-α receptor targeting as an effective treatment strategy in this clinical condition. Copyright © 2017 the American Physiological Society.

Evaluation of bone microstructure in CRPS-affected upper limbs by HR-pQCT

PubMed Central

Mussawy, Haider; Schmidt, Tobias; Rolvien, Tim; Rüther, Wolfgang; Amling, Michael

2017-01-01

Summary Introduction Complex regional pain syndrome (CRPS) is a major complication after trauma, surgery, and/or immobilization of an extremity. The disease often starts with clinical signs of local inflammation and develops into a prolonged phase that is characterized by trophic changes and local osteoporosis and sometimes results in functional impairment of the affected limb. While the pathophysiology of CRPS remains poorly understood, increased local bone resorption plays an undisputed pivotal role. The aim of this retrospective clinical study was to assess the bone microstructure in patients with CRPS. Methods Patients with CRPS type I of the upper limb whose affected and unaffected distal radii were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) were identified retrospectively. The osteology laboratory data and dual-energy X-ray absorptiometry (DXA) images of the left femoral neck and lumbar spine, which were obtained on the same day as HR-pQCT, were extracted from the medical records. Results Five patients were identified. The CRPS-affected upper limbs had significantly lower trabecular numbers and higher trabecular thicknesses than the unaffected upper limbs. However, the trabecular bone volume to total bone volume and cortical thickness values of the affected and unaffected sides were similar. Trabecular thickness tended to increase with time since disease diagnosis. Discussion CRPS associated with significant alterations in the bone microstructure of the affected upper limb that may amplify as the duration of disease increases. PMID:28740526

Reentrant Information Flow in Electrophysiological Rat Default Mode Network.

PubMed

Jing, Wei; Guo, Daqing; Zhang, Yunxiang; Guo, Fengru; Valdés-Sosa, Pedro A; Xia, Yang; Yao, Dezhong

2017-01-01

Functional MRI (fMRI) studies have demonstrated that the rodent brain shows a default mode network (DMN) activity similar to that in humans, offering a potential preclinical model both for physiological and pathophysiological studies. However, the neuronal mechanism underlying rodent DMN remains poorly understood. Here, we used electrophysiological data to analyze the power spectrum and estimate the directed phase transfer entropy (dPTE) within rat DMN across three vigilance states: wakeful rest (WR), slow-wave sleep (SWS), and rapid-eye-movement sleep (REMS). We observed decreased gamma powers during SWS compared with WR in most of the DMN regions. Increased gamma powers were found in prelimbic cortex, cingulate cortex, and hippocampus during REMS compared with WR, whereas retrosplenial cortex showed a reverse trend. These changed gamma powers are in line with the local metabolic variation of homologous brain regions in humans. In the analysis of directional interactions, we observed well-organized anterior-to-posterior patterns of information flow in the delta band, while opposite patterns of posterior-to-anterior flow were found in the theta band. These frequency-specific opposite patterns were only observed in WR and REMS. Additionally, most of the information senders in the delta band were also the receivers in the theta band, and vice versa. Our results provide electrophysiological evidence that rat DMN is similar to its human counterpart, and there is a frequency-dependent reentry loop of anterior-posterior information flow within rat DMN, which may offer a mechanism for functional integration, supporting conscious awareness.

Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.

PubMed

Vogel, Georg F; van Rijn, Jorik M; Krainer, Iris M; Janecke, Andreas R; Posovszky, Carsten; Cohen, Marta; Searle, Claire; Jantchou, Prevost; Escher, Johanna C; Patey, Natalie; Cutz, Ernest; Müller, Thomas; Middendorp, Sabine; Hess, Michael W; Huber, Lukas A

2017-07-20

Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18-2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID.

The Pathophysiology of Thyroid Eye Disease (TED): Implications for Immunotherapy

PubMed Central

Gupta, Shivani; Douglas, Raymond

2012-01-01

Purpose of Review Thyroid eye disease (TED) is a poorly understood autoimmune manifestation most commonly associated with Graves’ disease. Current nonspecific treatment paradigms offer symptomatic improvement but fail to target the underlying pathogenic mechanisms and thus, do not significantly alter the long-term disease outcome. The purpose of this review is to provide an update of the current understanding of the immunopathogenesis of TED and explore these implications for targeted immunotherapy. Recent Findings Orbital fibroblasts are integral to the pathogenesis of TED and may modulate immune responses by production of cytokines and hyaluronan in response to activation of shared autoantigens including thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-R1). Fibrocytes share many of these phenotypic and functional features, suggesting a link between systemic and site-specific disease. Use of targeted immunotherapies in TED is limited, though data from the use Rituximab (RTX), a B cell depleting agent, are encouraging. Sustained clinical response has been seen with RTX in several reports, despite return of peripheral B cell levels to pretreatment levels. Additionally, this response appears to be independent to cytokine and antibody production, suggesting possible modulation of antigen presentation as a mechanism of its effect. Summary Progressive advances in the understanding of the immunopathogenesis of TED continue to spur clinical trials utilizing targeted immune therapies. Continued understanding of the molecular mechanisms of disease will expand potential treatments for TED patients and obviate the need for reconstructive surgical therapies. PMID:21730841

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

PubMed Central

Rajandram, Retnagowri; Ong, Teng Aik; Razack, Azad H. A.; MacIver, Bryce; Zeidel, Mark

2016-01-01

Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg−1·day−1 ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis. PMID:26911853

Molecular Pathogenesis of Chlamydia Disease Complications: Epithelial-Mesenchymal Transition and Fibrosis.

PubMed

Igietseme, Joseph U; Omosun, Yusuf; Nagy, Tamas; Stuchlik, Olga; Reed, Matthew S; He, Qing; Partin, James; Joseph, Kahaliah; Ellerson, Debra; George, Zenas; Goldstein, Jason; Eko, Francis O; Bandea, Claudiu; Pohl, Jan; Black, Carolyn M

2018-01-01

The reproductive system complications of genital chlamydial infection include fallopian tube fibrosis and tubal factor infertility. However, the molecular pathogenesis of these complications remains poorly understood. The induction of pathogenic epithelial-mesenchymal transition (EMT) through microRNA (miRNA) dysregulation was recently proposed as the pathogenic basis of chlamydial complications. Focusing on fibrogenesis, we investigated the hypothesis that chlamydia-induced fibrosis is caused by EMT-driven generation of myofibroblasts, the effector cells of fibrosis that produce excessive extracellular matrix (ECM) proteins. The results revealed that the targets of a major category of altered miRNAs during chlamydial infection are key components of the pathophysiological process of fibrogenesis; these target molecules include collagen types I, III, and IV, transforming growth factor β (TGF-β), TGF-β receptor 1 (TGF-βR1), connective tissue growth factor (CTGF), E-cadherin, SRY-box 7 (SOX7), and NFAT (nuclear factor of activated T cells) kinase dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1a (Dyrk1a). Chlamydial induction of EMT resulted in the generation of α-smooth muscle actin (α-SMA)-positive myofibroblasts that produced ECM proteins, including collagen types I and III and fibronectin. Furthermore, the inhibition of EMT prevented the generation of myofibroblasts and production of ECM proteins during chlamydial infection. These findings may provide useful avenues for targeting EMT or specific components of the EMT pathways as a therapeutic intervention strategy to prevent chlamydia-related complications. Copyright © 2017 American Society for Microbiology.

Neuroinflammation as a possible link between cannabinoids and addiction.

PubMed

Rodrigues, Livia C M; Gobira, Pedro H; de Oliveira, Antonio Carlos; Pelição, Renan; Teixeira, Antonio Lucio; Moreira, Fabricio A; Campos, Alline Cristina

2014-12-01

Substance dependence disorder is a chronically relapsing condition characterised by neurobiological changes leading to loss of control in restricting a substance intake, compulsion and withdrawal syndrome. In the past few years, (endo)cannabinoids have been raised as a possible target in the aetiology of drug addiction. On the other hand, although the exact mechanisms of the genesis of addiction remain poorly understood, it is possible that neuroinflammation might also play a role in the pathophysiology of this condition. Studies demonstrated that (endo)cannabinoids act as immunomodulators by inhibiting cytokines production and microglial cell activation. Thus, in the present review, we explore the possible role of neuroinflammation on the therapeutic effects of cannabinoids on drug addiction. We conducted an evidence-based review of the literature in order to assess the role of cannabinoids on the neuroinflammatory hypothesis of addiction (terms: addiction, cannabinoids and inflammation). We searched PubMed and BioMedCentral databases up to April 2014 with no date restrictions. In all, 165 eligible articles were included in the present review. Existing evidence suggests that disruption in cannabinoid signalling during the drug addiction process leads to microglial activation and neuroinflammation. The literature showed that inflammation and changes in endocannabinod signalling occur in drug abuse; however, it remains uncertain whether these changes are causally or coincidentally associated with addiction. Additional studies, therefore, are needed to elucidate the contribution of neuroinflammation on the behavioural and neuroprotective effects of cannabinoids on drug addiction.

Transcranial Magnetic Stimulation: Basic Principles and Clinical Applications in Migraine.

PubMed

Barker, Anthony T; Shields, Kevin

2017-03-01

Transcranial magnetic stimulation (TMS) is a neurophysiological technique with a long established pedigree of safety, tolerability, and efficacy. Initially TMS was used to study the function of the cerebral cortex, but it has now become a treatment for migraine, one of the most common and debilitating neurological conditions. In this review we discuss the scientific background and development of the technique. We explore its application for the treatment of migraine and ponder the possible mechanisms of action in this most common neurological condition. The generation of brief magnetic pulses by a suitable coil can induce electrical fields in the body. When applied to the cerebral cortex, currents are painlessly induced in cortical neurons. These currents can lead to neuronal depolarization and may influence cortical excitability by means that are as yet not fully understood. This ability to modulate cortical excitability has been exploited as a treatment for migraine with aura. Aura is implicated in the pathophysiology of migraine. Experimental studies have shown that transcranial magnetic pulses can block waves of cortical spreading depression - the experimental equivalent of migrainous aura. Migraine is a debilitating condition characterized by headache, nausea, and sensory hypersensitivity. It may affect up to 15% of the population, yet current drug treatments are often poorly tolerated. Clinical studies have shown that TMS is an effective treatment for migraine. In addition, it has the added advantages of being safe and well tolerated by patients. © 2016 American Headache Society.

Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model.

PubMed

Scaini, Giselli; Comim, Clarissa M; Oliveira, Giovanna M T; Pasquali, Matheus A B; Quevedo, João; Gelain, Daniel P; Moreira, José Cláudio F; Schuck, Patrícia F; Ferreira, Gustavo C; Bogo, Maurício R; Streck, Emilio L

2013-09-01

Maple syrup urine disease (MSUD) is a neurometabolic disorder that leads to the accumulation of branched-chain amino acids (BCAAs) and their α-keto branched-chain by-products. Because the neurotoxic mechanisms of MSUD are poorly understood, this study aimed to evaluate the effects of chronic administration of a BCAA pool (leucine, isoleucine and valine). This study examined the effects of BCAA administration on spatial memory and the levels of brain-derived neurotrophic factor (BNDF). We examined both pro-BDNF and bdnf mRNA expression levels after administration of BCAAs. Furthermore, this study examined whether antioxidant treatment prevented the alterations induced by BCAA administration. Our results demonstrated an increase in BDNF in the hippocampus and cerebral cortex, accompanied by memory impairment in spatial memory tasks. Additionally, chronic administration of BCAAs did not induce a detectable change in pro-BDNF levels. Treatment with N-acetylcysteine and deferoxamine prevented both the memory deficit and the increase in the BDNF levels induced by BCAA administration. In conclusion, these results suggest that when the brain is chronically exposed to high concentrations of BCAA (at millimolar concentrations) an increase in BDNF levels occurs. This increase in BDNF may be related to the impairment of spatial memory. In addition, we demonstrated that antioxidant treatment prevented the negative consequences related to BCAA administration, suggesting that oxidative stress might be involved in the pathophysiological mechanism(s) underlying the brain damage observed in MSUD.

Hepatic hepcidin gene expression in dogs with a congenital portosystemic shunt.

