[EBOLA HEMORRHAGIC FEVER: DIAGNOSTICS, ETIOTROPIC AND PATHOGENETIC THERAPY, PREVENTION].

PubMed

Zhdanov, K V; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fisun, A Ya

2015-01-01

The data on diagnostics, etiotropic and pathogenetic therapy, prevention of Ebola hemorrhagic fever are presented including diagnostic algorithms for different clinical situations. Fundamentals of pathogenetic therapy are described. Various groups of medications used for antiviral therapy of conditions caused by Ebola virus are characterized. Experimental drugs at different stages of clinical studies are considered along with candidate vaccines being developed for the prevention of the disease.

[Correction of indigestion in chronic biliary pancreatitis].

PubMed

Trukhan, D I; Tarasova, L V

2013-01-01

Chronic pancreatitis (CP) is one of the most urgent and investigated problems in gastroenterology. Despite the variety of the spectrum of etiologic, pathogenetic and provoking factors for CP, one of the leading causes of disease pathology is pathology of biliary tract. A key element in the treatment of CP is a correction of the digestive system, with biliary pancreatitis feature that distinguishes it from other forms of pancreatitis, is a combination of exocrine pancreatic insufficiency with chronic biliary insufficiency. The variety of biochemical and immunological effects of ursodeoxycholic acid (UDCA) can treat it with biliary pancreatitis as the drug of etiological, pathogenetic and substitution therapy. UDCA (Ursosan) in combination with modern mini-microspheroidal polyfermental drugs significantly improves the clinical efficacy of the correction of the digestive system in biliary pancreatitis.

Aging and pathogenesis of erectile dysfunction.

PubMed

Corona, G; Mannucci, E; Mansani, R; Petrone, L; Bartolini, M; Giommi, R; Mancini, M; Forti, G; Maggi, M

2004-10-01

The prevalence and the severity of erectile dysfunction (ED) increase with advancing age; different pathogenetic factors could contribute to age-related ED. We studied organic, relational and intrapsychic components of ED as a function of patients' age in a consecutive series of 977 patients with ED, using the specifically designed structured interview SIEDY. A complete physical examination and a series of biochemical, hormonal, psychometric and penile vascular tests were also performed. Relational factors seems to be more relevant in patients aged over 60 y, while intrapsychic disturbances play a major role in younger subjects. Organic factors are the most important determinant of ED in all age groups, but their contribution is more important in older patients. In fact, basal and dynamic peak cavernosal velocity at Doppler ultrasound penile examination was reduced in older patients. Among hormonal factors, the body mass index-dependent reduction of testosterone in older patients does not seem to play a crucial role in the pathogenesis of ED. No significant correlation was observed between testosterone level and the severity of ED, although patients reporting hypoactive sexual desire showed significantly lower testosterone levels when compared with the rest of the sample. A better understanding of the relative contribution of age-related pathogenetic factors of ED could be of help in the design of appropriate therapeutic approaches.

Treatment of painful diabetic neuropathy

PubMed Central

Petropoulos, Ioannis N.; Alam, Uazman; Malik, Rayaz A.

2015-01-01

Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. PMID:25553239

Phenomenology and neurobiology of self disorder in schizophrenia: Secondary factors.

PubMed

Sass, Louis A; Borda, Juan P

2015-12-01

Schizophrenia is a diverse and varying syndrome that defies most attempts at classification and pathogenetic explanation. This is the second of two articles offering a comprehensive model meant to integrate an understanding of schizophrenia-related forms of subjectivity, especially anomalous core-self experience (disturbed ipseity), with neurocognitive and neurodevelopmental findings. Previously we discussed the primary or foundational role of disturbed intermodal perceptional integration ("perceptual dys-integration"). Here we discuss phenomenological alterations that can be considered secondary in a pathogenetic sense--whether as consequential products downstream from a more originary disruption, or as defensive reactions involving quasi-intentional or even volitional compensations to the more primary disruptions. These include secondary forms of: 1, hyperreflexivity, 2, diminished self-presence (self-affection), and 3. disturbed "rip" or "hold" on the cognitive/perceptual field of awareness. We consider complementary relations between these secondary abnormal experiences while also considering their temporal relationships and pathogenetic intertwining with the more primary phenomenological alterations discussed previously, all in relation to the neurodevelopmental model. The secondary phenomena can be understood as highly variable factors involving overall orientations or attitudes toward experience; they have some affinities with experiences of meditation, introspectionism, and depersonalization defense. Also, they seem likely to become more pronounced during adolescence as a result of new cognitive capacities related to development of the prefrontal lobes, especially attention allocation, executive functions, abstraction, and meta-awareness. Heterogeneity in these secondary alterations might help explain much of the clinical diversity in schizophrenia, both between patients and within individual patients over time--without however losing sight of key underlying commonalities. Copyright © 2015 Elsevier B.V. All rights reserved.

Primary biliary cirrhosis: From bench to bedside

PubMed Central

Kouroumalis, Elias; Notas, George

2015-01-01

Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient’s genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. PMID:26261733

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome.

PubMed

Araya, Carlos E; Wasserfall, Clive H; Brusko, Todd M; Mu, Wei; Segal, Mark S; Johnson, Richard J; Garin, Eduardo H

2006-05-01

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.

Refining psychiatric genetics: from ‘mouse psychiatry’ to understanding complex human disorders

PubMed Central

LaPorte, Justin L.; Ren-Patterson, Renee F.; Murphy, Dennis L.; Kalueff, Allan V.

2009-01-01

Investigating the pathogenesis of psychiatric disorders is a complicated and rigorous task for psychiatric geneticists, as the disorders often involve combinations of genetic, behavioral, personality, and environmental factors. To nurture further progress in this field, a new set of conceptual tools is needed in addition to the currently accepted approaches. Concepts that consider cross-species trait genetics and the interplay between the domains of disorders, as well as the full spectrum of potential symptoms and their place along the pathogenetic continuum, are particularly important to address these needs. Here, we outline recent concepts and approaches that can help refine the field and enable more precise dissection of the genetic mechanisms contributing to psychiatric disorders. PMID:18690099

Gastro-esophageal reflux disease and obesity, where is the link?

PubMed

Emerenziani, Sara; Rescio, Maria Paola; Guarino, Michele Pier Luca; Cicala, Michele

2013-10-21

The confluence between the increased prevalence of gastro-esophageal reflux disease (GERD) and of obesity has generated great interest in the association between these two conditions. Several studies have addressed the potential relationship between GERD and obesity, but the exact mechanism by which obesity causes reflux disease still remains to be clearly defined. A commonly suggested pathogenetic pathway is the increased abdominal pressure which relaxes the lower esophageal sphincter, thus exposing the esophageal mucosal to gastric content. Apart from the mechanical pressure, visceral fat is metabolically active and it has been strongly associated with serum levels of adipo-cytokines including interleukin-6 and tumor necrosis factor α, which may play a role in GERD or consequent carcinogenesis. This summary is aimed to explore the potential mechanisms responsible for the association between GERD and obesity, and to better understand the possible role of weight loss as a therapeutic approach for GERD.

Gene-environment interactions in the aetiology of systemic lupus erythematosus.

PubMed

Jönsen, Andreas; Bengtsson, Anders A; Nived, Ola; Truedsson, Lennart; Sturfelt, Gunnar

2007-12-01

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutation S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.

Pathogenetic Importance and Therapeutic Implications of NF-κB in Lymphoid Malignancies

PubMed Central

Lim, Kian-Huat; Yang, Yibin; Staudt, Louis M.

2014-01-01

Summary Derangement of the nuclear factor κB (NF-κB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-κB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be ‘addicted’ to NF-κB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-κB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-κB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies. PMID:22435566

Jervell and Lange-Nielsen Syndrome (Long QT Syndrome).

ERIC Educational Resources Information Center

Hulbert, T. P.

1994-01-01

Clinical features, pathogenetic hypotheses, and symptoms of the cardio-auditory or surdo-cardiac disorder first reported by Jervell and Lange-Nielsen are described, and methods of diagnosis and treatment are presented, to alert teachers and other professionals to potentially life-threatening symptoms they may observe when working with deaf and…

Altered Immune Regulation in Type 1 Diabetes

PubMed Central

Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

2013-01-01

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

Sleep Related Breathing Disorders in Adults with Down Syndrome.

ERIC Educational Resources Information Center

Resta, Onofrio; Barbaro, Maria Pia Foschino; Giliberti, Tiziana; Caratozzolo, Gennaro; Cagnazzo, Maria Grazia; Scarpelli, Franco; Nocerino, Maria Cristina

2003-01-01

This study evaluated sleep-related breathing disorders in six adults with Down syndrome. Five were found to have respiratory events justifying the diagnosis of sleep apnea syndrome. Results suggest that the nocturnal respiratory pattern of adults with Down syndrome depends on several pathogenetic factors such as age, severity of upper airway…

Induced pluripotent stem cells in hematology: current and future applications

PubMed Central

Focosi, D; Amabile, G; Di Ruscio, A; Quaranta, P; Tenen, D G; Pistello, M

2014-01-01

Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation. PMID:24813079

Pathogenesis diagnosis and management of paraneoplastic glomerulonephritis

PubMed Central

Lien, Yeong-Hau H.; Lai, Li-Wen

2011-01-01

Paraneoplastic glomerulonephritis is a rare complication of malignancy that is frequently mistaken for idiopathic glomerulonephritis. Failure to recognize paraneoplastic glomerulonephritis can subject patients to ineffective and potentially harmful therapy. Pathology of paraneoplastic glomerulonephritis varies between different types of malignancies. This Review describes the association of glomerulonephritis with both solid tumors and hematological malignancies The pathogenetic mechanisms of many glomerular lesions seem to relate to altered immune responses in the presence of a malignancy Studies in the Buffalo/Mna rat model of spontaneous thymoma and nephrotic syndrome indicate that polarization of the immune response toward a T-helper-2 (TH2) profile has an important role in the development of thymoma-associated glomerular lesions. Furthermore, overexpression of the TH2 cytokine interleukin 13 in transgenic rats induces minimal change disease. Such findings from experimental studies might facilitate the identification of biomarkers that can distinguish paraneoplastic glomerulonephritis from idiopathic and other secondary glomerulonephritides. This Review describes potential pathogenetic mechanisms for paraneoplastic glomerulonephritides associated with different malignancies and highlights the need for a multidisciplinary approach to the management of patients with paraneoplastic glomerulonephritis. PMID:21151207

A systems biology-led insight into the role of the proteome in neurodegenerative diseases.

PubMed

Fasano, Mauro; Monti, Chiara; Alberio, Tiziana

2016-09-01

Multifactorial disorders are the result of nonlinear interactions of several factors; therefore, a reductionist approach does not appear to be appropriate. Proteomics is a global approach that can be efficiently used to investigate pathogenetic mechanisms of neurodegenerative diseases. Here, we report a general introduction about the systems biology approach and mechanistic insights recently obtained by over-representation analysis of proteomics data of cellular and animal models of Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders, as well as of affected human tissues. Expert commentary: As an inductive method, proteomics is based on unbiased observations that further require validation of generated hypotheses. Pathway databases and over-representation analysis tools allow researchers to assign an expectation value to pathogenetic mechanisms linked to neurodegenerative diseases. The systems biology approach based on omics data may be the key to unravel the complex mechanisms underlying neurodegeneration.

Skin cancer risk in autoimmune connective tissue diseases.

PubMed

Kostaki, D; Antonini, A; Peris, K; Fargnoli, M C

2014-10-01

Cutaneous malignancies have been significantly associated with autoimmune connective tissue diseases (ACTDs). This review focuses on the current state of knowledge on skin cancer risk in the most prevalent ACTDs in dermatology including lupus erythematosus, scleroderma, dermatomyositis and Sjögren syndrome. Potential pathogenetic mechanisms for the association between ACTDs and malignancy involve disease-related impairment of immune system, sustained cutaneous inflammation, drug-associated immune suppression and increased susceptibility to acquired viral infections. An additional causal role might be played by environmental factors such as UV exposure and smoking. The occurrence of skin cancer can have a profound impact on the already compromised quality of life of ACTD patients. Therefore, effective screening and monitoring strategies are essential for ACTD patients as early detection and prompt therapeutic intervention can reduce morbidity and mortality in these patients.

Clustering of metabolic and cardiovascular risk factors in the polycystic ovary syndrome: a principal component analysis.

PubMed

Stuckey, Bronwyn G A; Opie, Nicole; Cussons, Andrea J; Watts, Gerald F; Burke, Valerie

2014-08-01

Polycystic ovary syndrome (PCOS) is a prevalent condition with heterogeneity of clinical features and cardiovascular risk factors that implies multiple aetiological factors and possible outcomes. To reduce a set of correlated variables to a smaller number of uncorrelated and interpretable factors that may delineate subgroups within PCOS or suggest pathogenetic mechanisms. We used principal component analysis (PCA) to examine the endocrine and cardiometabolic variables associated with PCOS defined by the National Institutes of Health (NIH) criteria. Data were retrieved from the database of a single clinical endocrinologist. We included women with PCOS (N = 378) who were not taking the oral contraceptive pill or other sex hormones, lipid lowering medication, metformin or other medication that could influence the variables of interest. PCA was performed retaining those factors with eigenvalues of at least 1.0. Varimax rotation was used to produce interpretable factors. We identified three principal components. In component 1, the dominant variables were homeostatic model assessment (HOMA) index, body mass index (BMI), high density lipoprotein (HDL) cholesterol and sex hormone binding globulin (SHBG); in component 2, systolic blood pressure, low density lipoprotein (LDL) cholesterol and triglycerides; in component 3, total testosterone and LH/FSH ratio. These components explained 37%, 13% and 11% of the variance in the PCOS cohort respectively. Multiple correlated variables from patients with PCOS can be reduced to three uncorrelated components characterised by insulin resistance, dyslipidaemia/hypertension or hyperandrogenaemia. Clustering of risk factors is consistent with different pathogenetic pathways within PCOS and/or differing cardiometabolic outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

[Clinical-pathogenetic features of meningococcal infection in children].

PubMed

Buriak, V N; Serhyenko, A S

2011-01-01

Analysis features of clinical manifestation and pathogenetic mechanisms of development of meningococcal infection is introduced. It is emphasized that in most cases mentioned infection is characterized by mild course as nasopharyngitidis. However relatively seldom developing generalize form put this phatology on third place after intestinal infections and septicemia in structure of child mortality from infection deseases. Occurence of generalize forms of meningococcal infection depend on peculiarity of immune response is followed by release of endotoxin and exotoxin in blood stream. This toxins start up pathogenetic mechanisms, which lead to toxic shock, adrenal glands hemorrhage, brain edema, brain stem wedge in big occipital foramen.

Decreased osteoprotegerin and increased bone turnover in young female patients with major depressive disorder and a lifetime history of anorexia nervosa.

PubMed

Kahl, Kai G; Rudolf, Sebastian; Dibbelt, Leif; Stoeckelhuber, Beate M; Gehl, Hans-Björn; Hohagen, Fritz; Schweiger, Ulrich

2005-04-01

Low bone mineral density (BMD) is a frequent, often persistent complication in patients with major depressive disorder (MDD) and anorexia nervosa (AN) that increases the risk of pathologic fractures. The pathogenetic process underlying osteopenia in MDD and AN is still unclear, although several factors, including a dysbalance of cytokines, are associated with loss of bone mass. Alterations in the serum levels of cytokines have been observed in patients with MDD, AN, and other psychiatric disorders. Therefore, we examined serum levels of cytokines, markers of bone turnover, and BMD in 13 patients with MDD and a lifetime history of AN. Bone turnover markers (osteocalcin and C-terminal degradation products of type I collagen) and tumor necrosis factor alpha (TNF-alpha) in patients were significantly increased compared with those of the control group. Osteoprotegerin (OPG) in patients was significantly decreased. Eight of 13 patients (62%) displayed osteopenia at the lumbar spine. TNF-alpha correlated significantly with C-terminal degradation products of type I collagen, an osteoclastic marker, but significantly negatively with OPG. Our data suggest that TNF-alpha and OPG may play a role in the pathogenetic process underlying osteopenia in these patients.

MicroRNA and receptor mediated signaling pathways as potential therapeutic targets in heart failure.

PubMed

Tuttolomondo, Antonino; Simonetta, Irene; Pinto, Antonio

2016-11-01

Cardiac remodelling is a complex pathogenetic pathway involving genome expression, molecular, cellular, and interstitial changes that cause changes in size, shape and function of the heart after cardiac injury. Areas covered: We will review recent advances in understanding the role of several receptor-mediated signaling pathways and micro-RNAs, in addition to their potential as candidate target pathways in the pathogenesis of heart failure. The myocyte is the main target cell involved in the remodelling process via ischemia, cell necrosis and apoptosis (by means of various receptor pathways), and other mechanisms mediated by micro-RNAs. We will analyze the role of some receptor mediated signaling pathways such as natriuretic peptides, mediators of glycogen synthase kinase 3 and ERK1/2 pathways, beta-adrenergic receptor subtypes and relaxin receptor signaling mechanisms, TNF/TNF receptor family and TWEAK/Fn14 axis, and some micro-RNAs as candidate target pathways in pathogenesis of heart failure. These mediators of receptor-mediated pathways and micro-RNA are the most addressed targets of emerging therapies in modern heart failure treatment strategies. Expert opinion: Future treatment strategies should address mediators involved in multiple steps within heart failure pathogenetic pathways.

IL-9 exhibits elevated expression in osteonecrosis of femoral head patients and promotes cartilage degradation through activation of JAK-STAT signaling in vitro.

PubMed

Geng, Wei; Zhang, Wen; Ma, Jinzhu

2018-05-15

Osteonecrosis of the femoral head (ONFH) often causes severe symptoms in young people and limits the mobility of the hip joint. Interleukin-9 (IL-9) is a multi-functional inflammatory factor that participates in lumbar disk herniation and arthritis and has been reported in many studies. However, the correlation between IL-9 and ONFH is unclear. The present study aimed to determine the role of IL-9 in the pathogenetic mechanism of osteonecrosis. To assess IL-9 expression in ONFH and femoral neck fracture patients, cartilage tissue was examined through western blot analysis and immunohistochemistry. Human primary chondrocytes were stimulated with IL-9, and inflammation-related cytokines and cartilage matrix-degrading enzymes were assessed via real-time PCR. After being treated with IL-9, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling were tested through western blot analysis. Our results showed a significant increase in the expression of IL-9 in ONFH patients. IL-9 raised the level of inflammation-related cytokines and cartilage matrix-degrading enzymes and enhanced the activation of JAK-STAT signaling. Furthermore, blocking the JAK-STAT signaling pathway reduced the secretion of inflammation-related cytokines and cartilage matrix-degrading enzymes and markedly alleviated the degradation of the cartilage matrix. These findings provide new insights into the role that IL-9 plays in the pathogenetic mechanism of osteonecrosis and also provide a potential treatment for ONFH. Copyright © 2018 Elsevier B.V. All rights reserved.

[NEWS IN ETIOLOGY AND PATHOGENESIS OF IRRITATED BOWEL SYNDROME].

PubMed

Sheptulin, A A; Vize-Khripunova, M A

2016-01-01

The concept of irritated bowel syndrome as a complex of functional disorders that can not be explained by organic changes and are totally due to intestinal motility and visceral sensitivity needs revision. The development of this syndrome also depends on a number of pathogenetic and etiological factors, such as inflammation of intestinal mucosa, changes of its permeability, previous infection, altered microflora, gene polymorphism, and food hypersensitivity.

[Osteoporosis: Current state of the art].

PubMed

Verbovoy, A F; Pashentseva, A V; Sharonova, L A

As of now, osteoporosis (OP) is one of the most important sociomedical problems because of its high prevalence and resultant disability, as well as significant mortality attributable to complications. The current strategy for providing care for patients of OP is its early diagnosis, by determining the high risk of fractures, and early pathogenetic treatment. The article gives an update on the epidemiology, risk factors, diagnosis, and treatment of OP.

Post-traumatic costochondritis caused by Candida albicans. Aetiology, diagnosis and treatment.

PubMed

Heckenkamp, J; Helling, H J; Rehm, K E

1997-01-01

Candida costochondritis is a rare disease of complex aetiology. Pathogenetic factors range from postoperative and posttraumatic complications to haematogenous dissemination in intravenous drug addicts. In addition to clinical examination, possible diagnostic procedures include scintiscan and magnetic resonance imaging. The treatment of choice is extensive debridement and resection of the structures affected by the inflammatory process. The long-term prognosis is good.

Naive CD8 T-Cells Initiate Spontaneous Autoimmunity to a Sequestered Model Antigen of the Central Nervous System

ERIC Educational Resources Information Center

Na, Shin-Young; Cao, Yi; Toben, Catherine; Nitschke, Lars; Stadelmann, Christine; Gold, Ralf; Schimpl, Anneliese; Hunig, Thomas

2008-01-01

In multiple sclerosis, CD8 T-cells are thought play a key pathogenetic role, but mechanistic evidence from rodent models is limited. Here, we have tested the encephalitogenic potential of CD8 T-cells specific for the model antigen ovalbumin (OVA) sequestered in oligodendrocytes as a cytosolic molecule. We show that in these "ODC-OVA" mice, the…

[Pathophysiology of hypertension in chronic kidney disease].

PubMed

Sawicka, Magdalena; Jędras, Mirosław

2014-01-01

Hypertension is both an important cause and consequence of chronic kidney disease (CKD). It is present in 80-85% of the patients. The article summarizes the main pathogenetic factors of hypertension in CKD such as: sodium retention, increased activity the renin-angiotensin-aldosterone system and sympathetic nervous system, impaired nitric oxide synthesis and endothelium-mediated vasodilatation, oxidative stress, disorders of calcium metabolism and parathyroid hormone secretion, vascular calcification and increased arterial stiffness.

Ossification of the posterior longitudinal ligament of the cervical spine: etiology and natural history.

PubMed

Matsunaga, Shunji; Sakou, Takashi

2012-03-01

Review article. To review the etiology, natural history, measurement tools, and image diagnosis of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. OPLL is a well-known disease that causes myelopathy. Genetic factors are very important for development of OPLL. However, the pathogenetic gene and natural history of OPLL have not been clarified. The authors reviewed studies about the etiology, natural history, measurement tools, and diagnosis of OPLL, which had been performed by the members of the Investigation Committee on the Ossification of the Spinal Ligaments of the Japanese Ministry of Health, Labour, and Welfare. The prevalence of OPLL in the general Japanese population was reported to be 1.9% to 4.3% among people older than 30 years. Genetic factors are important for development of OPLL, and some candidate genes have been reported. Clinical course of OPLL has been clarified by a prospective long-term follow-up study. Some radiographic predictors for development of myelopathy were introduced. Image diagnosis of OPLL is easy by plain radiographs, but magnetic resonance imaging and computed tomography are useful to determine cord compression by OPLL. OPLL should be managed on the basis of the consideration of its natural history. Elucidation of pathogenetic genes of OPLL will introduce a new approach for management of OPLL.

[Antibacterial therapy of cholecystocholangitis in viral hepatitis].

PubMed

Andreĭchin, M A; Kiĭko, L G; Il'ina, N I

1984-04-01

The chemotherapy of cholecystocholangitis in patients with virus hepatitis was estimated. Antibiotics, furagin and pathogenetic drugs were used for the treatment. The antibiotics were chosen with regard to their sensitivity to the bile microflora. This resulted in sanation of the bile ducts. Furagin was less effective. The use of the pathogenetic drugs alone was ineffective in the majority of patients.

The pathogenesis of pediatric cerebral malaria: eye exams, autopsies and neuro-imaging

PubMed Central

Taylor, Terrie E.; Molyneux, Malcolm E.

2015-01-01

Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuro-imaging studies which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed. PMID:25708306

[Biotoxic effects of aqueous humour-a unifying pathogenetic theory, based on certain hypothetic biotoxic factors in aqueus (author's transl)].

PubMed

Worst, J G

1975-09-01

A hypothesis is proposed attributing a number of biotoxic effects to aqueous humor (ABC equals Aqueous Biotoxic Complex). Under normal anatomical and physiological conditions aqueous humour is contained in the anterior and posterior chamber reservoir and the ABC effects remain silent because the boundaries of the aqueous humour reservoir are resistant to these biotoxic factors. These factors are biochemically undefined but fall in the category of collagenolysins and anti-vascular enzymes (Prostaglandins?). Outside the normal reservoir these biotoxic effects result in a specific pathology such as corneal edema, subconjunctival edema, lens fiber edema, macular edema, papilledema and chorioidal edema.

Familial pyrophosphate arthropathy. Occurrence and Crystal Identification.

PubMed

Bjelle, A

1981-01-01

Hereditary pyrophosphate arthropathy has been observed in three Swedish families and in a few other caucasian populations. The inheritance is most probably autosomal dominant with a variable penetrance. The most severe cases have been found in homozygotes among isolates of immigrants in Slovakia and Chile. Studies on genetic and etio-pathogenetic factors in hereditary pyrophosphate arthropathy, and the utilization of new diagnostic techniques for crystal identification, are important approaches towards a further understanding of the disease.

Genetic risk variants as therapeutic targets for Crohn's disease.

PubMed

Gabbani, Tommaso; Deiana, Simona; Marocchi, Margherita; Annese, Vito

2017-04-01

The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.

Die Virus-induzierten Lebererkrankungen des Menschen

NASA Astrophysics Data System (ADS)

Eisenburg, J.

1982-12-01

Although many viral agents may be associated with inflammatory hepatic changes, the vast majority of clinically important viral hepatitis is caused by hepatitis A, hepatitis B and the non A, non B agents. Infection of the liver of man by these hepatotropic agents is still a major public health problem in all parts of the world and constitutes a major hazard of the transfusion of blood and plasma derivatives. The magnitude of this hepatitis problem is not only documented by the about 200 million carriers of the hepatitis-B virus throughout the world, many of them asymptomatic, but also by the fact, that hepatitis B and non A, non B may progress to chronic liver disease, including cirrhosis and probably primary liver cancer. Potentially important pathogenetic determinants include viral factors such as subtype, dosage and mode of transmission and host factors such as age, sex, preexisting liver disease, coexisting non-liver disease (diabetes etc.), genetics and immune response to viral or autoantigens. As the virus itself seems not directly cytopathic, the diversity of lesions has been attributed to variation in the capacity of the host's response.

Tumor necrosis factor-alpha antagonists: differential clinical effects by different biotechnological molecules.

PubMed

Licastro, F; Chiappelli, M; Ianni, M; Porcellini, E

2009-01-01

Inhibitors of tumor necrosis factor-alpha have deeply changed the therapy of several inflammatory human diseases. For instance, clinical management of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools, such as antagonist of TNF-alpha molecule. These drugs include etanercept, a soluble TNF-alpha receptor antagonist, three anti-TNF-alpha antibodies, adalimumab, infliximab, golimumab and certolizumab a humanized Fab fragment combined with polyethylene glycol. These compounds efficiently inhibit several TNF-alpha biological-mediated effects, however, they have also shown differential clinical efficacy in several trials from different autoimmune diseases. It is of clinical relevance that non-responders to one of these drugs often positively responded to another. Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects. However, partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses. Therefore, these apparently homogeneous agents can not be considered equivalent in their clinically efficacy. Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual TNF-alpha inhibitors.

[Dementia and small vessel diseases of the brain].

PubMed

Damulin, I V

2014-01-01

Clinical and pathogenetic characteristics of dementia caused by small vessel lesions are presented. It is emphasized that this variant of vascular dementia is the most frequent in clinical practice. Clinical examination, accurate assessment of the disease history and using of modern neuroimaging techniques are important for the diagnosis. The drugs that impact on risk factors, including disaggregants, and metabolic drugs (nicergoline) are widely used in the treatment of dementia. These drugs are highly effective and safe.

Prognostic and Pathogenetic Value of Combining Clinical and Biochemical Indices in Patients With Acute Lung Injury

PubMed Central

Koyama, Tatsuki; Billheimer, D. Dean; Wu, William; Bernard, Gordon R.; Thompson, B. Taylor; Brower, Roy G.; Standiford, Theodore J.; Martin, Thomas R.; Matthay, Michael A.

2010-01-01

Background: No single clinical or biologic marker reliably predicts clinical outcomes in acute lung injury (ALI)/ARDS. We hypothesized that a combination of biologic and clinical markers would be superior to either biomarkers or clinical factors alone in predicting ALI/ARDS mortality and would provide insight into the pathogenesis of clinical ALI/ARDS. Methods: Eight biologic markers that reflect endothelial and epithelial injury, inflammation, and coagulation (von Willebrand factor antigen, surfactant protein D [SP-D]), tumor necrosis factor receptor-1, interleukin [IL]-6, IL-8, intercellular adhesion molecule-1, protein C, plasminogen activator inhibitor-1) were measured in baseline plasma from 549 patients in the ARDSNet trial of low vs high positive end-expiratory pressure. Mortality was modeled with multivariable logistic regression. Predictors were selected using backward elimination. Comparisons between candidate models were based on the receiver operating characteristics (ROC) and tests of integrated discrimination improvement. Results: Clinical predictors (Acute Physiology And Chronic Health Evaluation III [APACHE III], organ failures, age, underlying cause, alveolar-arterial oxygen gradient, plateau pressure) predicted mortality with an area under the ROC curve (AUC) of 0.82; a combination of eight biomarkers and the clinical predictors had an AUC of 0.85. The best performing biomarkers were the neutrophil chemotactic factor, IL-8, and SP-D, a product of alveolar type 2 cells, supporting the concept that acute inflammation and alveolar epithelial injury are important pathogenetic pathways in human ALI/ARDS. Conclusions: A combination of biomarkers and clinical predictors is superior to clinical predictors or biomarkers alone for predicting mortality in ALI/ARDS and may be useful for stratifying patients in clinical trials. From a pathogenesis perspective, the degree of acute inflammation and alveolar epithelial injury are highly associated with the outcome of human ALI/ARDS. PMID:19858233

Smoking Cessation Induces Profound Changes in the Composition of the Intestinal Microbiota in Humans

PubMed Central

Biedermann, Luc; Zeitz, Jonas; Mwinyi, Jessica; Sutter-Minder, Eveline; Rehman, Ateequr; Ott, Stephan J.; Steurer-Stey, Claudia; Frei, Anja; Frei, Pascal; Scharl, Michael; Loessner, Martin J.; Vavricka, Stephan R.; Fried, Michael; Schreiber, Stefan; Schuppler, Markus; Rogler, Gerhard

2013-01-01

Background The human intestinal microbiota is a crucial factor in the pathogenesis of various diseases, such as metabolic syndrome or inflammatory bowel disease (IBD). Yet, knowledge about the role of environmental factors such as smoking (which is known to influence theses aforementioned disease states) on the complex microbial composition is sparse. We aimed to investigate the role of smoking cessation on intestinal microbial composition in 10 healthy smoking subjects undergoing controlled smoking cessation. Methods During the observational period of 9 weeks repetitive stool samples were collected. Based on abundance of 16S rRNA genes bacterial composition was analysed and compared to 10 control subjects (5 continuing smokers and 5 non-smokers) by means of Terminal Restriction Fragment Length Polymorphism analysis and high-throughput sequencing. Results Profound shifts in the microbial composition after smoking cessation were observed with an increase of Firmicutes and Actinobacteria and a lower proportion of Bacteroidetes and Proteobacteria on the phylum level. In addition, after smoking cessation there was an increase in microbial diversity. Conclusions These results indicate that smoking is an environmental factor modulating the composition of human gut microbiota. The observed changes after smoking cessation revealed to be similar to the previously reported differences in obese compared to lean humans and mice respectively, suggesting a potential pathogenetic link between weight gain and smoking cessation. In addition they give rise to a potential association of smoking status and the course of IBD. PMID:23516617

Detrimental role of humoral signalling in cardio-renal cross-talk.

PubMed

Cantaluppi, Vincenzo; Dellepiane, Sergio; Quercia, Alessandro D; Ferrario, Silvia

2014-01-22

In critically ill patients, any acute organ injury is associated with a sudden change of circulating factors that may play a role in distant organ dysfunction through a complex cross-talk. In this issue, Virzì and colleagues discuss the relevance of humoral signalling between heart and kidney, focusing on type 1 and type 3 cardio-renal syndrome. We herein review the mechanisms of heart-kidney cross-talk, discussing the role of circulating detrimental mediators in the pathogenetic mechanisms of cardio-renal syndrome.

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells.