PubMed

Frowde, P E; Gow, A G; Burton, C A; Powell, R; Lipscomb, V J; House, A K; Mellanby, R J; Tivers, M S

2014-01-01

Microcytic anemia is common in dogs with a congenital portosystemic shunt (cPSS) and typically resolves after surgical attenuation of the anomalous vessel. However, the pathophysiology of the microcytic anemia remains poorly understood. Hepcidin has been a key role in controlling iron transport in both humans and animals and in mediating anemia of inflammatory disease in humans. The role of hepcidin in the development of microcytic anemia in dogs with a cPSS has not been examined. To determine whether hepatic hepcidin mRNA expression decreases, while red blood cell count (RBC) and mean corpuscular volume (MCV) increase in dogs after surgical attenuation of a cPSS. Eighteen client-owned dogs with confirmed cPSS undergoing surgical attenuation. Prospective study. Red blood cell count (RBC) and mean corpuscular volume (MCV), together with hepatic gene expression of hepcidin, were measured in dogs before and after partial attenuation of a cPSS. There was a significant increase in both RBC (median pre 6.17 × 10(12) /L, median post 7.08 × 10(12) /L, P < .001) and MCV (median pre 61.5fl, median post 65.5fl, P = .006) after partial surgical attenuation of the cPSS. Despite the increase in both measured red blood cell parameters, hepatic gene expression of hepcidin remained unchanged. This study found no evidence that dysregulated production of hepcidin was associated with anemia in dogs with a cPSS. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Calcitonin-gene related peptide and cerebral vasospasm.

PubMed

Schebesch, Karl-Michael; Herbst, Andreas; Bele, Sylvia; Schödel, Petra; Brawanski, Alexander; Stoerr, Eva-Maria; Lohmeier, Annette; Kagerbauer, Simone Maria; Martin, Jan; Proescholdt, Martin

2013-04-01

The pathophysiology of arterial vasospasm following subarachnoid hemorrhage (SAH) is poorly understood and the contribution of endogenous neuropeptides has not been sufficiently elucidated. Recently, we detected an excessive release of vasoconstrictive neuropeptide Y (NPY) in SAH patients and identified a significant correlation of NPY cerebrospinal fluid (CSF) levels with vasospasm-related ischemia. Here, we present the results of an experimental study on the possible role of the potent endogenous vasodilator calcitonin-gene related peptide (CGRP) in the acute stage of SAH. Twelve consecutive patients with SAH were included. Seven patients had severe arterial vasospasm, confirmed by transcranial doppler-sonography (TCD). Prospectively, CSF was collected from day 1 to day 10 after onset of the SAH. The levels of CGRP were determined in a competitive enzyme immunoassay and were correlated with the clinical course and hemodynamic changes. A cohort of 29 patients without CNS disease served as a control. CGRP was significantly higher in SAH patients compared with the control group (p<0.05). From day 1 to day 4, the CGRP levels in patients without vasospasm were significantly higher than the levels of CGRP in patients with vasospasm (p<0.05). These patients did not develop cerebral ischemia. The significantly increased levels of the CGRP during the first days after onset of the SAH in the non-vasospasm group indicate a potential protective role of CGRP. CGRP may alleviate arterial vasoconstriction and thus protect the brain from vasospasm and subsequent ischemia. Copyright © 2012 Elsevier Ltd. All rights reserved.

Paroxysmal anal hyperkinesis: a characteristic feature of proctalgia fugax.

PubMed

Rao, S S; Hatfield, R A

1996-10-01

Proctalgia fugax is a common problem, yet its pathophysiology is poorly understood. The objective was to characterise colorectal disturbances in a paraplegic patient with a 10 year history of proctalgia fugax that began two years after an attack of transverse myelitis. Standard anorectal manometry and prolonged 33 hour ambulatory colonic manometry at six sites in the colon were performed together with myoelectrical recording of the anus. Provocative tests designed to simulate psychological and physical stress and two types of meals were included. Anorectal manometry showed normal internal sphincter tone and normal rectoanal inhibitory reflex but an inability to squeeze or to bear down or to expel a simulated stool. Rectal sensation (up to 360 ml inflation) was absent. Pudendal nerve latency was prolonged (4.5 ms (normal < 2.2 ms). During colonic manometry, the patient reported 27 episodes of pain, of which 23 (85%) were associated with bursts (1-60 min) of a high amplitude (0.5 to > 3.2 mv), high frequency (5-50/min) anal myoelectrical activity, particularly after stress tests, meals, and at night. The myoelectrical disturbance only occurred with proctalgia. Intermittently, 16 bursts of 3 cycles/ min phasic rectal contractions were seen, but only six were associated with proctalgia. Colonic motility was reduced compared with normal subjects. The temporal association between a high amplitude, high frequency myoelectrical activity of the anal sphincter, and the occurrence of proctalgia suggests that paroxysmal hyperkinesis of the anus may cause proctalgia fugax.

Paroxysmal anal hyperkinesis: a characteristic feature of proctalgia fugax.

PubMed Central

Rao, S S; Hatfield, R A

1996-01-01

BACKGROUND AND AIMS: Proctalgia fugax is a common problem, yet its pathophysiology is poorly understood. The objective was to characterise colorectal disturbances in a paraplegic patient with a 10 year history of proctalgia fugax that began two years after an attack of transverse myelitis. METHODS: Standard anorectal manometry and prolonged 33 hour ambulatory colonic manometry at six sites in the colon were performed together with myoelectrical recording of the anus. Provocative tests designed to simulate psychological and physical stress and two types of meals were included. RESULTS: Anorectal manometry showed normal internal sphincter tone and normal rectoanal inhibitory reflex but an inability to squeeze or to bear down or to expel a simulated stool. Rectal sensation (up to 360 ml inflation) was absent. Pudendal nerve latency was prolonged (4.5 ms (normal < 2.2 ms). During colonic manometry, the patient reported 27 episodes of pain, of which 23 (85%) were associated with bursts (1-60 min) of a high amplitude (0.5 to > 3.2 mv), high frequency (5-50/min) anal myoelectrical activity, particularly after stress tests, meals, and at night. The myoelectrical disturbance only occurred with proctalgia. Intermittently, 16 bursts of 3 cycles/ min phasic rectal contractions were seen, but only six were associated with proctalgia. Colonic motility was reduced compared with normal subjects. CONCLUSIONS: The temporal association between a high amplitude, high frequency myoelectrical activity of the anal sphincter, and the occurrence of proctalgia suggests that paroxysmal hyperkinesis of the anus may cause proctalgia fugax. PMID:8944574

Mechanisms of Visceral Organ Crosstalk: Importance of Alterations in Permeability in Rodent Models

PubMed Central

Greenwood-Van Meerveld, B; Mohammadi, E; Tyler, K; Van Gordon, S; Parker, A; Towner, R; Hurst, R

2015-01-01

Purpose The pathophysiology of painful bladder syndrome (PBS) is poorly understood; however, there is evidence of female predominance and comorbidity with irritable bowel syndrome (IBS). Our hypothesis is that cross-sensitization between the bladder and colon is due to altered permeability in one organ affecting the other organ. Materials and methods Experiments were performed in anesthetized, ovariectomized (OVX) female rats. In separate groups, protamine sulfate was infused into the bladder or TNBS was infused into the colon, with untreated rats serving as controls. Both bladder and colonic tissue were harvested for all rats at 1, 3, and 5 days post-treatment. Permeability was assessed in vitro in Ussing chambers via measurements of transepithelial electrical resistance (TEER) and macromolecular flux of Fluorescein isothiocyanate (FITC)-4 dextran. Results Exposing the bladder to protamine sulfate induced a significant (p<0.05) decrease in bladder TEER and an increase in the translocation of FITC across the tissue compared to controls at 1 and 3 days. Colonic tissue from rats with enhanced bladder permeability exhibited a significant (p<0.05) decrease in TEER and increase in FITC when compared to untreated controls at all time points. Conversely, when colonic permeability was increased with TNBS, we observed an increase in bladder permeability in the absence of any changes to the bladder urothelium. Conclusions Changes in epithelial permeability may represent a novel mechanism for visceral organ crosstalk and may explain the overlapping symptomology of PBS and IBS. PMID:25776913

Shrinking lung syndrome as a manifestation of pleuritis: a new model based on pulmonary physiological studies.

PubMed

Henderson, Lauren A; Loring, Stephen H; Gill, Ritu R; Liao, Katherine P; Ishizawar, Rumey; Kim, Susan; Perlmutter-Goldenson, Robin; Rothman, Deborah; Son, Mary Beth F; Stoll, Matthew L; Zemel, Lawrence S; Sandborg, Christy; Dellaripa, Paul F; Nigrovic, Peter A

2013-03-01

The pathophysiology of shrinking lung syndrome (SLS) is poorly understood. We sought to define the structural basis for this condition through the study of pulmonary mechanics in affected patients. Since 2007, most patients evaluated for SLS at our institutions have undergone standardized respiratory testing including esophageal manometry. We analyzed these studies to define the physiological abnormalities driving respiratory restriction. Chest computed tomography data were post-processed to quantify lung volume and parenchymal density. Six cases met criteria for SLS. All presented with dyspnea as well as pleurisy and/or transient pleural effusions. Chest imaging results were free of parenchymal disease and corrected diffusing capacities were normal. Total lung capacities were 39%-50% of predicted. Maximal inspiratory pressures were impaired at high lung volumes, but not low lung volumes, in 5 patients. Lung compliance was strikingly reduced in all patients, accompanied by increased parenchymal density. Patients with SLS exhibited symptomatic and/or radiographic pleuritis associated with 2 characteristic physiological abnormalities: (1) impaired respiratory force at high but not low lung volumes; and (2) markedly decreased pulmonary compliance in the absence of identifiable interstitial lung disease. These findings suggest a model in which pleural inflammation chronically impairs deep inspiration, for example through neural reflexes, leading to parenchymal reorganization that impairs lung compliance, a known complication of persistently low lung volumes. Together these processes could account for the association of SLS with pleuritis as well as the gradual symptomatic and functional progression that is a hallmark of this syndrome.

EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness.

PubMed

Desjardins, Marie-Ève; Carrier, Julie; Lina, Jean-Marc; Fortin, Maxime; Gosselin, Nadia; Montplaisir, Jacques; Zadra, Antonio

2017-04-01

Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient's episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes' onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Yellow fever: an update.

PubMed

Monath, T P

2001-08-01

Yellow fever, the original viral haemorrhagic fever, was one of the most feared lethal diseases before the development of an effective vaccine. Today the disease still affects as many as 200,000 persons annually in tropical regions of Africa and South America, and poses a significant hazard to unvaccinated travellers to these areas. Yellow fever is transmitted in a cycle involving monkeys and mosquitoes, but human beings can also serve as the viraemic host for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean and Asia. Here I review the clinical features of the disease, its pathogenesis and pathophysiology. The disease mechanisms are poorly understood and have not been the subject of modern clinical research. Since there is no specific treatment, and management of patients with the disease is extremely problematic, the emphasis is on preventative vaccination. As a zoonosis, yellow fever cannot be eradicated, but reduction of the human disease burden is achievable through routine childhood vaccination in endemic countries, with a low cost for the benefits obtained. The biological characteristics, safety, and efficacy of live attenuated, yellow fever 17D vaccine are reviewed. New applications of yellow fever 17D virus as a vector for foreign genes hold considerable promise as a means of developing new vaccines against other viruses, and possibly against cancers.

Disruption of visual circuit formation and refinement in a mouse model of autism

PubMed Central

Khanbabaei, Maryam; Murari, Kartikeya; Rho, Jong M.

2016-01-01

Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye‐specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi‐ and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower‐level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2017, 10: 212–223. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. PMID:27529416

A Drosophila Model of Essential Tremor.

PubMed

Smith, Philip; Arias, Ronald; Sonti, Shilpa; Odgerel, Zagaa; Santa-Maria, Ismael; McCabe, Brian D; Tsaneva-Atanasova, Krasimira; Louis, Elan D; Hodge, James J L; Clark, Lorraine N

2018-05-16

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K + channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K + channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.

[Papillary oedema revealing Arnold Chiari malformation type 1: about a case].