PubMed

Smura, Teemu; Natri, Olli; Ylipaasto, Petri; Hellman, Marika; Al-Hello, Haider; Piemonti, Lorenzo; Roivainen, Merja

2015-12-02

Enterovirus infections have been suspected to be involved in the development of type 1 diabetes. However, the pathogenetic mechanism of enterovirus-induced type 1 diabetes is not known. Pancreatic ductal cells are closely associated with pancreatic islets. Therefore, enterovirus infections in ductal cells may also affect beta-cells and be involved in the induction of type 1 diabetes. The aim of this study was to assess the ability of different enterovirus strains to infect, replicate and produce cytopathic effect in human pancreatic ductal cells. Furthermore, the viral factors that affect these capabilities were studied. The pancreatic ductal cells were highly susceptible to enterovirus infections. Both viral growth and cytolysis were detected for several enterovirus serotypes. However, the viral growth and capability to induce cytopathic effect (cpe) did not correlate completely. Some of the virus strains replicated in ductal cells without apparent cpe. Furthermore, there were strain-specific differences in the growth kinetics and the ability to cause cpe within some serotypes. Viral adaptation experiments were carried out to study the potential genetic determinants behind these phenotypic differences. The blind-passage of non-lytic CV-B6-Schmitt strain in HPDE-cells resulted in lytic phenotype and increased progeny production. This was associated with the substitution of a single amino acid (K257E) in the virus capsid protein VP1 and the viral ability to use decay accelerating factor (DAF) as a receptor. This study demonstrates considerable plasticity in the cell tropism, receptor usage and cytolytic properties of enteroviruses and underlines the strong effect of single or few amino acid substitutions in cell tropism and lytic capabilities of a given enterovirus. Since ductal cells are anatomically close to pancreatic islets, the capability of enteroviruses to infect and destroy pancreatic ductal cells may also implicate in respect to enterovirus induced type 1 diabetes. In addition, the capability for rapid adaptation to different cell types suggests that, on occasion, enterovirus strains with different pathogenetic properties may arise from less pathogenic ancestors. Copyright © 2015 Elsevier B.V. All rights reserved.

EBV Chronic Infections

PubMed Central

Eligio, Pizzigallo; Delia, Racciatti; Valeria, Gorgoretti

2010-01-01

The infection from Epstein-Barr virus (EBV) or virus of infectious mononucleosis, together with other herpes viruses’ infections, represents a prototype of persistent viral infections characterized by the property of the latency. Although the reactivations of the latent infection are associated with the resumption of the viral replication and eventually with the “shedding”, it is still not clear if this virus can determine chronic infectious diseases, more or less evolutive. These diseases could include some pathological conditions actually defined as “idiopathic”and characterized by the “viral persistence” as the more credible pathogenetic factor. Among the so-called idiopathic syndromes, the “chronic fatigue syndrome” (CFS) aroused a great interest around the eighties of the last century when, just for its relationship with EBV, it was called “chronic mononucleosis” or “chronic EBV infection”. Today CFS, as defined in 1994 by the CDC of Atlanta (USA), really represents a multifactorial syndrome characterized by a chronic course, where reactivation and remission phases alternate, and by a good prognosis. The etiopathogenetic role of EBV is demonstrated only in a well-examined subgroup of patients, while in most of the remaining cases this role should be played by other infectious agents - able to remain in a latent or persistent way in the host – or even by not infectious agents (toxic, neuroendocrine, methabolic, etc.). However, the pathogenetic substrate of the different etiologic forms seems to be the same, much probably represented by the oxidative damage due to the release of pro-inflammatory cytokines as a response to the triggering event (infectious or not infectious). Anyway, recently the scientists turned their’s attention to the genetic predisposition of the subjects affected by the syndrome, so that in the last years the genetic studies, together with those of molecular biology, received a great impulse. Thanks to both these studies it was possibile to confirm the etiologic links between the syndrome and EBV or other herpesviruses or other persistent infectious agents. The mechanisms of EBV latency have been carefully examined both because they represent the virus strategy to elude the response of the immune system of the host, and because they are correlated with those oncologic conditions associated to the viral persistence, particularly lymphomas and lymphoproliferative disorders. Just these malignancies, for which a pathogenetic role of EBV is clearly documented, should represent the main clinical expression of a first group of chronic EBV infections characterized by a natural history where the neoplastic event aroused from the viral persistence in the resting B cells for all the life, from the genetic predisposition of the host and from the oncogenic potentialities of the virus that chronically persists and incurs reactivations. Really, these oncological diseases should be considered more complications than chronic forms of the illness, as well as other malignancies for which a viral – or even infectious - etiology is well recognized. The chronic diseases, in fact, should be linked in a pathogenetic and temporal way to the acute infection, from whom start the natural history of the following disease. So, as for the chronic liver diseases from HBV and HCV, it was conied the acronym of CAEBV (Chronic Active EBV infection), distinguishing within these pathologies the more severe forms (SCAEBV) mostly reported in Far East and among children or adolescents. Probably only these forms have to be considered expressions of a chronic EBV infection “sensu scrictu”, together with those forms of CFS where the etiopathogenetic and temporal link with the acute EBV infection is well documented. As for CFS, also for CAEBV the criteria for a case definition were defined, even on the basis of serological and virological findings. However, the lymphoproliferative disorders are excluded from these forms and mantain their nosographic (e.g. T or B cell or NK type lymphomas) and pathogenetic collocation, even when they occur within chronic forms of EBV infection. In the pathogenesis, near to the programs of latency of the virus, the genetic and environmental factors, independent from the real natural history of EBV infection, play a crucial role. Finally, it was realized a review of cases - not much numerous in literature – of chronic EBV infection associated to chronic liver and neurological diseases, where the modern techniques of molecular biology should be useful to obtain a more exact etiologic definition, not always possibile to reach in the past. The wide variety of clinical forms associated to the EBV chronic infection makes difficult the finding of a univocal pathogenetic link. There is no doubt, however, that a careful examination of the different clinical forms described in this review should be useful to open new horizons to the study of the persistent viral infections and the still not well cleared pathologies that they can induce in the human host. PMID:21415952

[Cranial nerve damage after neuroaxial methods of anesthesia in puerperas].

PubMed

Floka, S E; Shifman, E M

2007-01-01

The paper describes cranial nerve damage, a rare complication of neuroaxial anesthesia in obstetric care. In the literature, there are summarized data on 17 cases of neurological deficit developing after subarachnoidal or epidural anesthesia in puerperas. The etiological and pathogenetic factors of the above complications may be suggested to be the high disposition of a local anesthetic, arterial hypotension due to neuroaxial anesthetics, the outflow of cerebrospinal fluid after pachymeningeal puncture (including after unintended puncture during epidural anesthesia), and ischemic injury after the blood packing performed to relieve postpuncture headache. Closer consideration of these risk factors seems to reduce the incidence of cranial nerve damage in puerperas.

[Effects of "host factor" bile on adaptability and virulence of Vibrios, foodborne potential pathogenic agents].

PubMed

Di Pietro, A; Picerno, I; Visalli, G; Chirico, C; Scoglio, M E

2004-01-01

In order to improve the knowledge of host/pathogenic agent interaction and to obtain a more careful estimation of risk related to ingestion of food contaminated by Vibrio spp., the effects of bile extracts have been studied. The growth of one V. fluvialis, two V. alginolyticus, and three V. parahaemolyticus strains, isolated from mollusks and crustaceans, has been determined to evaluate their adaptability to intestinal environment. Moreover, the expression of virulence factors responsible for the colonization, as bacterial "swarming mobility", biofilm production, adherence on epithelial cells and hydrophobicity, has been evaluated. Using a bile concentration of 1.5%, all examined strains showed a constant inhibitory effect, quite moderate in the first growth phases. Bile increased the "swarming mobility" and biofilm production; also the adherence was favored, but only after adaptation and during the early logarithmic phase. The decreased hydrophobicity could explain the reduction of adherence during the stationary phase. Studying the phenotypic expression of virulence factors in "minor vibrios" in the presence of bile, it was possible to extend the knowledge about their pathogenetic mechanisms owing to the ingestion of contaminated food. That permits a more careful estimation of risk related to the contamination, considering the high frequency of isolation of these species in some seafood.

Pectus carinatum--first ultrastructural findings of a potential metabolic lesion.

PubMed

Brochhausen, Christoph; Müller, Felix Karl P; Turial, Salmai; James Kirkpatrick, C

2012-03-01

The histological and ultrastructural findings of rib specimens after two re-interventions in the case of recurrence of pectus carinatum (PC) are presented in this report. A 15-year-old boy developed recurrences of mild PC after re-chondroplasties using the Ravitch technique. Histological study of the resected cartilage showed markedly degenerative changes of the sternocostal cartilage. For the first time, intracellular crystalline inclusions in some of the chondrocytes were found. These findings indicate metabolic changes as a possible pathogenetic parameter in PC.

The TFPI-2 derived peptide EDC34 improves outcome of gram-negative sepsis.

PubMed

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-01-01

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections.

The TFPI-2 Derived Peptide EDC34 Improves Outcome of Gram-Negative Sepsis

PubMed Central

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E.; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-01-01

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections. PMID:24339780

The pathogenesis of pediatric cerebral malaria: eye exams, autopsies, and neuroimaging.

PubMed

Taylor, Terrie E; Molyneux, Malcolm E

2015-04-01

Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuroimaging studies, which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed. © 2015 New York Academy of Sciences.

Melasma update

PubMed Central

Sarkar, Rashmi; Arora, Pooja; Garg, Vijay Kumar; Sonthalia, Sidharth; Gokhale, Narendra

2014-01-01

Melasma is an acquired pigmentary disorder characterized by symmetrical hyperpigmented macules on the face. Its pathogenesis is complex and involves the interplay of various factors such as genetic predisposition, ultraviolet radiation, hormonal factors, and drugs. An insight into the pathogenesis is important to devise treatment modalities that accurately target the disease process and prevent relapses. Hydroquinone remains the gold standard of treatment though many newer drugs, especially plant extracts, have been developed in the last few years. In this article, we review the pathogenetic factors involved in melasma. We also describe the newer treatment options available and their efficacy. We carried out a PubMed search using the following terms “melasma, pathogenesis, etiology, diagnosis, treatment” and have included data of the last few years. PMID:25396123

The fecal microbiome of ALS patients.

PubMed

Brenner, David; Hiergeist, Andreas; Adis, Carolin; Mayer, Benjamin; Gessner, André; Ludolph, Albert C; Weishaupt, Jochen H

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease accompanied by both systemic and central nervous system-specific inflammation as well as deregulated energy metabolism. These potential pathogenetic factors have recently been found to mutually interact with the gut microbiota, raising the hypothesis of a link between microbiome alterations and ALS pathogenesis. The aim of our study was to assess whether ALS is associated with an altered composition of the fecal microbiota. We compared the fecal microbiota of 25 ALS patients with 32 age- and gender-matched healthy persons using 16S rRNA gene sequencing analysis. Confounding factors and secondary disease effects on the microbiome were minimized by selection of patients without dysphagia, gastrostomy, noninvasive ventilation, or reduced body mass index. Comparing the 2 carefully matched groups, the diversity and the abundance of the bacterial taxa on the different taxonomic levels as well as PICRUSt-predicted metagenomes were almost indistinguishable. Significant differences between ALS patients and healthy controls were only observed with regard to the overall number of microbial species (operational taxonomic units) and in the abundance of uncultured Ruminococcaceae. Conclusively, ALS patients do not exhibit a substantial alteration of the gut microbiota composition. Copyright © 2017 Elsevier Inc. All rights reserved.

Obstructive Sleep Apnea in Children: Implications for the Developing Central Nervous System

PubMed Central

Gozal, David

2008-01-01

Recent increases in our awareness to the high prevalence of sleep disorders in general, and of sleep-disordered breathing among children, in particular, has led to concentrated efforts aiming to understand the pathophysiological mechanisms, clinical manifestations and potential consequences of such conditions. In this review, I will briefly elaborate on some of the pathogenetic elements leading to the occurrence of obstructive sleep apnea (OSA) in children, focus on the psycho-behavioral consequences of pediatric OSA, and review the evidence on the potential mechanisms underlying the close association between CNS morbidity and the episodic hypoxia and sleep fragmentation that characterize OSA. PMID:18555196

Genetic risk factors for ovarian cancer and their role for endometriosis risk.

PubMed

Burghaus, Stefanie; Fasching, Peter A; Häberle, Lothar; Rübner, Matthias; Büchner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif B; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P

2017-04-01

Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

[Study of gene mutation and pathogenetic mechanism for a family with Waardenburg syndrome].

PubMed

Chen, Hongsheng; Liao, Xinbin; Liu, Yalan; He, Chufeng; Zhang, Hua; Jiang, Lu; Feng, Yong; Mei, Lingyun

2017-08-10

To explore the pathogenetic mechanism of a family affected with Waardenburg syndrome. Clinical data of the family was collected. Potential mutation of the MITF, SOX10 and SNAI2 genes were screened. Plasmids for wild type (WT) and mutant MITF proteins were constructed to determine their exogenous expression and subcellular distribution by Western blotting and immunofluorescence assay, respectively. A heterozygous c.763C>T (p.R255X) mutation was detected in exon 8 of the MITF gene in the proband and all other patients from the family. No pathological mutation of the SOX10 and SNAI2 genes was detected. The DNA sequences of plasmids of MITF wild and mutant MITF R255X were confirmed. Both proteins were detected with the expected size. WT MITF protein only localized in the nucleus, whereas R255X protein showed aberrant localization in the nucleus as well as the cytoplasm. The c.763C>T mutation of the MITF gene probably underlies the disease in this family. The mutation can affect the subcellular distribution of MITF proteins in vitro, which may shed light on the molecular mechanism of Waardenburg syndrome caused by mutations of the MITF gene.

Experimental-clinical validation of the use of amitetravit, ATP and autologous bone marrow in radiation injuries caused by prolonged radiation

NASA Technical Reports Server (NTRS)

Atamanova, O. M.; Vodyakova, L. M.; Gvozdeva, N. I.; Davydova, S. A.; Ignasheva, L. P.; Rogozkin, V. D.; Sbitneva, M. F.; Ostroumova, L. M.; Tikhomirova, M. V.; Fedotenkov, A. G.

1974-01-01

Experimental clinical studies show that early pathogenetic treatment against the effects of prolonged radiation includes amitetravit as a means of increasing natural radio resistance, ATP as protective therapeutic agent, and automyelotransplantation for early pathogenetic treatment. The high effectiveness of the combined use of ATP and amitetravit in tests on dogs indicates an ability to prevent primary damages to genetic structures and accelerated processes of reparation in the first stages of radiopathological processes.

Mechanism of low-intensity laser therapy as a different etiology for kidney lesion

NASA Astrophysics Data System (ADS)

Koultchavenia, Ekaterina V.

2001-05-01

Urological diseases are widespread among the population. Both infectious-inflammatory and oncological diseases are often diagnosed. Modern antibiotics permit to eradicate infectious agent, but efficiency of therapy is insufficient because of reduction of organ function. Thus, besides aetiotropic therapy pathogenetic effect is necessary. Low- intensity laser therapy (LT) is best pathogenetic treatment, so far as it has a few contraindications, low cost and good tolerance. Our goal was to investigate the influence of LT on different aetiology kidney lesion.

Homeopathic pathogenetic trials produce specific symptoms different from placebo.

PubMed

Möllinger, Heribert; Schneider, Rainer; Walach, Harald

2009-04-01

Homeopathy uses information gathered from healthy volunteers taking homeopathic substances (pathogenetic trials) for clinical treatment. It is controversial whether such studies produce symptoms different from those produced by placebo. To test whether homeopathic preparations produce different symptoms than placebo in healthy volunteers. Three armed, double-blind, placebo controlled randomised experimental pathogenetic study in 25 healthy volunteers who took either one of two homeopathic remedies, Natrum muriaticum and Arsenicum album in 30CH or identical placebo. Main outcome parameter was the number of remedy-specific symptoms per group. On average, 6 symptoms typical for Arsenicum album were experienced by participants taking arsenicum album, 5 symptoms typical for Natrum muriaticum by those taking natrum muriaticum, and 11 non-specific symptoms by those in the placebo group. Differences were significant overall (Kruskall Wallis test, p = 0.0002,) and significantly different from placebo (Mann-Whitney test, p = 0.001). Homeopathic remedies produce different symptoms than placebo. Copyright (c) 2009 S. Karger AG, Basel.

Cardiometabolic features of polycystic ovary syndrome.

PubMed

Hoffman, Leslie K; Ehrmann, David A

2008-04-01

Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.

[Secondary hypertension].

PubMed

Yoshida, Yuichi; Shibata, Hirotaka

2015-11-01

Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice.

Serratia marcescens Bullous Cellulitis in a Splenectomized Patient: A Case Report and Review of the Literature.

PubMed

Fournier, John B; Dabiri, Ganary; Thomas, Vinod; Skowron, Gail; Carson, Polly; Falanga, Vincent

2016-06-01

Serratia marcescens is a Gram-negative bacillus belonging to the Enterobacteriaceae family. Cutaneous infection with Serratia is rare, and usually occurs in immunocompromised individuals. Primary cutaneous infections are uncommon, but they are typically severe and are associated with significant morbidity and mortality. The pathogenetic factors leading to S. marcescens infection are not fully understood, but contributing virulence factors include proteases, secreted exotoxins, and the formation of biofilm. We report a case of cellulitis occurring in a splenectomized patient, which led to multiple wound debridements and a transmetatarsal amputation. This dramatic case led us to review the published literature on soft tissue infections caused by S. marcescens. © The Author(s) 2016.

Lymphocyte sensitization to nervous tissues and muscle in patients with the Guillain-Barré syndrome

PubMed Central

Caspary, E. A.; Currie, S.; Walton, J. N.; Field, E. J.

1971-01-01

By means of an electrophoretic method lymphocytes from patients with the Guillain-Barré syndrome (`acute idiopathic polyneuritis') have been shown to be sensitized to both encephalitogenic factor (EF) and a similar basic protein prepared from human sciatic nerve (SNBP). Sensitization was more marked in the acute stage of the disorder during which there also appeared to be a degree of sensitization to muscle. The results are consistent with the view that lymphocytic infiltration of peripheral nerves in the condition is of pathogenetic significance. PMID:5106345

[Pathogenetic characteristics of trigger mechanisms of preterm birth].

PubMed

Holota, V Ia; Beniuk, V O; Chernenko, V Iu

2000-01-01

A study was made into the immune factors capability to induce labour in physiologic delivery and in threat of preterm birth. The immune response reactivity was proved to be the case immediately before the physiological labour and in premature delivery. The studies made showed that a rise in the level of lymphocytes and in the subpopulations ratios is a matter of principle in the diagnosis and prognosis of the contractile activity of the uterus. Preclinical diagnosis of pregnancy suspension permit performing a rational drug correction to secure a positive effect on indices for perinatal pathology.

Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators.

PubMed

Mende, Susanne; Royer, Loic; Herr, Alexander; Schmiedel, Janet; Deschauer, Marcus; Klopstock, Thomas; Kostic, Vladimir S; Schroeder, Michael; Reichmann, Heinz; Storch, Alexander

2011-07-01

The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1 complex, nuclear factor Y and cAMP responsive element-binding protein-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome.

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

PubMed

Conway, Gerard; Dewailly, Didier; Diamanti-Kandarakis, Evanthia; Escobar-Morreale, Héctor F; Franks, Stephen; Gambineri, Alessandra; Kelestimur, Fahrettin; Macut, Djuro; Micic, Dragan; Pasquali, Renato; Pfeifer, Marija; Pignatelli, Duarte; Pugeat, Michel; Yildiz, Bulent O

2014-10-01

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS. © 2014 European Society of Endocrinology.

[Animal models of neurodegenerative diseases].

PubMed

Langui, Dominique; Lachapelle, François; Duyckaerts, Charles

2007-02-01

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.

[The interauricular laser therapy of rheumatoid arthritis].

PubMed

Sidorov, V D; Mamiliaeva, D R; Gontar', E V; Reformatskaia, S Iu

1999-01-01

Investigations have proved the ability of interauricular low-intensity infrared laser therapy (0.89 nm, 7.6 J/cm) to produce anti-inflammatory, immunomodulating action in patients with rheumatoid arthritis. The method has selective, pathogenetically directed immunomodulating effect the mechanism of which is similar to that of basic antirheumatic drugs and of intravenous laser radiation of blood. This laser therapy can be used as an alternative to intravenous blood radiation being superior as a noninvasive method. Interauricular laser therapy can potentiate the effects of nonsteroid anti-inflammatory drugs, cytostatics and diminish their side effects.

Pathobiology of Anaplastic Large Cell Lymphoma

PubMed Central

Piccaluga, Pier Paolo; Gazzola, Anna; Mannu, Claudia; Agostinelli, Claudio; Bacci, Francesco; Sabattini, Elena; Sagramoso, Carlo; Piva, Roberto; Roncolato, Fernando; Inghirami, Giorgio; Pileri, Stefano A.

2010-01-01

The authors revise the concept of anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented. PMID:21331150

Vitamin D and Diabetic Complications: True or False Prophet?

PubMed

Alam, Uazman; Arul-Devah, Vilashini; Javed, Saad; Malik, Rayaz A

2016-03-01

Vitamin D deficiency is now recognized as a condition of increasing prevalence worldwide. Vitamin D has an established role in calcium and bone metabolism; however, more recently associations with vitamin D deficiency and risk of developing diabetes, diabetes complications, and cardiovascular disease have all been acknowledged. The vitamin D receptor is ubiquitously expressed, and experimental, in vitro, and in vivo studies strongly suggest a role in regulating the transcription of multiple genes beyond calcium homeostasis. These include antiproliferative, immunomodulatory, angiogenic, inhibition of the renin-angiotensin-aldosterone system, and neurotrophic factor expression. Observational studies report a strong association between vitamin D deficiency and cardiovascular and metabolic disorders; however, there remains a paucity of large long-term randomized clinical trials showing a benefit with treatment. An increasing body of literature suggests a possible pathogenetic role of vitamin D in the long-term complications of diabetes and vitamin D deficiency may also exacerbate symptoms of painful diabetic peripheral neuropathy. It remains unknown if supplementation of vitamin D to normal or non-deficient levels alters pathogenetic processes related to diabetic microvascular complications. With the high prevalence of vitamin D deficiency in patients with diabetes and putative mechanisms linking vitamin D deficiency to diabetic complications, there is a compelling argument for undertaking large well-designed randomized controlled trials of vitamin D supplementation.

Pre-eclampsia part 1: current understanding of its pathophysiology

PubMed Central

Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Yeo, Lami; Romero, Roberto

2018-01-01

Pre-eclampsia is characterized by new-onset hypertension and proteinuria at ≥20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia. PMID:25003615

A systematic review of the quality of homeopathic pathogenetic trials published from 1945 to 1995.

PubMed

Dantas, F; Fisher, P; Walach, H; Wieland, F; Rastogi, D P; Teixeira, H; Koster, D; Jansen, J P; Eizayaga, J; Alvarez, M E P; Marim, M; Belon, P; Weckx, L L M

2007-01-01

The quality of information gathered from homeopathic pathogenetic trials (HPTs), also known as 'provings', is fundamental to homeopathy. We systematically reviewed HPTs published in six languages (English, German, Spanish, French, Portuguese and Dutch) from 1945 to 1995, to assess their quality in terms of the validity of the information they provide. The literature was comprehensively searched, only published reports of HPTs were included. Information was extracted by two reviewers per trial using a form with 87 items. Information on: medicines, volunteers, ethical aspects, blinding, randomization, use of placebo, adverse effects, assessments, presentation of data and number of claimed findings were recorded. Methodological quality was assessed by an index including indicators of internal and external validity, personal judgement and comments of reviewers for each study. 156 HPTs on 143 medicines, involving 2815 volunteers, produced 20,538 pathogenetic effects (median 6.5 per volunteer). There was wide variation in methods and results. Sample size (median 15, range 1-103) and trial duration (mean 34 days) were very variable. Most studies had design flaws, particularly absence of proper randomization, blinding, placebo control and criteria for analysis of outcomes. Mean methodological score was 5.6 (range 4-16). More symptoms were reported from HPTs of poor quality than from better ones. In 56% of trials volunteers took placebo. Pathogenetic effects were claimed in 98% of publications. On average about 84% of volunteers receiving active treatment developed symptoms. The quality of reports was in general poor, and much important information was not available. The HPTs were generally of low methodological quality. There is a high incidence of pathogenetic effects in publications and volunteers but this could be attributable to design flaws. Homeopathic medicines, tested in HPTs, appear safe. The central question of whether homeopathic medicines in high dilutions can provoke effects in healthy volunteers has not yet been definitively answered, because of methodological weaknesses of the reports. Improvement of the method and reporting of results of HPTs are required. References to all included RCTs are available on-line at.

Microenvironmental Regulation by Fibrillin-1

PubMed Central

Sengle, Gerhard; Tsutsui, Ko; Keene, Douglas R.; Tufa, Sara F.; Carlson, Eric J.; Charbonneau, Noe L.; Ono, Robert N.; Sasaki, Takako; Wirtz, Mary K.; Samples, John R.; Fessler, Liselotte I.; Fessler, John H.; Sekiguchi, Kiyotoshi; Hayflick, Susan J.; Sakai, Lynn Y.

2012-01-01

Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes. PMID:22242013

The integrated effect of moderate exercise on coronary heart disease.

PubMed

Mathews, Marc J; Mathews, Edward H; Mathews, George E

Moderate exercise is associated with a lower risk for coronary heart disease (CHD). A suitable integrated model of the CHD pathogenetic pathways relevant to moderate exercise may help to elucidate this association. Such a model is currently not available in the literature. An integrated model of CHD was developed and used to investigate pathogenetic pathways of importance between exercise and CHD. Using biomarker relative-risk data, the pathogenetic effects are representable as measurable effects based on changes in biomarkers. The integrated model provides insight into higherorder interactions underlying the associations between CHD and moderate exercise. A novel 'connection graph' was developed, which simplifies these interactions. It quantitatively illustrates the relationship between moderate exercise and various serological biomarkers of CHD. The connection graph of moderate exercise elucidates all the possible integrated actions through which risk reduction may occur. An integrated model of CHD provides a summary of the effects of moderate exercise on CHD. It also shows the importance of each CHD pathway that moderate exercise influences. The CHD risk-reducing effects of exercise appear to be primarily driven by decreased inflammation and altered metabolism.

An Up-to-date Approach to a Patient with a Suspected Autoinflammatory Disease

PubMed Central

Lidar, Merav; Giat, Eitan

2017-01-01

Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID. PMID:28178435

Factors Affecting Pro- and Anti-Oxidant Properties of Fragments of the b-Protein Precursor (bPP): Implication for Alzheimer's Disease.

PubMed

Andorn, Anne C.; Kalaria, Rajesh N.

2000-06-01

Oxidative stress may have a key pathogenetic role in neurodegenerative diseases including Alzheimer's disease (AD). While there is evidence that some amyloid-b (Ab) peptides can initiate oxidative stress at micromolar doses, there is also some evidence that oxidative stress increases the concentration of the b-protein precursor (bPP) and the potential for increased formation of the Ab peptides. The following studies were performed to test the hypothesis that fragments of bPP could be antioxidants and hence that oxidative stress might be an early event in AD. We found that several fragments of bPP, including the Ab peptides, inhibit ascorbate-stimulated lipid peroxidation (ASLP) in membrane fragment preparations of postmortem human brain. In contrast, other fragments of bPP enhance ASLP. These data indicate that bPP or fragments of bPP could play a key role in the redox status of cells and that alterations in bPP processing could have profound effects on the cellular response to oxidative stress.

Transformation of a MGUS to overt multiple myeloma: the possible role of a pituitary macroadenoma secreting high levels of insulin-like growth factor 1 (IGF-1).

PubMed

Tucci, Alessandra; Bonadonna, Stefania; Cattaneo, Chiara; Ungari, Marco; Giustina, Andrea; Guiseppe, Rossi

2003-03-01

We present a female patient with monoclonal gammopathy of undetermined significance who has remained stable for five years but evolved to overt myeloma in strict temporal relationship with the diagnosis of GH-secreting pituitary macroadenoma. IGF-I serum levels correlated with serum and urine M component. Since the in vitro role of IGF-I on proliferation and survival of normal and neoplastic plasma cells has been recently emphasized, the pathogenetic link between acromegaly and transformation of gammopathy to overt myeloma in this case is discussed.

[Ulcer. New approach to the problem].

PubMed

Ilćhenko, A A

1994-01-01

The paper deals with the issues of ulcerogenesis, including the value of Helicobacter pylori (HP) as one of the etiological and pathogenetic factors of ulcer diseases. The data available in the literature and the author's own findings have allowed the author to study the spread of HP infection. There is a higher incidence of ulcer disease among endoscopists than that in therapeutists and inhabitants in Moscow. Light and electron microscopies have demonstrated abnormal changes in the gastric mucosa if there is HP infection. The paper also analyzes the therapeutical efficiency of antiulcer drugs and their effects on the degree of gastric sanitation from HP.

Gastric mucosal-associated lymphoid tissue lymphoma.

PubMed

Fischbach, Wolfgang

2013-06-01

Gastric marginal zone B-cell lymphoma of mucosal-associated lymphoid tissue (MALT) is the predominant entity within the primary gastrointestinal lymphomas. Helicobacter pylori represents the decisive pathogenetic factor for gastric MALT lymphoma. The goal of treating gastric MALT lymphoma should be complete cure. The first choice of treatment is H pylori eradication. Patients with histologically persistent residual lymphoma after successful H pylori eradication and normalization of endoscopic findings should be managed by a watch-and-wait strategy. Patients who do not respond to H pylori eradication should be referred for radiation or chemotherapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Polycystic Kidney Disease: Pathogenesis and Potential Therapies

PubMed Central

Takiar, Vinita; Caplan, Michael J.

2011-01-01

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, inherited condition for which there is currently no effective specific clinical therapy. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function. Current interests in the field focus on understanding and exploiting signaling mechanisms underlying disease pathogenesis as well as delineating the role of the primary cilium in cystogenesis. This review highlights the pathogenetic pathways underlying renal cyst formation as well as novel therapeutic targets for the treatment of PKD. PMID:21146605

Diuretics as pathogenetic treatment for heart failure

PubMed Central

Guglin, Maya

2011-01-01

Increased intracardiac filling pressure or congestion causes symptoms and leads to hospital admissions in patients with heart failure, regardless of their systolic function. A history of hospital admission, in turn, predicts further hospitalizations and morbidity, and a higher number of hospitalizations determine higher mortality. Congestion is therefore the driving force of the natural history of heart failure. Congestion is the syndrome shared by heart failure with preserved and reduced systolic function. These two conditions have almost identical morbidity, mortality, and survival because the outcomes are driven by congestion. A small difference in favor of heart failure with preserved systolic function comes from decreased ejection fraction and left ventricular remodeling which is only present in heart failure with decreased systolic function. The magnitude of this difference reflects the contribution of decreased systolic function and ventricular remodeling to the progression of heart failure. The only treatment available for congestion is fluid removal via diuretics, ultrafiltration, or dialysis. It is the only treatment that works equally well for heart failure with reduced and preserved systolic function because it affects congestion, the main pathogenetic feature of the disease. Diuretics are pathogenetic therapy for heart failure. PMID:21403798

[Comparative analysis on the biological basis of blood stasis syndrome induced by qi-stagnation and qi-deficiency in patients with unstable angina pectoris].

PubMed

Ren, Jian-xun; Liu, Jian-xun; Lin, Cheng-ren

2010-04-01

To comparatively analyse the objective characteristics of different syndrome types of qi-disturbance-induced blood stasis syndrome (QDBS) in the pathogenetic evolution of unstable angina coronary heart disease (UA-CHD). Seventy-eight patients with UA-CHD of QDBS were differentiated into 2 groups: 55 in the qi-deficiency-induced blood-stasis syndrome group (A) and 23 in the qi-stagnation-induced blood-stasis syndrome group (B). The comparative analysis on them was carried out through comparing their blood pressure, glucose and lipid metabolisms, coagulation function, thyroid function and inflammation reaction changes, etc. In the pathogenetic process of qi-disturbance induced blood stasis, the initiating age, levels of HbA1c, TSH, PT and APTT between the two groups were significantly different (P < 0.05). Levels of TNF-alpha and LN were higher and levels of sIgA lower in patients than those in healthy subjects (P < 0.05). Inflammation immune reaction may play an important role in the pathogenetic process of blood-stasis syndrome, and the functional disturbance of hypothalamus, pituitary and endocrinal secretion induced by emotional stress is possibly the essence of qi-stagnation induced blood stasis syndrome.

Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration.

PubMed

Luzzi, Simona; Colleoni, Lara; Corbetta, Paola; Baldinelli, Sara; Fiori, Chiara; Girelli, Francesca; Silvestrini, Mauro; Caroppo, Paola; Giaccone, Giorgio; Tagliavini, Fabrizio; Rossi, Giacomina

2017-06-01

Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation. Copyright © 2017 Elsevier Inc. All rights reserved.

[Study on vaginal production of human defensins and the correlated pathogenetic factors of vulvovaginal candidiasis].

PubMed

Wang, Wen; DI, Wen; Liao, Qin-ping; Liu, Zhao-hui; Zhang, Ning; Zhang, Hui-ying; Zhang, Dai; Geng, Li; Fan, Shang-rong; Hu, Li-na

2008-07-01

To investigate the correlated pathogenetic factors and vaginal local immunity in vulvovaginal candidiasis (VVC). A case control study was conducted to compare VVC group (60 cases) with normal group (60 cases). All of the women filled up the specific questionnaires. Routine examination, pH test and bacterial culture were done on the vaginal discharge. Cytokines of the vaginal lavage were measured by enzyme linked immunosorbent assay. (1) Outcomes of the questionnaires: there was no significant difference between the two groups in educational background, knowledge of gynecologic infection, history of gynecologic infection, hygienic habit, sex life, or use of medicine (P > 0.05). The incidence of chronic cervicitis in normal group (43%, 26/60) was higher than in VVC group (22%, 13/60; P < 0.05). (2) There was no difference in vaginal pH between the two groups (P > 0.05). (3) Detection rate of candida albicans by vaginal discharge routine examination was 72% (43/60). (4) The concentrations of interleukin (IL) 2, and IL-4 in vaginal lavage did not show significant difference between the two groups (P > 0.05), but the concentrations of human defensin 5, human beta-defensin (HBD) 1, and HBD2 in VVC group [(0.94 +/- 0.44) mg/L, (3.1 +/- 0.4) microg/L, (10 +/- 6) microg/L] were higher than normal group (P < 0.05). VVC is a common vulvovaginitis. There is no significant correlation between the incidence of VVC and educational background, knowledge of gynecologic infection, history of gynecologic infection, hygienic habit, sex life, or use of medicine in the child-bearing period. Human defensin may be closely correlated with the pathogenesis of VVC.

High levels of 15-oxygenated steroids in circulation of patients with multiple sclerosis: fact or fiction?

PubMed

Björkhem, I; Lövgren-Sandblom, A; Piehl, F; Khademi, M; Pettersson, H; Leoni, V; Olsson, T; Diczfalusy, U

2011-01-01

15-Oxygenated cholesterol species such as 5α-cholest-8(14)ene-3β,15α-diol (15HC) and 3β-hydroxy-5α-cholest-8(14)-en-15-one (15KC) are commercially available synthetic products unlikely to occur in biological systems. Surprisingly, Farez et al. recently reported that these two steroids occur in human circulation at levels considerably higher than those of any other endogenous oxysterol [Farez, M. et al. 2009. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat. Immunol. 10: 958-964]. The levels were reported to be increased in patients with multiple sclerosis in a progressive phase and the authors suggested that this could be utilized diagnostically. Based on extensive in vitro experiments exposing cells to the same high levels of 15HC as found in vivo (1000 ng/ml) the authors concluded that 15HC may be an important pathogenetic factor in multiple sclerosis. Using combined gas chromatography-mass spectrometry we fail to detect significant plasma levels of 15HC either in healthy controls or in patients with multiple sclerosis (levels < 2 ng/ml). If 15KC is present in these plasma samples, the concentration of it must be <10 ng/ml. Our failure to detect significant levels of the above steroids could not be due to loss during hydrolysis and work-up because recovery of the added two oxysterols was close to 100%. Autoxidation of lipoprotein-bound cholesterol resulted in extensive conversion of cholesterol into 7-oxygenated but not 15-oxygenated sterols. We conclude that if present there are trace amounts only of the above 15-oxygenated steroids in human circulation and that the role of such oxysterols as pathogenetic factors and biomarkers must be reconsidered.

Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis.

PubMed

Antoniou, Katerina M; Pataka, Athanasia; Bouros, Demosthenes; Siafakas, Nikolaos M

2007-01-01

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease. Current therapeutic approaches target at apoptosis, epithelial replacement, fibroblasts/myofibroblasts, procoagulant activity, growth factors production, angiogenesis, Th1 and Th2 cytokines and oxidative stress. Increased epithelial cells apoptosis can contribute to fibrosis, while on the other hand, decreased fibroblast or myofibroblast apoptosis promotes fibrosis. Recent findings support the notion that therapy directed at either inhibition of angiogenic or augmentation of angiostatic CXC chemokines may be a novel approach in the treatment of IPF. Additionally, there is little doubt that the development of novel therapeutic strategies for pulmonary fibrosis should target some profibrotic growth factors and key type II cytokines, such as inteleukin-13. Importantly, persistent activation of intra-alveolar procoagulant activity and subsequent abnormal fibrin turnover enhances a fibrotic response. Furthermore, increased procoagulant activity may interfere with fibrin accumulation and lack of activation of some matrix metalloproteinases responsible for an imbalance in matrix turnover. Finally, oxidative stress with increased production of oxidants in IPF is an additional mechanism proposed to explain epithelial cell apoptosis in this disease. The challenge of future targets for therapeutic intervention is to reconcile different pathogenetic pathways, and we strongly suspect that no single approach will be sufficient for a lethal disease with few therapeutic options.

Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications.

PubMed

Cipriani, Paola; Franca Milia, Anna; Liakouli, Vasiliki; Pacini, Alessandra; Manetti, Mirko; Marrelli, Alessandra; Toscano, Annarita; Pingiotti, Elisa; Fulminis, Antonietta; Guiducci, Serena; Perricone, Roberto; Kahaleh, Bashar; Matucci-Cerinic, Marco; Ibba-Manneschi, Lidia; Giacomelli, Roberto

2006-09-01

Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc.

Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo.

PubMed Central

Sanders, P W; Herrera, G A; Chen, A; Booker, B B; Galla, J H

1988-01-01

To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), beta-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (JV), chloride (JCl) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to BJP1 or BLG, JV, JCl, and JG were less (P less than 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter JV, JCl, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI less than 7.4 precipitated in the distal nephron, forming acellular casts. Thus, certain nephrotoxic LMWPs damaged the PT, while others precipitated in the distal tubule, obstructing the nephron. These two pathogenetic mechanisms may independently be responsible for tubulointerstitial nephropathy of LMWPs in humans. Images PMID:3198767

Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links.

PubMed

De Rosa, Salvatore; Arcidiacono, Biagio; Chiefari, Eusebio; Brunetti, Antonio; Indolfi, Ciro; Foti, Daniela P

2018-01-01

Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field.

Urinary tract infections in children after renal transplantation.

PubMed

John, Ulrike; Kemper, Markus J

2009-06-01

Urinary tract infections (UTI) after pediatric kidney transplantation (KTX) are an important clinical problem and occur in 15-33% of patients. Febrile UTI, whether occurring in the transplanted kidney or the native kidney, should be differentiated from afebrile UTI. The latter may cause significant morbidity and is usually associated with acute graft dysfunction. Risk factors for (febrile) UTI include anatomical, functional, and demographic factors as well as baseline immunosuppression and foreign material, such as catheters and stents. Meticulous surveillance, diagnosis, and treatment of UTI is important to minimize acute morbidity and compromise of long-term graft function. In febrile UTI, parenteral antibiotics are usually indicated, although controlled data are not available. As most data concerning UTI have been accumulated retrospectively, future prospective studies have to be performed to clarify pathogenetic mechanisms and risk factors, improve prophylaxis and treatment, and ultimately optimize long-term renal graft survival.

Pathogenetic role of Factor VII deficiency and thrombosis in cross-reactive material positive patients.

PubMed

Girolami, A; Sambado, L; Bonamigo, E; Ferrari, S; Lombardi, A M

2013-12-01

Congenital Factor VII (FVII) deficiency can be divided into two groups: cases of "true" deficiency, or cross-reactive material (CRM) negative and variants that are cross-reactive material positive.The first form is commonly recognized as Type I condition whereas the second one is known as Type II. FVII deficiency has been occasionally associated with thrombotic events, mainly venous. The reasons underlying this peculiar manifestation are unknown even though in the majority of associated patients thrombotic risk factors are present. The purpose of the present study was to investigate if a thrombotic event was more frequent in Type I or in Type II defect.The majority of patients with FVII deficiency and thrombosis belong to Type II defects. In the following paper we discuss the possible role of the dysfunctional FVII cross-reaction material as a contributory cause for the occurrence of thrombosis.

CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.

PubMed

Deaglio, Silvia; Capobianco, Andrea; Bergui, Luciana; Dürig, Jan; Morabito, Fortunato; Dührsen, Ulrich; Malavasi, Fabio

2003-09-15

The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell-receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2-treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.

Sirt1 Protects against Oxidative Stress-Induced Apoptosis in Fibroblasts from Psoriatic Patients: A New Insight into the Pathogenetic Mechanisms of Psoriasis.

PubMed

Becatti, Matteo; Barygina, Victoria; Mannucci, Amanda; Emmi, Giacomo; Prisco, Domenico; Lotti, Torello; Fiorillo, Claudia; Taddei, Niccolò

2018-05-25

Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in our study which aimed to clarify the potential role of SIRT1 in the pathogenetic mechanisms of the disease. We firstly detected the presence of oxidative stress (lipid peroxidation and total antioxidant capacity), significantly reduced SIRT1 expression level and activity, mitochondrial damage and apoptosis (caspase-3, -8 and -9 activities) in psoriatic fibroblasts. Upon SIRT1 activation, redox balance was re-established, mitochondrial function was restored and apoptosis was no longer evident. Furthermore, we examined p38, ERK and JNK activation, which was strongly altered in psoriatic fibroblasts, in response to SIRT1 activation and we measured caspase-3 activity in the presence of specific MAPK inhibitors demonstrating the key role of the SIRT1 pathway against apoptotic cell death via MAPK modulation. Our results clearly demonstrate the involvement of SIRT1 in the protective mechanisms related to fibroblast injury in psoriasis. SIRT1 activation exerts an active role in restoring both mitochondrial function and redox balance via modulation of MAPK signaling. Hence, SIRT1 can be proposed as a specific tool for the treatment of psoriasis.

Integrative Etiopathogenetic Models of Psychotic Disorders: Methods, Evidence and Concepts

PubMed Central

Gaebel, Wolfgang; Zielasek, Jürgen

2011-01-01

Integrative models of the etiopathogesnesis of psychotic disorders are needed since a wealth of information from such diverse fields as neurobiology, psychology, and the social sciences is currently changing the concepts of mental disorders. Several approaches to integrate these streams of information into coherent concepts of psychosis are feasible and will need to be assessed in future experimental studies. Common to these concepts are the notion of psychotic disorders as brain disorders and a polythetic approach in that it is increasingly realized that a multitude of interindividually partially different pathogenetic factors interact in individual persons in a complex fashion resulting in the clinical symptoms of psychosis. PMID:21860047

[EFFICACY OF CYCLOFERON LINIMENT IN THE COMBINED TREATMENT OF CHRONIC GINGIVITIS IN PATIENTS WITH CHRONIC INFECTIOUS DISEASES].

PubMed

Soboleva, L A; Shul'dyakov, A A; Bulkina, N V

2015-01-01

In order to study the clinical-pathogenetic efficacy of using cycloferon liniment in the combined therapy of patients with gingivitis on the background of chronic infectious diseases (HIV infection, hepatitis C, brucellosis), medical examination and treatment of 42 patients with this diagnosis has been carried out. It is established, that the use of cycloferon liniment in the combined therapy decreases the infection load in periodontal recess and manifestation of local inflammation, normalizes the immunity indices, and reduces the level of endogenous intoxication. All these factors provide acceleration of the recuperation processes and decrease the frequency of recidivating.

Renal calculi in primary hyperaldosteronism.

PubMed Central

Kabadi, U. M.

1995-01-01

Increased urinary calcium (Ca++) excretion and the presence of negative Ca++ balance is well documented in primary hyperaldosteronism. However, renal calculi as a major manifestation of this disorder has not previously been described. This report describes a patient who presented with renal calculi in association with primary hyperaldosteronism. We believe that primary hyperaldosteronism was a major pathogenetic factor in the formation of renal calculi since the increased urinary excretion of Ca++ and uric acid noted at onset declined following a short-term spironolactone administration and remission from renal calculi has persisted following initial nephrolithotomy and continued spironolactone therapy, which also corrected hypertension and hypokalemia, a hallmark of this disorder. Images Figure PMID:7479473

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

PubMed Central

Nelson, Peter T.; Katsumata, Yuriko; Nho, Kwangsik; Artiushin, Sergey C.; Jicha, Gregory A.; Wang, Wang-Xia; Abner, Erin L.; Saykin, Andrew J.; Kukull, Walter A.; Fardo, David W.

2016-01-01

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n=2,113, including 241 autopsy-confirmed HS cases). Further, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer’s Disease Neuroimaging Initiative data; n=1,239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer’s disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker. PMID:27815632

[Family environment risk factors of depression in adolescence].

PubMed

Greszta, Elzbieta

2006-01-01

General psychosocial theories of developmental psychopathology assert that family environment plays a significant role in forming both adaptive and maladaptive functioning of children. Also virtually all theories of depression assert that faulty parent-child relationships play a major role in the aetiology of this disorder. According these theoretical formulations familial risk factors have been the focus of most research on depression in adolescence. Several studies have shown that insecure attachment and parenting characterized by coldness, rejection, harsh discipline and unsupportive behaviour is positively related to adolescent depressive symptoms. Some research indicates that authoritative parenting, conceptualized as a composite of warmth, accept-involvement, firm control, and democratic discipline, is associated with the least depressive symptoms among adolescents. Pathogenetic factors within the family environment, such as parental depression, changes of family structure, violence or neglect, can also contribute to depression in adolescence. A causal relationship between anomalous parenting and depression is probably the interplay among genetic, cognitive, emotional, interpersonal and family environmental factors.

A study on operative findings and pathogenic factors in ulnar neuropathy at the elbow.

PubMed

Kojima, T; Kurihara, K; Nagano, T

1979-01-01

A study was made of operative findings obtained in 44 cases of ulnar nerve neuropathy at the elbow in an attempt to help elucidate the pathogenetic factors for the condition. Distinction must be made between Lig. epitrochleo-anconeum or a ligament-like thickening at the same site and the tendinous arch of M. flexor carpi ulnaris. These 2 sites constitute the entrapment points for the condition. A thick tendinous arch, Lig. epitrochleo-anconeum of M. anconeus epitrochlearis deters the ulnar nerve from being mobile, thereby contributing to the development of neuropathy with trauma acting as a precipitating factor. Dislocation of the ulnar nerve cannot be considered a factor of major etiologic significance. An important part is played by the tendinous arch in the pathogenesis of neuropathy, regardless of whether it is in association with ganglion, osteochondromatosis or osteoarthritis. In surgery for ulnar neuropathy decompression of the nerve is of primary necessity. Division of the tendinous arch is mandatory. Medial epicondylectomy may be added as required.

Hyperirisinemia is independently associated with subclinical hypothyroidism: correlations with cardiometabolic biomarkers and risk factors.

PubMed

Stratigou, Theodora; Dalamaga, Maria; Antonakos, Georgios; Marinou, Ioanna; Vogiatzakis, Evaggelos; Christodoulatos, Gerasimos Socrates; Karampela, Irene; Papavassiliou, Athanasios G

2018-02-17

Irisin, a newly discovered adipo-myokine, is implicated in the modulation of the adipose phenotype, increasing energy expenditure and ameliorating systemic metabolism. Our aim was to investigate circulating irisin in subclinical hypothyroidism (SH) and study its associations with cardiometabolic risk factors. In a large case-control study, serum irisin, insulin resistance and lipid parameters, classic adipokines, inflammatory and hepatic biomarkers, and cardiovascular risk factors were determined in 120 consecutive patients with SH and 120 healthy controls matched on age, gender, and date of blood draw. Sixteen patients with SH received L-T4 treatment and, after 6 months, serum irisin and other biomarkers were assessed. SH cases exhibited significantly higher circulating irisin than controls (p < 0.001). In all participants, irisin was positively associated with TSH, anti-TG, HOMA-IR, C-peptide, lipid and inflammatory biomarkers, leptin, and cardiovascular risk factors, including Framigham score and apolipoprotein B/apolipoprotein A-I. Irisin was negatively correlated with adiponectin, HDL-C, and thyroid hormones. Serum irisin was independently associated with SH, above and beyond body mass index and cardiometabolic factors (p = 0.02). TSH was an independent predictor of circulating irisin (p = 0.003). L-T4 therapy did not reverse considerably the hyperirisinemic status in treated SH patients (p = 0.09). Irisin may represent an adipo-myokine counterbalancing a potential, gradual deterioration of lipid metabolism and insulin sensitivity in SH as well as reflecting a protective compensatory mechanism against oxidative muscle and thyroid cell stress. More mechanistic and prospective studies shedding light on the pathogenetic role of irisin in SH are needed to confirm and extend these data.

IL-6 blockade in the management of non-infectious uveitis.

PubMed

Lopalco, Giuseppe; Fabiani, Claudia; Sota, Jurgen; Lucherini, Orso Maria; Tosi, Gian Marco; Frediani, Bruno; Iannone, Florenzo; Galeazzi, Mauro; Franceschini, Rossella; Rigante, Donato; Cantarini, Luca

2017-07-01

Several pathogenetic studies have paved the way for a newer more rational therapeutic approach to non-infectious uveitis, and treatment of different forms of immune-driven uveitis has drastically evolved in recent years after the advent of biotechnological drugs. Tumor necrosis factor-α targeted therapies, the first-line recommended biologics in uveitis, have certainly led to remarkable results in patients with non-infectious uveitis. Nevertheless, the decision-making process turns out to be extremely difficult in anti-tumor necrosis factor or multidrug-resistant cases. Interleukin (IL)-6 holds a critical role in the pathogenic pathways of uveitis, due to its extended and protean range of effects. On this background, manipulation of IL-6 inflammatory cascade has unraveled encouraging outcomes. For instance, rising evidence has been achieved regarding the successful use of tocilizumab, the humanized monoclonal antibody targeted against the IL-6 receptor, in treating uveitis related to juvenile idiopathic arthritis or Behçet's disease. Similar findings have also been reported for uveitis associated with systemic disorders, such as rheumatoid arthritis or multicentric Castleman disease, but also for idiopathic uveitis, the rare birdshot chorioretinopathy, and even in cases complicated by macular edema. This work provides a digest of all current experiences and evidences concerning IL-6 blockade, as suggested by the medical literature, proving its potential role in the management of non-infectious uveitis.

Alteration of Endothelins: A Common Pathogenetic Mechanism in Chronic Diabetic Complications

PubMed Central

Khan, Zia Ali; Cukiernik, Mark; Fukuda, Gen; Chen, Shali; Mukherjee, Suranjana

2002-01-01

Endothelin (ET) peptides perform several physiological, vascular, and nonvascular functions and are widely distributed in a number of tissues. They are altered in several disease processes including diabetes. Alteration of ETs have been demonstrated in organs of chronic diabetic complications in both experimental and clinical studies. The majority of the effects of ET alteration in diabetes are due to altered vascular function. Furthermore, ET antagonists have been shown to prevent structural and functional changes induced by diabetes in animal models. This review discusses the contribution of ETs in the pathogenesis and the potential role of ET antagonism in the treatment of chronic diabetic complications. PMID:12546275

A review of infectious bovine rhinotracheitis, shipping fever pneumonia and viral-bacterial synergism in respiratory disease of cattle.

PubMed Central

Yates, W D

1982-01-01

Unanswered questions on the etiology and prevention of shipping fever pneumonia have allowed this disease to remain one of the most costly to the North American cattle industry. Research in this area has indirected that while Pasteurella haemolytica and, to a lesser extent, P. multocida are involved in most cases, they seem to require additional factors to help initiate the disease process. Bovine herpes virus 1 has been shown experimentally to be one such factor. This review examines in some detail the topics of infectious bovine rhinotracheitis, shipping fever, and viral-bacterial interactions in the production of respiratory disease in various species. It deals with history, definitions, etiologies, clinical signs and lesions, and considers exposure levels, transmission and various pathogenetic mechanisms that are postulated or known to occur. PMID:6290011

A review of pharmacotherapy for treating gastroesophageal reflux disease (GERD).

PubMed

Savarino, Edoardo; Zentilin, Patrizia; Marabotto, Elisa; Bodini, Giorgia; Della Coletta, Marco; Frazzoni, Marzio; de Bortoli, Nicola; Martinucci, Irene; Tolone, Salvatore; Pellegatta, Gaia; Savarino, Vincenzo

2017-09-01

Medical therapy of gastroesophageal reflux disease (GERD) is based on the use of proton pump inhibitors (PPIs) as first choice treatment. Despite their effectiveness, about 20-30% of patients report an inadequate response and alternative drugs are required. Areas covered: This review provides an overview of current pharmacotherapy for treating GERD by showing the results of PPIs, reflux inhibitors, antidepressants and mucosa protective medications. Expert opinion: Medical therapy of GERD does not definitely cure the disease, because even PPIs are not able to change the key factors responsible for it. However, they remain the mainstay of medical treatment, allowing us to alleviate symptoms, heal esophagitis and prevent complications in the majority of cases. Nevertheless, many patients do not respond, because acid does not play any pathogenetic role. Prokinetics and reflux inhibitors have the potential to control motor abnormalities, but the results of clinical trials are inconsistent. Antidepressant drugs are effective in specific subgroups of NERD patients with visceral hypersensitivity, but larger, controlled clinical studies are necessary. Protective drugs or medical devices have been recently adopted to reinforce mucosal resistance and preliminary trials have confirmed their efficacy either combined with or as add-on medication to PPIs in refractory patients.

Autoimmunity and primary immunodeficiency: two sides of the same coin?

PubMed

Schmidt, Reinhold E; Grimbacher, Bodo; Witte, Torsten

2017-12-19

Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.

Management in Acute Liver Failure

PubMed Central

Shalimar; Acharya, Subrat K.

2015-01-01

Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available. PMID:26041950

[The scombroid syndrome, a potentially serious ichthyotoxicosis of uncertain pathogenesis: personal experience].

PubMed

Di Grande, A; Giuffrida, C; Gatta, C; Condorelli, B

1999-01-01

The aim of this report is to point out the potential seriousness of the scombroid syndrome which, on the basis of our experience, can be characterized by extremely serious symptoms. We describe 12 cases of scombroid syndrome: two-thirds of the patients presented with rapid worsening of their clinical condition and hypotension severe enough to require use of plasma-expanders and hospitalization in an Internal Medicine Department. In the youngest patient, hypotension and symptoms were so marked that intravenous administration of epinephrine, and hospitalization in the Intensive Care Unit were required. Thus, in contrast to reports in the literature, the scombroid syndrome should be considered as a potentially serious ichthyotoxicosis. The pathogenetic role played by histamine, poorly absorbed by the intestine and rapidly metabolized by the liver, should be reevaluated. The potential onset of serious clinical symptoms warrants prolonged observation of the patient in an environment equipped to deal with the not infrequent emergencies that can arise, even in young and healthy subjects.

Can glomerular mRNAs in human type 1 diabetes be used to predict transition from normoalbuminuria to microalbuminuria?

PubMed

Adler, Sharon G; Kang, Shin-Wook; Feld, Stella; Cha, Dae Ryong; Barba, Lilly; Striker, Liliane; Striker, Gary; Riser, Bruce L; LaPage, Janine; Nast, Cynthia C

2002-07-01

mRNAs of pathogenetic importance in the development of diabetic nephropathy were measured in subjects with type 1 diabetes to determine whether these might be used to predict progression from normoalbuminuria to microalbuminuria. We proposed that conversion from normoalbuminuria to microalbuminuria would be most likely in subjects whose connective tissue growth factor (CTGF) and collagen mRNAs were above the 95% confidence interval (CI) for live renal donors and within the 95% CI for subjects with abnormal albuminuria. Glomerular CTGF, collagen alpha2(IV), and control glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs were measured in microdissected glomeruli from living renal donors (n = 10), and subjects with normoalbuminuria (n = 12), microalbuminuria (n = 5), and overt proteinuria (n = 6). After 44 +/- 2 months of follow-up, one subject converted from normoalbuminuria to microalbuminuria. Although the data are limited, progression from normoalbuminuria to microalbuminuria occurred in the only normoalbuminuric subject whose mRNA levels were above the live renal donors' 95% CI for CTGF and collagen alpha2(IV) and within the 95% CI of subjects with abnormal albuminuria. No clinical or histopathologic finding distinguished the progressor from the nonprogressors at the time of biopsy. This case report provides proof-of-principle that a panel of glomerular mRNA markers chosen because of their pathogenetic relevance may be useful adjuncts to albuminuria and histology in predicting clinical stability or clinical progression in diabetic nephropathy. Copyright 2002 by the National Kidney Foundation, Inc.

[Beta-endorphin and obesity. Possible pathogenetic implications].

PubMed

Giugliano, D; Saccomanno, F; Quatraro, A; Ceriello, A; Torella, R

1990-01-01

Several experimental data have documented the ability of both opiates and opioid peptides to stimulate food intake. On the other hand, the plasma beta-endorphin levels found in obese patients are higher than those observed in normal-weight controls, which may have pathogenetic implications. We have investigated the responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin in formerly obese subjects who had obtained by dieting the normalization of body weight and in lean controls. The data show that: a) the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; b) formerly obese subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin.

Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.

PubMed

Capalbo, Donatella; Scala, Maria Giuseppa; Melis, Daniela; Minopoli, Giorgia; Improda, Nicola; Palamaro, Loredana; Pignata, Claudio; Salerno, Mariacarolina

2012-09-20

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity.

[Immunological aspects of ulcerative colitis. Treatment with disodium cromoglycate].

PubMed

Cavallini, L; Marchi, S; Spisni, L; Li Calzi, M

1980-01-01

The various components of the normal intestinal immunological system have been examined, i.e. immunocompetent cells (isolated and in clusters) and humoral factors. The modifications observed in this system during ulcerous colitis are then analysed, mention being made of the various pathogenetic interpretations that have been put forward to explain this condition. The pharmacology and action mechanism of DSCG are then examined. This drug has been in use for some years in the treatment of a number of extraintestinal and immuno-allergic based conditions and, recently, of some enteropathis attributed to food allergies. The reported results of using DSCG in ulcerous colitis are then reviewed. They would appear to be fairly encouraging.

[Modern view on etiology, pathogenesis and treatment of chronic pelvic pain syndrome].

PubMed

Vinarov, A Z

2017-04-01

The manuscript presents the analysis of scientific manuscripts written by Russian and foreign researchers devoted to chronic pelvic pain syndrome (CPPS) studies. In spite of widespread disease, there is no clear understanding on etiopathogenetic mechanisms of CPPS development and it is shown that besides infectious process cardiovascular, neuronal, locomotor, endocrine and immune systems are involved into pathological process of CPPS. Mentioned factors complicate the doctors task on effective therapy choice and stress the reasonability of complex approach to CPPS treatment. Combination drug containing affinity purified antibodies to endothelial NO-synthase and prostate-specific antigen in released-active form influences different pathogenetic mechanisms of CPPS and thereby reveals pronounced clinical efficacy.

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

PubMed Central

2014-01-01

Background Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. Methods We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Results Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. Conclusions These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci. PMID:24885462

Interferon regulatory factor 5 is a potential target of autoimmune response triggered by Epstein-barr virus and Mycobacterium avium subsp. paratuberculosis in rheumatoid arthritis: investigating a mechanism of molecular mimicry.

PubMed

Bo, Marco; Erre, Gian Luca; Niegowska, Magdalena; Piras, Marco; Taras, Loredana; Longu, Maria Giovanna; Passiu, Giuseppe; Sechi, Leonardo A

2018-01-01

Rheumatoid arthritis (RA) is a chronic disease characterised by a pro-inflammatory cytokines linked erosive joint damage and by humoral and cellular response against a broad range of self-peptides. Molecular mimicry between Epstein-Barr virus (EBV), Mycobacterium avium subsp. paratuberculosis (MAP) and host peptides has long been regarded as an RA pathogenetic mechanism. Using bioinformatic analysis we identified high sequence homology among interferon regulatory factor 5 (IRF5), EBV antigen BOLF1 and MAP antigen MAP_4027. Our objective was to evaluate the presence in sera of RA patients of antibodies (Abs) directed against human homologous IRF5 cross-reacting with BOLF1 and MAP_4027. Frequency of reactivity against IRF5424-434, BOLF1305-320 and MAP_402718-32 was tested by indirect ELISA in sera from 71 RA patients and 60 healthy controls (HCs). RA sera show a remarkable high frequency of reactivity against IRF5424-434 in comparison to HCs (69% vs. 8%; p<0.0001). Similarly, seroreactivity against BOLF1305-320 was more frequently detected in RA sera than in HCs counterpart (58% vs. 8%; p<0.0001). Frequency of Abs against MAP_402718-32 was 17% in RA sera vs. 5% in HCs with a p-value at the threshold level (p<0.051). Prevalence of Abs against at least one of the assessed epitopes reached 72% in RA patients and 15% among HCs. Levels of Abs in RA patients were significantly related to systemic inflammation. IRF5 is a potential autoimmune target of RA. Our results support the hypothesis that EBV and MAP infections may be involved in the pathogenesis of RA, igniting a secondary immune response that cross-reacts against RA self-peptides.

The osteogenic response of undifferentiated human mesenchymal stem cells (hMSCs) to mechanical strain is inversely related to body mass index of the donor.

PubMed

Friedl, Gerald; Windhager, Reinhard; Schmidt, Helena; Aigner, Reingard

2009-08-01

While the importance of physical factors in the maintenance and regeneration of bone tissue has been recognized for many years and the mechano-sensitivity of bone cells is well established, there is increasing evidence that body fat constitutes an independent risk factor for complications in bone fracture healing and aseptic loosening of implants. Although mechanical causes have been widely suggested, we hypothesized that the osteogenic mechano-response of human mesenchymal stem cells (hMSCs) may be altered in obese patients. We determined the phenotypic and genotypic response of undifferentiated hMSCs of 10 donors to cyclic tensile strain (CTS) under controlled in vitro conditions and analyzed the potential relationship relevant to the donor's anthropomorphometric and biochemical parameters related to donor's fat and bone metabolism. The osteogenic marker genes were all statistically significantly upregulated by CTS, which was accompanied by a significant increase in cell-based ALP activity. Linear correlation analysis revealed that there was a significant correlation between phenotypic CTS response and the body mass index of the donor (r = -0.91, p < 0.001) and phenotypic CTS response was also significantly related to leptin levels (r = -0.68) and estradiol levels (r = 0.67) within the bone marrow microenvironment of the donor. Such an upstream imprinting process mediated by factors tightly related to the donor's fat metabolism, which hampers the mechanosensitivity of hMSCs in obese patients, may be of pathogenetic relevance for the complications associated with obesity that are seen in orthopedic surgery.

Antiphospholipid Syndrome Nephropathy: From Pathogenesis to Treatment.

PubMed

Tektonidou, Maria G

2018-01-01

Kidney damage is a well-recognized complication of the antiphospholipid syndrome (APS), either primary or systemic lupus erythematosus (SLE)-associated APS. Kidney involvement in APS involves a variety of manifestations, such as renal artery thrombosis or stenosis, renal vein thrombosis, allograft loss due to thrombosis after kidney transplantation, and injury to the renal microvasculature, also known as APS nephropathy. Biopsy in patients with APS nephropathy includes acute thrombotic microangiopathy lesions and chronic intrarenal vascular lesions such as interlobular fibrous intimal hyperplasia, arterial and arteriolar recanalizing thrombosis, fibrous arterial occlusion, and focal cortical atrophy. The most frequent clinical features are hypertension, microscopic hematuria, proteinuria (ranging from mild to nephritic levels), and renal insufficiency. It is uncertain whether antiphospholipid antibodies or other factors are implicated in the development of APS nephropathy, and whether it is driven mainly by thrombotic or by inflammatory processes. Experimental models and clinical studies of thrombotic microangiopathy lesions implicate activation of the complement cascade, tissue factor, and the mTORC pathway. Currently, the management of APS nephropathy relies on expert opinion, and consensus is lacking. There is limited evidence about the effect of anticoagulants, and their use remains controversial. Treatment approaches in patients with APS nephropathy lesions may include the use of heparin based on its role on complement activation pathway inhibition or the use of intravenous immunoglobulin and/or plasma exchange. Targeted therapies may also be considered based on potential APS nephropathy pathogenetic mechanisms such as B-cell directed therapies, complement inhibition, tissue factor inhibition, mTOR pathway inhibition, or anti-interferon antibodies, but prospective multicenter studies are needed to address their role.