PubMed

Imane, Mouhoub; Asmae, Maadane; Toufik, Ramdani; Rachid, Sekhsoukh

2016-01-01

Arnold Chiari malformation type 1 is defined as a herniation of the cerebellar tonsils into the foramen magnum of more than 5 mm. Symptoms are most commonly dominated by occipital headache, torticollis and sometimes swallowing disorders. Ophthalmologically abnormal convergences, oculomotor palsy and diplopia are the main clinical signs. We report the case of a 9 year old child, who presented with visual loss evolving since 6 months. Ophthalmologic examination showed visual acuity of 4/10 in both eyes, retained ocular motility and rotational nystagmus. The examination of the anterior segment of the eye showed megalocornea with no evidence of goniodysgenesis, iridodonesis associated with atrophy of the dilator muscle and microcoria with lazy photomotor reflex. Normal intraocular pressure was 14 mmHg. Ocular fundus examination, despite difficulties in performing it, objectified bilateral papilledema (stage II). General physical examination showed torticollis, scoliosis and a tetra-pyramidal syndrome. MRI showed Chiari malformation type I associated with hydrocephalus and syringomyelia. Neurosurgical intervention based on internal CSF drainage with occipitocervical osteo-dural decompression was proposed. The evolution was favorable with regression of clinical signs. Ophthalmologically, there was a regression of papilledema but visual acuity remained stationary. The occurrence of papilledema associated with Chiari malformation type 1 is rare, it has been only reported in 2% of symptomatic patients. Its pathophysiology is still poorly understood. The originality of our study consists in the association of cerebellar malformations with ocular malformations including megalocornea and microcoria which make ophthalmologic examination more difficult to perform.

Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report.

PubMed

Ramsey, Bonnie W; Banks-Schlegel, Susan; Accurso, Frank J; Boucher, Richard C; Cutting, Garry R; Engelhardt, John F; Guggino, William B; Karp, Christopher L; Knowles, Michael R; Kolls, Jay K; LiPuma, John J; Lynch, Susan; McCray, Paul B; Rubenstein, Ronald C; Singh, Pradeep K; Sorscher, Eric; Welsh, Michael

2012-04-15

Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled "Future Research Directions in Early CF Lung Disease" on September 21-22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene-environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease.

Orthostatic Tremor: An Update on a Rare Entity

PubMed Central

Benito-León, Julián; Domingo-Santos, Ángela

2016-01-01

Background Orthostatic tremor (OT) remains among the most intriguing and poorly understood of movement disorders. Compared to Parkinson’s disease or even essential tremor, there are very few articles addressing more basic science issues. In this review, we will discuss the findings of main case series on OT, including data on etiology, pathophysiology, diagnostic approach, treatment strategies, and outcome. Methods Data for this review were identified by searching PUBMED (January 1966 to August 2016) for the terms “orthostatic tremor” or “shaky leg syndrome,” which yielded 219 entries. We did not exclude papers on the basis of language, country, or publication date. The electronic database searches were supplemented by articles in the authors’ files that pertained to this topic. Results Owing to its rarity, the current understanding of OT is limited and is mostly based on small case series or case reports. Despite this, a growing body of evidence indicates that OT might be a progressive condition that is clinically heterogeneous (primary vs. secondary cases) with a broader spectrum of clinical features, mainly cerebellar signs, and possible cognitive impairment and personality disturbances. Along with this, advanced neuroimaging techniques are now demonstrating distinct anatomical and functional changes, some of which are consistent with neuronal loss. Discussion OT might be a family of diseases, unified by the presence of leg tremor, but further characterized by etiological and clinical heterogeneity. More work is needed to understand the pathogenesis of this condition. PMID:27713855

Does Education Have Any Influence on Symptom Score of IBS Patients: A Randomized Controlled Study.

PubMed

Sarkar, S K; Tarafder, A J; Chowdhury, M; Alam, M S; Mohsin, M

2016-04-01

Despite much research, the pathophysiology of IBS remains poorly understood. So it is very difficult to treat. There is no standard treatment for IBS. Because IBS symptoms can be elicited or exacerbated by diet and stress, this suggests that patient education regarding his or her illness might be beneficial to patients in managing their symptoms. This study was done to see the short term effects of outpatient education in relation to change of symptom score in IBS patients. This is a prospective randomized comparative study. In this study a total of 80 patients were included. Forty patients were given only pharmacological management with Mebevarine hydrochloride 135mg thrice daily half an hour before meal and Amitryptline 10mg at night for six months and another forty were given education in addition to the same pharmacological treatment. In both the study group [medical management only versus medical management with education] changes of symptoms and quality of life of patients of IBS were assessed by using previously used, specially designed symptoms scoring system and a validated IBS-QOL instrument. There was no significant difference in severity of symptoms between only drug treatment group (118.973) and education plus drug treatment group (119.57) before treatment. The difference of improvement between the education group and without education group was not statistically significant (P>0.05), though the subsidence of pain in both the group before and after treatment was statistically significant (P<0.01).

Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.

PubMed

Patel, Kruti R; Bai, Yan; Trieu, Kenneth G; Barrios, Juliana; Ai, Xingbin

2017-10-01

Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas β2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. © FASEB.

PhenoPredict: A disease phenome-wide drug repositioning approach towards schizophrenia drug discovery.

PubMed

Xu, Rong; Wang, QuanQiu

2015-08-01

Schizophrenia (SCZ) is a common complex disorder with poorly understood mechanisms and no effective drug treatments. Despite the high prevalence and vast unmet medical need represented by the disease, many drug companies have moved away from the development of drugs for SCZ. Therefore, alternative strategies are needed for the discovery of truly innovative drug treatments for SCZ. Here, we present a disease phenome-driven computational drug repositioning approach for SCZ. We developed a novel drug repositioning system, PhenoPredict, by inferring drug treatments for SCZ from diseases that are phenotypically related to SCZ. The key to PhenoPredict is the availability of a comprehensive drug treatment knowledge base that we recently constructed. PhenoPredict retrieved all 18 FDA-approved SCZ drugs and ranked them highly (recall=1.0, and average ranking of 8.49%). When compared to PREDICT, one of the most comprehensive drug repositioning systems currently available, in novel predictions, PhenoPredict represented clear improvements over PREDICT in Precision-Recall (PR) curves, with a significant 98.8% improvement in the area under curve (AUC) of the PR curves. In addition, we discovered many drug candidates with mechanisms of action fundamentally different from traditional antipsychotics, some of which had published literature evidence indicating their treatment benefits in SCZ patients. In summary, although the fundamental pathophysiological mechanisms of SCZ remain unknown, integrated systems approaches to studying phenotypic connections among diseases may facilitate the discovery of innovative SCZ drugs. Copyright © 2015 Elsevier Inc. All rights reserved.

Coeliac Disease – New Pathophysiological Findings and Their Implications for Therapy

PubMed Central

Stein, Jürgen; Schuppan, Detlef

2014-01-01

Summary Coeliac disease (CD) is one of the most common diseases worldwide, resulting from a combination of environmental (gluten) and genetic (human leucocyte antigen (HLA) and non-HLA genes) factors. Depending on the geographical location, the prevalence of CD has been estimated to approximate 0.5-1%. The only treatment currently available for CD is a gluten-free diet (GFD) excluding gluten-containing cereals such as wheat, rye, and barley, and other foodstuffs with natural or added gluten. However, adherence rates and patient acceptance are often poor. Moreover, even in fully adherent patients, the diet may fail to induce clinical or histological improvement. Hence, it is unsurprising that studies show CD patients to be highly interested in non-dietary alternatives. The following review focuses on current pathophysiological concepts of CD, spotlighting those pathways which may serve as new possible, non-dietary therapeutic targets in the treatment of CD. PMID:26288589

Primary Headaches and School Performance-Is There a Connection?

PubMed

Genizi, J; Guidetti, V; Arruda, M A

2017-07-01

Headache is a common complaint among children and adolescents. School functioning is one of the most important life domains impacted by chronic pain in children. This review discusses the epidemiological and pathophysiological connections between headaches and school functioning including a suggested clinical approach. The connection between recurrent and chronic headache and learning disabilities might be psychosocial (fear of failure) or anatomical (malfunctioning of the frontal and prefrontal areas). Only few population-based and clinical studies were done and good studies are still needed in order to understand the complex relationship better. However, relating to our patients' learning and school performance, history is crucial when a child with primary headaches is evaluated. Learning disabilities seem to have a high prevalence among children with primary headache syndromes especially migraine. The connection between the two is complex and might be either part of a common brain pathophysiology and/or a consequence of poor quality of life.

[Ascites and acute kidney injury].

PubMed

Piano, Salvatore; Tonon, Marta; Angeli, Paolo

2016-07-01

Ascites is the most common complication of cirrhosis. Ascites develops as a consequence of an abnormal splanchnic vasodilation with reduction of effecting circulating volume and activation of endogenous vasoconstrictors system causing salt and water retention. Patients with ascites have a high risk to develop further complications of cirrhosis such as hyponatremia, spontaneous bacterial peritonitis and acute kidney injury resulting in a poor survival. In recent years, new studies helped a better understanding of the pathophysiology of ascites and acute kidney injury in cirrhosis. Furthermore, new diagnostic criteria have been proposed for acute kidney injury and hepatorenal syndrome and a new algorithm for their management has been recommended with the aim of an early diagnosis and treatment. Herein we will review the current knowledge on the pathophysiology, diagnosis and treatment of ascites and acute kidney injury in patients with cirrhosis and we will identify the unmet needs that should be clarified in the next years.

What physicians need to know about dreams and dreaming.

PubMed

Pagel, James F

2012-11-01

An overview of the current status of dream science is given, designed to provide a basic background of this field for the sleep-interested physician. No cognitive state has been more extensively studied and is yet more misunderstood than dreaming. Much older work is methodologically limited by lack of definitions, small sample size, and constraints of theoretical perspective, with evidence equivocal as to whether any special relationship exists between rapid eye movement (REM) sleep and dreaming. As the relationship between dreams and REM sleep is so poorly defined, evidence-based studies of dreaming require a dream report. The different aspects of dreaming that can be studied include dream and nightmare recall frequency, dream content, dreaming effect on waking behaviors, dream/nightmare associated medications, and pathophysiology affecting dreaming. Whether studied from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives, dreaming reveals itself to be a complex cognitive state affected by a wide variety of medical, psychological, sleep and social variables.

Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): an intriguing EEG phenomenon.

PubMed

Silveira, Mariana Ribeiro Marcondes da; Andrade, Joaquina; Garzon, Eliana

2013-12-01

SIRPIDs, an acronym for stimulus-induced rhythmic, periodic, or ictal discharges, were first named in 2004. This is a pattern observed in continuous electroencephalogram (CEEG) consistently elicited by stimulation in comatose patients. The pathophysiology of SIRPIDs probably involves dysregulation of subcortico-cortical projections, particularly thalamocortical circuit, in a markedly abnormal brain with hyperexci-table cortex. This may explain some studies found an association of prolonged periodic epileptiform discharges (PEDs) activity and a higher incidence of concurrent electrographic seizures and SIRPIDs. An association of SIRPIDs and poor prognosis has already been described. However, it is not yet possible to assert whether these discharges can cause neuronal injury or if they are simply a marker of severe brain injury. Objective of this paper is to review clinical relevance and pathophysiology of SIRPIDs, as well as its role as a brain response in the critically ill patient.

Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives.

PubMed

Pal, Gopal Krushna; Pal, Pravati; Nanda, Nivedita; Amudharaj, Dharmalingam; Adithan, Chandrasekaran

2013-01-01

Hypertension (HTN) and prehypertension (pre-HTN) have been identified as independent risk factors for adverse cardiovascular events. Recently, increased psychosocial stress and work stress have contributed to the increased prevalence of HTN and pre-HTN, in addition to the contribution of obesity, diabetes, poor food habits and physical inactivity. Irrespective of the etiology, sympathetic overactivity has been recognized as the main pathophysiologic mechanism in the genesis of HTN and pre-HTN. Sympathovagal imbalance owing to sympathetic overactivity and vagal withdrawal is reported to be the basis of many clinical disorders. However, the role played by vagal withdrawal has been under-reported. In this review, we have analyzed the pathophysiologic involvement of sympathovagal imbalance in the development of HTN and pre-HTN, and the link of sympathovagal imbalance to cardiovascular dysfunctions. We have emphasized that adaptation to a healthier lifestyle will help improve sympathovagal homeostasis and prevent the occurrence of HTN and pre-HTN.

Left Atrial trajectory impairment in Hypertrophic Cardiomyopathy disclosed by Geometric Morphometrics and Parallel Transport

NASA Astrophysics Data System (ADS)

Piras, Paolo; Torromeo, Concetta; Re, Federica; Evangelista, Antonietta; Gabriele, Stefano; Esposito, Giuseppe; Nardinocchi, Paola; Teresi, Luciano; Madeo, Andrea; Chialastri, Claudia; Schiariti, Michele; Varano, Valerio; Uguccioni, Massimo; Puddu, Paolo E.