PRRX2 as a novel TGF-β-induced factor enhances invasion and migration in mammary epithelial cell and correlates with poor prognosis in breast cancer.

PubMed

Juang, Yu-Lin; Jeng, Yung-Ming; Chen, Chi-Long; Lien, Huang-Chun

2016-12-01

TGF-β and cancer progression share a multifaceted relationship. Despite the knowledge of TGF-β biology in the development of cancer, several factors that mediate the cancer-promoting role of TGF-β continue to be identified. This study aimed to identify and characterise novel factors potentially related to TGF-β-mediated tumour aggression in breast cells. We treated the human mammary epithelial cell line MCF10A with TGF-β and identified TGF-β-dependent upregulation of PRRX2, the gene encoding paired-related homeobox 2 transcription factor. Overexpression of PRRX2 enhanced migration, invasion and anchorage-independent growth of MCF10A cells and induced partial epithelial mesenchymal transition (EMT), as determined by partial fibroblastoid morphology of cells, upregulation of EMT markers and partially disrupted acinar structure in a three-dimensional culture. We further identified PLAT, the gene encoding tissue-type plasminogen activator (tPA), as the highest differentially expressed gene in PRRX2-overexpressing MCF10A cells, and demonstrated direct binding and transactivation of the PLAT promoter by PRRX2. Furthermore, PLAT knockdown inhibited PRRX2-mediated enhanced migration and invasion, suggesting that tPA may mediate PRRX2-induced migration and invasion. Finally, the significant correlation of PRRX2 expression with poor survival in 118 primary breast tumour samples (P = 0.027) and the increased PRRX2 expression in metaplastic breast carcinoma samples, which is pathogenetically related to EMT, validated the biological importance of PRRX2-enhanced migration and invasion and PRRX2-induced EMT. Thus, our data suggest that upregulation of PRRX2 may be a mechanism contributing to TGF-β-induced invasion and EMT in breast cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A Pathogenetic Classification of Diabetic Macular Edema.

PubMed

Parodi Battaglia, Maurizio; Iacono, Pierluigi; Cascavilla, Marialucia; Zucchiatti, Ilaria; Bandello, Francesco

2018-04-11

The aim of this study was to define a new pathogenetic classification of diabetic macular edema (DME) and to present the results of its application in common clinical practice. One hundred and seventy-seven consecutive patients with center-involving DME, central retinal thickness (CRT) ≥250 µm, were prospectively enrolled. A complete ophthalmological examination included best-corrected visual acuity (BCVA) assessment, fundus photography, and spectral-domain optical coherence tomography (OCT). The DME classification was broken down into 4 categories, combining the presence of retinal thickening with the presence/absence of visible vascular dilations and OCT-detectable macular traction. The OCT parameters included were as follows: CRT, subretinal fluid, intraretinal cysts, and hyper- reflective foci (HF). Four subtypes of DME were identified: vasogenic (131 eyes, DME with vascular dilation), nonvasogenic (46 eyes, DME without vascular dilation), tractional (11 eyes), and mixed DME (13 eyes). Vasogenic DME was the pattern mainly represented in each subclass of CRT (< 300, 300-400, and > 400 µm), with tractional DME observed especially with CRT > 400 µm. Internal and external cysts and a greater presence of hard exudates were predominantly found in vasogenic DME, whereas HF was equally distributed in the 4 DME subgroups. The study offers a new pathogenetic classification able to detect significant differences among DME subtypes. A tailored therapeutic approach could take into consideration specific changes associated with the different DME subtypes. © 2018 S. Karger AG, Basel.

[Pathogenetic and Prognostic Role of Growth Factors in the Development of Chronic Heart Failure].

PubMed

Teplyakov, A T; Berezikova, E N; Shilov, S N; Efremova, A V; Pustovetova, M G; Popova, A A; Grakova, E V; Torim, Y Y; Safronov, I D; Andriyanova, A V

2017-10-01

To study the role of growth factors ((vascular endothelial growth factor (VEGF), platelet derived growth factor AB (PDGF-AB) and basic fibroblast growth factor (FGF-basic)) in the development and progression of chronic heart failure (CHF) in patients with ishcemic heart disease (IHD). We included in this study 94 patients with CHF. The control group comprised 32 persons. Blood serum levels of growth factors were determined at baseline and after 12 months of observation by enzyme-linked immunosorbent assay. VEGF, PDGF-AB and FGF-basic play an important role in the pathogenesis and progression of heart failure in patients with IHD, determining the increased risk of adverse cardiovascular events in this pathology. Serum activity of growth factors characterizes the severity and course of CHF: with disease progression levels of VEGF and FGF-basic decrease and PDGF-AB concentration increases. Initial low level of VEGF expression regardless of the sex of the patient's sex, significantly low level of FGF-basic and significantly high PDGF-AB in men characterizes unfavorable course of CHF. A correlation has been established between blood serum levels of VEGF, PDGF-AB and FGF-basic and severity and course of CHF.

Grain dust and the lungs.

PubMed Central

Chan-Yeung, M.; Ashley, M. J.; Grzybowski, S.

1978-01-01

Grain dust is composed of a large number of materials, including various types of grain and their disintegration products, silica, fungi, insects and mites. The clinical syndromes described in relation to exposure to grain dust are chronic bronchitis, grain dust asthma, extrinsic allergic alveolitis, grain fever and silo-filler's lung. Rhinitis and conjunctivitis are also common in grain workers. While the concentration and the quality of dust influence the frequency and the type of clinical syndrome in grain workers, host factors are also important. Of the latter, smoking is the most important factor influencing the frequency of chronic bronchitis. The role of atopy and of bronchial hyperreactivity in grain dust asthma has yet to be assessed. Several well designed studies are currently being carried out in North America not only to delineate the frequency of the respiratory abnormalities, the pathogenetic mechanisms and the host factors, but also to establish a meaningful threshold limit concentration for grain dust. Images p1272-a PMID:348288

[Diagnosis and clinical management of urinary tract infection].

PubMed

Heilberg, Ita Pfeferman; Schor, Nestor

2003-01-01

A review about recent aspects on diagnosis and clinical management of urinary tract infection (UTI) is presented. There is a wide variation in clinical presentation of UTI which include different forms as cystitis, pyelonephritis, urethral syndrome and the clinical relevance of asymptomatic bacteriuria and low-count bacteriuria that must be distinguished from contamination. Pathogenetic aspects concerning bacterial virulence as well as host factors in susceptibility to UTI as urinary tract obstruction, vesicoureteral reflux, indwelling bladder catheters, pregnancy, diabetes mellitus, sexual activity, contraceptive methods, prostatism, menopause, advanced age and renal transplantation are discussed. Diagnostic criteria and the most common tests utilized for differentiation between lower and upper UTI have been reviewed. The authors conclude that a careful evaluation of the underlying factors is required for the correct diagnosis of UTI and to prevent recurrence and that appropriate strategies and specific therapeutic regimens may maximize the benefit while reducing costs and adverse reactions.

[Etiopathogenic factors of arterial hypertension].

PubMed

Pérez-Olea, J

1992-06-01

High blood pressure of unknown etiology has been related to many pathogenetic factors, mainly dietary salt intake, mental stress, alcohol consumption, sedentary living and aging. Hypertension is more common in condition such as obesity and diabetes mellitus. Sustained elevation of arterial pressure is mediated by vasoconstriction in response to catecholamine release and activation of the renin-angiotensin-aldosterone system. In obese and diabetic subjects, insulin resistance and hyperinsulinemia have been found to be related to development of hypertension. The hypertension phenotype may correspond to many different genotypes codifying various alterations of hormone and receptor function, as well as inherited diseases linked to hypertension. An outstanding epidemiologic example of how hypertension may appear in a community is found in Easter Island. Hypertension among native adults increased from 3 to 30% in a 10 year period, in relation to influx of tourism and changes in salt intake and diet.

Mastitis in sheep--The last 10 years and the future of research.

PubMed

Gelasakis, A I; Mavrogianni, V S; Petridis, I G; Vasileiou, N G C; Fthenakis, G C

2015-12-14

Bacterial mastitis is a significant welfare and financial problem in sheep flocks. This paper reviews the recently published literature, including publications that highlight the significance and virulence factors of the causal agents, especially Staphylococcus aureus and Mannheimia haemolytica, the primary causes of the disease. Research has also contributed to the understanding of risk factors, including genetic susceptibility of animals to infections, supporting future strategies for sustainable disease control. Pathogenetic mechanisms, including the role of the local defenses in the teat, have also been described and can assist formulation of strategies that induce local immune responses in the teat of ewes. Further to well-established diagnostic techniques, i.e., bacteriological tests and somatic cell counting, advanced methodologies, e.g., proteomics technologies, will likely contribute to more rapid and accurate diagnostics, in turn enhancing mastitis control efforts. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel potential for the management of Alzheimer disease.

PubMed

Ginter, E; Simko, V; Weinrebova, D; Ladecka, Z

2015-01-01

Pathologic characteristics of Alzheimer disease (AD) are β-amyloid (Aβ) plaques, neurofibrillary tangles (NFT) and neurodegeneration. Currently, there is no cure for AD. Cilostazol, a selective inhibitor of type 3 phosphodiesterase, is likely to be a promising agent for AD. In the brain of the experimental animals it significantly reduced the Aβ amyloid plaques. Initial clinical reports on the effect of Cilostazol in AD patients are promising. In mice, stem cells favourably influence the pathogenetic process critical in AD, by reducing deposits of Aβ plaques. Clinical trials of the drug, called Betablock, are already underway in Britain. Successful management and resolution of AD in man will still require further intensive research (Fig. 4, Ref. 11).

Update in clinical allergy and immunology.

PubMed

von Gunten, S; Marsland, B J; von Garnier, C; Simon, D

2012-12-01

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field. © 2012 John Wiley & Sons A/S.

[The role of microRNAs in molecular pathology of esophageal cancer and their potential usage in clinical oncology].

PubMed

Kovaříková, A; Héžová, R; Srovnal, J; Rédová-Lojová, M; Slabý, O

2014-01-01

MicroRNAs are an abundant class of noncoding RNAs (approx. 18- 25 nucleotides in length) that suppress translation through binding to their target mRNAs, eventually leading to mRNAs degradation. Sequences of these endogenous RNA molecules are highly conserved, even among unrelated species, indicating their involvement in basic bio-logical processes, such as development, differentiation, proliferation or apoptosis. MiRNAs also participate on regulation of cancer stem cell functioning, immune system and malignant transformation. This review provides a comprehensive overview of miRNAs functions in esophageal cancer, their roles in key pathogenetic pathways and disease development, as well as their potential usage in clinical routine as bio-markers improving dia-gnosis, prognosis and prediction of therapeutic response. Through regulation of signaling pathways important in malignant transformation, miRNAs present also promising therapeutic targets.

Drug Induced Liver Injury: Can Biomarkers Assist RUCAM in Causality Assessment?

PubMed Central

Teschke, Rolf; Schulze, Johannes; Eickhoff, Axel; Danan, Gaby

2017-01-01

Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available. PMID:28398242

Vulvovaginitis in childhood.

PubMed

Dei, Metella; Di Maggio, Floriana; Di Paolo, Gilda; Bruni, Vincenzina

2010-04-01

Symptoms related to vulvitis and vulvovaginitis are a frequent complaint in the paediatric age. Knowledge of the risk factors and the pathogenetic mechanisms, combined with thorough clinical examination, helps to distinguish between dermatological diseases, non-specific vulvitis and vulvovaginitis proper. On the basis of microbiological data, the most common pathogens prove to be Streptococcus pyogenes, Haemophilus influenzae and Enterobius vermicularis; fungal and viral infections are less frequent. The possibility of isolating opportunistic pathogens should also be considered. In rare situations, the isolation of a micro-organism normally transmitted by sexual contact should prompt a careful evaluation of possible sexual abuse. Current treatments for specific and non-specific forms are outlined, together with pointers for the evaluation of recurrence. Copyright 2009 Elsevier Ltd. All rights reserved.

Inhibitor of prostacyclin production in sporadic haemolytic uraemic syndrome.

PubMed Central

Levin, M; Elkon, K B; Nokes, T J; Buckle, A M; Dillon, M J; Hardisty, R M; Barratt, T M

1983-01-01

Prostacyclin (PGI2) production was diminished when rat aortic rings were incubated with plasma from 5 of 6 patients with the sporadic form of haemolytic uraemic syndrome but was normal in the presence of plasma from 7 patients with the epidemic form of haemolytic uraemic syndrome or from patients with other renal diseases. The reduced PGI2 production was caused by an unstable inhibitor, extractable into polar lipid solvents, in sporadic haemolytic uraemic plasma. These results suggest that there may be at least 2 different pathogenetic mechanisms in epidemic and sporadic haemolytic uraemic syndrome and that the reduced PGI2 production observed in the sporadic type is due to an inhibitor of PGI2 production rather than a deficiency of stimulating factors. PMID:6354101

[Modern technologies and prospects of rehabilitation of patients after ischemic stroke].

PubMed

Ekusheva, E V

Despite the great achievements in the field of neurorehabilitation, a significant proportion of patients after an ischemic stroke have persistent motor disturbances even after timely and adequately carried out restorative measures. The article discusses the issues of neuroplasticity, modern diagnostic technologies for studying this phenomenon; prognostic factors for recovery deficit following stroke and determining the effectiveness of ongoing treatment. The principles of neuroprotective therapy in ischemic stroke are considered, which is a pathogenetically justified direction at all stages of restorative treatment after cerebral circulation disorders. One of the most studied original cytoprotectors, demonstrating safety, efficacy and good tolerability, is cytoflavin. The results of numerous clinical trials have revealed a significant positive clinical and morphological dynamics when taking cytoflavin in patients after ischemic stroke.

The overlooked "nonclassical" functions of major histocompatibility complex (MHC) class II antigens in immune and nonimmune cells.

PubMed

Altomonte, M; Pucillo, C; Maio, M

1999-06-01

Besides their "classical" antigenic peptide-presenting activity, major histocompatibility complex (MHC) class II antigens can activate different cellular functions in immune and nonimmune cells. However, this "nonclassical" role and its functional consequences are still substantially overlooked. In this review, we will focus on these alternative functional properties of MHC class II antigens, to reawaken attention to their present and foreseeable immunobiologic and pathogenetic implications. The main issues that will be addressed concern 1) the role of MHC class II molecules as basic components of exchangeable oligomeric protein complexes with intracellular signaling ability; 2) the nonclassical functions of MHC class II antigens in immune cells; 3) the pathogenetic role of MHC class II antigens in inflammatory/autoimmune and infectious disease; and 4) the functional role of MHC class II antigens in solid malignancies.

Reliable and versatile immortal muscle cell models from healthy and myotonic dystrophy type 1 primary human myoblasts.

PubMed

Pantic, Boris; Borgia, Doriana; Giunco, Silvia; Malena, Adriana; Kiyono, Tohru; Salvatori, Sergio; De Rossi, Anita; Giardina, Emiliano; Sangiuolo, Federica; Pegoraro, Elena; Vergani, Lodovica; Botta, Annalisa

2016-03-01

Primary human skeletal muscle cells (hSkMCs) are invaluable tools for deciphering the basic molecular mechanisms of muscle-related biological processes and pathological alterations. Nevertheless, their use is quite restricted due to poor availability, short life span and variable purity of the cells during in vitro culture. Here, we evaluate a recently published method of hSkMCs immortalization, relying on ectopic expression of cyclin D1 (CCND1), cyclin-dependent kinase 4 (CDK4) and telomerase (TERT) in myoblasts from healthy donors (n=3) and myotonic dystrophy type 1 (DM1) patients (n=2). The efficacy to maintain the myogenic and non-transformed phenotype, as well as the main pathogenetic hallmarks of DM1, has been assessed. Combined expression of the three genes i) maintained the CD56(NCAM)-positive myoblast population and differentiation potential; ii) preserved the non-transformed phenotype and iii) maintained the CTG repeat length, amount of nuclear foci and aberrant alternative splicing in immortal muscle cells. Moreover, immortal hSkMCs displayed attractive additional features such as structural maturation of sarcomeres, persistence of Pax7-positive cells during differentiation and complete disappearance of nuclear foci following (CAG)7 antisense oligonucleotide (ASO) treatment. Overall, the CCND1, CDK4 and TERT immortalization yields versatile, reliable and extremely useful human muscle cell models to investigate the basic molecular features of human muscle cell biology, to elucidate the molecular pathogenetic mechanisms and to test new therapeutic approaches for DM1 in vitro. Copyright © 2016 Elsevier Inc. All rights reserved.

The human immune response to streptococcal extracellular antigens: clinical, diagnostic, and potential pathogenetic implications.

PubMed

Johnson, Dwight R; Kurlan, Roger; Leckman, James; Kaplan, Edward L

2010-02-15

Determination of an immune response to group A Streptococcus (GAS) antigens, frequently anti-streptolysin O and anti-DNase B, is crucial for documentation of bona fide GAS infection. Although the importance of immunologic confirmation of infection is widely accepted, the immediate and long-term immunokinetics of the human antibody response are incompletely documented and poorly understood. Pediatric study participants (n = 160) were followed during a 2-year study with monthly throat cultures (n = 3491) and blood samples (n = 1679) obtained every 13 weeks. Recovered GAS were characterized; serum anti-streptolysin O and anti-DNase B antibody titers were determined. Antibody titers and GAS culture results were temporally correlated and analyzed. The analyses clearly document, in some instances for the first time, that an increase in antibody titer more accurately defines infection than does an absolute titer (eg, "upper limit of normal"), that antibody titers can remain elevated for many months even without GAS, and that some individuals may harbor GAS continuously for months or years without symptoms of infection and without an associated immune response. Measuring 2 different antibodies is more accurate in defining infection. Single time-point cultures and single antibody titers are often misleading. Sequential samples more accurately define infection, allowing correlation of titer increases with temporal confirmation of GAS acquisition. Understanding kinetics of the immune response(s) to GAS infection is necessary in formulating accurate clinical diagnostic conclusions, to appropriate design of clinical and epidemiological studies examining the association of GAS with subsequent sequelae, and to providing insight into pathogenetic mechanisms associated with this important human pathogen.

Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold

PubMed Central

Cruz-Monteagudo, Maykel; Borges, Fernanda; Cordeiro, M. Natália D. S.; Helguera, Aliuska Morales; Tejera, Eduardo; Paz-y-Miño, Cesar; Sánchez-Rodríguez, Aminael; Perera-Sardiña, Yunier; Perez-Castillo, Yunierkis

2017-01-01

Background: In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson´s disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD. Currently, only two chemical scaffolds has been proposed as potential dual MAO-B inhibitors/A2AAR antagonists (caffeine derivatives and benzothiazinones). Methods: In this study, we conduct a series of chemoinformatics analysis in order to evaluate and advance the potential of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold. Results: The information provided by SAR data mining analysis based on network similarity graphs and molecular docking studies support the suitability of the chromone nucleus as a potential MAO-B/A2AAR dual binding scaffold. Additionally, a virtual screening tool based on a group fusion similarity search approach was developed for the prioritization of potential MAO-B/A2AAR dual binder candidates. Among several data fusion schemes evaluated, the MEAN-SIM and MIN-RANK GFSS approaches demonstrated to be efficient virtual screening tools. Then, a combinatorial library potentially enriched with MAO-B/A2AAR dual binding chromone derivatives was assembled and sorted by using the MIN-RANK and then the MEAN-SIM GFSS VS approaches. Conclusion: The information and tools provided in this work represent valuable decision making elements in the search of novel chromone derivatives with a favorable dual binding profile as MAO-B inhibitors and A2AAR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson´s disease. PMID:28093976

[Genetic predisposition and Pediatric Acute Respiratory Distress Syndrome: New tools for genetic study].

PubMed

Erranz, M Benjamín; Wilhelm, B Jan; Riquelme, V Raquel; Cruces, R Pablo

2015-01-01

Acute respiratory distress syndrome (ARDS) is the most severe form of respiratory failure. Theoretically, any acute lung condition can lead to ARDS, but only a small percentage of individuals actually develop the disease. On this basis, genetic factors have been implicated in the risk of developing ARDS. Based on the pathophysiology of this disease, many candidate genes have been evaluated as potential modifiers in patient, as well as in animal models, of ARDS. Recent experimental data and clinical studies suggest that variations of genes involved in key processes of tissue, cellular and molecular lung damage may influence susceptibility and prognosis of ARDS. However, the pathogenesis of pediatric ARDS is complex, and therefore, it can be expected that many genes might contribute. Genetic variations such as single nucleotide polymorphisms and copy-number variations are likely associated with susceptibility to ARDS in children with primary lung injury. Genome-wide association (GWA) studies can objectively examine these variations, and help identify important new genes and pathogenetic pathways for future analysis. This approach might also have diagnostic and therapeutic implications, such as predicting patient risk or developing a personalized therapeutic approach to this serious syndrome. Copyright © 2015. Publicado por Elsevier España, S.L.U.

[Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation].

PubMed

Aitbaev, K A; Murkamilov, I T; Fomin, V V

The paper gives an update on the role of the gut microbiome (GM) in the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver cirrhosis (LC), and its complications, such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), and discusses the possibilities of its correction with prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The pathophysiology of the liver diseases in question demonstrates some common features that are characterized by pathogenic changes in the composition of the gastrointestinal tract microflora, by intestinal barrier impairments, by development of endotoxemia, by increased liver expression of proinflammatory factors, and by development of liver inflammation. In progressive liver disease, the above changes are more pronounced, which contributes to the development of LC, HE, and HCC. GM modulation using prebiotics, probiotics, synbiotics, antibiotics, and FMT diminishes dysbacteriosis, strengthens the intestinal mucosal barrier, reduces endotoxemia and liver damage, and positively affects the clinical manifestations of HE. Further investigations are needed, especially in humans, firstly, to assess a relationship of GM to the development of liver diseases in more detail and, secondly, to obtain evidence indicating the therapeutic efficacy of GM-modulating agents in large-scale, well-designed, randomized, controlled, multicenter studies.

Flexibility and variability in lexicon usage among Yoruba-speaking Nigerian outpatients with schizophrenia: a controlled study.

PubMed

Adewuya, Abiola O; Adewuya, Abiodun O

2008-01-01

The studies on language dysfunction in schizophrenia are few, inconclusive and have all been done in the western culture. There may be cross-cultural and cross-lingual differences in problems with speeches of patients with schizophrenia. This study aims to examine the flexibility or variability in the use of words among a group of Nigerian patients with schizophrenia compared with healthy controls. The spoken samples of 48 outpatients with schizophrenia and 48 matched controls were assessed using the mean segmental type-token ratio (MSTTR). The sociodemographic and clinical variables of the patients with schizophrenia were also compared with their MSTTR scores. The MSTTR score for the patients with schizophrenia was significantly lower compared with that of healthy controls (p < 0.001). The factors independently associated with a lower MSTTR in patients with schizophrenia include younger age at onset of illness, presence of negative formal thought disorder and simple or hebephrenic subtype of schizophrenia. The problem with flexibility and variability in lexicon usage among patients with schizophrenia is a cross-cultural phenomenon. The MSTTR may have value in predicting clinical judgements of thought disorder or in identifying deviant language. These may have broad potentials for application in longitudinal and pathogenetic studies of schizophrenia. (c) 2008 S. Karger AG, Basel.

Clinical trials for neuroprotection in ALS.

PubMed

Siciliano, G; Carlesi, C; Pasquali, L; Piazza, S; Pietracupa, S; Fornai, F; Ruggieri, S; Murri, L

2010-07-01

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.

Trophoblastic progranulin expression is upregulated in cases of fetal growth restriction and preeclampsia.

PubMed

Stubert, Johannes; Schattenberg, Florian; Richter, Dagmar-Ulrike; Dieterich, Max; Briese, Volker

2012-05-13

The expression of the anti-inflammatory glycoprotein progranulin and the hypoxia-induced transcription factor 1α (HIF-1α) in the villous trophoblast was compared between placentae from patients with preeclampsia (PE), fetal growth restriction (FGR), and normal controls. Matched pairs analysis of third trimester placentae specimens (mean gestational age 36+2) was performed by semiquantitative measurements of the immunohistochemical staining intensities for progranulin and HIF-1α expression (PE n=13, FGR n=9 and controls n=11). Further, placental progranulin mRNA expression was analyzed by qRT-PCR on term placentae (n=3 for each group). Compared to controls, villous trophoblast revealed a significantly higher expression of progranulin in cases of PE (P<0.05) and FGR (P<0.01). Similar results were shown for HIF-1α expression (P<0.01 for PE and <0.05 for FGR). The increase of the progranulin protein was not accompanied by an increase of the progranulin mRNA in term placentae. Increased expression of progranulin protein in villous trophoblast cells in cases of PE and FGR may result from disturbed placental development and, therefore, may be of pathogenetic importance. The increase was correlated to HIF-1α expression. Further evaluation of this potential mechanism of regulation is required.

[Metabolic effects of static physical load under the conditions of pharmakologicheskoĭ mobilization of physical endurance].

PubMed

Nagornev, S N; Kalinkin, S V; Bobrovnitskiĭ, I P; Sytnik, S I; Petrova, T V; Orlova, T A

2000-01-01

The model of static physical loading (SPL) was used to study the biochemical effects of graded static tension and potentiality for pharmacological mobilization of physical endurance with participation of male volunteers. A close pathogenetic linkage between the established metabolic effects of the model and their adaptive adequacy to the stressing factor show that there is every reason to arrange the observed shifts in a SPL syndrome. The SPL syndrome is primarily manifested by exaggerated tone of the adrenoactive structures, inhibition of insulin production by the pancreas, activation of the neuropeptide anti-stress mechanisms, predominant utilization of the lipid substrate in energy production, intensification of protein catabolism, and increase in myocyte membrane permeability due to energy deficit. The investigation demonstrated that improvement of static physical endurance can be attained with a mobilizing stimulator (sidnocarb) and a combination of sidnocarb with a nonmediatory preparation (bemytil). This pharmacological combination levels side-effects of exorbitant activation of the adrenal system. On the contrary, a metabolic vitamin-microelements complex ("cocktail C") perceivably enhances SPL endurance (sidnocarb dose was lowered in three times), possesses the stress-protective effect, the ability to moderate the intensity of free (uninvolved in phosphorylation) oxidation and to optimize energy-plastic processes with predominant utilization of the lipid substrate.

[Pathogenetic basis of treatment for chronic obstructive pulmonary disease].

PubMed

Kozak-Szkopek, E; Dworzański, W; Hanzlik, J

1996-07-01

The pathological reactions are discussed as a basis of applied therapy in patients with chronic obstructive pulmonary disease. The pharmacokinetic mechanisms of contemporary used drugs are presented with indication of interaction in allergic reaction.

Exosomes released in vitro from Epstein-Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs.

PubMed

Canitano, Andrea; Venturi, Giulietta; Borghi, Martina; Ammendolia, Maria Grazia; Fais, Stefano

2013-09-01

EBV is a human herpesvirus associated with a number of malignancies. Both lymphoblastoid cell lines (LCLs), and EBV-infected nasopharyngeal carcinoma (NPC) cells have been demonstrated to release exosomes containing the EBV-encoded latent membrane protein 1 (LMP1), and mature micro-RNAs (EBV-miRNAs). Here we analyze the EBV protein and nucleic acid content of exosomes from different EBV-infected cells (LCL, 721 and Daudi) and we show for the first time that exosomes released from LCLs and 721 also contain EBV-encoded latent phase mRNAs. This confirms and strengthens exosomes pathogenetic potential, and might provide insights for development of novel diagnostic and therapeutic strategies. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Local Control of Aldosterone Production and Primary Aldosteronism.

PubMed

Lalli, Enzo; Barhanin, Jacques; Zennaro, Maria-Christina; Warth, Richard

2016-03-01

Primary aldosteronism (PA) is caused by excessive production of aldosterone by the adrenal cortex and is determined by a benign aldosterone-producing adenoma (APA) in a significant proportion of cases. Local mechanisms, as opposed to circulatory ones, that control aldosterone production in the adrenal cortex are particularly relevant in the physiopathological setting and in the pathogenesis of PA. A breakthrough in our understanding of the pathogenetic mechanisms in APA has been the identification of somatic mutations in genes controlling membrane potential and intracellular calcium concentrations. However, recent data show that the processes of nodule formation and aldosterone hypersecretion can be dissociated in pathological adrenals and suggest a model envisaging different molecular events for the pathogenesis of APA. Copyright © 2016 Elsevier Ltd. All rights reserved.

Secondary osteoporosis.

PubMed

Gennari, C; Martini, G; Nuti, R

1998-06-01

Generalized osteoporosis currently represents a heterogeneous group of conditions with many different causes and pathogenetic mechanisms, that often are variably associated. The term "secondary" is applied to all patients with osteoporosis in whom the identifiable causal factors are other than menopause and aging. In this heterogeneous group of conditions, produced by many different pathogenetic mechanisms, a negative bone balance may be variably associated with low, normal or increased bone remodeling states. A consistent group of secondary osteoporosis is related to endocrinological or iatrogenic causes. Exogenous hypercortisolism may be considered an important risk factor for secondary osteoporosis in the community, and probably glucocorticoid-induced osteoporosis is the most common type of secondary osteoporosis. Supraphysiological doses of corticosteroids cause two abnormalities in bone metabolism: a relative increase in bone resorption, and a relative reduction in bone formation. Bone loss, mostly of trabecular bone, with its resultant fractures is the most incapacitating consequence of osteoporosis. The estimated incidence of fractures in patients prescribed corticosteroid is 30% to 50%. Osteoporosis is considered one of the potentially serious side effects of heparin therapy. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (over 4-5 months), and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts, and by enhancing the activity of individual osteoclasts. Hyperthyroidism is frequently associated with loss of trabecular and cortical bone; the enhanced bone turnover that develops in thyrotoxicosis is characterized by an increase in the number of osteoclasts and resorption sites, and an increase in the ratio of resorptive to formative bone surfaces, with the net result of bone loss. Despite these findings, the occurrence of pathological fractures in patients with hyperthyroidism is relatively low, and probably due to the fact that deficiencies in bone mass may be reversed by treatment of the thyroid disease. Most, but not all, studies on insulin-dependent diabetes mellitus (IDDM) report an association with osteopenia. In IDDM, the extent of bone loss is usually slight, which helps explain the discrepancy between the frequency of decreased bone mineral density, and the frequency of osteoporotic fractures in long-standing diabetes. Contradictory results have been obtained in non-insulin-dependent diabetes mellitus (NIDDM) patients. Increased rates of bone loss at the radius and lumbar spine were demonstrated either in patients with two-thirds gastric resection and Billroth II reconstruction, or in those with one-third resection and Billroth I anastomosis, and the metabolic bone disease following gastrectomy may consist also of osteomalacia or mixed pattern of osteoporosis-osteomalacia, with secondary hyperparathyroidism. Miscellaneous causes of secondary osteoporosis are also immobilization, pregnancy and lactation, and alcohol abuse.

WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities.

PubMed

Ravizza, Teresa; Onat, Filiz Y; Brooks-Kayal, Amy R; Depaulis, Antoine; Galanopoulou, Aristea S; Mazarati, Andrey; Numis, Adam L; Sankar, Raman; Friedman, Alon

2017-03-01

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory.

PubMed

Palmeri, Agostino; Ricciarelli, Roberta; Gulisano, Walter; Rivera, Daniela; Rebosio, Claudia; Calcagno, Elisa; Tropea, Maria Rosaria; Conti, Silvia; Das, Utpal; Roy, Subhojit; Pronzato, Maria Adelaide; Arancio, Ottavio; Fedele, Ernesto; Puzzo, Daniela

2017-07-19

High levels of amyloid-β peptide (Aβ) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aβ are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aβ levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aβ function, by using anti-murine Aβ antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aβ levels in the healthy brain which, in turn, boosts synaptic plasticity and memory. SIGNIFICANCE STATEMENT Amyloid-β (Aβ) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aβ, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aβ levels and function during LTP. We show that cGMP enhances Aβ production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aβ, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aβ. Copyright © 2017 the authors 0270-6474/17/376926-12$15.00/0.

Anencephaly with incomplete twinning (diprosopus).

PubMed

Riccardi, V M; Bergmann, C A

1977-10-01

A case of diprosopus with anencephaly is presented. It is suggested that such concurrence of neural tube defects and incomplete twinning corroborates the notion that a single pathogenetic mechanism may be common to both neural tube defects and monozygotic twinning.

Severe Mental Retardation in Children in a Northern Swedish County

ERIC Educational Resources Information Center

And Others; Gustavson, K. H.

1977-01-01

Presented are results of a study of the incidence, prevalence, gestational age, birth weight, associated central nervous system disorders, and etiological and pathogenetic aspects of 161 severely mentally retarded children in Northern Sweden. (CL)

De novo development of artistic creativity in Alzheimer's disease.

PubMed

Chakravarty, Ambar

2011-10-01

The case of an 82-year-old female with probable Alzheimer's disease (AD), who developed unusual artistic creativity after development of her disease, is described. The possible pathogenetic mechanism is discussed. The patient showed no inclination toward visual arts during her premorbid years. However, 4 years after development of AD suggestive symptoms she started painting beautiful pictures rather impulsively. Some such paintings have been appreciated even by a qualified art expert. Such de novo development of artistic creativity had been described earlier in subjects with the semantic form of fronto-temporal dementia (FTD), but not in AD. The prevailing concept of lateralized compromise and paradoxical functional facilitation, proposed in connection with FTD subjects, may not be applicable in AD subjects where the affection is more diffuse and more posterior in the brain. Hence, the likely pathogenetic mechanism involved in the case described may remain uncertain. Possibilities are discussed.

De novo development of artistic creativity in Alzheimer's disease

PubMed Central

Chakravarty, Ambar

2011-01-01

The case of an 82-year-old female with probable Alzheimer's disease (AD), who developed unusual artistic creativity after development of her disease, is described. The possible pathogenetic mechanism is discussed. The patient showed no inclination toward visual arts during her premorbid years. However, 4 years after development of AD suggestive symptoms she started painting beautiful pictures rather impulsively. Some such paintings have been appreciated even by a qualified art expert. Such de novo development of artistic creativity had been described earlier in subjects with the semantic form of fronto-temporal dementia (FTD), but not in AD. The prevailing concept of lateralized compromise and paradoxical functional facilitation, proposed in connection with FTD subjects, may not be applicable in AD subjects where the affection is more diffuse and more posterior in the brain. Hence, the likely pathogenetic mechanism involved in the case described may remain uncertain. Possibilities are discussed. PMID:22346020

Malassezia virulence determinants.

PubMed

Hort, Wiebke; Mayser, Peter

2011-04-01

Malassezia yeasts are associated with a number of dermatologic and systemic diseases in humans and animals. Pityriasis versicolor is amongst these diseases and represents one of the most common human skin diseases. Beyond that, the role of Malassezia yeasts in the pathogenesis of other skin diseases such as psoriasis, seborrheic dermatitis and confluent and reticulate papillomatosis is discussed but remains less clear. Clear pathogenetic mechanisms of the above-mentioned diseases are not known so far. The review presents new findings on virulence factors of Malassezia yeasts, shedding light on the pathogenesis of Malassezia-associated diseases. Several virulence factors in Malassezia yeasts are known, based on their enzymatic lipolytic activity resulting in the production of distinct metabolites and special cell wall features. Recently, a secondary metabolic pathway possibly implicated in the pathogenesis of pityriasis versicolor was described. The article presents virulence factors of Malassezia yeasts ranging from irritant metabolic byproducts to highly bioactive indole derivatives and attempts to clarify their pathogenic implications in the different diseases. Special emphasis is given to the pathogenesis of pityriasis versicolor, as it represents the disease wherein the causative relationship with Malassezia yeasts appears the most obvious.

Toxic metal(loid)-based pollutants and their possible role in autism spectrum disorder.

PubMed

Bjørklund, Geir; Skalny, Anatoly V; Rahman, Md Mostafizur; Dadar, Maryam; Yassa, Heba A; Aaseth, Jan; Chirumbolo, Salvatore; Skalnaya, Margarita G; Tinkov, Alexey A

2018-06-11

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-κB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects' genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies. Copyright © 2018 Elsevier Inc. All rights reserved.

Integrative comparison of mRNA expression patterns in breast cancers from Caucasian and Asian Americans with implications for precision medicine

PubMed Central

Wang, Jianan; He, Max M; Li, Liren; Zhang, Jinfeng

2016-01-01

Asian Americans (AS) have significantly lower incidence and mortality rates of breast cancer (BRCA) than Caucasian Americans (CA). While this racial disparity has been documented the underlying pathogenetic factors explaining it are obscure. We addressed this issue by an integrative genomics approach to compare mRNA expression between AS and CA cases of BRCA. RNA-seq data from the Cancer Genome Atlas showed that mRNA expression revealed significant differences at gene and pathway levels. Increased susceptibility and severity in CA patients were likely the result of synergistic environmental and genetic risk factors, with arachidonic acid metabolism and PPAR signaling pathways implicated in linking environmental and genetic factors. An analysis that also added eQTL data from the Genotype-Tissue Expression Project and single nucleotide polymorphism (SNP) data from the 1000 Genomes Project identified several SNPs associated with differentially expressed genes. Overall, the associations we identified may enable a more focused study of genotypic differences that may help explain the disparity in BRCA incidence and mortality rates in CA and AS populations and inform precision medicine. PMID:28069798

[Scimitar syndrome. Correlation anatomo-embryological].

PubMed

Muñoz-Castellanos, Luis; Kuri-Nivon, Magdalena

2016-01-01

To describe morphologically a toracoabdominal visceral block of a scimitar's syndrome case. We propose a pathogenetic theory wich explains the development of the pulmonary venous connection in this syndrome. The anatomic specimen was described with the segmental sequential system. The situs was solitus, the connections between the cardiac segments and the associated anomalies were determined. The anatomy of both lungs, including the venous pulmonary connection, was described. A pathogenetic hypothesis was made, which explains the pulmonary venous connection throw a correlation between the pathology of this syndrome and the normal development of the pulmonary veins. The situs was solitus, the connections of the cardiac chambers were normal; there were hypoplasia and dysplasia of the right lung with sequestration of the inferior lobe; the right pulmonary veins were connected with a curved collector which drainaged into the suprahepatic segment of the inferior vena cava; the left pulmonary veins were open into the left atrium. The sequestered inferior lobe of the right lung received irrigation throw a collateral aortopulmonary vessel. There was an atrial septal defect. The pathogenetic hypothesis propose that the pulmonary venous connection in this syndrome represent the persistent of the Streeter's horizon xiv (28-30 days of development), period in which the sinus of the pulmonary veins has double connection, with the left atrium and with a primitive collector into the right viteline vein which forms the suprahepatic segment of the inferior vena cava. Copyright © 2015 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

Reversible severe hepatitis in anorexia nervosa: a case report and overview.

PubMed

Ramsoekh, Dewkoemar; Taimr, Pavel; Vanwolleghem, Thomas

2014-04-01

Mildly elevated transaminases are often observed in anorexia nervosa patients, but severe hepatitis is less common. We suggest that hypoperfusion is the pathogenetic factor that causes severe hepatitis in a patient with a very poor nutritional status and present an overview of previous case reports. In our patient, early initiation of intravenous fluids resulted in rapid recovery of the liver test abnormalities, despite minimal oral caloric intake, the refusal of enteral feeding and the development of a hypoglycemic coma. Two months after admission, transaminases had normalized. Reversible severe hepatitis has been described in most of the cases, with only one anorexia nervosa-related fatal hepatitis. In general, both adequate hydration and gradual enteral feeding with monitoring of electrolytes are essential in the management of anorexia patients with severe hepatitis.

Pathogenesis of African swine fever in domestic pigs and European wild boar.

PubMed

Blome, Sandra; Gabriel, Claudia; Beer, Martin

2013-04-01

African swine fever (ASF) is among the most important viral diseases that can affect domestic and feral pigs. Both clinical signs and pathomorphological changes vary considerably depending on strain virulence and host factors. Acute infections with highly virulent virus strains lead to a clinical course that resembles a viral haemorrhagic fever that is characterized by pronounced depletion of lymphoid tissues, apoptosis of lymphocyte subsets, and impairment of haemostasis and immune functions. It is generally accepted that most lesions can be attributed to cytokine-mediated interactions triggered by infected and activated monocytes and macrophages, rather than by virus-induced direct cell damage. Nevertheless, most pathogenetic mechanisms are far from being understood. This review summarizes the current knowledge and discusses implications and research gaps. Copyright © 2012 Elsevier B.V. All rights reserved.

Silent Thyroiditis

PubMed Central

Walker, Peter

1984-01-01

Silent or painless thyroiditis is a frequent cause of transient hyperthyroidism, which is characterized by recent onset of symptoms in a patient with a normal to modestly enlarged and firm thyroid gland. The hallmarks of the disease are the absence of thyroidal pain or tenderness and a markedly reduced radioiodine uptake. Histologically, the gland is characterized by an important lymphocytic infiltration, occasionally to the point of lymphoid follicle formation. However, other indices of an autoimmune cause are usually absent. The disease appears to have a predilection for the postpartum period. Relapses may occur with subsequent pregnancies. Otherwise, the course is usually benign and transient, requiring moderate doses of β-adrenergic blocking agents for symptomatic relief. No pathogenetic factors are known, but the disease may conceivably have an autoimmune basis, particularly in the postpartum patient. PMID:21278944

[Neurosis and genetic theory of etiology and pathogenesis of ulcer disease].

PubMed

Kolotilova, M L; Ivanov, L N

2014-01-01

Based on the analysis of literature data and our own research, we have developed the original concept of etiology and pathogenesis of peptic ulcer disease. An analysis of the literature shows that none of the theories of pathogenesis of peptic ulcer disease does not cover the full diversity of the involved functions and their shifts, which lead to the development of ulcers in the stomach and the duodenum. Our neurogenic-genetic theory of etiology and pathogenesis of gastric ulcer and duodenal ulcer very best explains the cause-and-effect relationships in the patient peptic ulcer, allowing options for predominance in one or the other case factors of neurosis or genetic factors. However, it is clear that the only other: combination of neurogenic factor with genetically modified reactivity of gastroduodenal system (the presence of the target organ) cause the chronicity of the sores. The theory of peptic ulcer disease related to psychosomatic pathologies allows us to develop effective schema therapy, including drugs with psychocorrective action. On the basis of our theory of the role of Helicobacter pylori infection is treated as a pathogenetic factor in the development of peptic ulcer disease.

How Obesity Affects Tendons?

PubMed

Abate, Michele; Salini, Vincenzo; Andia, Isabel

Several epidemiological and clinical observations have definitely demonstrated that obesity has harmful effects on tendons. The pathogenesis of tendon damage is multi-factorial. In addition to overload, attributable to the increased body weight, which significantly affects load-bearing tendons, systemic factors play a relevant role. Several bioactive peptides (chemerin, leptin, adiponectin and others) are released by adipocytes, and influence tendon structure by means of negative activities on mesenchymal cells. The ensuing systemic state of chronic, sub-clinic, low-grade inflammation can damage tendon structure. Metabolic disorders (diabetes, impaired glucose tolerance, and dislipidemia), frequently associated with visceral adiposity, are concurrent pathogenetic factors. Indeed, high glucose levels increase the formation of Advanced Glycation End-products, which in turn form stable covalent cross-links within collagen fibers, modifying their structure and functionality.Sport activities, so useful for preventing important cardiovascular complications, may be detrimental for tendons if they are submitted to intense acute or chronic overload. Therefore, two caution rules are mandatory: first, to engage in personalized soft training program, and secondly to follow regular check-up for tendon pathology.

[Psychoemotional stress and somatic diseases in veterans of special risk units].

PubMed

Alishev, N V; Tsygan, V N; Drabkin, B A; Apchel, V Ia; Nikolaeva, N A; Tarumov, A V; Fesiun, A D; Fedoseev, V M

2008-01-01

Participants of nuclear-powered submarine accident liquidation and special risk units' veterans participating in surface nuclear weapon tests as well as in liquidation of their consequences have been examined. It has been established that functional state of this category of people is difficult to interpret only in the context of radioactive irradiation effect or injuring stress factor exposure. This state is determined by a complex of psychotraumatic factors tending to become aggravated and characterizing by their individual significance and absolute or relative insolvability. In most representatives of this category the disease is manifested by psychopathologic syndrome of neurotic disorders (low spirits, emotional lability, asthenia, anxiety) and somatic disturbances as dysfunction of the cardiovascular, respiratory, digestive and other systems. The results obtained provide the pathogenetic substantiation of efficient ways and methods for rehabilitation of the special risk units' veterans. The data prove the necessity of appropriate correction of cardiovascular disorders in practically healthy servicemen residing under conditions of psychoemotional tension.

Antiphospholipid Syndrome during pregnancy: the state of the art

PubMed Central

Di Prima, Fosca A. F.; Valenti, Oriana; Hyseni, Entela; Giorgio, Elsa; Faraci, Marianna; Renda, Eliana; De Domenico, Roberta; Monte, Santo

2011-01-01

Obstetric complications are the hallmark of antiphospholipid syndrome. Recurrent miscarriage, early delivery, oligohydramnios, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/eclampsia, HELLP syndrome, arterial or venous thrombosis and placental insufficiency are the most severe APS-related complication for pregnant women. Antiphospholipid antibodies promote activation of endothelial cells, monocytes and platelets, causing an overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. These factors, associated with the typical changes in the hemostatic system during normal pregnancy, result in a hypercoagulable state. This is responsible of thrombosis that is presumed to provoke many of the pregnancy complications associated with APS. Obstetric care is based on combined medical-obstetric high-risk management and treatment with the association between aspirin and heparin. This review aims to deter- mine the current state of the art of APS by investigating the knowledge achievements of recent years, to provide the most appropriate diagnostic and therapeutic management for pregnant women suffering from this syndrome. PMID:22439075

Opposing Functions of the ETS Factor Family Define Shh Spatial Expression in Limb Buds and Underlie Polydactyly

PubMed Central

Lettice, Laura A.; Williamson, Iain; Wiltshire, John H.; Peluso, Silvia; Devenney, Paul S.; Hill, Alison E.; Essafi, Abdelkader; Hagman, James; Mort, Richard; Grimes, Graeme; DeAngelis, Carlo L.; Hill, Robert E.

2012-01-01

Summary Sonic hedgehog (Shh) expression during limb development is crucial for specifying the identity and number of digits. The spatial pattern of Shh expression is restricted to a region called the zone of polarizing activity (ZPA), and this expression is controlled from a long distance by the cis-regulator ZRS. Here, members of two groups of ETS transcription factors are shown to act directly at the ZRS mediating a differential effect on Shh, defining its spatial expression pattern. Occupancy at multiple GABPα/ETS1 sites regulates the position of the ZPA boundary, whereas ETV4/ETV5 binding restricts expression outside the ZPA. The ETS gene family is therefore attributed with specifying the boundaries of the classical ZPA. Two point mutations within the ZRS change the profile of ETS binding and activate Shh expression at an ectopic site in the limb bud. These molecular changes define a pathogenetic mechanism that leads to preaxial polydactyly (PPD). PMID:22340503

[Hashimoto's thyroiditis(chronic thyroiditis), IgG4-related thyroiditis].

PubMed

Itoh, Mitsuyasu

2012-11-01

Hashimoto's thyroiditis emerges in patients who have genetic preponderance such as SNPs of CTLA-4 and risk factors such as excess intake of iodine, pregnancy or postpartum period, and smoking. Such risk factors also affect the entire clinical course. One of the major outcomes in Hashimoto's thyroiditis appears to be increased in cardio-vascular risks through subclinical hypothyroidism and concomitant metabolic syndrome, but in most cases, treatment with L-T4 has little effects on cardio-vascular benefit or quality of life. The pregnant women also have risks for obstetric complications and postpartum thyroid dysfunction. The women who have anti-TPO antibodies, type 1 diabetes, or previous history of post-partum thyroid dysfunction are recommended to be measured their TSH. It is noteworthy that Hashimoto's thyroiditis is sometimes complicated with encephalopathy, papillary carcinoma, or IgG4-related thyroiditis. IgG4-related thyroiditis is partly similar but partly discerned from a variant of Hashimoto's thyroiditis. The pathogenetic roles of this variant on autoimmune-based thyroiditis remain unclear.

Diabetic nephropathy among Mexican Americans.

PubMed

Debnath, Subrata; Thameem, Farook; Alves, Tahira; Nolen, Jacqueline; Al-Shahrouri, Hania; Bansal, Shweta; Abboud, Hanna E; Fanti, Paolo

2012-04-01

The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations.

[Relationships between psychosomatics and somatopsychiatry in modern medicine].

PubMed

Paleev, N R; Krasnov, V N

2009-01-01

Progress in many clinical disciplines and neurobiology for the last decades give reason to reconsider some fundamental provisions of psychosomatic medicine and its relationships with somatopsychiatry. The universally accepted biopsychosocial model of the disease as proposed by V.N.Bekhterev implies involvement of psychological and psychosocial factors at early stages of many forms of somatic pathology. Intricate interplay between somatic and psychic components is exemplified by correlation of cardiovascular disorders and depression. Depression is diagnosed in 17-27% of the patients with coronary heart disease undergoing coronary angiography and in 16-45% of the post-infarction cases. Frequency of depression/hypertensive disease comorbidity is estimated at 30%. Similarity of pathogenetic mechanisms of cardiovascular diseases and depressive states is due to stress as their common provoking factor. Another important aspect of the relationship between medicine and psychiatry (disregarded until recently) is high frequency of somatic disorders in psychiatric patients. Cooperation of psychiatrists and representatives of different medical disciplines in such areas as research and practical health care is needed to address this problem.

Diabetic nephropathy among Mexican Americans

PubMed Central

Debnath, Subrata; Thameem, Farook; Alves, Tahira; Nolen, Jacqueline; Al-Shahrouri, Hania; Bansal, Shweta; Abboud, Hanna E.; Fanti, Paolo

2012-01-01

The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations. PMID:22445478

Prenatal Ontogeny as a Susceptibility Period for Cortical GABA Neuron Disturbances in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2013-01-01

Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex. Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the prefrontal cortex in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia. PMID:23769891

Meta-analysis of factor V Leiden and prothrombin G20210A polymorphism in migraine.

PubMed

Lippi, Giuseppe; Mattiuzzi, Camilla; Cervellin, Gianfranco

2015-01-01

Migraine is a frequent and disabling condition, which exhibits a substantial genetic background and is frequently associated with abnormalities of primary and secondary hemostasis. We performed a systematic literature search and a meta-analysis of available data about the potential associations between migraine and factor V (FV) Leiden or prothrombin (FII) G20210A gene polymorphism. The final number of studies included was 15 (all cross-sectional) about migraine and FV Leiden, and 12 (all cross-sectional) about migraine and FII G20210A polymorphism, with broad inter-study heterogeneity (I², 82 and 85%). The cumulative prevalence of the FV 1691A allele was found to be similar between cases (n = 1450; 4.9%) and controls (n = 3468; 4.7%; P = 0.74). The cumulative prevalence of the FII 20210A allele was also found to be similar between cases (n = 1226; 4.2%) and controls (n = 3144; 4.5%; P = 0.59). Nevertheless, sub-analysis of studies in adults and children revealed that both polymorphisms were not associated with migraine in adults, but FV Leiden and the FII 20210A allele were approximately two-fold more prevalent in children with migraine than in those without. In conclusion, despite migraine exhibits a clear neurovascular origin and is frequently associated with thrombotic disorders, isolate thrombophilic mutations seem to play a negligible pathogenetic role in this condition in adults, whereas the increased prevalence of FV Leiden and the FII 20210A allele in children with migraine deserves further scrutiny.

miR-185 and miR-29a are similarly expressed in the bronchoalveolar lavage cells in IPF and lung cancer but common targets DNMT1 and COL1A1 show disease specific patterns

PubMed Central

Bibaki, Eleni; Tsitoura, Eliza; Vasarmidi, Eirini; Margaritopoulos, George; Trachalaki, Athina; Koutoulaki, Chara; Georgopoulou, Theodora; Spandidos, Demetrios A.; Tzanakis, Nikos; Antoniou, Katerina M.

2018-01-01

Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) constitute two progressively devastating lung diseases with common risk factors including aging and smoking. There is an increasing interest in the investigation of common pathogenic mechanisms between IPF and LC with therapeutic implications. Several oncomirs, microRNAs associated with malignancy, are also linked with IPF. miR-29a and miR-185 downregulation is probably involved both in carcinogenesis and fibrogenesis. We have previously observed miR-29a and miR-185 downregulation in IPF cells from bronchoalveolar lavage (BAL) and in this study we investigated their expression in LC BAL cells. Common targets of miR-29a and miR-185 such as DNA methyltransferase (DNMT)1, DNMT3b, COL1A1, AKT1 and AKT2 were measured. Potential correlations with pulmonary function tests, smoking status and endobronchial findings were investigated. Similar levels of miR-29a and miR-185 were detected in IPF and LC while their common targets AKT1 and DNMT3b were not found to differ, suggesting potential pathogenetic similarities at the level of key epigenetic regulators. By conrast, COL1A1 mRNA levels were increased in IPF suggesting a disease-specific mRNA signature. Notably, DNMT1 was downregulated in the LC group and its expression was further reduced in the presence of increasing malignant burden as it was implied by the endobronchial findings. PMID:29568927

Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic

PubMed Central

Bredesen, Dale E.

2016-01-01

Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins. The appropriate recognition of IAD as a potentially important pathogenetic condition in patients with cognitive decline offers the opportunity for successful treatment of a large number of patients whose current prognoses, in the absence of accurate diagnosis, are grave. PMID:26870879

Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic kidney disease?

PubMed

Paschou, E; Gavriilaki, E; Papaioannou, G; Tsompanakou, A; Kalaitzoglou, A; Sabanis, N

2016-11-01

Febuxostat is a xanthine oxidase inhibitor that during the last years has successfully replaced allopurinol treatment in patients with chronic kidney disease (CKD) and hyperuricemia. Several adverse events have been observed during therapy with febuxostat. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome induced by febuxostat has been poorly described, mainly in patient with CKD who previously developed allopurinol hypersensitivity syndrome. DRESS syndrome is characterized by manifold cutaneous reactions and systemic disorders with potential devastating consequences. The underlying pathogenetic mechanisms remain unidentified, though immune responses are often complicated. P-i concept can partially explain the phenomenon. The role of renal insufficiency appears to be crucial and further investigation is required. The present article describes the case of a CKD patient that developed febuxostat-related DRESS syndrome.

Next-generation sequencing of cancer genomes: back to the future

PubMed Central

Walter, Matthew J; Graubert, Timothy A; DiPersio, John F; Mardis, Elaine R; Wilson, Richard K; Ley, Timothy J

2010-01-01

The systematic karyotyping of bone marrow cells was the first genomic approach used to personalize therapy for patients with leukemia. The paradigm established by cytogenetic studies in leukemia (from gene discovery to therapeutic intervention) now has the potential to be rapidly extended with the use of whole-genome sequencing approaches for cancer, which are now possible. We are now entering a period of exponential growth in cancer gene discovery that will provide many novel therapeutic targets for a large number of cancer types. Establishing the pathogenetic relevance of individual mutations is a major challenge that must be solved. However, after thousands of cancer genomes have been sequenced, the genetic rules of cancer will become known and new approaches for diagnosis, risk stratification and individualized treatment of cancer patients will surely follow. PMID:20161678

Blood-based diagnostics of traumatic brain injuries

PubMed Central

Mondello, Stefania; Muller, Uwe; Jeromin, Andreas; Streeter, Jackson; Hayes, Ronald L; Wang, Kevin KW

2011-01-01

Traumatic brain injury is a major health and socioeconomic problem that affects all societies. However, traditional approaches to the classification of clinical severity are the subject of debate and are being supplemented with structural and functional neuroimaging, as the need for biomarkers that reflect elements of the pathogenetic process is widely recognized. Basic science research and developments in the field of proteomics have greatly advanced our knowledge of the mechanisms involved in damage and have led to the discovery and rapid detection of new biomarkers that were not available previously. However, translating this research for patients' benefits remains a challenge. In this article, we summarize new developments, current knowledge and controversies, focusing on the potential role of these biomarkers as diagnostic, prognostic and monitoring tools of brain-injured patients. PMID:21171922

The role of vitamin K in vascular calcification of patients with chronic kidney disease.

PubMed

Wuyts, Julie; Dhondt, Annemieke

2016-12-01

Patients with chronic kidney disease (CKD) are prone to vascular calcification. Pathogenetic mechanisms of vascular calcifications have been broadly studied and discussed such as the role of hyperphosphatemia, hypercalcemia, parathormone, and vitamin D. In recent years, new insights have been gained pointing to vitamin K as a main actor. It has been discovered that vitamin K is an essential cofactor for the activation of matrix Gla protein (MGP), a calcification inhibitor in the vessel wall. Patients with CKD often suffer from vitamin K deficiency, resulting in low active MGP and eventually a lack of inhibition of vascular calcification. Vitamin K supplementation and switching warfarin to new oral anticoagulants are potential treatments. In addition, MGP may have a role as a non-invasive biomarker for vascular calcification.

[Pathogenetic mechanisms of action of tarry substances and Mycobacterium tuberculosis in guinea pigs and rats].

PubMed

Pavlov, V A; Sabadash, E V; Fadina, O V; Mironova, A L

2002-01-01

Harmful environmental agents [polycyclic aromatic hydrocarbons (PAH)] have been ascertained to greatly stimulate the biosynthesis of arginine and urea and reduce the amount of sulfur-containing metabolites in the liver of experimental animals by increasing the level of sulfur sulfate. Against this background, contamination with Mycobacteria tuberculosis (MBT) inhibits the activity of arginine and drastically decreases its amount by elevating the concentration of sulfur-containing metabolites. The supplementary administration of sodium glutamate to animals receiving PAH and MBT potentiates a decrease in nitrogen-rich metabolites and increases the level of sulfur-containing metabolites guinea pigs, tuberculosis resistance being on the rise. Under the influence of a combined action of PAH and MBT, the mutagenic effect of the former lowered in rats.

Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy

PubMed Central

Tavakoli, Mitra; Asghar, Omar; Alam, Uazman; Petropoulos, Ioannis N.; Fadavi, Hassan; Malik, Rayaz A.

2010-01-01

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy. PMID:23148152

[Biliary ileus. Case report and therapeutic considerations].

PubMed

Ferranti, F; Mancini, G; Ippoliti, A; De Ascentis, G; D'Aristotile, A; Rossi, M; Ciampaglia, F; Monteferrante, E; Rotolo, A; Marcotullio, S

1995-01-01

The authors, after having described, a case of biliary ileus, analyse the principal pathogenetic aspects of the disease, and underline the diagnostic and therapeutic difficulties. They believe that the simple enterolithotomy represents, initially, the best therapy, in particular with patients in poor clinical conditions.

75 FR 66771 - National Heart, Lung, and Blood Institute; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-29

... Institute Special Emphasis Panel; Common Pathogenetic Mechanisms of Lung Cancer and COPD. Date: November 19... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Heart, Lung, and... clearly unwarranted invasion of personal privacy. [[Page 66772

Ameloblastic fibrosarcoma. Report of a case in a Nigerian.

PubMed

Adekeye, E O; Edwards, M B; Goubran, G F

1978-08-01

Ameloblastic fibrosarcoma is very rare and has not previously been reported from Nigeria. The case described here had typical clinical features, but the microscopic findings were unusual and difficult to interpret. The pathogenetic relationship between ameloblastic fibroma and fibrosarcoma is discussed.

Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

PubMed

Pescarmona, E; Pignoloni, P; Mauro, F R; Cerretti, R; Anselmo, A P; Mandelli, F; Baroni, C D

2000-08-01

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus

PubMed Central

Tay, Sen Hee; Mak, Anselm

2015-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately 1–45.3 per 100,000 people worldwide. Although deaths as a result of active and renal diseases have been substantially declining amongst SLE patients, disease involving the central nervous system (CNS), collectively termed neuropsychiatric systemic lupus erythematosus (NPSLE), remains one of the important causes of death in these patients. Cognitive dysfunction is one of the most common manifestations of NPSLE, which comprises deficits in information-processing speed, attention and executive function, in conjunction with preservation of speech. Albeit a prevalent manifestation of NPSLE, the pathogenetic mechanisms of cognitive dysfunction remain unclear. Recent advances in genetic studies, molecular techniques, neuropathology, neuroimaging and cognitive science have gleaned valuable insights into the pathophysiology of lupus-related cognitive dysfunction. In recent years, a role for autoantibodies, molecular and cellular mechanisms in cognitive dysfunction, has been emerging, challenging our previous concept of the brain as an immune privileged site. This review will focus on the potential pathogenic factors involved in NPSLE, including anti-N-methyl-d-aspartate receptor subunit NR2A/B (anti-NR2A/B) antibodies, matrix metalloproteinase-9, neutrophil extracellular traps and pro-inflammatory mediators. Better understanding of these mechanistic processes will enhance identification of new therapeutic modalities to halt the progression of cognitive decline in SLE patients. PMID:25955648

Overexpression of Mafb in Podocytes Protects against Diabetic Nephropathy

PubMed Central

Yoh, Keigyou; Ojima, Masami; Okamura, Midori; Nakamura, Megumi; Hamada, Michito; Shimohata, Homare; Moriguchi, Takashi; Yamagata, Kunihiro; Takahashi, Satoru

2014-01-01

We previously showed that the transcription factor Mafb is essential for podocyte differentiation and foot process formation. Podocytes are susceptible to injury in diabetes, and this injury leads to progression of diabetic nephropathy. In this study, we generated transgenic mice that overexpress Mafb in podocytes using the nephrin promoter/enhancer. To examine a potential pathogenetic role for Mafb in diabetic nephropathy, Mafb transgenic mice were treated with either streptozotocin or saline solution. Diabetic nephropathy was assessed by renal histology and biochemical analyses of urine and serum. Podocyte-specific overexpression of Mafb had no effect on body weight or blood glucose levels in either diabetic or control mice. Notably, albuminuria and changes in BUN levels and renal histology observed in diabetic wild-type animals were ameliorated in diabetic Mafb transgenic mice. Moreover, hyperglycemia-induced downregulation of Nephrin was mitigated in diabetic Mafb transgenic mice, and reporter assay results suggested that Mafb regulates Nephrin directly. Mafb transgenic glomeruli also overexpressed glutathione peroxidase, an antioxidative stress enzyme, and levels of the oxidative stress marker 8-hydroxydeoxyguanosine decreased in the urine of diabetic Mafb transgenic mice. Finally, Notch2 expression increased in diabetic glomeruli, and this effect was enhanced in diabetic Mafb transgenic glomeruli. These data indicate Mafb has a protective role in diabetic nephropathy through regulation of slit diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes and suggest that Mafb could be a therapeutic target. PMID:24722438

Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development.

PubMed

Sakai, Daisuke; Trainor, Paul A

2016-09-01

One-third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue-specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies. © 2016 Japanese Society of Developmental Biologists.

Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development

PubMed Central

Sakai, Daisuke; Trainor, Paul A.

2016-01-01

One-third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However our understanding of the mechanisms that induce tissue-specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies. PMID:27481486

[Problems of epidemic safety of drinking water use by the population of Russia].

PubMed

Nedachin, A E; Artemova, T Z; Dmitrieva, R A; Doskina, T V; Talaeva, Iu G; Ivanova, L V; Butorina, N N; Lavrova, D V; Sanamian, A G; Zagaĭnova, A V; Aleshnia, V V; Zhuravlev, P V; Golovina, S V; Panasovets, O P; Savilov, E D; Mamontova, L M; Anganova, E V

2005-01-01

Quantitative relationships were studied between the indicators (common coliform bacteria (CCP), glucose-positive bacteria (GPB), thermoduric bacteria (TDB), coliform bacteria, enterococci, clostridia, coliphages) and the opportunistic (Pseudomonas aeruginosa, Proteus, Klebsiella) and pathogenetic (Salmonella and intestinal viruses) microorganisms at the stages of effluent purification and decontamination, in processes of self-purification in the water reservoirs and of water preparation at water-supplying stations, as well as in the association with the incidence of acute intestinal infections of bacterial and viral genesis in different climatic zones of the country. Salmonella and the opportunistic bacteria of the Enterobacteriaceae family and Pseudomonas aeruginosa were found to be highly resistant to detoxifying agents and environmental factors, adaptable, able to reproduce in pure water, to long survive in underground waters, and to accumulate when water is desalinated at the erections. The cases of intestinal infections were found in the population using the portable water of the standard quality in terms of E. coli, TDB, CCB, and enterococci. In this case only the wider integral index of GPB, which includes the indices of E. coli, TDB, CCB, as well as lactose-negative pathogenic and opportunistic species retains its sanitary significance in terms of all signs and is a reliable indicator of the potential epidemic hazard of drinking water use. Long-term studies have provided evidence for the sanitary value of coliphages as indicators of viral drinking water contamination.

Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ.

PubMed

Kırça, M; Oğuz, N; Çetin, A; Uzuner, F; Yeşilkaya, A

2017-04-01

Hyperuricemia and angiotensin II (Ang II) may have a pathogenetic role in the development of hypertension and atherosclerosis as well as cardiovascular disease (CVD) and its prognosis. The purpose of this study was to investigate whether uric acid can induce proliferative pathways of vascular smooth muscle cell (VSMC) that are thought to be responsible for the development of CVD. The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and platelet-derived growth factor receptor β (PDGFRβ) was measured by Elisa and Western blot techniques to determine the activation of proliferative pathways in primary cultured VSMCs from rat aorta. Results demonstrated that uric acid can stimulate p38 MAPK, p44/42 MAPK and PDGFRβ phosphorylation in a time- and concentration-dependent manner. Furthermore, treatment of VSMCs with the angiotensin II type I receptor (AT1R) inhibitor losartan suppressed p38 MAPK and p44/42 MAPK induction by uric acid. The stimulatory effect of uric acid on p38 MAPK was higher compared to that of Ang II. The results of this study show for the first time that uric acid-induced PDGFRβ phosphorylation plays a crucial role in the development of CVDs and that elevated uric acid levels could be a potential therapeutical target in CVD patients.

Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

PubMed Central

Park, Sung Ok; Wankhede, Mamta; Lee, Young Jae; Choi, Eun-Jung; Fliess, Naime; Choe, Se-Woon; Oh, Seh-Hoon; Walter, Glenn; Raizada, Mohan K.; Sorg, Brian S.; Oh, S. Paul

2009-01-01

Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor–like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limitations to observing the initial stages of AVM formation. Here we present in vivo evidence that physiological or environmental factors such as wounds in addition to the genetic ablation are required for Alk1-deficient vessels to develop to AVMs in adult mice. Using the dorsal skinfold window chamber system, we have demonstrated for what we believe to be the first time the entire course of AVM formation in subdermal blood vessels by using intravital bright-field images, hyperspectral imaging, fluorescence recordings of direct arterial flow through the AV shunts, and vascular casting techniques. We believe our data provide novel insights into the pathogenetic mechanisms of HHT and potential therapeutic approaches. PMID:19805914

Anti-IgLON 5 Disease.

PubMed

Heidbreder, Anna; Philipp, Konstanze

2018-06-23

This review aims to give an overview about the current knowledge of this novel neurological disorder associated to IgLON-5 antibodies and its treatment. Anti-IgLON5 disease was first formally described in 2014. This newly discovered disorder recaps a complex neurological disorder with sleep, movement, and neuroimmunological and neurodegenerative aspects. The clinical manifestation of the anti-IgLON5 disease is very heterogeneous mostly including a sleep disorder with non-rapid eye movement (REM) sleep parasomnia and REM behavior disorder besides obstructive sleep apnea syndrome and stridor. Other neurological features (bulbar symptoms, gait abnormalities, cognitive dysfunction) are common. Until today, the mean age of diagnosis was mostly above the age of 60 with a balanced distribution of sex. Neuropathological examination showed neuronal loss and gliosis associated with an atypical tauopathy mainly involving the tegmentum of brainstem and hypothalamus. Although the function of the antibodies stays unclear so far, the evidence for the pathogenetic role of the antibody becomes more evident. Among the association to HLA-DRB1*10:01 and HLA-DQB1*05:01 as a potential factor for susceptibility, immunopathological findings are promising. So far, the pathophysiology of anti-IgLON5 disease is not sufficiently enlightened and needs more interdisciplinary approach to a better understanding of this interesting disorder at the border of autoimmunity and neurodegeneration. Immunotherapy has been frequently used but its therapeutic effect is limited.

Low-level chromosome 12 amplification in a primary lipoma of the lung: evidence for a pathogenetic relationship with common adipose tissue tumors.

PubMed

Bridge, J A; Roberts, C A; Degenhardt, J; Walker, C; Lackner, R; Linder, J

1998-02-01

Cytogenetic analysis of a primary lipoma of the lung removed from a 56-year-old woman revealed the presence of a supernumerary marker chromosome in all metaphase cells analyzed; namely, 47,XX,+mar. To the best of our knowledge, this is the first cytogenetic description of a primary lipoma of lung. Genetic analysis of intramuscular lipoma, atypical lipoma, and well-differentiated liposarcoma have revealed the presence of one to three supernumerary ring or giant marker chromosomes composed of chromosome 12 segments as the characteristic anomaly. The marker chromosome in the present case was shown to be composed entirely of chromosome 12 material by subsequent analysis with a chromosome 12-specific paint probe and fluorescence in situ hybridization. Thus, analogous to intramuscular lipoma, atypical lipoma, and well-differentiated liposarcoma, extra chromosome 12 material is present. These findings support a pathogenetic relationship between this lipoma of unusual anatomic location and common adipose tissue tumors.

[Pneumonia in wounded].

PubMed

Ovchinnikov, Iu V; Kharitonov, M A; Sadykov, R R; Shelukhin, V A; Gaĭduk, S V; Bogomolov, A B; Ivanov, V V; Dobrovol'skaia, L M

2015-02-01

Pneumonia is one of the common complications of wounds of any localization. Therapists are involved into the treatment of lung lesions in wounded in the ICU, in the surgical and if the patient arrives "on follow-up care,"--in the medical ward. The article analyzes the main statistical indicators reflecting the prevalence and clinical and pathogenetic characteristics of lung pathology in wounded during the Great Patriotic War, during the fighting Soviet troops in the Republic of Afghanistan, the 1st and 2nd Chechen campaign. Pneumonia as a manifestation of traumatic disease can occur in two ways. Primary pneumonia is in close connection with the pathogenetic traumatic injury. Secondary lung lesions complicate the injury at a later date and are due to the introduction of a nosocomial infection process flora. We describe the clinical picture of pneumonia in the affected, the basic pathogenesis, principles of therapy. Successful treatment of lung pathology in wounded depends on the performance of a complex of activities involving a wide range of doctors of various specialties.

Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON)

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

Johns, D.R.; Neufeld, M.J.

1993-10-01

Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease. The authors found a number of mtDNA polymorphisms that occur adjacent to known LHON-associated mutations and that confound their molecular genetic detection. These transition mutations occur at mtDNA nt 11779 (SfaNI site loss, 11778 mutation), nt 3459 (BsaHI site loss, 3460 mutation), nt 15258 (AccI site loss, 15257 mutation), nt 14485 (mismatch primer Sau3AI site loss,more » 14484 mutation), and nt 13707 (BstNI site loss, 13708 mutation). Molecular genetic detection of the most common pathogenetic mtDNA mutations in LHON, using a single restriction enzyme, may be confounded by adjacent polymorphisms that occur with a false-positive rate of 2%-7%. 19 refs.« less

CALCIFIC AORTIC VALVE DISEASE: PART 1 – MOLECULAR PATHOGENETIC ASPECTS, HEMODYNAMICS AND ADAPTIVE FEEDBACKS

PubMed Central

Pasipoularides, Ares

2016-01-01

Aortic valvular stenosis (AVS), produced by calcific aortic valve disease (CAVD) causing reduced cusp opening, afflicts mostly older persons eventually requiring valve replacement. CAVD had been considered “degenerative,” but newer investigations implicate active mechanisms similar to atherogenesis—genetic predisposition and signaling pathways, lipoprotein deposits, chronic inflammation and calcification/osteogenesis. Consequently, CAVD may eventually be controlled/reversed by lifestyle and pharmacogenomics remedies. Its management should be comprehensive, embracing not only the valve but also the left ventricle and the arterial system with their interdependent morphomechanics/hemodynamics, which underlie the ensuing diastolic and systolic LV dysfunction. Compared to even a couple of decades ago, we now have an increased appreciation of genomic and cytomolecular pathogenetic mechanisms underlying CAVD. Future pluridisciplinary studies will characterize better and more completely its pathobiology, evolution and overall dynamics, encompassing intricate feedback processes involving specific signaling molecules and gene network cascades. They will herald more effective, personalized medicine treatments of CAVD/AVS. PMID:26891845

[The pathogenetic substantiation of the periods of traumatic brain disease].

PubMed

Romodanov, A P; Kop'ev, O V; Pedachenko, E G; Parkhomets, V P; Vasil'eva, I G

1990-01-01

Advances in the study of the molecular mechanisms of the pathogenesis of closed craniocerebral trauma (CCCT) which was conducted on an experimental model, a clinical equivalent of CCCT, allow one to form a new view of the course of traumatic disease and its division into periods. The data obtained provide evidence that increase of the pathological process in the posttraumatic period is of a skipping and cascade character. The existence of such breaks makes it possible to distinguish periods with consideration for the pathogenetic essence of the pathological changes. 1. The period of intensified metabolic processes, "conflagration of metabolism". 2. The period of development of energy deficit in the nerve tissue. 3. The period of development of cell intoxication processes and secondary structural changes. 4. The period of formation of posttraumatic homeostasis (a) in the regimen of stable homeostasis, (b) in the regimen of stress and subsequent exhaustion of the activity of adaptation systems with the formation of late-term progressive sequelae.

Updating the mild encephalitis hypothesis of schizophrenia.

PubMed

Bechter, K

2013-04-05

Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from reactivation related to persistent infection) may be involved and other pathomechanisms including dysfunction of the blood-brain barrier or the blood-CSF barrier, CNS-endogenous immunity and the volume transmission mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity, and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of 1,25-dihydroxycholecalciferol on 47calcium absorption in post-menopausal osteoporosis.

PubMed

Caniggia, A; Vattimo, A

1979-07-01

Measurement of 47Calcium absorption was performed on eleven women with post-menopausal osteoporosis. The study was repeated after 10 days treatment with 1 microgram daily of 1,25(OH)2D3. These patients showed a statistically significant improvement of fractional calcium absorption that was inversely correlated to the basal values. The prompt improvement of the intestinal calcium transport in post-menopausal osteoporotic women, a few days after the administration of physiological doses of 1,25(OH)2D3, suggests that these patients synthesize inappropriately small amounts of 1,25(OH)2D3 because of their oestrogen deficiency. This could be an important pathogenetic factor in post-menopausal osteoporosis, as the efficiency of the adaptation of calcium absorption to low calcium intakes is dependent on 1,25(OH)2D3.

[Novel current and future therapy options for treatment of dry eye disease].

PubMed

Messmer, E M

2018-02-01

Dry eye disease was redefined by the dry eye workshop (DEWS II) in May 2017. According to the new definition "dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms". The current definition encompasses etiological factors, such as instability and hyperosmolarity of the tear film, ocular surface inflammation and damage as well as a new aspect compared to the former definition, neurosensory abnormalities. Recent and future therapeutic options for dry eye focus on treatment of the aforementioned pathogenetic events. New tear substitutes, medications and devices to stimulate tear production, innovative anti-inflammatory treatment, medications to influence corneal innervation and new methods for treatment of Meibomian gland dysfunction are already available or will be available in the near future.

HCV proteins and immunoglobulin variable gene (IgV) subfamilies in HCV-induced type II mixed cryoglobulinemia: a concurrent pathogenetic role.

PubMed

Sautto, Giuseppe; Mancini, Nicasio; Solforosi, Laura; Diotti, Roberta A; Clementi, Massimo; Burioni, Roberto

2012-01-01

The association between hepatitis C virus (HCV) infection and type II mixed cryoglobulinemia (MCII) is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV) gene subfamilies frequently endowed with rheumatoid factor (RF) activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved.

HCV Proteins and Immunoglobulin Variable Gene (IgV) Subfamilies in HCV-Induced Type II Mixed Cryoglobulinemia: A Concurrent Pathogenetic Role

PubMed Central

Sautto, Giuseppe; Mancini, Nicasio; Solforosi, Laura; Diotti, Roberta A.; Clementi, Massimo; Burioni, Roberto

2012-01-01

The association between hepatitis C virus (HCV) infection and type II mixed cryoglobulinemia (MCII) is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV) gene subfamilies frequently endowed with rheumatoid factor (RF) activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved. PMID:22690241

Dense Deposit Disease and C3 Glomerulopathy

PubMed Central

Barbour, Thomas D.; Pickering, Matthew C.; Terence Cook, H.

2013-01-01

Summary C3 glomerulopathy refers to those renal lesions characterized histologically by predominant C3 accumulation within the glomerulus, and pathogenetically by aberrant regulation of the alternative pathway of complement. Dense deposit disease is distinguished from other forms of C3 glomerulopathy by its characteristic appearance on electron microscopy. The extent to which dense deposit disease also differs from other forms of C3 glomerulopathy in terms of clinical features, natural history, and outcomes of treatment including renal transplantation is less clear. We discuss the pathophysiology of C3 glomerulopathy, with evidence for alternative pathway dysregulation obtained from affected individuals and complement factor H (Cfh)-deficient animal models. Recent linkage studies in familial C3 glomerulopathy have shown genomic rearrangements in the Cfh-related genes, for which the novel pathophysiologic concept of Cfh deregulation has been proposed. PMID:24161036

Interstitial nephritis.

PubMed

Papper, S

1980-01-01

There are many causes of interstitial nephritis other than pyelonephritis. The term interstitial nephritis does not connote a single etiologic or pathogenetic mechanism; it rather arbitrarily places together a wider variety of renal diseases that have a predilection for early and major involvement of the renal interstitium. The prototype of acute interstitial nephritis is acute pyelonephritis. In addition, there is a drug-related acute interstitial disease that is probably of immunological nature and usually reverses with discontinuance of the offending drug. Chronic interstitial nephritis includes many diverse illnesses. Nonobstructive pyelonephritis occurs but its prevalence is debated. Analgesic abuse nephropathy is not rare and is potentially reversible. Papillary necrosis has many causes and a wide spectrum of clinical presentations. Heavy metals, such as lead, cause interstitial nephritis. Balkan nephropathy occurs in an endemic area and although not bacterial in origin is of unknown cause.

Cytokines and bullous pemphigoid.

PubMed

D'Auria, L; Cordiali Fei, P; Ameglio, F

1999-06-01

This report reviews the data presented in the literature concerning the presence and levels of different cytokines in sera, lesional tissue or blister fluids of patients with bullous pemphigoid. The list of cytokines analysed includes 21 molecules: interleukins (IL)-1 => 8, IL-10 => 13, IL-15, granulocyte-monocyte-colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), oncostatin-M (OSM), regulated upon activation normal T cell expressed and presumably secreted (RANTES), transforming growth factor-beta 1 (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF). Basic information regarding the functions of these cytokines and their possible involvement in the pathogenetic steps of the disease, such as autoantigen expression, autoantibody induction, complement activation, local cell recruitment and stimulation, resident cell activation, release of various effector molecules and tissue damage are also reported. A specific function for each cytokine in bullous pemphigoid induction cannot be still defined, however, the literature attributes a major role to IL-1, IL-4, IL-5, IL-6, IL-8 and IFN-gamma. On the basis of significant (direct or inverse) correlations found between disease intensity and the blister fluid/serum levels, the following cytokines IL-7, IL-15, RANTES, VEGF and TNF-alpha, besides those previously mentioned, may also be involved in this disease.

New targeted therapies in pancreatic cancer.

PubMed

Seicean, Andrada; Petrusel, Livia; Seicean, Radu

2015-05-28

Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

[The role of urinary tract infection in the development of recurrent nephrolithiasis].

PubMed

Khamidullin, K R; Pushkarev, A M; Tarasenko, A I; Pavlov, V N

2017-10-01

This is a literature review on the role of microbial flora in the development of recurrent urolithiasis. The authors outline pathogenetic aspects of recurrent stone formation associated bacterial flora. A number of studies reported that standard urine culture has limited sensitivity in detecting urinary tract infection.

[The use of eurespal for the treatment of chronic laryngitis].

PubMed

Riabova, M A

2011-01-01

The author provides a rationale for the use of eurespal for the treatment of chronic laryngitis based on the pathogenetic concept of pathological condition. The results of a clinical study designed to evaluate the efficiency and safety of eurespal therapy in patients with chronic laryngitis are presented.

Familial autoimmune myasthenia gravis with different pathogenetic antibodies.

PubMed Central

Provenzano, C; Arancio, O; Evoli, A; Rocca, B; Bartoccioni, E; de Grandis, D; Tonali, P

1988-01-01

Two cases of familial myasthenia gravis are reported. One patient is a typical case of autoimmune myasthenia with positive anti acetylcholine receptor antibodies, while in the second patient the impairment of neuromuscular transmission is likely to be due to antibodies directed against determinants other than the acetylcholine receptors. PMID:3225607

Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers.

PubMed

Pyrpasopoulou, Athina; Douma, Stella; Triantafyllou, Areti; Simoulidou, Elisavet; Samara, Magda; Parapanisiou, Efthymia; Aslanidis, Spyros

2010-02-01

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Elevated TGF β2 serum levels in Emery-Dreifuss muscular dystrophy: implications for myocyte and tenocyte differentiation and fibrogenic processes.

PubMed

Bernasconi, Pia; Carboni, Nicola; Ricci, Giulia; Siciliano, Gabriele; Politano, Luisa; Maggi, Lorenzo; Mongini, Tiziana; Vercelli, Liliana; Rodolico, Carmelo; Biagini, Elena; Boriani, Giuseppe; Ruggiero, Lucia; Santoro, Lucio; Schena, Elisa; Prencipe, Sabino; Evangelisti, Camilla; Pegoraro, Elena; Morandi, Lucia; Columbaro, Marta; Lanzuolo, Chiara; Sabatelli, Patrizia; Cavalcante, Paola; Cappelletti, Cristina; Bonne, Gisèle; Muchir, Antoine; Lattanzi, Giovanna

2018-04-25

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss muscular dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance?

PubMed

Pomytkin, Igor A; Cline, Brandon H; Anthony, Daniel C; Steinbusch, Harry W; Lesch, Klaus-Peter; Strekalova, Tatyana

2015-01-01

Depression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recent meta-analyses have highlighted an asymmetrical relationship between the two conditions as depressed patients were found to display a higher risk of developing type 2 diabetes than those individuals suffering from diabetes are to become depressed. Based on recent findings, we favor a hypothesis where by decreased peripheral serotonin (5-HT) transporter (5-HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inflammatory pathogenetic mechanisms of both conditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinal permeability in 5-HTT deficient mice, which is viewed one of the most relevant animal models of depression. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheral Toll-like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute to the pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant therapies, which also suppress intestinal 5-HTT, may have potentiating effects on the association between depression and diabetes. It is also of interest that high carbohydrate and fat intake ("cafeteria-type diet") increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inflammation owing to increased intestinal 5-HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression and not vice versa. The evidence presented here shows the further investigation into peripheral mechanisms that linked diabetes to depression is clearly warranted. Copyright © 2014. Published by Elsevier B.V.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

PubMed

Chung, Clement; Ma, Hilary

2017-09-01

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. © 2017 Pharmacotherapy Publications, Inc.

[Cardiovascular diseases in the population of industrial towns and environmental factors].

PubMed

Ibraeva, L K; Azhimetova, G N; Amanbekova, A U; Bakirova, R E

2015-01-01

To study the influence of environmental factors (EFs) on the development of cardiovascular diseases in the population of industrial towns of the Republic of Kazakhstan. The investigation covered an 18-59-year-old adult population who had been living in the urbanized areas of the Republic of Kazakhstan for at least 10 years, who worked in harmless conditions and were unregistered as having chronic diseases. At Stage 1, screening (a therapist's examination, blood general and immunological tests, and electrocardiography) was carried out for risk group persons who underwent in-depth clinical examination (blood biochemical test) at Stage 2. Multivariate statistical analysis has revealed that the development of hypertension is associated with the high concentration of sulfur dioxide in atmospheric air, copper in dust sediments, and zinc in soil and that of coronary heart disease (CHD) is related to the high levels of nitrogen dioxide in atmospheric air and zinc in dust sediments. Based on pathogenetic and statistical data and information available in the literature, hypertension and CHD are referred to as the diseases that may result from the influence of EFs.

[Nephrology-part 3: Urinary tract infections].

PubMed

Fünfstück, Reinhard; Stein, Günter; Naber, Kurt G; Hacker, Jörg; Marget, Walter

2003-07-15

Urinary tract infections are one of the most common bacterial infectious diseases in humans. Depending on the localization and the effectiveness of pathogenetic factors, various clinical pictures (lower urinary tract infection, pyelonephritis, asymptomatic bacteriuria) have to be differentiated. There are virulence factors of microorganisms on the one hand and defense mechanisms on the other, which influence the manifestation and the course of disease. The process of bacterial attachment to the epithelial cells of the boundary layer, the internalization and invasion of bacteria could be important for acute and chronic disease. Disturbances of local defense mechanisms, such as increased urinary glucose concentration in diabetes or variations of Tamm-Horsfall protein and defensin levels, may influence the course of infection. On the basis of microbiological and laboratory findings as well as the results of clinical and ultrasound procedures, the decision on the therapeutic strategy should be made. There are different treatment recommendations for acute uncomplicated and complicated cases as well as for chronic diseases. Future investigations should focus on effective therapeutic options for special immunocompromised patients in relation to the microbiological aspects and defense mechanisms of the host.

Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes

PubMed Central

Carter, C. J.

2011-01-01

Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens. PMID:22567321

[Contrast-induced acute kidney injury in cardiology].

PubMed

Genovesi, Eugenio; Romanello, Mattia; De Caterina, Raffaele

2016-12-01

The intravascular administration of contrast media is an important tool in cardiovascular imaging, especially in percutaneous coronary interventions (PCI). Owing to the widespread use of these procedures, contrast-induced acute kidney injury (CI-AKI) has become one of the most common types of acute renal failures. CI-AKI is mainly mediated by mechanisms of oxidative damage, and its onset is associated with prolonged hospitalization and significant morbidity and mortality. Preexisting chronic kidney disease, diabetes, age, heart failure, and characteristics related to the procedure (primary or elective PCI, type and amount of contrast medium) are the most important risk factors for the development of post-PCI CI-AKI.For this serious complication, prevention is more important than treatment, and various preventive measures have been widely tested in recent years. However, none of the strategies so far evaluated, with the exception of pre-procedural hydration with isotonic saline, has been shown to effectively prevent CI-AKI in randomized trials in large populations. In this review, we discuss the incidence, risk factors, main pathogenetic mechanisms and current strategies for the prevention of CI-AKI.

Osthole Preconditioning Protects Rats Against Renal Ischemia-Reperfusion Injury.

PubMed

Xie, D-Q; Sun, G-Y; Zhang, X-G; Gan, H

2015-01-01

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms of renal I/R injury involve inflammation, oxidative stress, and apoptosis. Osthole, a natural coumarin derivative, has potential anti-inflammatory effects. This study investigated the effect of osthole on renal I/R injury and its potential mechanism. We induced renal I/R injury by clamping the left renal artery for 45 min followed by reperfusion, along with a contralateral nephrectomy. We randomly assigned 30 rats to 3 groups (n = 10): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intra-peritoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 45 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in renal tissue and serum were examined by means of RT-PCR and ELISA, respectively. The expression of p-p85, p85, p-Akt, Akt, p-p65, and p65 were measured by means of Western blotting. Osthole pre-treatment significantly attenuated renal dysfunction, renal histological changes, NF-κB activation, and the expression of TNF-α, IL-8, and IL-6 induced by I/R injury, but the activation of PI3K/Akt signaling was further increased. Osthole pre-treatment protects rats against renal I/R injury by suppressing NF-κB activation, which is involved in PI3K/Akt signaling activation. Thus, osthole may be a novel practical strategy to prevent renal I/R injury. Copyright © 2015 Elsevier Inc. All rights reserved.

The spectrum of motor function abnormalities in gastroesophageal reflux disease and Barrett's esophagus.

PubMed

Ang, D; Blondeau, K; Sifrim, D; Tack, J

2009-01-01

Barrett's esophagus has traditionally been regarded as the most severe end of the spectrum of gastroesophageal reflux disease and is of great clinical importance in view of the association with esophageal adenocarcinoma. Studies have documented high levels of esophageal acid exposure in Barrett's esophagus. Various pathogenetic mechanisms underlie this phenomenon. These include abnormalities in esophageal peristalsis, defective lower esophageal sphincter pressures, gastric dysmotility and bile reflux. Whilst these factors provide evidence for an acquired cause of Barrett's esophagus, an underlying genetic predisposition cannot be ruled out. Although the past decade has brought about many new discoveries in the pathogenesis of Barrett's esophagus, it has also added further controversy to this complex disorder. A detailed analysis of the gastrointestinal motor abnormalities occurring in Barrett's esophagus follows, with a review of the currently available literature and an update on this condition that continues to be of interest to the gastroenterologist.

The genetics of Alzheimer disease: back to the future.

PubMed

Bertram, Lars; Lill, Christina M; Tanzi, Rudolph E

2010-10-21

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

Proposed Pharmacological Countermeasures Against Apoptotic Cell Death in Experimental Models Mimicking Space Environment Damage

NASA Astrophysics Data System (ADS)

Lulli, Matteo; Papucci, Laura; Witort, Ewa; Donnini, Martino; Lapucci, Andrea; Lazzarano, Stefano; Mazzoni, Tiziano; Simoncini, Madine; Falciani, Piergiuseppe; Capaccioli, Sergio

2008-06-01

Several damaging agents have been suggested to affect human vision during long term space travels. Recently, apoptosis induced by DNA-damaging agents has emerged as frequent pathogenetic mechanism of ophthalmologic pathologies. Here, we propose two countermeasures: coenzyme Q10 and bcl-2 downregulation preventing antisense oligoribonucleotides (ORNs), aimed to inhibit cellular apoptotic death. Our studies have been carried out on retina and neuronal cultured cells treated with the following apoptotic stimuli mimicking space environment: a several-day exposure to either 3H-labeled tymidine or to the genotoxic drug doxorubicin, UV irradiation, hypoxia and glucose/growth factor starvation (Locke medium). The preliminary results clearly indicate that CoQ10, as well as bcl-2 down-regulation preventing ORNs, significantly counteract apoptosis in response to different DNA damaging agents in cultured eye and in neuronal cells. This supports the possibility that both could be optimal countermeasures against ophthalmologic lesions during space explorations.

Acalculous cholecystitis and septicemia caused by non-O1 Vibrio cholerae: first reported case and review of biliary infections with Vibrio cholerae.

PubMed

West, B C; Silberman, R; Otterson, W N

1998-03-01

The first case of septicemic acute acalculous cholecystitis caused by non-O1 Vibrio cholerae is described in a healthy traveler, and biliary tract infections from V. cholerae are reviewed. Immediately after a vacation in Cancun, Mexico, a 55-year-old man developed acute cholecystitis. Blood and bile cultures grew non-O1 V. cholerae. At surgery, the gallbladder was acalculous, inflamed, distended, and nearly ruptured. Pathogenetic factors may have included diarrhea prophylaxis with bismuth subsalicylate, distension of the gallbladder from illness-induced fasting, and bacterial toxins in the gallbladder. The patient received i.v. cephapirin, followed by oral cephradine for a total of 10 days, and he made a quick and complete recovery. V. cholerae should be considered in the differential diagnosis of persons from endemic areas who present with cholecystitis or acute jaundice.

Alzheimer's disease: molecular concepts and therapeutic targets

NASA Astrophysics Data System (ADS)

Fassbender, K.; Masters, C.; Beyreuther, K.

2001-06-01

The beta amyloid peptide is the major component of the neuritic plaques, the characteristic lesions in Alzheimer's disease. Mutations in three genes (APP, PS-1, and PS-2) cause familial Alzheimer's disease by alteration of the rate of generation of amyloid peptide or the length of this peptide. However, in the 90% non-familial cases, other factors play a major pathogenetic role. These include the apolipoprotein E genotype, the "plaque-associated" proteins promoting the formation of toxic fibrillar aggregates or the chronic inflammatory responses. The aim of this review is to explain the steps in the complex cascade leading to Alzheimer's disease and, based on this, to report the current efforts to intervene in these different pathophysiological events in order to prevent progression of Alzheimer's disease. Whereas acetylcholine substitution is currently used in clinical practice, future therapeutical strategies to combat Alzheimer's disease may include anti-inflammatory treatments, vaccination against beta amyloid peptide, or treatment with cholesterol-lowering drugs.

Cerebral blood flow measured by arterial spin labeling MRI at resting state in normal aging and Alzheimer's disease.

PubMed

Zhang, Nan; Gordon, Marc L; Goldberg, Terry E

2017-01-01

Arterial spin labeling (ASL) magnetic resonance imaging uses arterial blood water as an endogenous tracer to measure cerebral blood flow (CBF). In this review, based on ASL studies in the resting state, we discuss state-of-the-art technical and data processing improvements in ASL, and ASL CBF changes in normal aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and other types of dementia. We propose that vascular and AD risk factors should be considered when evaluating CBF changes in aging, and that other validated biomarkers should be used as inclusion criteria or covariates when evaluating CBF changes in MCI and AD. With improvements in hardware and experimental design, ASL is proving to be an increasingly promising tool for exploring pathogenetic mechanisms, early detection, monitoring disease progression and pharmacological response, and differential diagnosis of AD. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Estimation of soluble serum CD30 in the diagnosis of early renal allograft dysfunction].

PubMed

Trailin, A V

2009-10-01

We aimed to reveal factors influencing serum soluble CD30 level in the recipients of kidney allograft and to estimate its pathogenetic significance. We tested the sCD30 level in the serum before and the 4th day after operation by ELISA. It was established, thats CD30 levels before transplantation were virtually the same in patients who experienced rejection and in non-rejecting patients. However, there was a significant decrease in the level of sCD30 after transplantation in non-rejecting patients, contrary to rejecting patients. A significant decrease of sCD30 level was detected on the day 4th after the transplantation independently of dialysis requirement. The decrease of sCD30 on the day 4th after operation in the patients with delayed graft function and its stability in the patients with acute rejection may be used distinguish these complications.

Pathogenetic aspects of uncomplicated urinary tract infection: recent advances.

PubMed

Fünfstück, R; Smith, J W; Tschäpe, H; Stein, G

1997-01-01

Urinary tract infections mostly are caused by Enterobacteriaceae; E. coli dominating in 80-90% for uncomplicated diseases. Microorganisms possessing the ability to colonize the uroepithelium (fimbriae/pili) and to cytotoxically damage cells and tissue (hemolysin) may initiate acute infection. Properties such as serum resistance, iron sequesteration, hydroxamate production and the presence of K-antigen are found in strains which persist in the host without initiating clinical symptoms. The ability of bacteria to adhere to cells of the epithelial boundary layer of the host organisms is of initial importance in the origin and progress of an infection. A variety of specific factors, e.g. glycolipids on the surface of the uroepithelium as well as cellular and humoral disorders of immunoreactions in the host determine the course of a disease. The immune response may ameliorate clinical symptoms and select urovirulent characteristics of the causative microorganism in recurrent diseases.

Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis.

PubMed

Ghezzi, A; Comi, G; Federico, A

2011-02-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS caused by the interplay of genetic and environmental factors. In the last years, it has been suggested that an abnormal venous drainage due to stenosis or malformation of the internal jugular and/or azygous veins may play a major pathogenetic role in MS. This abnormality called chronic cerebro-spinal venous insufficiency (CCSVI) could result in increased permeability of blood brain barrier, local iron deposition and secondary multifocal inflammation. In the present paper, literature data in favour and against this hypothesis are reported. A great variability of CCSVI has been found in both MS patients (ranging from 0 to 100%) and in control subjects (from 0 to 23%). This large variability is explained by methodological aspects, problems in assessing CCSVI, and differences among clinical series. It is urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS.

[Campylobacter (Helicobacter) pylori in chronic erosive gastritis, duodenitis and gastroduodenitis].