2016-10-01

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction.

Abnormal small-world brain functional networks in obsessive-compulsive disorder patients with poor insight.

PubMed

Lei, Hui; Cui, Yan; Fan, Jie; Zhang, Xiaocui; Zhong, Mingtian; Yi, Jinyao; Cai, Lin; Yao, Dezhong; Zhu, Xiongzhao

2017-09-01

There are limited data on neurobiological correlates of poor insight in obsessive-compulsive disorder (OCD). This study explored whether specific changes occur in small-world network (SWN) properties in the brain functional network of OCD patients with poor insight. Resting-state electroencephalograms (EEGs) were recorded for 12 medication-free OCD patients with poor insight, 50 medication-free OCD patients with good insight, and 36 healthy controls. Both of the OCD groups exhibited topological alterations in the brain functional network characterized by abnormal small-world parameters at the beta band. However, the alterations at the theta band only existed in the OCD patients with poor insight. A relatively small sample size. Subjects were naïve to medications and those with Axis I comorbidity were excluded, perhaps limiting generalizability. Disrupted functional integrity at the beta bands of the brain functional network may be related to OCD, while disrupted functional integrity at the theta band may be associated with poor insight in OCD patients, thus this study might provide novel insight into our understanding of the pathophysiology of OCD. Copyright © 2017 Elsevier B.V. All rights reserved.

IMPACT OF ATRA ON OVALBUMIN AND MOLD-SENSITIZED F344 RATS AND REVERSAL OF HEALTH-RELATED IMPLICATIONS BY CITRAL.

PubMed

Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Benghuzzi, Hamed

2017-01-01

The role of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of hypervitaminosis A pathophysiology is not well understood or established in the literature. As well, the role of Citral (inhibitor of retinoid function; a non-toxic chemical that exists in two forms (diethyl; C1 or cis-trans dimethyl; C2).) in the reversal of pathophysiological implications is also not ascertained under an in vivo setting. Therefore, it is hypothesized that ovalbumin exposure will sensitize the body to supra-physiologic levels of retinoic acid leading to a negative pathophysiological impact and that Citrals 1 and 2 will reverse or ameliorate the related damage to the body's pathophysiology. Even though ovalbumin and retinoic have been previously applied through intra-tracheal route in cancer prevention and immunological research, the objective of this study was to evaluate their interaction as a remedy for hypervitaminosis A. This IACUC approved in vivo study used Fischer 344 rats ( n = 80 ;229 to 273g), which were randomly assigned to controls as well as ovalbumin and mold-sensitized treatment groups (0.80 mg/kg and 1X109 mold spores combined from 4 strains/100 μl intra-tracheal; all others were dosed by intra-peritoneal injection at days 1 and 7 with 80 mg/kg each of ATRA as well as 20 and 50 mg/kg each of Citrals 1 or 2 individually or in combination to represent all four chemicals and mold spores treatments.. Positive and negative controls for each treatment were also included in the study. Animals were housed in rat cages at the JSU Research Animal Core Facilities and were placed on a 12:12 light dark cycle. A standard rodent diet and water access were provided ad-libidum. Rat weights were recorded on day 1 and 21, all animals were sacrificed on day 21 and blood was collected and processed for hematological parameters. Results showed that even though C1 and C2 were not toxic individually, their combination at high dosing was lethal. Exposure of ovalbumin-sensitized rats to ATRA showed various levels of weight losses and negative hematological implications that were ameliorated by exposure to Citrals at various combinations with retinoic acid. Taken together, the study showed that there are variable pathophysiological responses from the interaction of ovalbumin, mold spores and retinoic acid and that Citrals were found to be individually effective in reversing health-related pathophysiologies. These findings warrants further investigations as to the actual role of these interactions in relation to acute pathophysiologic health implications and the possibility of reversing hypervitaminosis A-mediated health-related impacts.

What does productivity really mean? Towards an integrative paradigm in the search for biodiversity-productivity relationships

Treesearch

Liangjun Hu; Qinfeng Guo

2013-01-01

How species diversity relates to productivity remains a major debate. To date, however, the underlying mechanisms that regulate the ecological processes involved are still poorly understood. Three major issues persist in early efforts at resolution. First, in the context that productivity drives species diversity, how the pathways operate is poorly-explained. Second,...

Low serum omega-3 and omega-6 polyunsaturated fatty acids and other metabolites are associated with poor linear growth in young children from rural Malawi

USDA-ARS?s Scientific Manuscript database

Stunting affects ~25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood. The purpose of this study was to identify altered metabolic pathways associated with child stunting...

Increased expression of electron transport chain genes in uterine leiomyoma.

PubMed

Tuncal, Akile; Aydin, Hikmet Hakan; Askar, Niyazi; Ozkaya, Ali Burak; Ergenoglu, Ahmet Mete; Yeniel, Ahmet Ozgur; Akdemir, Ali; Ak, Handan

2014-01-01

The etiology and pathophysiology of uterine leiomyomas, benign smooth muscle tumors of the uterus, are not well understood. To evaluate the role of mitochondria in uterine leiomyoma, we compared electron transport gene expressions of uterine leiomyoma tissue with myometrium tissue in six uterine leiomyoma patients by RT-PCR array. Our results showed an average of 1.562 (±0.445) fold increase in nuclear-encoded electron transport genes. These results might suggest an increase in size, number, or activity of mitochondria in uterine leiomyoma that, to our knowledge, has not been previously reported. © 2014 by the Association of Clinical Scientists, Inc.

Turning over renal osteodystrophy dogma: direct actions of FGF23 on osteoblast β-catenin pathway.

PubMed

Schiavi, Susan C; Moysés, Rosa M A

2016-07-01

Although recognized as a major complication of chronic kidney disease (CKD), the pathophysiology of the CKD-related mineral and bone disorder (CKD-MBD) is not completely understood. Recently, the inhibition of Wnt/β-catenin pathway in osteocytes by sclerostin has been shown to play a role in CKD-MBD. The study by Carrilo-Lopez et al. confirms this inhibition in an experimental model of CKD. Moreover, they describe direct actions of FGF23-Klotho on osteoblasts, increasing the expression of DKK1, another Wnt/β-catenin pathway inhibitor. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Optical microangiography enabling visualization of change in meninges after traumatic brain injury in mice in vivo

NASA Astrophysics Data System (ADS)

Choi, Woo June; Qin, Wan; Qi, Xiaoli; Wang, Ruikang K.

2016-03-01

Traumatic brain injury (TBI) is a form of brain injury caused by sudden impact on brain by an external mechanical force. Following the damage caused at the moment of injury, TBI influences pathophysiology in the brain that takes place within the minutes or hours involving alterations in the brain tissue morphology, cerebral blood flow (CBF), and pressure within skull, which become important contributors to morbidity after TBI. While many studies for the TBI pathophysiology have been investigated with brain cortex, the effect of trauma on intracranial tissues has been poorly studied. Here, we report use of high-resolution optical microangiography (OMAG) to monitor the changes in cranial meninges beneath the skull of mouse after TBI. TBI is induced on a brain of anesthetized mouse by thinning the skull using a soft drill where a series of drilling exert mechanical stress on the brain through the skull, resulting in mild brain injury. Intracranial OMAG imaging of the injured mouse brain during post-TBI phase shows interesting pathophysiological findings in the meningeal layers such as widening of subdural space as well as vasodilation of subarachnoid vessels. These processes are acute and reversible within hours. The results indicate potential of OMAG to explore mechanism involved following TBI on small animals in vivo.

Digestive tract absorption of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in a nursing infant

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLachlan, M.S.

The digestive tract absorption of environmental contaminants is an important but poorly understood parameter in contaminant is an important but poorly understood parameter in contaminant risk assessments. The net absorption of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in a nursing infant was measured under natural conditions over 12 days. The levels of the substances in the mother's milk were typical for Germany. It was found that for almost all congeners over 90% of the ingested compound was absorbed. This indicates that the common assumption of 100% absorption in nursing infants is reasonable. No firm conclusions could be drawn regarding the absorptionmore » of Cl7- and Cl8DD/F due to high blank levels in the cotton diapers used.« less

Poorly Understood Aspects of Striated Muscle Contraction

PubMed Central

Månsson, Alf

2015-01-01

Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP). Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs. PMID:25961006

Poorly understood aspects of striated muscle contraction.

PubMed

Månsson, Alf; Rassier, Dilson; Tsiavaliaris, Georgios

2015-01-01

Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP). Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs.

Linking Early Environmental Exposures to Adult Diseases

MedlinePlus

... diseases. Given that many disorders arise during fetal development from disruptions in the dynamic but still poorly understood interplay of genes, environment and nutrition, prevention may have to occur decades ...

An inexpensive and portable drill rig for bedrock groundwater studies in headwater catchments

Treesearch

C. Gabrielli; J.J. McDonnell

2011-01-01

Bedrock groundwater dynamics in headwater catchments are poorly understood and poorly characterized. Here, we present an inexpensive and portable bedrock drilling system designed for use in remote locations. Our system is capable of drilling bedrock wells up to 11 m deep and 38 mm in diameter in a wide range of bedrock types. The drill consists of a lawn mower engine...

Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

PubMed Central

Back, Adam; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

2013-01-01

Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations. PMID:22196764

Researchers Realize Major Breakthrough in Understanding Endometriosis

MedlinePlus

... a rarely studied and poorly understood disease that affects many, many women.” Health Terms: Women's Health RELATED LINKS RSS LISTSERV YOUTUBE FACEBOOK TWITTER GOOGLE+ NIH...T URNING D ISCOVERY I ...

Energy Metabolism Impairment in Migraine.

PubMed

Cevoli, Sabina; Favoni, Valentina; Cortelli, Pietro

2018-06-22

Migraine is a common disabling neurological disorder which is characterised by recurring headache associated with a variety of sensory and autonomic symptoms. The pathophysiology of migraine remains not entirely understood, although many mechanisms involving the central and peripheral nervous system are now becoming clear. In particular, it is widely accepted that migraine is associated with energy metabolic impairment of the brain. The purpose of this review is to present an update overview of the energy metabolism involvement in the migraine pathophysiology. Several biochemical, morphological and magnetic resonance spectroscopy studies have confirmed the presence of energy production deficiency together with an increment of energy consumption in migraine patients. An increment of energy demand over a certain threshold create metabolic and biochemical preconditions for the onset of the migraine attack. The defect of oxidative energy metabolism in migraine is generalized. It remains to be determined if the mitochondrial deficit in migraine is primary or secondary. Riboflavin and Co-Enzyme Q10, both physiologically implicated in mitochondrial respiratory chain functioning, are effective in migraine prophylaxis, supporting the hypothesis that improving brain energy metabolism may reduce the susceptibility to migraine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fetal optimization during maternal sepsis: relevance and response of the obstetric anesthesiologist.

PubMed

Chau, Anthony; Tsen, Lawrence C

2014-06-01

In many labor and delivery units, the obstetric anesthesiologist is often responsible for managing and stabilizing the acutely septic parturient. The management of maternal sepsis has been summarized previously; this study will focus on the implications of maternal sepsis on the fetus, and ways to optimize fetal outcomes. Although the complex pathophysiology of sepsis is being better understood, the incidence of maternal severe sepsis and deaths continues to increase. The differential sensitivities of systemic and uterine vasculature to catecholamines during pregnancy and the role of fetal inflammatory responses have recently been further elucidated. Additional investigations on methods of fetal monitoring are needed to assist in early identification of the compromised fetus. Despite decades of research, management of a septic parturient and her fetus, including the most appropriate resuscitation fluids, vasopressors and hemodynamic monitoring systems to maximize maternal and fetal outcomes, remain controversial. In the setting of maternal sepsis, fetal optimization is frequently best accomplished by meeting maternal hemodynamic, oxygenization, and infection treatment goals. Understanding the circulatory and pathophysiologic changes that occur within the uteroplacental unit and fetus is essential to identifying and resolving potential conflicts between maternal and fetal management goals.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis.

PubMed

Hughes, Alexandria; Oxford, Alexandra E; Tawara, Ken; Jorcyk, Cheryl L; Oxford, Julia Thom

2017-03-20

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.

[Fat embolism syndrome following injuries and limb fractures].