PubMed

Kolarski, V; Tsenova, V; Petrova-Shopova, K; Nikolov, S; Kaleva, M; Petrova, D

1991-01-01

The presence and degree of manifestation of Campylobacter (Helicobacter) pylori in gastroduodenal mucosa were studied in 100 patients (56 men, mean age 51.4 years, and 44 women, mean age 46.5 years) with endoscopically proved chronic erosive gastritis (52 patients), erosive duodenitis (36 patients) and erosive gastroduodenitis (12 patients). The examinations revealed the presence of Campylobacter (Helicobacter) pylori in mean 77% of the patients with erosive gastritis, duodenitis and gastroduodenitis. Campylobacter (Helicobacter) pylori was found most often in patients with chronic erosive duodenitis--83.3%, whereas in the patients with erosive gastritis it was found in 73.07%. In 83.33% of the patients with chronic erosive gastritis, duodenitis and gastroduodenitis the campylobacter infection was well manifested--(++) according to Le Bodie et al (1987). The results allow the conclusion that one of the important pathogenetic factors of erosive gastritis, duodenitis and gastroduodenitis is the Campylobacter (Helicobacter) pylori infection of gastroduodenal mucosa.

Infections and systemic lupus erythematosus.

PubMed

Esposito, S; Bosis, S; Semino, M; Rigante, D

2014-09-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents a protean spectrum of clinical manifestations, and may affect any organ. The typical course of SLE is insidious, slow, and progressive, with potential exacerbations and remissions, and even dramatically acute and rapidly fatal outcomes. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their possible causative and/or protective role has been largely emphasized in the medical literature. However, the etiopathogenesis of SLE is still obscure and far from being completely elucidated. Among infections, particularly Epstein-Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal pathogenetic role. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections, primarily protozoan infections, might confer protection from autoimmune processes, depending on the unique interaction between the microorganism and host. Further studies are needed in order to demonstrate that infectious agents might, indeed, be causative of SLE, and to address the potential clinical sequelae of infections in the field of autoimmunity.

Assessment of oxygen and carbogen therapy effect in Meniere's disease according to clinical and electroencephalographic data

NASA Technical Reports Server (NTRS)

Boronoyev, A. B.

1980-01-01

The method of constructing fields on the basis of EEG data gives a quantitative characterization of bioelectrical activity. Fields of average rates of the change of potentials in healthy people have a well defined configuration, where the greatest rates are found in the occipital zones, lower in the frontal and parietal, and least in the temporal zones. In response to functional loads the form of the field remains the same because of a synchronous change in the average rates in both hemispheres of the cerebrum to the same extent. The configuration of the fields of background bioelectric activity of the cerebrum in people with Meniere's disease is not uniform. On the basis of this investigation, a clear correlation was found between the subjective sensations of patients during oxygen and carbogen therapy and the changes in the spatial characteristics of the field of potentials of the cerebrum. This correlation makes it possible to objectively identify the nature of the vascular disturbances in Meniere's disease, develop a pathogenetic treatment plan, and evaluate its effectiveness.

Renal involvement in Gaucher's disease.

PubMed Central

Siegal, A.; Gutman, A.; Shapiro, M. S.; Griffel, B.

1981-01-01

A patient with chronic Gaucher's disease is described who developed glomerulopathy 24 years after splenectomy terminating in renal failure. The pathological changes of this very rare complication of Gaucher's disease are described. The few similar cases reported in the literature are reviewed and the possible pathogenetic pathways discussed. Images Fig. 1 Fig. 2 Fig. 3 PMID:7301691

[Canine atopic dermatitis].

PubMed

Bensignor, Emmanuel

2010-10-01

Canine atopic dermatitis is an inflammatory skin disease characterized by typical clinical signs and affecting up to 10 % of dogs aged from 1 to 3 years. The diagnosis is mainly clinical and the treatment is complex. This canine form may offer a good model of human atopic dermatitis, as the two diseases show many pathogenetic, clinical and therapeutic similarities.

Pathogenetic Basis of Aortopathy and Aortic Valve Disease

ClinicalTrials.gov

2018-02-19

Aortopathies; Thoracic Aortic Aneurysm; Aortic Valve Disease; Thoracic Aortic Disease; Thoracic Aortic Dissection; Thoracic Aortic Rupture; Ascending Aortic Disease; Descending Aortic Disease; Ascending Aortic Aneurysm; Descending Aortic Aneurysm; Marfan Syndrome; Loeys-Dietz Syndrome; Ehlers-Danlos Syndrome; Shprintzen-Goldberg Syndrome; Turner Syndrome; PHACE Syndrome; Autosomal Recessive Cutis Laxa; Congenital Contractural Arachnodactyly; Arterial Tortuosity Syndrome

A unique case of right-sided Poland syndrome with true dextrocardia and total situs inversus.

PubMed

Atasoy, Halil I; Yavuz, Taner; Altunrende, Sevil; Guven, Melih; Kılıcgun, Ali; Polat, Omer; Yesiller, Erkan; Duzenli, Selma

2013-02-01

Poland syndrome has been reported to be associated with true dextrocardia, but not with true situs inversus. In this report, we describe the first patient with total situs inversus in medical literature and try to highlight the syndrome's probable etiology and pathogenetic mechanisms in utero.

[Atypical retinitis pigmentosa in Laurence-Moon-Biedl-Bardet syndrome. Report of a case of chronic renal insufficiency under periodic hemodialysis treatment].

PubMed

Bianco, G; Carlesimo, S C; Mazzarrino, R; Palestini, M

1993-03-01

A case of Laurence-Moon-Biedl-Bardet syndrome in a patient undergoing hemodialysis is reported. The principal characteristics of this congenital syndrome are described. A possible pathogenetic mechanism of the atypical form of retinitis pigmentosa (sine pigmento) is discussed.

A Multidisciplinary Approach to the Management of Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Alanay, Y.; Unal, F.; Turanli, G.; Alikasifoglu, M.; Alehan, D.; Akyol, U.; Belgin, E.; Sener, C.; Aktas, D.; Boduroglu, I.; Utine, E.; Volkan-Salanci, B.; Ozusta, S.; Genc, A.; Basar, F.; Sevinc, S.; Tuncbilek, E.

2007-01-01

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Since the identification of the responsible gene ("FMR1") and its protein (FMRP), there has been enormous progress in both clinical and pathogenetic research on the neurobehavioural aspects of the condition. However, studies regarding other medical…

Sydenham chorea: clinical, EEG, MRI and SPECT findings in the early stage of the disease.

PubMed

Heye, N; Jergas, M; Hötzinger, H; Farahati, J; Pöhlau, D; Przuntek, H

1993-02-01

An 18-year-old man suffered from acute Sydenham chorea appearing coincidently with beta-haemolytic streptococcal throat infection. Imaging techniques documented lesions of basal ganglia and substantia nigra. In the early course of the disease vascular lesions may be important pathogenetic mechanisms of this acquired movement disorder.

Significance of anti-phospholipid antibodies in patients with lupus nephritis.

PubMed

Frampton, G; Hicks, J; Cameron, J S

1991-06-01

Anti-phospholipid antibodies (APA) as markers or mediators of thrombosis in lupus could be of pathogenetic significance in nephritis, since glomerular capillary thrombi are an indicator of subsequent renal dysfunction. Isotype specific APA antibodies were measured, using cardiolipin as the antigen, in 76 patients with lupus nephritis. Twenty-nine percent of the patients had elevated IgG APA. Overall, 43% of patients showed raised levels of at least one isotype. In general, APA had specificity for anionic phospholipids. In vitro lupus anticoagulant activity was associated with all three isotypes of APA, but only the IgM isotype correlated with the biological false positive test for syphilis. APA were not associated with thromboses or neurological involvement, and only the IgA isotype correlated with thrombocytopenia. We confirmed an association between the presence of intraglomerular thrombi and serum IgG APA. However, we found no association between APA and renal histological pattern, or long-term renal function. Our data, therefore, do not support a major pathogenetic role for APA in the nephritis of lupus in treated patients.

Role of immune cells in animal models for inherited neuropathies: facts and visions.

PubMed

Mäurer, Mathias; Kobsar, Igor; Berghoff, Martin; Schmid, Christoph D; Carenini, Stefano; Martini, Rudolf

2002-04-01

Mice heterozygously deficient in the peripheral myelin adhesion molecule P0 (P0+/- mice) are models for some forms of Charcot-Marie-Tooth (CMT) neuropathies. In addition to the characteristic hallmarks of demyelination, elevated numbers of CD8-positive T-lymphocytes and F4/80-positive macrophages are striking features in the nerves of these mice. These immune cells increase in number with age and progress of demyelination, suggesting that they might be functionally related to myelin damage. In order to investigate the pathogenetic role of lymphocytes, the myelin mutants were cross-bred with recombination activating gene 1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. The immunodeficient myelin mutants showed a less severe myelin degeneration. The beneficial effect of lymphocyte-deficiency was reversible, since demyelination worsened in immunodeficient myelin-mutants when reconstituted with bone marrow from wild-type mice. Ultrastructural analysis revealed macrophages in close apposition to myelin and demyelinated axons. We therefore cross-bred the P0+/- mice with spontaneous osteopetrotic (op) mutants deficient in the macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the corresponding double mutants the numbers of macrophages were not elevated in the peripheral nerves, and the demyelinating phenotype was less severe than in the genuine P0+/- mice, demonstrating that macrophages are also functionally involved in the pathogenesis of genetically mediated demyelination. We also examined other models for inherited neuropathies for a possible involvement of immune cells. We chose mice deficient in the gap junction component connexin 32, a model for the X-linked form of CMT. Similar to P0-deficient mice, T-lymphocytes and macrophages were elevated and macrophages showed a close apposition to degenerating myelin. We conclude that the involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies.

Targets to treat androgen excess in polycystic ovary syndrome.

PubMed

Luque-Ramírez, Manuel; Escobar-Morreale, Héctor Francisco

2015-01-01

The polycystic ovary syndrome (PCOS) is a common androgen disorder in reproductive-aged women. Excessive biosynthesis and secretion of androgens by steroidogenic tissues is its central pathogenetic mechanism. The authors review the potential targets and new drugs to treat androgen excess in PCOS. Besides our lab's experience, a systematic search (MEDLINE, Cochrane library, ClinicalTriasl.gov, EU Clinical Trials Register and hand-searching) regarding observational studies, randomized clinical trials, systematic reviews, meta-analyses and patents about this topic was performed. PCOS has a heterogeneous clinical presentation. It is unlikely that a single drug would cover all its possible manifestations. Available treatments for androgen excess are not free of side effects that are of particular concern in these women who suffer from cardiometabolic risk even without treatment. A precise characterization of the source of androgen excess must tailor antiandrogenic management in each woman, avoiding undesirable side effects.

[Current aspects of the physiopathology of the infectious process. II. Cybernetic elements in the pathogenetic structure of infectious diseases].

PubMed

Dragomirescu, M; Buzinschi, S

1980-01-01

The authors discuss the applicability of general cybernetic principles (the theory of systems and self-regulated mechanisms based on inversed connections) to the pathophysiologic structure of infections. With reference to concrete examples they outline the following elements: the appartenance of the infectious process to the notion of system (as conceived in the theory of systems), the previsible character of the functional potential of the structured system in the components of infection, and the sequental correspondence between system dynamics and the dynamics of the infectious process. Starting from the mechanism of action of the main microbial toxins, the aptitude of the latter to act upon the functional code of the macroorganism, altering the cellular and supracellular self-regulated biosystems, is demonstrated. Finally, the practical implications of assimilating cybernetic processes in the pathophysiology of infectious diseases are analyzed.

Emerging Common Molecular Pathways for Primary Dystonia

PubMed Central

LeDoux, Mark S; Dauer, William T; Warner, Thomas T

2013-01-01

Background The dystonias are a group of hyperkinetic movement disorders whose principal cause is neuron dysfunction at one or more interconnected nodes of the motor system. The study of genes and proteins which cause familial dystonia provides critical information about the cellular pathways involved in this dysfunction which disrupts the motor pathways at systems level. In recent years study of the increasing number of DYT genes has implicated a number of cell functions which appear to be involved in the pathogenesis of dystonia. Methods Review of literature published in English language publications available on Pubmed relating to the genetics and cellular pathology of dystonia Results and Conclusions Numerous potential pathogenetic mechanisms have been identified. We describe those which fall into three emerging thematic groups: cell cycle and transcriptional regulation in the nucleus, endoplasmic reticulum and nuclear envelope function, and control of synaptic function. PMID:23893453

Aortic Involvement in Pediatric Marfan syndrome: A Review.

PubMed

Ekhomu, Omonigho; Naheed, Zahra J

2015-06-01

Outlining specific protocols for the management of pediatric patients with Marfan syndrome has been challenging. This is mostly due to a dearth of clinical studies performed in pediatric patients. In Marfan syndrome, the major sources of morbidity and mortality relate to the cardiovascular system. In this review, we focus on aortic involvement seen in pediatric patients with Marfan syndrome, ranging from aortic dilatation to aortic rupture and heart failure. We discuss the histological, morphological, and pathogenetic basis of the cardiac manifestations seen in pediatric Marfan syndrome and use a specific case to depict our experienced range of cardiovascular manifestations. The survival for patients with Marfan syndrome may approach the expected survival for non-affected patients, with optimal management. With this potentiality in mind, we explore possible and actual management considerations for pediatric Marfan syndrome, examining both medical and surgical therapy modalities that can make the possibility of improved survival a reality.

Investigating Mechanisms of Chronic Kidney Disease in Mouse Models

PubMed Central

Eddy, Allison A.; Okamura, Daryl M.; Yamaguchi, Ikuyo; López-Guisa, Jesús M.

2011-01-01

Animal models of chronic kidney disease (CKD) are important experimental tools that are used to investigate novel mechanistic pathways and to validate potential new therapeutic interventions prior to pre-clinical testing in humans. Over the past several years, mouse CKD models have been extensively used for these purposes. Despite significant limitations, the model of unilateral ureteral obstruction (UUO) has essentially become the high throughput in vivo model, as it recapitulates the fundamental pathogenetic mechanisms that typify all forms of CKD in a relatively short time span. In addition, several alternative mouse models are available that can be used to validate new mechanistic paradigms and/or novel therapies. Several models are reviewed – both genetic and experimentally induced – that provide investigators with an opportunity to include renal functional study end-points together with quantitative measures of fibrosis severity, something that is not possible with the UUO model. PMID:21695449

Atherosclerosis, cholesterol, nutrition, and statins – a critical review

PubMed Central

Gebbers, Jan-Olaf

2007-01-01

Atherosclerosis, which causes approximately half of all deaths of adults over age 60 in industrialized nations, is a pandemic among inappropriately nourished and/or physically hypoactive children, adolescents, and adults world wide. Although nowadays statins are widely prescribed to middle age and elderly adults with high blood lipid levels as pharmacological prevention for the late complications of atherosclerosis, from a critical point of view statins seem not to solve the problem, especially when compared with certain natural ingredients of our nutrition like micronutrients as alternative strategy. Statin ingestion is associated with lowering of serum cholesterol and low-density lipoprotein concentrations; some prospective studies have shown statistical associations with subsequent modest reduction of mortality from cardiovascular disease. However, specific biochemical pathways and pharmacological roles of statins in prevention of atherosclerosis, if any, are unknown. Moreover, there have been no systematic cost-benefit analyses of life-style prophylaxis versus statin prophylaxis versus combined life-style plus statin prophylaxis versus neither life-style nor statin prophylaxis for clinically significant complications of cardiovascular diseases in the elderly. Further, in the trials of effectiveness statins were not compared with management of nutrition, which is the most appropriate alternative intervention. Such studies seem to be important, as the ever increasing world population, especially in developing countries, now demand expensive statins, which may be unaffordable for mitigating the pandemic. Studies of this kind are necessary to identify more precisely those patients for whom cardiovascular benefits will outweigh the risks and costs of the statin treatment in comparison with nutritional interventions. Against the background of the current pathogenetic concept of atherogenesis some of its possible risk factors, particularly the roles of cholesterol and homocysteine, and the effects of statins versus nutritional (micronutrients) interventions in prevention and treatment of the disease are discussed. The prevailing opinion that serum cholesterol as a mediator of the disease is increased by eating saturated fats and decreased by eating polyunsaturated fats is being challenged. Evidently, the beneficial effects of statins in atherosclerosis are not mainly due to its cholesterol lowering effect, rather than to its “pleiotropic effects”. Other pathogenetic factors in atherosclerosis are involved, like inflammatory and immunologic processes, that can be modulated by statins as well as by other drugs or by the Mediterranean-style nutrition and by micronutrients (folate, B-vitamins). PMID:19675712

Microvesicles/exosomes as potential novel biomarkers of metabolic diseases

PubMed Central

Müller, Günter

2012-01-01

Biomarkers are of tremendous importance for the prediction, diagnosis, and observation of the therapeutic success of common complex multifactorial metabolic diseases, such as type II diabetes and obesity. However, the predictive power of the traditional biomarkers used (eg, plasma metabolites and cytokines, body parameters) is apparently not sufficient for reliable monitoring of stage-dependent pathogenesis starting with the healthy state via its initiation and development to the established disease and further progression to late clinical outcomes. Moreover, the elucidation of putative considerable differences in the underlying pathogenetic pathways (eg, related to cellular/tissue origin, epigenetic and environmental effects) within the patient population and, consequently, the differentiation between individual options for disease prevention and therapy – hallmarks of personalized medicine – plays only a minor role in the traditional biomarker concept of metabolic diseases. In contrast, multidimensional and interdependent patterns of genetic, epigenetic, and phenotypic markers presumably will add a novel quality to predictive values, provided they can be followed routinely along the complete individual disease pathway with sufficient precision. These requirements may be fulfilled by small membrane vesicles, which are so-called exosomes and microvesicles (EMVs) that are released via two distinct molecular mechanisms from a wide variety of tissue and blood cells into the circulation in response to normal and stress/pathogenic conditions and are equipped with a multitude of transmembrane, soluble and glycosylphosphatidylinositol-anchored proteins, mRNAs, and microRNAs. Based on the currently available data, EMVs seem to reflect the diverse functional and dysfunctional states of the releasing cells and tissues along the complete individual pathogenetic pathways underlying metabolic diseases. A critical step in further validation of EMVs as biomarkers will rely on the identification of unequivocal correlations between critical disease states and specific EMV signatures, which in future may be determined in rapid and convenient fashion using nanoparticle-driven biosensors. PMID:22924003

Overexpression of Mafb in podocytes protects against diabetic nephropathy.

PubMed

Morito, Naoki; Yoh, Keigyou; Ojima, Masami; Okamura, Midori; Nakamura, Megumi; Hamada, Michito; Shimohata, Homare; Moriguchi, Takashi; Yamagata, Kunihiro; Takahashi, Satoru

2014-11-01

We previously showed that the transcription factor Mafb is essential for podocyte differentiation and foot process formation. Podocytes are susceptible to injury in diabetes, and this injury leads to progression of diabetic nephropathy. In this study, we generated transgenic mice that overexpress Mafb in podocytes using the nephrin promoter/enhancer. To examine a potential pathogenetic role for Mafb in diabetic nephropathy, Mafb transgenic mice were treated with either streptozotocin or saline solution. Diabetic nephropathy was assessed by renal histology and biochemical analyses of urine and serum. Podocyte-specific overexpression of Mafb had no effect on body weight or blood glucose levels in either diabetic or control mice. Notably, albuminuria and changes in BUN levels and renal histology observed in diabetic wild-type animals were ameliorated in diabetic Mafb transgenic mice. Moreover, hyperglycemia-induced downregulation of Nephrin was mitigated in diabetic Mafb transgenic mice, and reporter assay results suggested that Mafb regulates Nephrin directly. Mafb transgenic glomeruli also overexpressed glutathione peroxidase, an antioxidative stress enzyme, and levels of the oxidative stress marker 8-hydroxydeoxyguanosine decreased in the urine of diabetic Mafb transgenic mice. Finally, Notch2 expression increased in diabetic glomeruli, and this effect was enhanced in diabetic Mafb transgenic glomeruli. These data indicate Mafb has a protective role in diabetic nephropathy through regulation of slit diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes and suggest that Mafb could be a therapeutic target. Copyright © 2014 by the American Society of Nephrology.

SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity

PubMed Central

Care, Matthew A.; Cocco, Mario; Laye, Jon P.; Barnes, Nicholas; Huang, Yuanxue; Wang, Ming; Barrans, Sharon; Du, Ming; Jack, Andrew; Westhead, David R.; Doody, Gina M.; Tooze, Reuben M.

2014-01-01

Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL. PMID:24875472

[Methodological approaches to the experimental study of the impact of environmental pollution on the human body].

PubMed

Sosedova, L M

2014-01-01

In the materials there are presented features of methodological approaches in the performing of experimental studies concerning of the investigation of the impacts of environmental factors on the human body. There were shown the results of our experiments performed at the Institute, in the modeling of biological effects of antimicrobial nanobiocomposites with nanosilver particles, toxic encephalopathy, in the study of the combined effect of the factors of biological and chemical nature. There was proved the importance of intracellular of proteomics in the assessment of the effects of the action of nanoparticles and nanomaterials on the body. There were revealed key parts of progredient course of mercury poisoning in the long-term. The special section is presented by the study of long-term effects of anthropogenic environmental factors on subsequent generations. There are presented results witnessing to a deterioration of the functional state of the central nervous system in rats in the first and second generations, whose parents were exposed to neurotoxicants. There was proved the aggravating role of prenatal hypoxia in the development of toxicity in rats in sexually mature age. Experimental biomodeling is aimed at sighting of pathogenetically substantiated treatment and preventive measures: initially, in experimental conditions, and in the future in the rehabilitation of sick or injured patients.

Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development.

PubMed

Breccia, Massimo; Alimena, Giuliana

2010-09-01

Despite the beneficial effect of imatinib treatment in chronic myeloid leukemia patients, some patients develop resistance and/or intolerance and need a switch to second-generation tyrosine kinase inhibitors. Dasatinib is indicated for chronic myeloid leukemia patients with resistance or intolerance to imatinib; it has 325-fold increase potency compared to imatinib and is active in mutated and unmutated resistant patients. Pleural/pericardic effusions are frequent complications during treatment with dasatinib, and usually are reported to require dose reduction or drug discontinuation. Changing the dasatinib regimen from 70 mg twice daily to 100 mg once daily reduces the risk of pleural effusions. In this article, we review the incidence of the phenomenon observed in different dasatinib trials (Phase I - III) and the currently suggested management. We also describe the identified pathogenetic mechanisms related to the development and discuss the associated risk factors. The aim of this paper is to provide healthcare professionals with clear guidance on the management of pleural effusions associated with dasatinib treatment. Recommendations are based on the published data and clinical experience from a number of different centers. Literature evidences support the fact that with adequate management and monitoring of patients with predisposing factors, pleural effusions can be easily managed.

Benign Prostatic Hyperplasia: A New Metabolic Disease of the Aging Male and Its Correlation with Sexual Dysfunctions

PubMed Central

Corona, Giovanni; Vignozzi, Linda; Lotti, Francesco; Cipriani, Sarah

2014-01-01

Metabolic syndrome (MetS) is a well-recognized cluster of cardiovascular (CV) risk factors including obesity, hypertension, dyslipidemia, and hyperglycaemia, closely associated with an increased risk of forthcoming cardiovascular disease and type 2 diabetes mellitus. Emerging evidence indicates that benign prostate hyperplasia (BPH) and its related lower urinary tract symptoms (LUTS) represent other clinical conditions frequently observed in subjects with MetS. Several modifiable factors involved in MetS determinism, such as inadequate diet, lack of physical exercise, and smoking and drinking behaviours are emerging as main contributors to the development of BPH. The pathogenetic mechanisms underlying the connection between MetS and BPH have not been completely clarified. MetS and its components, hypogonadism, and prostate inflammation probably play an important role in inducing BPH/LUTS. Although historically considered as a “normal” consequence of the aging process, BPH/LUTS should now be faced proactively, as a preventable disorder of the elderly. Type of diet and level of physical activity are now considered important factors affecting prostate health in the aging male. However, whether physical exercise, weight loss, and modifications of dietary habit can really alter the natural history of BPH/LUTS remains to be determined. Further research is advisable to better clarify these points. PMID:24688539

[Immunodiagnostic methods in lupus erythematosus disseminatus].

PubMed

Storch, H; Schwenke, H; Helbig, W

1975-12-01

In 27 patients with lupus erythematodes diseminatus the determinations of the LE-cells according to the macromethod (Zimmer and Hargraves) and the micromethod (Mudrik and co-workers) were compared with the demonstration of antinuclear factors according to the indirect immunofluorescence and immune enzyme technique. The sensitiveness of the two last-mentioned immunomorphological methods is somewhat larger. In these cases the size of the titre of the antinuclear factor almost always correlates positively with the number of the LE-cells. For the purpose of the initial diagnostics and the judgment of the course a morphological method cannot be renounced, since in the acute episode a high consumption of the antinuclear factor the immunological methods negatively correlate with the number of the LE-cells. The immune enzyme technique is to be recommended on account of the smaller expenditure, permanence of the preparations and high sensitiveness as alternative method of the immunofluorescence technique. In the micromethod the large variation is opposite to the advantage of the slight quantity of blood and to an always existing evaluability. Investigations of the lymphocytes of patients with lupus erythematodes disseminatus by means of the lymphocyte transformation test and the determination of the B-cells with the help of the direct immune peroxidase technique refer to the close pathogenetic connections of cellular and humoral immune reactions in this disease.

[Anatomy and pathogenesis of diverticular disease].

PubMed

Wedel, T; Böttner, M

2014-04-01

Although diverticular disease is one of the most frequent gastrointestinal disorders the pathogenesis is not yet sufficiently clarified. The aim is to define the anatomy and pathogenesis of diverticular disease considering the risk factors and description of structural and functional alterations of the bowel wall. This article gives an appraisal of the literature, presentation and evaluation of classical etiological factors, analysis and discussion of novel pathogenetic concepts. Colonic diverticulosis is defined as an acquired out-pouching of multiple and initially asymptomatic pseudodiverticula through muscular gaps in the colon wall. Diverticular disease is characterized by diverticular bleeding and/or inflammatory processes (diverticulitis) with corresponding complications (e.g. abscess formation, fistula, covered and open perforation, peritonitis and stenosis). Risk factors for diverticular disease include increasing age, genetic predisposition, congenital connective tissue diseases, low fiber diet, high meat consumption and pronounced overweight. Alterations of connective tissue cause a weakening of preformed exit sites of diverticula and rigidity of the bowel wall with reduced flexibility. It is assumed that intestinal innervation disorders and structural alterations of the musculature induce abnormal contractile patterns with increased intraluminal pressure, thereby promoting the development of diverticula. Moreover, an increased release of pain-mediating neurotransmitters is considered to be responsible for persistent pain in chronic diverticular disease. According to the present data the pathogenesis of diverticular disease cannot be attributed to a single factor but should be considered as a multifactorial event.

[Contemporary aspects of maintenance and promotion of health of the workers employed at the aluminum production enterprises].

PubMed

Izmerov, N F; Bukhtiiarov, I V; Prokopenko, L V; Kuz'mina, L P; Sorkina, N S; Burmistrova, T B; Lagutina, G N

2012-01-01

The exposure of the combined occupational hazards on the workers of aluminum plants results in the development of the occupational chronic diseases of bronchopulmonary and bone systems and oncopathology. Pathogenetic mechanisms of the toxic exposure of fluorides on the body as well as molecular and cellular structures are presented.

[Malassezia related diseases].

PubMed

Sei, Yoshihiro

2012-01-01

Genusmalassezia are now divided to fourteen species. Different species will start or aggravate different skin diseases. In the seborrheic dermatitis, M.restricta will play an important role, in the atopic dermatitis, M.globosa and/or M.restricta are major cutaneous microflora. The availability of new tools such as genomic and proteomic analyses has begun to provide a new insight into the pathogenetic mechanisms involved.

Perinatal White Matter Injury: The Changing Spectrum of Pathology and Emerging Insights into Pathogenetic Mechanisms

ERIC Educational Resources Information Center

Back, Stephen A.

2006-01-01

Perinatal brain injury in survivors of premature birth has a unique and unexplained predilection for periventricular cerebral white matter. Periventricular white-matter injury (PWMI) is now the most common cause of brain injury in preterm infants and the leading cause of chronic neurological morbidity. The spectrum of chronic PWMI includes focal…

Update on embryology of the upper limb.

PubMed

Al-Qattan, Mohammad M; Kozin, Scott H

2013-09-01

Current concepts in the steps of upper limb development and the way the limb is patterned along its 3 spatial axes are reviewed. Finally, the embryogenesis of various congenital hand anomalies is delineated with an emphasis on the pathogenetic basis for each anomaly. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Necrobiosis lipoidica associated with Hashimoto's thyroiditis and positive detection of ANA and ASMA autoantibodies.

PubMed

Borgia, Francesco; Russo, Giuseppina T; Villari, Provvidenza; Guarneri, Fabrizio; Cucinotta, Domenico; Cannavò, Serafinella P

2015-07-01

Necrobiosis lipoidica (NL) is a rare idiopathic cutaneous condition exceptionally associated with autoimmune thyroiditis. We describe the first case of NL, Hashimoto's thyroiditis and positive detection of autoantibodies. Appropriate screening for NL in patients with autoimmune thyroiditis may clarify its real incidence and the existence of a common pathogenetic pathway.

Crystal-proven Gout and Characteristic Gout Severity Factors are Associated with Cardiovascular Disease.

PubMed

Disveld, Iris J M; Fransen, Jaap; Rongen, Gerard A; Kienhorst, Laura B E; Zoakman, Sahel; Janssens, Hein J E M; Janssen, Matthijs

2018-04-15

Our aim was to examine the prevalence of cardiovascular disease (CVD) in patients with crystal-proven gout compared to arthritis controls. Further, we analyzed the association between characteristic gout severity factors and CVD to provide further support for a pathogenetic relationship between gout and CVD. Patients with arthritis referred for diagnosis were consecutively included in the Gout Arnhem-Liemers cohort. Joint fluid analysis was performed in all referred patients; controls were negative for crystals. Patients' characteristics and different manifestations of CVD and gout severity factors (disease duration, attack frequency, tophi, affected joints, high serum urate acid level, joint damage) were collected. Gout patients were compared with controls for the prevalence of CVD. In addition, the association between characteristic gout severity factors and presence of CVD was analyzed. Data from 700 gout patients and 276 controls were collected. CVD was present in 47% (95% CI 44%-51%) and 24% (95% CI 19%-29%) of gout patients and controls, respectively. Corrected for confounders, gout was still strongly associated with an increased prevalence of CVD compared to controls (OR 3.39, 95% CI 2.37-4.84). In patients with gout, disease duration ≥ 2 years, oligo- or polyarthritis, serum urate acid > 0.55 mmol/l at presentation, and joint damage were independently (p < 0.05) associated with prevalent CVD. Crystal-proven gout was strongly associated with an increased prevalence of CVD. In patients with gout, characteristic gout severity factors were associated with CVD.

NF-κB deregulation in Hodgkin lymphoma.

PubMed

Weniger, Marc A; Küppers, Ralf

2016-08-01

Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-κB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-κB inhibition. Multiple factors contribute to the strong NF-κB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14). In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor. NF-κB activity is also seen in the tumor cells of the rare nodular lymphocyte predominant form of HL, but the causes for this activity are largely unclear. Copyright © 2016 Elsevier Ltd. All rights reserved.

[On the mechanism of noopept action: decrease in activity of stress-induced kinases and increase in expression of neutrophines].

PubMed

Ostrovskaia, R U; Vakhitova, Iu V; Salimgareeva, M Kh; Iamidanov, R S; Sadovnikov, S V; Kapitsa, I G; Seredenin, S B

2010-12-01

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.

Diabetes and sexual dysfunction: current perspectives

PubMed Central

Maiorino, Maria Ida; Bellastella, Giuseppe; Esposito, Katherine

2014-01-01

Diabetes mellitus is one of the most common chronic diseases in nearly all countries. It has been associated with sexual dysfunction, both in males and in females. Diabetes is an established risk factor for sexual dysfunction in men, as a threefold increased risk of erectile dysfunction was documented in diabetic men, as compared with nondiabetic men. Among women, evidence regarding the association between diabetes and sexual dysfunction are less conclusive, although most studies have reported a higher prevalence of female sexual dysfunction in diabetic women as compared with nondiabetic women. Female sexual function appears to be more related to social and psychological components than to the physiological consequence of diabetes. Hyperglycemia, which is a main determinant of vascular and microvascular diabetic complications, may participate in the pathogenetic mechanisms of sexual dysfunction in diabetes. Moreover, diabetic people may present several clinical conditions, including hypertension, overweight and obesity, metabolic syndrome, cigarette smoking, and atherogenic dyslipidemia, which are themselves risk factors for sexual dysfunction, both in men and in women. The adoption of healthy lifestyles may reduce insulin resistance, endothelial dysfunction, and oxidative stress – all of which are desirable achievements in diabetic patients. Improved well-being may further contribute to reduce and prevent sexual dysfunction in both sexes. PMID:24623985

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: implications for disease pathogenesis and treatment

PubMed Central

ten Hacken, Elisa; Burger, Jan A.