PubMed

Volpin, Gershon; Gorski, Albert; Shtarker, Haim; Makhoul, Nicola

2010-05-01

Fat embolism syndrome is a clinical entity characterized by varying degrees of cerebral dysfunction, pulmonary changes and petechial rash that usually develop within 24-48 hours in a small percentage of victims after trauma and Long bone fractures. Deterioration can occur within a few hours Leading to unconsciousness or acute respiratory insufficiency, similar to adult respiratory distress syndrome (ARDS). The pathophysiology is still not clearly understood and there are two theories--the mechanical and biochemical cascade of events. It seems that the most significant diagnostic sign is hypoxemia with relatively normaL values of PaCO2 leading to development of radiographic "snow-like appearance" of the Lungs, resulting from the typical interstitial lung edema. Treatment consists of early fracture fixation, volume replacement, respiratory support and analgesia carefully managed since some of the patients may develop acute respiratory distress. The role of steroids and other drugs is still under debate. The vast majority of patients may heal without any complications, while 5%-10% of the patients may develop some neurological complications manifesting as behavior disturbances. The aim of this review is to update the clinical and pathophysiological aspects of fat embolism syndrome and to describe the various aspects of prevention and treatment.

Intrathecal Baclofen Therapy for Painful Muscle Spasms in a Patient with Friedreich's Ataxia.

PubMed

Kalyvas, Aristotelis V; Drosos, Evangelos; Korfias, Stefanos; Gatzonis, Stylianos; Themistocleous, Marios; Sakas, Damianos E

2018-06-08

Friedreich's ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11-15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, we attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary. © 2018 S. Karger AG, Basel.

A Review of Esophageal Chest Pain

PubMed Central

Coss-Adame, Enrique

2015-01-01

Noncardiac chest pain is a term that encompasses all causes of chest pain after a cardiac source has been excluded. This article focuses on esophageal sources for chest pain. Esophageal chest pain (ECP) is common, affects quality of life, and carries a substantial health care burden. The lack of a systematic approach toward the diagnosis and treatment of ECP has led to significant disability and increased health care costs for this condition. Identifying the underlying cause(s) or mechanism(s) for chest pain is key for its successful management. Common etiologies include gastroesophageal reflux disease, esophageal hypersensitivity, dysmotility, and psychological conditions, including panic disorder and anxiety. However, the pathophysiology of this condition is not yet fully understood. Randomized controlled trials have shown that proton pump inhibitor therapy (either omeprazole, lansoprazole, or rabeprazole) can be effective. Evidence for the use of antidepressants and the adenosine receptor antagonist theophylline is fair. Psychological treatments, notably cognitive behavioral therapy, may be useful in select patients. Surgery is not recommended. There remains a large unmet need for identifying the phenotype and prevalence of pathophysiologic mechanisms of ECP as well as for well-designed multicenter clinical trials of current and novel therapies. PMID:27134590

A patient with heart failure and worsening kidney function.

PubMed

Sarnak, Mark J

2014-10-07

There is high prevalence of CKD, defined by reduced GFR, in patients with heart failure. Reduced kidney function is associated with increased morbidity and mortality in this patient population. The cardiorenal syndrome (CRS) involves a bidirectional relationship between the heart and kidneys whereby dysfunction in either may exacerbate the function of the other, but this syndrome has been difficult to precisely define because it has many complex physiologic, biochemical, and hormonal abnormalities. The pathophysiology of CRS is not completely understood, but potential mechanisms include reduced kidney perfusion due to decreased forward flow, increased right ventricular and venous pressure, and neurohormonal adaptations. Treatment options include inotropic medications; diuretics; ultrafiltration; and medications, such as β-blockers, inhibitors of the renin-angiotensin-aldosterone system, and more novel treatments that focus on unique aspects of the pathophysiology. Recent observational studies suggest that treatments that result in a decrease in venous pressure and lead to hemoconcentration may be associated with improved outcomes. Patients with CRS that is not responsive to medical interventions should be considered for ventricular assist devices, heart transplantation, or combined heart and kidney transplantation. Copyright © 2014 by the American Society of Nephrology.

Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach

PubMed Central

Wassmer, Samuel C.; Taylor, Terrie E.; Rathod, Pradipsinh K.; Mishra, Saroj K.; Mohanty, Sanjib; Arevalo-Herrera, Myriam; Duraisingh, Manoj T.; Smith, Joseph D.

2015-01-01

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program. PMID:26259939

Mechanisms and management of functional abdominal pain.

PubMed

Farmer, Adam D; Aziz, Qasim

2014-09-01

Functional abdominal pain syndrome is characterised by frequent or continuous abdominal pain associated with a degree of loss of daily activity. It has a reported population prevalence of between 0.5% and 1.7%, with a female preponderance. The pathophysiology of functional abdominal pain is incompletely understood although it has been postulated that peripheral sensitisation of visceral afferents, central sensitisation of the spinal dorsal horn and aberrancies within descending modulatory systems may have an important role. The management of patients with functional abdominal pain requires a tailored multidisciplinary approach in a supportive and empathetic environment in order to develop an effective therapeutic relationship. Patient education directed towards an explanation of the pathophysiology of functional abdominal pain is in our opinion a prerequisite step and provides the rationale for the introduction of interventions. Interventions can usefully be categorised into general measures, pharmacotherapy, psychological interventions and 'step-up' treatments. Pharmacotherapeutic/step-up options include tricyclic antidepressants, serotonin noradrenergic reuptake inhibitors and the gabapentinoids. Psychological treatments include cognitive behavioural therapy and hypnotherapy. However, the objective evidence base for these interventions is largely derived from other chronic pain syndrome, and further research is warranted in adult patients with functional abdominal pain. © The Royal Society of Medicine.

Renal Transport of Uric Acid: Evolving Concepts and Uncertainties

PubMed Central

Bobulescu, Ion Alexandru; Moe, Orson W.

2013-01-01

In addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiology and pathophysiology and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels, by reabsorbing around 90% of filtered urate, while being responsible for 60–70% of total body uric acid excretion. Defective renal handling of urate is a frequent pathophysiologic factor underpinning hyperuricemia and gout. In spite of tremendous advances over the past decade, the molecular mechanisms of renal urate transport are still incompletely understood. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Understanding these transporters is increasingly important for the practicing clinician as new research unveils their physiology, importance in drug action, and genetic association with uric acid levels in human populations. The future may see the introduction of new drugs that specifically act on individual renal urate transporters for the treatment of hyperuricemia and gout. PMID:23089270

Pre-operative Functional Cardiovascular Reserve Is Associated with Acute Kidney Injury after Intervention.

PubMed

Saratzis, A; Shakespeare, J; Jones, O; Bown, M J; Mahmood, A; Imray, C H E

2017-05-01

Acute kidney injury (AKI) is a common complication after endovascular intervention, associated with poor short and long-term outcomes. However, the mechanisms underlying AKI development remain poorly understood. The impact of pre-existing cardiovascular disease and low cardiovascular reserve (CVR) in AKI is unclear; it remains unknown whether AKI is primarily related to pre-existing comorbidity or to procedural parameters. The association between CVR and AKI after EVAR was therefore assessed. This is a case control study. From a database of 484 patients, 292 undergoing elective endovascular aneurysm repair (EVAR) of an infrarenal abdominal aortic aneurysm (AAA) in two tertiary centres were included. Of these, 73 patients who had developed AKI after EVAR were case matched, based on pre-operative estimated glomerular filtration rate (eGFR; within 5 mL/min/1.73 m 2 ) and age, with patients who had not developed AKI. Cardiopulmonary exercise testing (CPET) was used to assess CVR using the anaerobic threshold (AT). Development of AKI was defined using the Kidney Disease Improving Outcomes (KDIGO) guidance. Associations between CVR (based on AT levels) and AKI development were then analysed. Pre-operative AT levels were significantly different between those who did and did not develop AKI (12.1±2.9 SD vs. 14.8±3.0 mL/min/kg, p < .001). In multivariate analysis, a higher level of AT (per 1 mL/min/kg) was associated with a lower odds ratio (OR) of 0.72 (95% CI, 0.63-0.82, p < .001), relative to AKI development. A pre-operative AT level of < 11 mL/min/kg was associated with post-operative AKI development in adjusted analysis, with an OR of 7.8 (95% CI, 3.75-16.51, p < .001). The area under the curve (receiver operating characteristic) for AT as a predictor of post-operative AKI was 0.81 (standard error, 0.06, 95% CI, 0.69-0.93, p < .001). Poor CVR was strongly associated with the development of AKI. This provides pathophysiological insights into the mechanisms underlying AKI. Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

76 FR 61379 - Final Recovery Plan, Bexar County Karst Invertebrates

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-04

... 200, Austin, TX (512-490-0057 ext. 223). FOR FURTHER INFORMATION CONTACT: Adam Zerrenner, at the above... poorly understood, recovery is also dependant on incorporating research findings into adaptive management...

Fine-scale landscape genetics of the American badger (Taxidea taxus): disentangling landscape effects and sampling artifacts in a poorly understood species

PubMed Central

Kierepka, E M; Latch, E K

2016-01-01

Landscape genetics is a powerful tool for conservation because it identifies landscape features that are important for maintaining genetic connectivity between populations within heterogeneous landscapes. However, using landscape genetics in poorly understood species presents a number of challenges, namely, limited life history information for the focal population and spatially biased sampling. Both obstacles can reduce power in statistics, particularly in individual-based studies. In this study, we genotyped 233 American badgers in Wisconsin at 12 microsatellite loci to identify alternative statistical approaches that can be applied to poorly understood species in an individual-based framework. Badgers are protected in Wisconsin owing to an overall lack in life history information, so our study utilized partial redundancy analysis (RDA) and spatially lagged regressions to quantify how three landscape factors (Wisconsin River, Ecoregions and land cover) impacted gene flow. We also performed simulations to quantify errors created by spatially biased sampling. Statistical analyses first found that geographic distance was an important influence on gene flow, mainly driven by fine-scale positive spatial autocorrelations. After controlling for geographic distance, both RDA and regressions found that Wisconsin River and Agriculture were correlated with genetic differentiation. However, only Agriculture had an acceptable type I error rate (3–5%) to be considered biologically relevant. Collectively, this study highlights the benefits of combining robust statistics and error assessment via simulations and provides a method for hypothesis testing in individual-based landscape genetics. PMID:26243136

Studying Protein Synthesis-Dependent Synaptic Changes in Tuberous Sclerosis

DTIC Science & Technology

2013-04-01

proteins have been implicated in autism . For example, both Shank 2 and 3 are mutated in families with autism (3, 4). Shank 3 is also associated with...obsessive-compulsive disorder as well as stereotypy in autism . Shank3 deleted mice also show poor social interaction. Furthermore, two patients with a...pathophysiology of autism where it is elevated in CSF (Veenstra-VanderWeele and Blakely). (3) 5-HT2CR has a PDZ-binding domain and has been shown to interact with

Mitral valve prolapse and Marfan syndrome.

PubMed

Thacoor, Amitabh

2017-07-01

Marfan syndrome is a multisystemic genetic condition affecting connective tissue. It carries a reduced life expectancy, largely dependent on cardiovascular complications. More common cardiac manifestations such as aortic dissection and aortic valve incompetence have been widely documented in the literature. Mitral valve prolapse (MVP), however, has remained poorly documented. This article aims at exploring the existing literature on the pathophysiology and diagnosis of MVP in patients with Marfan syndrome, defining its current management and outlining the future developments surrounding it. © 2017 Wiley Periodicals, Inc.

Sexual pain.

PubMed

Boardman, Lori A; Stockdale, Colleen K

2009-12-01

Sexual pain is an underrecognized and poorly treated constellation of disorders that significantly impact affected women and their partners. Recognized as a form of chronic pain, sexual pain disorders are heterogeneous and include dyspareunia (superficial and deep), vaginismus, vulvodynia, vestibulitis, and noncoital sexual pain disorder. Women too often tolerate pain in the belief that this will meet their partners' needs. This article provides a review of the terminology and definition of the condition, theories on the pathophysiology, diagnostic considerations, and recommendations on the management of female sexual pain.

The use of an investigational radiopharmaceutical in neuroblastoma: A nursing perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelly, J.U.

Children with advanced-stage neuroblastoma usually have a poor prognosis. While conventional treatment with surgery, chemotherapy, and radiation may provide some palliation, long-term survival is rare. A number of investigational therapies are being performed nationwide in an attempt to improve the prognosis for children with neuroblastoma. One such treatment is the use of {sup 131}I-metaiodobenzylguanidine. This article will review the pathophysiology of neuroblastoma, give an overview of this investigational treatment, and discuss the nursing care associated with radioactive treatment.

Biodiversity and ecosystem function in species-poor communities: community structure and leaf litter breakdown in a Pacific island stream

Treesearch

Jonathan P. Benstead; James G. March; Catherine M. Pringle; Katherine C. Ewel; John W. Short

2009-01-01

Pacific island stream communities are species-poor because of the effects of extreme geographic isolation on colonization rates of taxa common to continental regions. The effects of such low species richness on stream ecosystem function are not well understood. Here, we provide data on community structure and leaf litter breakdown rate in a virtually pristine stream on...

Delayed Ejaculation: Pathophysiology, Diagnosis, and Treatment

PubMed Central

2018-01-01

Delayed ejaculation (DE) is a poorly defined and uncommon form of male sexual dysfunction, characterized by a marked delay in ejaculation or an inability to achieve ejaculation. It is often quite concerning to patients and their partners, and sometimes frustrates couples' attempts to conceive. This article aims to review the pathophysiology of DE and anejaculation (AE), to explore our current understanding of the diagnosis, and to present the treatment options for this condition. Electronic databases were searched from 1966 to October 2017, including PubMed (MEDLINE) and Embase. We combined “delayed ejaculation,” “retarded ejaculation,” “inhibited ejaculation,” or “anejaculation” as Medical Subject Headings (MeSH) terms or keywords with “epidemiology,” “etiology,” “pathophysiology,” “clinical assessment,” “diagnosis,” or “treatment.” Relevant sexual medicine textbooks were searched as well. The literature suggests that the pathophysiology of DE/AE is multifactorial, including both organic and psychosocial factors. Despite the many publications on this condition, the exact pathogenesis is not yet known. There is currently no single gold standard for diagnosing DE/AE, as operationalized criteria do not exist. The history is the key to the diagnosis. Treatment should be cause-specific. There are many approaches to treatment planning, including various psychological interventions, pharmacotherapy, and specific treatments for infertile men. An approved form of drug therapy does not exist. A number of approaches can be employed for infertile men, including the collection of nocturnal emissions, prostatic massage, prostatic urethra catheterization, penile vibratory stimulation, probe electroejaculation, sperm retrieval by aspiration from either the vas deferens or the epididymis, and testicular sperm extraction. PMID:29299903

Dissecting the pathobiology of altered MRI signal in amyotrophic lateral sclerosis: A post mortem whole brain sampling strategy for the integration of ultra-high-field MRI and quantitative neuropathology.

PubMed

Pallebage-Gamarallage, Menuka; Foxley, Sean; Menke, Ricarda A L; Huszar, Istvan N; Jenkinson, Mark; Tendler, Benjamin C; Wang, Chaoyue; Jbabdi, Saad; Turner, Martin R; Miller, Karla L; Ansorge, Olaf

2018-03-13

Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically. One route to understanding and validating the pathophysiological correlates of MRI signal changes in ALS is to directly compare MRI to histology in post mortem human brains. The article delineates a universal whole brain sampling strategy of pathologically relevant grey matter (cortical and subcortical) and white matter tracts of interest suitable for histological evaluation and direct correlation with MRI. A standardised systematic sampling strategy that was compatible with co-registration of images across modalities was established for regions representing phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) patterns that were topographically recognisable with defined neuroanatomical landmarks. Moreover, tractography-guided sampling facilitated accurate delineation of white matter tracts of interest. A digital photography pipeline at various stages of sampling and histological processing was established to account for structural deformations that might impact alignment and registration of histological images to MRI volumes. Combined with quantitative digital histology image analysis, the proposed sampling strategy is suitable for routine implementation in a high-throughput manner for acquisition of large-scale histology datasets. Proof of concept was determined in the spinal cord of an ALS patient where multiple MRI modalities (T1, T2, FA and MD) demonstrated sensitivity to axonal degeneration and associated heightened inflammatory changes in the lateral corticospinal tract. Furthermore, qualitative comparison of R2* and susceptibility maps in the motor cortex of 2 ALS patients demonstrated varying degrees of hyperintense signal changes compared to a control. Upon histological evaluation of the same region, intensity of signal changes in both modalities appeared to correspond primarily to the degree of microglial activation. The proposed post mortem whole brain sampling methodology enables the accurate intraindividual study of pathological propagation and comparison with quantitative MRI data, to more fully understand the relationship of imaging signal changes with underlying pathophysiology in ALS.

Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life-a case study.

PubMed

Bajnok, Anna; Berta, László; Orbán, Csaba; Tulassay, Tivadar; Toldi, Gergely

2018-06-22

The perinatal period carries the highest risk for stroke in childhood; however, the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. A new pathophysiological model describes the development of neonatal arterial ischemic stroke (NAIS) as the combined result of prenatal inflammation and hypoxic-ischemic insult. Neuroinflammation and a systemic inflammatory response are also important features of NAIS. Identifying key players of the inflammatory system is in the limelight of current research. We present four NAIS cases, in whom detailed analysis of intracellular and plasma cytokine levels are available from the first month of life. All neonates were admitted with the initial diagnosis of hypoxic ischemic encephalopathy (HIE); however, early MRI examination revealed NAIS. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Peripheral blood mononuclear cells were assessed with flow cytometry and plasma cytokine levels were measured. Pooled data from the cohort of four NAIS patients were compared to infants with HIE. At 6 and 72 h of age, the prevalence of IL10+ CD8+ lymphocytes remained lower in NAIS. At 6 h, CD8+ lymphocytes in NAIS produced more IL-17. At 72 h, CD8+ cells produced more IL-6 in severe HIE than in NAIS, but IL-6 production remained elevated in CD8 cells at 1 month in NAIS, while it decreased in HIE. At 1 week, the prevalence of TGF-β + lymphocytes prone to enter the CNS was elevated in NAIS. On the other hand, by 1 month of age, the prevalence of TGF-β + CD4+ lymphocytes decreased in NAIS compared to HIE. At 72 h, we found elevated plasma levels of IL-5, MCP-1, and IL-17 in NAIS. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE. Differences in the cytokine network are present between NAIS and HIE. CD8 lymphocytes appear to shift towards the pro-inflammatory direction in NAIS. The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month.

What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion.

PubMed

Sin, Don D; Miravitlles, Marc; Mannino, David M; Soriano, Joan B; Price, David; Celli, Bartolome R; Leung, Janice M; Nakano, Yasutaka; Park, Hye Yun; Wark, Peter A; Wechsler, Michael E

2016-09-01

Patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies. Copyright ©ERS 2016.

International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology.

PubMed

Nowak-Węgrzyn, Anna; Chehade, Mirna; Groetch, Marion E; Spergel, Jonathan M; Wood, Robert A; Allen, Katrina; Atkins, Dan; Bahna, Sami; Barad, Ashis V; Berin, Cecilia; Brown Whitehorn, Terri; Burks, A Wesley; Caubet, Jean-Christoph; Cianferoni, Antonella; Conte, Marisa; Davis, Carla; Fiocchi, Alessandro; Grimshaw, Kate; Gupta, Ruchi; Hofmeister, Brittany; Hwang, J B; Katz, Yitzhak; Konstantinou, George N; Leonard, Stephanie A; Lightdale, Jennifer; McGhee, Sean; Mehr, Sami; Sopo, Stefano Miceli; Monti, Giovanno; Muraro, Antonella; Noel, Stacey Katherine; Nomura, Ichiro; Noone, Sally; Sampson, Hugh A; Schultz, Fallon; Sicherer, Scott H; Thompson, Cecilia C; Turner, Paul J; Venter, Carina; Westcott-Chavez, A Amity; Greenhawt, Matthew

2017-04-01

Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

PubMed Central

Dumesic, Daniel A.; Oberfield, Sharon E.; Stener-Victorin, Elisabet; Marshall, John C.; Laven, Joop S.

2015-01-01

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. PMID:26426951

Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer

PubMed Central

Liu, Guangbo; Pei, Fen; Yang, Fengqing; Li, Lingxiao; Amin, Amit Dipak; Liu, Songnian; Buchan, J. Ross; Cho, William C.

2017-01-01

Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics. PMID:28208579

Fibromyalgia Pathogenesis and Treatment Options Update.

PubMed

Chinn, Steven; Caldwell, William; Gritsenko, Karina

2016-04-01

This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.

Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.

PubMed

Witsch, Thilo J; Turowski, Pawel; Sakkas, Elpidoforos; Niess, Gero; Becker, Simone; Herold, Susanne; Mayer, Konstantin; Vadász, István; Roberts, Jesse D; Seeger, Werner; Morty, Rory E

2014-02-01

Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.

BOK promotes chemical-induced hepatocarcinogenesis in mice.

PubMed

Rabachini, Tatiana; Fernandez-Marrero, Yuniel; Montani, Matteo; Loforese, Giulio; Sladky, Valentina; He, Zhaoyue; Bachmann, Daniel; Wicki, Simone; Villunger, Andreas; Stroka, Deborah; Kaufmann, Thomas

2018-03-01

BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver. Of note, induction of CHOP and the pro-apoptotic BH3-only proteins PUMA and BIM by DEN was strongly reduced in the absence of BOK. Accordingly, Bok -/- mice were significantly protected from DEN-induced acute hepatocellular apoptosis and associated inflammation. As a consequence, Bok -/- animals were partially protected against chemical-induced hepatocarcinogenesis showing fewer and, surprisingly, also smaller tumors than WT controls. Gene expression profiling revealed that downregulation of BOK results in upregulation of genes involved in cell cycle arrest. Bok -/- hepatocellular carcinoma (HCC) displayed higher expression levels of the cyclin kinase inhibitors p19 INK4d and p21 cip1 . Accordingly, hepatocellular carcinoma in Bok -/- animals, BOK-deficient human HCC cell lines, as well as non-transformed cells, showed significantly less proliferation than BOK-proficient controls. We conclude that BOK is induced by DEN, contributes to DEN-induced hepatocellular apoptosis and resulting hepatocarcinogenesis. In line with its previously reported predominant localization at the endoplasmic reticulum, our findings support a role of BOK that links the cell cycle and cell death machineries upstream of mitochondrial damage.

Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells

PubMed Central

Clear, Andrew; Owen, Andrew; Iqbal, Sameena; Lee, Abigail; Matthews, Janet; Wilson, Andrew; Calaminici, Maria; Gribben, John G.

2013-01-01

CD4+ T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFα/IFNγ/interleukin-2 (IL-2) and less TH2-associated CCR3/CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activation-associated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate. PMID:24004665

Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells.

PubMed

Greaves, Paul; Clear, Andrew; Owen, Andrew; Iqbal, Sameena; Lee, Abigail; Matthews, Janet; Wilson, Andrew; Calaminici, Maria; Gribben, John G

2013-10-17

CD4(+) T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFα/IFNγ/interleukin-2 (IL-2) and less TH2-associated CCR3/CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activation-associated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate.

Altered brain network modules induce helplessness in major depressive disorder.

PubMed

Peng, Daihui; Shi, Feng; Shen, Ting; Peng, Ziwen; Zhang, Chen; Liu, Xiaohua; Qiu, Meihui; Liu, Jun; Jiang, Kaida; Fang, Yiru; Shen, Dinggang

2014-10-01

The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. Resting-state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naïve MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness. Copyright © 2014 Elsevier B.V. All rights reserved.

Altered brain network modules induce helplessness in major depressive disorder

PubMed Central

Peng, Daihui; Shi, Feng; Shen, Ting; Peng, Ziwen; Zhang, Chen; Liu, Xiaohua; Qiu, Meihui; Liu, Jun; Jiang, Kaida; Shen, Dinggang

2017-01-01

Objective The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. Methods Resting-state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naïve MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. Results Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. Limitation The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. Conclusions The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness. PMID:25033474

Protein Tyrosine Nitration: Role in Aging.

PubMed

Chakravarti, Bulbul; Chakravarti, Deb N

2017-01-01

Aging is the inevitable fate of all living organisms, but the molecular basis of physiological aging is poorly understood. Oxidative stress is believed to play a key role in the aging process. In addition to Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS) are generated during aerobic metabolism in living organisms. Although protein damage and functional modification by ROS have been demonstrated in details, fewer studies have been reported on protein damage by RNS and its implication in the aging process. Proteins undergoing tyrosine nitration are associated with pathophysiology of several diseases, as well as physiological aging. The purpose of the current review article is to provide a brief summary of the biochemical mechanisms of tyrosine nitration, methodologies used for the detection of these modified proteins, effect of RNS induced post translational modification on biological functions and the putative role of tyrosine nitrated proteins in the aging process. Published studies on the role of RNS in age related functional alteration of various organs/ tissues were critically reviewed and evaluated. Covalent modification of various proteins by tyrosine nitration is associated with modification of biological functions of various organs/tissues such as skeletal muscle, heart, brain and liver due to aging. This information will be helpful to further investigate the interplay of different biochemical pathways and networks involved in the tyrosine nitration of various proteins due to aging with the ultimate goal to prevent the detrimental effects of RNS on the functional activities of these proteins. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Small bowel lymphangiectasia and angiodysplasia: a positive association; novel clinical marker or shared pathophysiology?

PubMed

Macdonald, Jonathan; Porter, Victoria; Scott, Neil W; McNamara, Deirdre

2010-10-01

Small bowel angiodysplasia accounts for 30 to 40% of cases of obscure gastrointestinal bleeding and is associated with significant morbidity and mortality. Identifying lesions can be difficult. Small bowel capsule endoscopy (SBCE) is a significant advance on earlier diagnostic techniques. The cause of angiodysplasia is unknown and the natural history poorly understood. Many lesions are thought to arise from a degenerative process associated with ageing, local vascular anomalies, and tissue hypoxia. Nonpathologic lymphangiectasias are commonly seen throughout the small bowel and are considered a normal finding. To determine whether there is an association between lymphangiectasias, angiodysplasia, and atherosclerosis related conditions. Relevant information was collected from a dedicated SBCE database. Logistic regression analysis was used to examine associations between angiodysplasia, lymphangiectasia, patient demographics, and comorbidity. In all, 180 patients underwent SBCE during the study period, 46 (25%) had angiodysplasia and 47 (26%) lymphangiectasia. Lymphangiectasia were seen in 24 (52%) of 46 with angiodysplasia, in 16 (19%) of 84 with obscure gastrointestinal bleeding without angiodysplasia and in 7 (14%) of 50 without gastrointestinal bleeding. Logistic regression analysis confirmed a strong positive association between angiodysplasia and lymphangiectasia; odds ratio 4.42, P<0.003. Angiodysplasias were also associated with increasing age; odds ratio 1.1. There was no correlation with any other patient characteristic. Lymphangiectasia are strongly associated with the presence of small intestinal angiodysplasia and may represent a useful clinical marker for this condition. Angiodysplasia are also associated with increasing age. Conditions associated with systemic atherosclerosis did not increase the risk of angiodysplasia.

The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans*♦

PubMed Central

Chun, Haarin; Sharma, Anuj Kumar; Lee, Jaekwon; Chan, Jefferson; Jia, Shang; Kim, Byung-Eun

2017-01-01

Copper plays key catalytic and regulatory roles in biochemical processes essential for normal growth, development, and health. Defects in copper metabolism cause Menkes and Wilson's disease, myeloneuropathy, and cardiovascular disease and are associated with other pathophysiological states. Consequently, it is critical to understand the mechanisms by which organisms control the acquisition, distribution, and utilization of copper. The intestinal enterocyte is a key regulatory point for copper absorption into the body; however, the mechanisms by which intestinal cells transport copper to maintain organismal copper homeostasis are poorly understood. Here, we identify a mechanism by which organismal copper homeostasis is maintained by intestinal copper exporter trafficking that is coordinated with extraintestinal copper levels in Caenorhabditis elegans. Specifically, we show that CUA-1, the C. elegans homolog of ATP7A/B, localizes to lysosome-like organelles (gut granules) in the intestine under copper overload conditions for copper detoxification, whereas copper deficiency results in a redistribution of CUA-1 to basolateral membranes for copper efflux to peripheral tissues. Worms defective in gut granule biogenesis exhibit defects in copper sequestration and increased susceptibility to toxic copper levels. Interestingly, however, a splice isoform CUA-1.2 that lacks a portion of the N-terminal domain is targeted constitutively to the basolateral membrane irrespective of dietary copper concentration. Our studies establish that CUA-1 is a key intestinal copper exporter and that its trafficking is regulated to maintain systemic copper homeostasis. C. elegans could therefore be exploited as a whole-animal model system to study regulation of intra- and intercellular copper trafficking pathways. PMID:27881675

Malnutrition induces gut atrophy and increases hepatic fat infiltration: studies in a pig model of childhood malnutrition.

PubMed

Lykke, Mikkel; Hother, Anne-Louise; Hansen, Christian F; Friis, Henrik; Mølgaard, Christian; Michaelsen, Kim F; Briend, André; Larsen, Torben; Sangild, Per T; Thymann, Thomas

2013-01-01

Childhood malnutrition is a problem in developing countries, and pathological changes in digestive organs such as the intestine and liver are poorly understood. An animal model to study the progression of severe acute malnutrition could elucidate pathological changes in the intestine and liver. We sought to characterize growth and clinical changes during malnutrition related to structural and functional indices in the intestine and liver. Newly weaned piglets were given ad libitum access to a maize flour diet (MAIZE, n=9) or a nutritionally optimized reference diet (REFERENCE, n=12) for 7 weeks. Growth, hematology and clinical biochemistry where recorded weekly. After 7 weeks, the MAIZE pigs had lower body weights than the REF pigs (8.3 kg vs. 32.4 kg, P < 0.001), indicating severe stunting and moderate to severe wasting. This was paralleled by lower values for hematocrit, hemoglobin and mean cell volume in MAIZE vs. REFERENCE (P < 0.01), indicating anemia. Although the observed temporal changes in MAIZE were associated with atrophy of the small intestinal mucosa (P < 0.001), digestive enzyme activity was only marginally reduced. Serum alanine aminotransferase, bilirubin and albumin were increased in the MAIZE pigs (P < 0.001), and the liver had a vacuolated appearance and tendency toward increased triglyceride content (P=0.054). We conclude that liver and intestinal indices are compromised during malnutrition and are associated with temporal changes in growth and hematological and biochemical endpoints. The pig model is relevant for malnourished infants and can act as a valuable tool for understanding the pathophysiology of malnutrition.

Dynamic cycling in atrial size and flow during obstructive apnoea.

PubMed

Pressman, Gregg S; Cepeda-Valery, Beatriz; Codolosa, Nicolas; Orban, Marek; Samuel, Solomon P; Somers, Virend K

2016-01-01

Obstructive sleep apnoea (OSA) is strongly associated with cardiovascular disease. However, acute cardiovascular effects of repetitive airway obstruction are poorly understood. While past research used a sustained Mueller manoeuver to simulate OSA we employed a series of gasping efforts to better simulate true obstructive apnoeas. This report describes acute changes in cardiac anatomy and flow related to sudden changes in intrathoracic pressure. 26 healthy, normal weight participants performed 5-6 gasping efforts (target intrathoracic pressure -40 mm Hg) while undergoing Doppler echocardiography. 14 participants had sufficient echocardiographic images to allow comparison of atrial areas during the manoeuver with baseline measurements. Mitral and tricuspid E-wave and A-wave velocities postmanoeuver were compared with baseline in all participants. Average atrial areas changed little during the manoeuver, but variance in both atrial areas was significantly greater than baseline. Further, an inverse relationship was noted with left atrial collapse and right atrial enlargement at onset of inspiratory effort. Significant inverse changes were noted in Doppler flow when comparing the first beat postmanoeuver (pMM1) with baseline. Mitral E-wave velocity increased 9.1 cm/s while tricuspid E-wave velocity decreased 7.0 cm/s; by the eighth beat postmanoeuver (pMM8) values were not different from baseline. Mitral and tricuspid A-wave velocities were not different from baseline at pMM1, but both were significantly higher by pMM8. Repetitive obstructive apnoeas produce dynamic, inverse changes in atrial size and Doppler flow across the atrioventricular valves. These observations have important implications for understanding the pathophysiology of OSA.

Heritability of Addison's disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins.

PubMed

Skov, Jakob; Höijer, Jonas; Magnusson, Patrik K E; Ludvigsson, Jonas F; Kämpe, Olle; Bensing, Sophie

2017-12-01

The pathophysiology behind autoimmune Addison's disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins. A population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964-2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies. We identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40-0.90) and the heritability 0.97 (95% CI 0.88-99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8-116) on the number of shared autoimmune diagnoses within pairs. The heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.

Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection

PubMed Central

Nairz, Manfred; Schroll, Andrea; Haschka, David; Dichtl, Stefanie; Tymoszuk, Piotr; Demetz, Egon; Moser, Patrizia; Haas, Hubertus; Fang, Ferric C.; Theurl, Igor; Weiss, Günter

2017-01-01

Genetic and dietary forms of iron overload have distinctive clinical and pathophysiological features. HFE-associated hereditary hemochromatosis is characterized by overwhelming intestinal iron absorption, parenchymal iron deposition, and macrophage iron depletion. In contrast, excessive dietary iron intake results in iron deposition in macrophages. However, the functional consequences of genetic and dietary iron overload for the control of microbes are incompletely understood. Using Hfe+/+ and Hfe−/− mice in combination with oral iron overload in a model of Salmonella enterica serovar Typhimurium infection, we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner. As predicted, Hfe−/− mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content, which translated into improved control of Salmonella replication. Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing the expression of its siderophore iron-uptake machinery. Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe−/− mice, although Hfe deficiency still resulted in better pathogen control and improved survival. This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria. Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection. Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection, indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens. PMID:28443246

The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia

PubMed Central

Fox, Amy C.; McConnell, Kevin W.; Yoseph, Benyam P.; Breed, Elise; Liang, Zhe; Clark, Andrew T.; O'Donnell, David; Zee-Cheng, Brendan; Jung, Enjae; Dominguez, Jessica A.; Dunne, W. Michael; Burd, Eileen M.; Coopersmith, Craig M.

2012-01-01

The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. All GF mice died within two days while 44% of conventional mice survived for 7 days (p=0.001). Diluting the dose of bacteria 10-fold in GF mice led to similar survival in GF and conventional mice. When animals with similar mortality were assayed for intestinal integrity, GF mice had lower levels of intestinal epithelial apoptosis but similar levels of proliferation and intestinal permeability. GF mice had significantly lower levels of TNF and IL-1β in BAL fluid compared to conventional mice without changes in systemic cytokine production. Under conventional conditions, sepsis unmasks lymphocyte control of intestinal epithelial apoptosis, since sepsis induces a greater increase in gut apoptosis in Rag-1−/− mice than wild type (WT) mice. However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1−/− mice and septic GF WT mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local pro-inflammatory response. Additionally, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria. PMID:23042193

The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia.

PubMed

Fox, Amy C; McConnell, Kevin W; Yoseph, Benyam P; Breed, Elise; Liang, Zhe; Clark, Andrew T; O'Donnell, David; Zee-Cheng, Brendan; Jung, Enjae; Dominguez, Jessica A; Dunne, W Michael; Burd, Eileen M; Coopersmith, Craig M

2012-11-01

The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ-free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. All GF mice died within 2 days, whereas 44% of conventional mice survived for 7 days (P = 0.001). Diluting the dose of bacteria 10-fold in GF mice led to similar survival in GF and conventional mice. When animals with similar mortality were assayed for intestinal integrity, GF mice had lower levels of intestinal epithelial apoptosis but similar levels of proliferation and intestinal permeability. Germ-free mice had significantly lower levels of tumor necrosis factor and interleukin 1β in bronchoalveolar lavage fluid compared with conventional mice without changes in systemic cytokine production. Under conventional conditions, sepsis unmasks lymphocyte control of intestinal epithelial apoptosis, because sepsis induces a greater increase in gut apoptosis in Rag-1 mice than in wild-type mice. However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1 mice and septic GF wild-type mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local proinflammatory response. In addition, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria.

Sustained apnea induces endothelial activation.

PubMed

Eichhorn, Lars; Dolscheid-Pommerich, Ramona; Erdfelder, Felix; Ayub, Muhammad Ajmal; Schmitz, Theresa; Werner, Nikos; Jansen, Felix

2017-09-01

Apnea diving has gained worldwide popularity, even though the pathophysiological consequences of this challenging sport on the human body are poorly investigated and understood. This study aims to assess the influence of sustained apnea in healthy volunteers on circulating microparticles (MPs) and microRNAs (miRs), which are established biomarkers reflecting vascular function. Short intermittent hypoxia due to voluntary breath-holding affects circulating levels of endothelial cell-derived MPs (EMPs) and endothelial cell-derived miRs. Under dry laboratory conditions, 10 trained apneic divers performed maximal breath-hold. Venous blood samples were taken, once before and at 4 defined points in time after apnea. Samples were analyzed for circulating EMPs and endothelial miRs. Average apnea time was 329 seconds (±103), and SpO 2 at the end of apnea was 79% (±12). Apnea was associated with a time-dependent increase of circulating endothelial cell-derived EMPs and endothelial miRs. Levels of circulating EMPs in the bloodstream reached a peak 4 hours after the apnea period and returned to baseline levels after 24 hours. Circulating miR-126 levels were elevated at all time points after a single voluntary maximal apnea, whereas miR-26 levels were elevated significantly only after 30 minutes and 4 hours. Also miR-21 and miR-92 levels increased, but did not reach the level of significance. Even a single maximal breath-hold induces acute endothelial activation and should be performed with great caution by subjects with preexisting vascular diseases. Voluntary apnea might be used as a model to simulate changes in endothelial function caused by hypoxia in humans. © 2017 Wiley Periodicals, Inc.

Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes.

PubMed

Mato, Susana; Victoria Sánchez-Gómez, María; Matute, Carlos

2010-11-01

Heavy marijuana use has been linked to white matter histological alterations. However, the impact of cannabis constituents on oligodendroglial pathophysiology remains poorly understood. Here, we investigated the in vitro effects of cannabidiol, the main nonpsychoactive marijuana component, on oligodendrocytes. Exposure to cannabidiol induced an intracellular Ca(2+) rise in optic nerve oligodendrocytes that was not primarily mediated by entry from the extracellular space, nor by interactions with ryanodine or IP(3) receptors. Application of the mitochondrial protonophore carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP; 1 μM) completely prevented subsequent cannabidiol-induced Ca(2+) responses. Conversely, the increase in cytosolic Ca(2+) levels elicited by FCCP was reduced after previous exposure to cannabidiol, further suggesting that the mitochondria acts as the source of cannabidiol-evoked Ca(2+) rise in oligodendrocytes. n addition, brief exposure to cannabidiol (100 nM-10 μM) led to a concentration-dependent decrease of oligodendroglial viability that was not prevented by antagonists of CB(1), CB(2), vanilloid, A(2A) or PPARγ receptors, but was instead reduced in the absence of extracellular Ca(2+). The oligodendrotoxic effect of cannabidiol was partially blocked by inhibitors of caspase-3, -8 and -9, PARP-1 and calpains, suggesting the activation of caspase-dependent and -independent death pathways. Cannabidiol also elicited a concentration-dependent alteration of mitochondrial membrane potential, and an increase in reactive oxygen species (ROS) that was reduced in the absence of extracellular Ca(2+). Finally, cannabidiol-induced cytotoxicity was partially prevented by the ROS scavenger trolox. Together, these results suggest that cannabidiol causes intracellular Ca(2+) dysregulation which can lead to oligodendrocytes demise.

A Perspective on the Interplay of Ultraviolet-Radiation, Skin Microbiome and Skin Resident Memory TCRαβ+ Cells.

PubMed

Patra, VijayKumar; Laoubi, Léo; Nicolas, Jean-François; Vocanson, Marc; Wolf, Peter

2018-01-01

The human skin is known to be inhabited by diverse microbes, including bacteria, fungi, viruses, archaea, and mites. This microbiome exerts a protective role against infections by promoting immune development and inhibiting pathogenic microbes to colonize skin. One of the factors having an intense effect on the skin and its resident microbes is ultraviolet-radiation (UV-R). UV-R can promote or inhibit the growth of microbes on the skin and modulate the immune system which can be either favorable or harmful. Among potential UV-R targets, skin resident memory T cells (T RM ) stand as well positioned immune cells at the forefront within the skin. Both CD4 + or CD8 + αβ T RM cells residing permanently in peripheral tissues have been shown to play prominent roles in providing accelerated and long-lived specific immunity, tissue homeostasis, wound repair. Nevertheless, their response upon UV-R exposure or signals from microbiome are poorly understood compared to resident TCRγδ cells. Skin T RM survive for long periods of time and are exposed to innumerable antigens during lifetime. The interplay of T RM with skin residing microbes may be crucial in pathophysiology of various diseases including psoriasis, atopic dermatitis and polymorphic light eruption. In this article, we share our perspective about how UV-R may directly shape the persistence, phenotype, specificity, and function of skin T RM ; and moreover, whether UV-R alters barrier function, leading to microbial-specific skin T RM , disrupting the healthy balance between skin microbiome and skin immune cells, and resulting in chronic inflammation and diseased skin.

Urea-induced ROS cause endothelial dysfunction in chronic renal failure.

PubMed

D'Apolito, Maria; Du, Xueliang; Pisanelli, Daniela; Pettoello-Mantovani, Massimo; Campanozzi, Angelo; Giacco, Ferdinando; Maffione, Angela Bruna; Colia, Anna Laura; Brownlee, Michael; Giardino, Ida

2015-04-01

The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20mM urea for 48 h. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Hypertension caused by prenatal testosterone excess in female sheep.

PubMed

King, Andrew J; Olivier, N Bari; Mohankumar, P S; Lee, James S; Padmanabhan, Vasantha; Fink, Gregory D

2007-06-01

Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects approximately 10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multifaceted and includes reproductive abnormalities and components of the metabolic syndrome such as insulin resistance, obesity, dyslipidemia, and hypertension. Exposure to excess testosterone (T) during the prenatal period may predispose individuals to PCOS phenotype. The goal of this study was to determine whether hypertension and dyslipidemia occur in a well-characterized model of PCOS produced by prenatal treatment of sheep with T. Radiotelemetry was used to measure blood pressure over a 24-h period in conscious, undisturbed animals. To normalize circulating estradiol levels across treatment, control (n = 4) and prenatal T-treated (100 mg T propionate im twice weekly from days 30 to 90 of fetal life, n = 4) 2-yr-old females were ovariectomized, instrumented with a radiotelemetry transmitter, and clamped with early follicular phase levels of estrogen using an implant. Six days later, a 24-h recording period commenced. Prenatal T-treated sheep were hypertensive compared with control sheep, and heart rate tended to be higher. T-treated sheep had hyperglycemia, insulin resistance, hypernatremia, and hyperchloremia, and both total and LDL cholesterol tended to be higher. Plasma aldosterone and epinephrine were significantly lower in T-treated sheep, whereas norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild hypertension, a risk factor reported in some women with PCOS, is also a feature of the sheep model of PCOS produced by prenatal T treatment.

Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia.

PubMed

Storzer, Lena; Butz, Markus; Hirschmann, Jan; Abbasi, Omid; Gratkowski, Maciej; Saupe, Dietmar; Vesper, Jan; Dalal, Sarang S; Schnitzler, Alfons

2017-10-01

Freezing of gait is a poorly understood symptom of Parkinson disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing, suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia. We present the first local field potential recordings directly comparing bicycling and walking in Parkinson disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22Hz) and high (23-35Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson disease patients (57.5 ± 5.9 years old, 4 female). The study group consisted of 5 patients with and 8 patients without freezing of gait. In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13-35Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement-induced, narrowband power increase around 18Hz, which was evident even in the absence of freezing. These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ∼18Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. Ann Neurol 2017;82:592-601. © 2017 American Neurological Association.

Brain glutamate in anorexia nervosa: a magnetic resonance spectroscopy case control study at 7 Tesla.

PubMed

Godlewska, Beata R; Pike, Alexandra; Sharpley, Ann L; Ayton, Agnes; Park, Rebecca J; Cowen, Philip J; Emir, Uzay E

2017-02-01

Anorexia nervosa (AN) is a serious psychiatric disorder with high morbidity and mortality. There are no established pharmacological treatments and the neurobiology of the condition is poorly understood. Previous studies using magnetic resonance spectroscopy (MRS) have shown that AN may be associated with reductions in indices of brain glutamate; however, at conventional field strengths (≤3 T), it is difficult to separate glutamate from its precursor and metabolite, glutamine. The objective of the present study was to use high field (7 T) MRS to measure concentrations of glutamate, in three separate brain voxels, in women with AN. We studied 13 female participants with AN and 12 healthy female controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen. Neurometabolites were calculated using the unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid concentration in the voxel. We found that participants with AN had significantly lower concentrations of glutamate in all three voxels (mean reduction 8%, p = 0.002) but glutamine levels were not altered. Concentrations of N-acetylaspartate, creatine, GABA and glutathione were also unchanged. However, inositol was lower in AN participants in anterior cingulate (p = 0.022) and occipital cortex (p = 0.002). Women with AN apparently have widespread reductions in brain glutamate. Further work will be needed to assess if this change has pathophysiological relevance or whether it is a consequence of the many physical changes produced in AN by food restriction.

Exogenous melatonin in periodic limb movement disorder: an open clinical trial and a hypothesis.

PubMed

Kunz, D; Bes, F

2001-03-15

The etiology of Periodic Limb Movement Disorder (PLMD) as well as the precise role of melatonin in human physiology remains poorly understood. Inspired by a single case observation we performed the presented study in order to obtain first evidence for the hypothesis that exogenous melatonin would decrease PLM's and thereby improves symptoms of PLMD patients. N/A. N/A. Nine patients with first time diagnosis of PLMD without RLS were treated over a six-week period with 3 mg melatonin, taken between 10 and 11 p.m. N/A. Melatonin improved well-being in 7 of the 9 patients. Polysomnography, performed prior and at the end of melatonin treatment, demonstrated a significant reduction of investigated movement parameters, such as PLMs, PLM index, PLMs with arousals and PLM-arousal index. Actigraphy, measured over 14 nights prior and during the last 14 days of melatonin treatment, showed a significant reduction in movement rate and minutes with movements during Time in Bed. The temporal distribution of PLMs, as well as the coupling of PLMs with the phase position of circadian temperature curve, suggest an involvement of the circadian timing system in the pathophysiology of PLMD. Locomotor activity in animals clearly exhibits a circadian pattern and can be strongly influenced by exogenous melatonin. Results suggest a chronobiotic effect of exogenous melatonin in PLMD. More specifically, we hypothesize that the mode of action of melatonin in the presented PLMD patients might have been an increase of output-amplitude of the circadian timing system, thereby enhancing the circadian rhythmicity of locomotor activity with a reduction of sleep motor activity.

Apathy is related to cortex morphology in CADASIL. A sulcal-based morphometry study.

PubMed

Jouvent, E; Reyes, S; Mangin, J-F; Roca, P; Perrot, M; Thyreau, B; Hervé, D; Dichgans, M; Chabriat, H

2011-04-26

Apathy is a debilitating symptom in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the pathophysiology of which remains poorly understood. The aim of this study was to evaluate the neuroanatomic correlates of apathy, using new MRI postprocessing methods based on the identification of cortical sulci, in a large cohort of patients with CADASIL. A total of 132 patients with genetically confirmed diagnosis were included in this prospective cohort study. Global cognitive performances were assessed by the Mattis Dementia Rating Scale (MDRS) and disability by the modified Rankin score (mRS). Apathy was defined according to standard criteria. Depth, width, and cortical thickness of 10 large sulci of the frontal lobe in each hemisphere were measured. Logistic regression modeling was used to evaluate the links between apathy and cortical thickness, depth, or width of the different sulci. All models were adjusted for age, gender, level of education, MDRS, mRS, depression, and global brain volume. Complete MRI datasets of high quality were available in 119 patients. Depth of the posterior cingulate sulcus exhibited the strongest association with apathy in fully adjusted models (right: p value = 0.0006; left: p value = 0.004). Depth and width of cortical sulci in mediofrontal and orbitofrontal areas were independently associated with apathy. By contrast, cortical thickness was not. Cortical morphology in mediofrontal and orbitofrontal areas, by contrast to cortical thickness, is strongly and independently associated with apathy. These results suggest that apathy is related to a reduction of cortical surface rather than of cortical thickness secondary to lesion accumulation in CADASIL.