2015-01-01

Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. PMID:26193078

Exercise improves cardiac autonomic function in obesity and diabetes.

PubMed

Voulgari, Christina; Pagoni, Stamatina; Vinik, Aaron; Poirier, Paul

2013-05-01

Physical activity is a key element in the prevention and management of obesity and diabetes. Regular physical activity efficiently supports diet-induced weight loss, improves glycemic control, and can prevent or delay type 2 diabetes diagnosis. Furthermore, physical activity positively affects lipid profile, blood pressure, reduces the rate of cardiovascular events and associated mortality, and restores the quality of life in type 2 diabetes. However, recent studies have documented that a high percentage of the cardiovascular benefits of exercise cannot be attributed solely to enhanced cardiovascular risk factor modulation. Obesity in concert with diabetes is characterized by sympathetic overactivity and the progressive loss of cardiac parasympathetic influx. These are manifested via different pathogenetic mechanisms, including hyperinsulinemia, visceral obesity, subclinical inflammation and increased thrombosis. Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes. The same is true for the role of physical exercise in the restoration of the heart cardioprotective autonomic modulation in these individuals. This review addresses the interplay of cardiac autonomic function in obesity and diabetes, and focuses on the importance of exercise in improving cardiac autonomic dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of growth conditions on extracellular products (ECPs) of Aeromonas hydrophila.

PubMed

Di Pietro, A; Picerno, I; Scoglio, M E

2004-01-01

Owing to the significant role in gastrointestinal illness of A. hydrophila, frequently detected in various raw and ready-to eat foods, its pathogenetic mechanisms are particularly studied. In this paper we report the results obtained studying in vitro the effect of O2 tension and inoculum age on the extra cellular products (ECPs) of seven strains food-borne isolated and cultured at 37 degrees. The considered factors influenced markedly bacterial growth as well as ECPs production and the more notable differences were detected among 15 hours old strains let grown slowly shaking (15SH), that showed the highest bacterial yield, and 24 h old strains cultured statically (24ST), whose haemolysin and cytotoxin production was favoured. Wilcoxon test shows as, in these latter conditions, the strains needed short time to adapt the haemolysin and cytotoxin production. The oxygen tension reduction, extending the replication time, induces the bacterial metabolism toward secondary products, as verified by Spearman test applied to ECPs indexes. The increased production per cell of virulence-associated factors could be responsible of gastrointestinal disorders caused by food-borne A. hydrophila strains, even without a massive gut colonization, especially when immunocompromised individuals ingest contaminated foods.

Mechanisms of inhibition of viral replication in plants

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

Not Available

1990-01-01

We have made a number of interesting observations of importance to the fields of virology and plant molecular biology. Topics include the genome of cucumber mosaic virus (CMV), recombination of the CMV genome, transgenic plants and viral movement genes, mapping resistance breakage sequences in the tomato mosaic virus (TMV) genome, and mapping pathogeneticity domains and viral RNA heterogeneity. 1 fig., 1 tab.

[Importance of toxicological studies in animals for elaboration of pathogenetic therapy of hydrazine intoxication].

PubMed

Baryshnikov, I I

1997-01-01

Pathogenesis of poisoning with hydrazine seems complicated. Hydrazines inhibit pyridoxal-dependent enzymes, interfere with carbohydrates transformation and lipid metabolism, alter the processes of energy metabolism. Treatment of poisoning with hydrazine is effective only when containing drug combinations. Based experimentally, recommendations on the combination (phenazepam, be methyl, piracetam, ionol) were supported by chemical testing of the drugs.

Activation of normal neutrophils by anti-neutrophil cytoplasm antibodies.

PubMed Central

Keogan, M T; Esnault, V L; Green, A J; Lockwood, C M; Brown, D L

1992-01-01

Anti-neutrophil cytoplasm antibodies (ANCA) are markers of systemic vasculitis for which a pathogenetic role has been postulated. We have examined the effect of these autoantibodies on the function of normal human neutrophils in vitro. In the presence of ANCA positive sera luminol-amplified chemiluminescence was significantly increased compared to the values seen in the presence of normal or anti-double stranded DNA positive sera (P < 0.01). Five of six ANCA positive F(ab)2 preparations also produced significant neutrophil activation as demonstrated by the chemiluminescence response. This response was totally abrogated by the addition of neutrophil cytoplasm extract, containing the ANCA antigen. Addition of inhibitors to the chemiluminescence system demonstrated that the chemiluminescence response was inhibited by azide and salicylhydroxamic acid and reduced by histidine, suggesting that the chemiluminescence response was due to activation of myeloperoxidase, with generation of singlet oxygen. The chemotactic response to f-Met-Leu-Phe, a bacterial chemotactic peptide, was significantly augmented in the presence of ANCA. Chemotaxis to zymosan-activated serum and chemokinesis was not affected. Phagocytosis was also unaffected. We propose that neutrophil activation and modulation of neutrophil migration by ANCA may be of pathogenetic significance in systemic vasculitis. PMID:1424279

Crypto-glandular fistulous paraproctites--is the surgical prophylaxis of reccurences imperative?

PubMed

Radionov, M; Ziya, D D; Sechanov, I

2013-01-01

It is done an analysis of 191 patients operated on for crypto-glandular chronic fistulous paraproctitis. The age of the patients vary 21 to 76 years and the male:female proportion is 2,25 to 1. In 164 patients it was first operation for fistula-in-ano and in 27 cases it was a consecutive one for reccurence. There was intervened a concomitant other disease of the anal channel which pathogenetically predispose the development of fistula in 54 (28%) cases. The patients were discharged 1-3 days after surgery. Ambulant control and ligature procedures up to the 30th day were done. A follow up was done of 118 patients (68%) for period of 3 to 12 months. In all the followed up patients was registered full continence and good tonus of the anal sphincters. Recurrences were registered in 8 cases with fibrin glue occlusion of the fistula. There are no registered cases of recurrences by the followed up patients after fistulotomy and excision-ligature methods. The authors review in the discussion the pathogenetical predisposition for paraproctitis in consequence of other diseases of the anal channel and the necessity of surgical prophylaxis of recurrences.

Wells syndrome and its relationship to Churg-Strauss syndrome.

PubMed

Ratzinger, Gudrun; Zankl, Julia; Zelger, Bernhard

2013-08-01

  Wells syndrome has been described as an inflammatory disorder based on typical clinical appearance combined with the histopathological presence of eosinophilic infiltrates and flame figures in the absence of vasculitis. Churg-Strauss syndrome, on the other hand, is primarily a diffuse, necrotizing vasculitis but is also typically displaying eosinophils and flame figures. Despite several parallels, the present understanding of these two diseases excludes any pathogenetic relationship.   We describe the clinical course and histopathological appearance of three patients who had initially been diagnosed with Wells syndrome that developed into Churg-Strauss syndrome during the course of their disease.   The clinical presentation of all three patients led to the diagnosis of Wells syndrome by independent specialists. Histopathology showed an eosinophilic infiltrate and flame figures next to features of leukocytoclastic vasculitis. Detailed examination revealed asthma bronchiale and additional symptoms indicating Churg-Strauss syndrome. The initial diagnosis of Wells syndrome had to be revised to Churg-Strauss syndrome.   We conclude that Wells syndrome could be the starting point of a pathogenetic process that might reach its maximum in Churg-Strauss syndrome. As a clinical consequence, patients with Wells syndrome should be evaluated and followed for Churg-Strauss syndrome. © 2013 The International Society of Dermatology.

GI-POP: a combinational annotation and genomic island prediction pipeline for ongoing microbial genome projects.

PubMed

Lee, Chi-Ching; Chen, Yi-Ping Phoebe; Yao, Tzu-Jung; Ma, Cheng-Yu; Lo, Wei-Cheng; Lyu, Ping-Chiang; Tang, Chuan Yi

2013-04-10

Sequencing of microbial genomes is important because of microbial-carrying antibiotic and pathogenetic activities. However, even with the help of new assembling software, finishing a whole genome is a time-consuming task. In most bacteria, pathogenetic or antibiotic genes are carried in genomic islands. Therefore, a quick genomic island (GI) prediction method is useful for ongoing sequencing genomes. In this work, we built a Web server called GI-POP (http://gipop.life.nthu.edu.tw) which integrates a sequence assembling tool, a functional annotation pipeline, and a high-performance GI predicting module, in a support vector machine (SVM)-based method called genomic island genomic profile scanning (GI-GPS). The draft genomes of the ongoing genome projects in contigs or scaffolds can be submitted to our Web server, and it provides the functional annotation and highly probable GI-predicting results. GI-POP is a comprehensive annotation Web server designed for ongoing genome project analysis. Researchers can perform annotation and obtain pre-analytic information include possible GIs, coding/non-coding sequences and functional analysis from their draft genomes. This pre-analytic system can provide useful information for finishing a genome sequencing project. Copyright © 2012 Elsevier B.V. All rights reserved.

Misconceptions regarding the pathogenicity of silicas and silicates.

PubMed

Feigin, D S

1989-01-01

Several inhaled substances, from occupational or other environmental exposure, produce significant pulmonary disease and abnormalities demonstrated by pulmonary imaging. Areas of controversy and misconception relate principally to the extent and nature of both the clinical disease and the imaging abnormalities specific to each substance. The size and shape of the inhaled particles is an important determinant of the nature and severity of the disease produced, with fibrous shapes usually being the most pathogenetic. Fibrogenicity is another important pathogenetic characteristic of talc and kaolin, as well as asbestos. Talc produces four distinct forms of pulmonary disease, depending not only on the other substances with which it is inhaled, but also whether it is inhaled or injected intravenously. When inhaled alone, talc does not appear to produce significant pulmonary fibrosis or malignancy. Kaolin, mica, fuller's earth, zeolite, and fiberglass all vary in disease production according to their shape and fibrogenicity. Silica, diatomaceous earth, and other forms of silica are all highly fibrogenic and thus produce clinically obvious disease with sufficient inhalation. The largest particles usually produce nodular patterns in the upper pulmonary fields, as is typical of silicosis. The fibrous particles are more likely to manifest themselves as interstitial patterns in the lower pulmonary fields.

Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

PubMed Central

Kode, Aruna; Manavalan, John S.; Mosialou, Ioanna; Bhagat, Govind; Rathinam, Chozha V.; Luo, Na; Khiabanian, Hossein; Lee, Albert; Vundavalli, Murty; Friedman, Richard; Brum, Andrea; Park, David; Galili, Naomi; Mukherjee, Siddhartha; Teruya-Feldstein, Julie; Raza, Azra; Rabadan, Raul; Berman, Ellin; Kousteni, Stavroula

2014-01-01

Summary Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML. PMID:24429522

Endoplasmic reticulum and lysosomal Ca²⁺ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts.

PubMed

Kilpatrick, Bethan S; Magalhaes, Joana; Beavan, Michelle S; McNeill, Alisdair; Gegg, Matthew E; Cleeter, Michael W J; Bloor-Young, Duncan; Churchill, Grant C; Duchen, Michael R; Schapira, Anthony H; Patel, Sandip

2016-01-01

Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca(2+) signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of β-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca(2+) signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca(2+) store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca(2+) stores by pathogenic GBA1 mutations may therefore feature in PD. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

PubMed Central

Salvadori, Maurizio; Bertoni, Elisabetta

2013-01-01

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both “traditional therapy” (including plasma therapy, kidney and kidney-liver transplantation) and “new therapies”. The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody “eculizumab”. Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases I and II. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy. PMID:24255888

Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

PubMed

Romani, Luigina; Oikonomou, Vasilis; Moretti, Silvia; Iannitti, Rossana G; D'Adamo, Maria Cristina; Villella, Valeria R; Pariano, Marilena; Sforna, Luigi; Borghi, Monica; Bellet, Marina M; Fallarino, Francesca; Pallotta, Maria Teresa; Servillo, Giuseppe; Ferrari, Eleonora; Puccetti, Paolo; Kroemer, Guido; Pessia, Mauro; Maiuri, Luigi; Goldstein, Allan L; Garaci, Enrico

2017-05-01

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

Thymosin α1 represents a potential potent single molecule-based therapy for cystic fibrosis

PubMed Central

Romani, Luigina; Oikonomou, Vasilis; Moretti, Silvia; Iannitti, Rossana G.; D’Adamo, Maria Cristina; Villella, Valeria R.; Pariano, Marilena; Sforna, Luigi; Borghi, Monica; Bellet, Marina M.; Fallarino, Francesca; Pallotta, Maria Teresa; Servillo, Giuseppe; Ferrari, Eleonora; Puccetti, Paolo; Kroemer, Guido; Pessia, Mauro; Maiuri, Luigi; Goldstein, Allan L.; Garaci, Enrico

2017-01-01

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride-channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF —which include impaired chloride permeability and persistent lung inflammation—a multidrug approach is required for efficacious CF therapy. To date, no individual, drug with pleiotropic beneficial effects for CF is available. Here we report on the ability of thymosin alpha 1 (Tα1)—a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent—to rectify the multiple tissue defects in CF mice as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology; namely, it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 offers a strong potential to be an efficacious single molecule-based therapeutic agent in CF. PMID:28394330

New approaches for identifying and testing potential new anti-asthma agents.

PubMed

Licari, Amelia; Castagnoli, Riccardo; Brambilla, Ilaria; Marseglia, Alessia; Tosca, Maria Angela; Marseglia, Gian Luigi; Ciprandi, Giorgio

2018-01-01

Asthma is a chronic disease with significant heterogeneity in clinical features, disease severity, pattern of underlying disease mechanisms, and responsiveness to specific treatments. While the majority of asthmatic patients are controlled by standard pharmacological strategies, a significant subgroup has limited therapeutic options representing a major unmet need. Ongoing asthma research aims to better characterize distinct clinical phenotypes, molecular endotypes, associated reliable biomarkers, and also to develop a series of new effective targeted treatment modalities. Areas covered: The expanding knowledge on the pathogenetic mechanisms of asthma has allowed researchers to investigate a range of new treatment options matched to patient profiles. The aim of this review is to provide a comprehensive and updated overview of the currently available, new and developing approaches for identifying and testing potential treatment options for asthma management. Expert opinion: Future therapeutic strategies for asthma require the identification of reliable biomarkers that can help with diagnosis and endotyping, in order to determine the most effective drug for the right patient phenotype. Furthermore, in addition to the identification of clinical and inflammatory phenotypes, it is expected that a better understanding of the mechanisms of airway remodeling will likely optimize asthma targeted treatment.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

PubMed Central

Gammella, Elena; Recalcati, Stefania; Rybinska, Ilona; Buratti, Paolo; Cairo, Gaetano

2015-01-01

The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies. PMID:25878762

Dysferlinopathy course and sportive activity: clues for possible treatment.

PubMed

Angelini, C; Peterle, E; Gaiani, A; Bortolussi, L; Borsato, C

2011-10-01

LGMD2B is a frequent proximo-distal myopathy with rapid evolution after age 20. Exacerbating factors may be physical exercise and inflammation. There is very little information about the effect of sportive activity in LGMD2B, since eccentric exercise frequently results in muscle damage. LGMD2B has often an onset with myalgia and MRI imaging (STIR-sequences) shows myoedema. In a prolonged observational study of a series of 18 MM/LGMD2B patients we have studied the pattern of clinical and radiological evolution. The disease has an abrupt onset in the second decade and most patients perform sports before definite disease onset. On the basis of Gardner-Medwin and Walton scale, grade 4 is reached two years faster in patients who performed sports (over 1000 hours). Other considerations regarding pathogenetic mechanism and response to treatment show a poor response to immunosuppressive treatment of muscle inflammation. Preventing a strenuous physical activity should be recommended in patients with high CK and diagnosed or suspected to have dysferlin deficiency.

Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing.

PubMed

Cenni, Vittoria; D'Apice, Maria Rosaria; Garagnani, Paolo; Columbaro, Marta; Novelli, Giuseppe; Franceschi, Claudio; Lattanzi, Giovanna

2018-03-01

Mandibuloacral dysplasia (MAD) is a rare genetic condition characterized by bone abnormalities including localized osteolysis and generalized osteoporosis, skin pigmentation, lipodystrophic signs and mildly accelerated ageing. The molecular defects associated with MAD are mutations in LMNA or ZMPSTE24 (FACE1) gene, causing type A or type B MAD, respectively. Downstream of LMNA or ZMPSTE24 mutations, the lamin A precursor, prelamin A, is accumulated in cells and affects chromatin dynamics and stress response. A new form of mandibuloacral dysplasia has been recently associated with mutations in POLD1 gene, encoding DNA polymerase delta, a major player in DNA replication. Of note, involvement of prelamin A in chromatin dynamics and recruitment of DNA repair factors has been also determined under physiological conditions, at the border between stress response and cellular senescence. Here, we review current knowledge on MAD clinical and pathogenetic aspects and highlight aspects typical of physiological ageing. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Inherited variation in immune response genes in follicular lymphoma and diffuse large B-cell lymphoma.

PubMed

Nielsen, Kaspar Rene; Steffensen, Rudi; Haunstrup, Thure Mors; Bødker, Julie Støve; Dybkær, Karen; Baech, John; Bøgsted, Martin; Johnsen, Hans Erik

2015-01-01

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) both depend on immune-mediated survival and proliferation signals from the tumor microenvironment. Inherited genetic variation influences this complex interaction. A total of 89 studies investigating immune-response genes in DLBCL and FL were critically reviewed. Relatively consistent association exists for variation in the tumor necrosis factor alpha (TNFA) and interleukin-10 loci and DLBCL risk; for DLBCL outcome association with the TNFA locus exists. Variations at chromosome 6p31-32 were associated with FL risk. Importantly, individual risk alleles have been shown to interact with each other. We suggest that the pathogenetic impact of polymorphic genes should include gene-gene interaction analysis and should be validated in preclinical model systems of normal B lymphopoiesis and B-cell malignancies. In the future, large cohort studies of interactions and genome-wide association studies are needed to extend the present findings and explore new risk alleles to be studied in preclinical models.

Nutritional evaluation and management of AKI patients.

PubMed

Fiaccadori, Enrico; Maggiore, Umberto; Cabassi, Aderville; Morabito, Santo; Castellano, Giuseppe; Regolisti, Giuseppe

2013-05-01

Protein-energy wasting is common in patients with acute kidney injury (AKI) and represents a major negative prognostic factor. Nutritional support as parenteral and/or enteral nutrition is frequently needed because the early phases of this are often a highly catabolic state, although the optimal nutritional requirements and nutrient intake composition remain a partially unresolved issue. Nutrient needs of patients with AKI are highly heterogeneous, depending on different pathogenetic mechanisms, catabolic rate, acute and chronic comorbidities, and renal replacement therapy (RRT) modalities. Thus, quantitative and qualitative aspects of nutrient intake should be frequently evaluated in this clinical setting to achieve better individualization of nutritional support, to integrate nutritional support with RRT, and to avoid under- and overfeeding. Moreover, AKI is now considered a kidney-centered inflammatory syndrome; indeed, recent experimental data indicate that specific nutrients with anti-inflammatory effects could play an important role in the prevention of renal function loss after an episode of AKI. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Cachexia and protein-energy wasting in children with chronic kidney disease.

PubMed

Mak, Robert H; Cheung, Wai W; Zhan, Jian-Ying; Shen, Qian; Foster, Bethany J

2012-02-01

Children with chronic kidney disease (CKD) are at risk for "cachexia" or "protein-energy wasting" (PEW). These terms describe a pathophysiologic process resulting in the loss of muscle, with or without loss of fat, and involving maladaptive responses, including anorexia and elevated metabolic rate. PEW has been defined specifically in relation to CKD. We review the diagnostic criteria for cachexia and PEW in CKD and consider the limitations and applicability of these criteria to children with CKD. In addition, we present an overview of the manifestations and mechanisms of cachexia and PEW. A host of pathogenetic factors are considered, including systemic inflammation, endocrine perturbations, and abnormal neuropeptide signaling, as well as poor nutritional intake. Mortality risk, which is 100- to 200-fold higher in patients with end-stage renal disease than in the general population, is strongly correlated with the components of cachexia/PEW. Further research into the causes and consequences of wasting and growth retardation is needed in order to improve the survival and quality of life for children with CKD.

[Hypogonadism, a serious complication of chronic renal insufficiency].

PubMed

Zofková, I; Bubenícek, P; Sotorník, I

2007-06-01

Hypogonadism is a frequent complication in patients with chronic renal insufficiency (CHRI). From a pathogenetic point of view, it is a disorder at the level of the hypothalamus caused by central inhibition of the pulsatile generation of gonadotropin releasing hormone (GnRH) and by a primary disorder of gonads. The cause of hypogonadism in dialysed patients is not completely known. The effect of inhibition of erythropoietin production is believed to be one of the factors, as well as the adverse effects of complicated therapeutic procedures and malnutrition. In men, the affection manifests itself as a disorder of sexual functions, inhibition ofspermatogenesis, premature andropause and severe fatigue syndrome. Menstruation disorders, premature menopause and anovulation cycles are frequent symptoms in dialysed women. Androgen or estrogen substitution improves the quality of life in both sexes and slows down the loss of bone mass. Complete remission of hypogonadism is obtained, in the majority of patients, by renal transplant. The overview study deals with the pathogenesis, diagnosis and treatment of hypogonadism in dialysed patients.

Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy

PubMed Central

Tahmasebi Birgani, Maryam; Carloni, Vinicio

2017-01-01

Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu. PMID:28216578

[The clinical significance of hepcidin detection in the patients with anemia and rheumatoid arthritis].

PubMed

Galushko, E A

2014-01-01

The prevalence of anemia in patients with rheumatoid arthritis (RA) varies from 30 to 70%. 25% of the cases are diagnosed within 1 year after onset of the disease. On the whole, anemia in RA is described as anemia of a chronic disease (ACD). Pathogenesis ofACD is a multifactor process underlain by an immune mechanism: cytokines and cells ofthe reticuloendothelial system cause changes in iron homeostasis, proliferation of erythroid precursors, erythropoietin production and lifespan of erythrocytes. The key pathogenetic factor is disordered iron metabolism. IL-6 increasing hepatic production acute-phase protein (hepcidin) is the most important cytokine involved in ACD pathogenesis. Hence the necessity to measure its serum level for differential diagnostics of anemic syndrome in patients with RA and the choice of effective basal therapy. Recent data on the therapeutic potency of tocilizumab (IL-6 receptor inhibitor) demonstrate not its safety and sustainable beneficial clinical effect in combination with the favourable action on hemoglobin profile and reduction offatigue.

Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: report of two cases.

PubMed

Vaquero, Eva C; Salcedo, Maria T; Cuatrecasas, Míriam; De León, Hannah; Merino, Xavier; Navarro, Salvador; Ginès, Angels; Abu-Suboh, Monder; Balsells, Joaquim; Fernández-Cruz, Laureano; Molero, Xavier

2014-01-01

Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation. Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.

[Sexuality in the elderly].

PubMed

Wilk, Bartosz

2015-03-01

Sustaining and strengthening the ability of the elderly to continue their sexual needs can be realized as part of improving their quality of life, health and well-being. There is no age at which ends the expression of sexuality and intimacy. Through education, quality of life and advances in medicine, the average life expectancy is still increasing. Sexual activity of older people society usually describe using pejorative terms as an inappropriate, bizarre or obscene, but these labels are different than reality. Hormonal changes and other physiological changes associated with aging affect sexual interest. Erectile dysfunction is a problem in men increasing with age. There is no evidence that premature ejaculation is more common in older age. Cross-sectional studies showed no difference in sexual dysfunction between older and younger women. Age is not a barrier to sexually transmitted diseases. The most common pathogenetic factors for male erectile dysfunction are vascular diseases. In women, the most important symptoms of sexual dysfunction are lack of emotional wellbeing and a sense of intimacy during sexual intercourse. © 2015 MEDPRESS.

[Balneotherapeutics of non-alcoholic fatty liver disease with the use of the Essentuki-type drinking mineral waters].

PubMed

Fedorova, T E; Efimenko, N V; Kaĭsinova, A S

2012-01-01

The objective of the present work was to estimate the effectiveness of combined spa-and-resort treatment with the use of the Essentuki-type drinking mineral waters for the patients presenting with non-alcoholic fatty liver disease. A total of 40 patients presening with non-alcoholic fatty liver disease (NOFLD) were available for the examination. The study has demonstrated positive dynamics of clinical symptoms and results of liver functional tests, characteristics of intrahepatic dynamics, lipid metabolism, antioxidant hemostais, and the hormonal status of the patients with non-alcoholic fatty liver disease. The intake of the Essentuki-type drinking mineral waters promoted normalization of adiponectin and leptin levels in conjunction with the reduction in the degree of insulin resistance, i.e., the key pathogenetic factors responsible for hepatic steatosis and non-alcoholic steatohepatitis. It is concluded that the Essentuki-type drinking mineral waters may be recommended for the inclusion in the combined treatment and prevention of the progression of non-alcoholic fatty liver disease.

[Alcohol brain disease: systematization of metalcohol psychoses].

PubMed

Sivolap, Iu P

2006-01-01

Based on the own clinical observations, the author analyzes pathogenetic hypotheses and contemporary typology of metalcohol psychoses, proposes a concept of alcohol brain disease, including typical and atypical forms. It is suggested that typical forms rest on specific neurometabolic disturbances while the constitutional predisposition plays a main role in the forming of atypical variants. The principles of effective treatment of alcohol brain disease are considered.

Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an institute of child neuropsychiatry.

PubMed

Battaglia, A; Bianchini, E; Carey, J C

1999-01-01

The Consensus Conference of the American College of Medical Genetics has established guidelines regarding the evaluation of patients with mental retardation (MR) [Curry et al., Am. J. Med. Genet. 72:468-477, 1997]. They emphasized the high diagnostic utility of cytogenetic studies and of neuroimaging in certain clinical settings. However, data on the diagnostic yield of these studies in well-characterized populations of individuals with MR are scant. Majnemer and Shevell [J. Pediatr. 127:193-199, 1995] attained a diagnostic yield of 63%. However, this study included only 60 patients and the classification included pathogenetic and causal groups. The Stella Maris Institute has evaluated systematically patients with developmental delay (DD)/MR and performed various laboratory studies and neuroimaging in almost all patients. We report a retrospective analysis of the diagnostic yield of 120 consecutive patients observed at our Institute during the first 6 months of 1996. There were 77 males and 43 females; 47 were mildly delayed (IQ 70-50), 31 were moderately delayed (IQ 50-35), and 42 were severely delayed (IQ 35-20). Diagnostic studies (history, physical examination, standard cytogenetics, fragile X testing, molecular studies, electroencephalography, electromyography, nerve conduction studies, neuroimaging, and metabolic screening tests) yielded a causal diagnosis in 50 (41.6%) and a pathogenetic diagnosis in 47 (39.2%) of the 120 patients. Causal categories included chromosomal abnormalities (14), Fra(X) syndromes (4), known MCA/MR syndromes (19), fetal environmental syndromes (1), neurometabolic (3) disorders, neurocutaneous (3) disorders, hypoxic-ischemic encephalopathy (3), other encephalopathies (1), and congenital bilateral perisylvian syndrome (2). Pathogenetic categories included idiopathic MCA/MR syndromes (35), epileptic syndromes (10), and isolated lissencephaly sequence (2). Diagnostic yield did not differ across categories and degree of DD. Our results, while confirming the diagnostic utility of cytogenetic/molecular genetic, and neuroimaging studies, suggest the usefulness of accurate electroencephalogram recordings, and stress the importance of a thorough physical examination. Referral to a university child neurology and psychiatry service, where a comprehensive assessment with a selected battery of investigations is possible, yields etiologic findings in a high percentage of DD/MR patients, with important implications for management, prognosis and recurrence risk estimate.

Dermasence refining gel modulates pathogenetic factors of rosacea in vitro.

PubMed

Borelli, C; Becker, B; Thude, S; Fehrenbacher, B; Isermann, D

2017-12-01

Over the counter cosmetics sold for local treatment of slight to moderate rosacea often state the claim of actively modulating rosacea pathogenesis. Factors involved in the pathogenesis of this common yet complex skin disorder include kallikrein-related peptidase 5 (KLK5), LL-37, as well as protease-activated receptor 2 (PAR2) and vascular endothelial growth factor (VEGF). The objective was to prove the modulating effect of the cosmetic skin care agent Dermasence Refining Gel (DRG) on factors involved in rosacea pathogenesis. We analyzed the effect of DRG on the expression of KLK5, LL-37, PAR2, and VEGF in an in vitro skin model of human reconstituted epidermis. The expression of CAMP (LL-37 gene, fold change -4.19 [±0.11]), VEGFA (fold change -2.55 [±0.12]) and PAR2 (-1.33 [±0.12]) was reduced, KLK5 expression increased (fold change 2.06 (±0.08)) after 18 h of treatment with DRG in comparison to treatment with the matrix gel only. The reduction in CAMP expression was significant (P<.01). The protein expression of all four inflammatory markers was markedly reduced after 18 hours of DRG treatment in comparison to baseline (0 hour), by measure of fluorescence intensity. We show evidence explaining the anti-inflammatory effect of Dermasence Refining Gel in rosacea pathogenesis in vitro. The adjunctive use of DRG in mild to moderate rosacea as a topical cosmetic seems medically reasonable. © 2017 Wiley Periodicals, Inc.

Nosocomial pneumonia.

PubMed

Myrianthefs, Pavlos M; Kalafati, Maria; Samara, Irini; Baltopoulos, George J

2004-01-01

Nosocomial pneumonia (NP) is defined as pneumonia that develops within 48 hours or more of hospital admission and which was not developing at the time of admission. Nosocomial pneumonia, also known as hospital-acquired pneumonia (HAP), is the second most common hospital infection, while ventilator-associated pneumonia represents the most common intensive care unit (ICU) infection. Nosocomial pneumonia significantly contributes to morbidity, mortality, and escalating healthcare costs because of increases in antibiotic prescription and administration, length of ICU stay, and length of hospital stay. Aspiration and colonization of the upper respiratory tract seem to be the major pathogenetic mechanisms for the development of NP, either in intubated or spontaneously breathing patients. The microbiology of NP depends on the timing of onset. In early-onset NP, the responsible pathogens are generally endogenous community-acquired pathogens. In late-onset NP, the responsible microbes include potentially multi-drug-resistant nosocomial organisms residing in oropharyngeal or gastric contents. Important risk factors for development of NP include coma, intubation, prolonged mechanical ventilation, repeated intubations, supine positioning, and long-term antibiotic use. The most significant preventive measures include routine hand washing and avoidance of (1) the supine position, (2) inappropriate antibiotics, and (3) overuse of H2-antagonists for stress ulcer prophylaxis. Accurate diagnosis of NP is difficult and controversial, warranting consideration for the application of invasive quantitative culture techniques over tracheal aspirates. Empiric antibiotic treatment should be prompt, starting on clinical suspicion, and based on local ICU pathogen epidemiology and antibiotic resistance patterns and on a deescalating antibiotic strategy. Innovative antibiotic strategies, such as antibiotic rotation, to help prevent the emergence of multi-drug-resistant pathogens and improve survival should be considered.

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

PubMed Central

Busnadiego, Oscar; Loureiro-Álvarez, Jesús; Sandoval, Pilar; Lagares, David; Dotor, Javier; Pérez-Lozano, María Luisa; López-Armada, María J.; Lamas, Santiago; López-Cabrera, Manuel

2015-01-01

In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-β1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-β1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-β1–blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-β1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-β1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD-associated dysfunction. PMID:25012164

Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension

PubMed Central

Panzenboeck, Adelheid; Winter, Max P; Schubert, Uwe; Voswinckel, Robert; Frey, Maria K; Jakowitsch, Johannes; Alimohammadi, Arman; Hobohm, Lukas; Mangold, Andreas; Bergmeister, Helga; Sibilia, Maria; Wagner, Erwin F; Mayer, Eckhard; Klepetko, Walter; Hoelzenbein, Thomas J; Preissner, Klaus T; Lang, Irene M

2015-01-01

Objective Restoration of patency is a natural target of vascular remodeling following venous thrombosis that involves vascular endothelial cells and smooth muscle cells as well as leukocytes. Acute pulmonary emboli usually resolve within six months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results Mice with an endothelial-cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGF-R2/Kdr) were utilized in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of non-resolving venous thromboembolism. Endothelial cell-specific deletion of Kdr and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes such as KDR, vascular endothelial cadherin and podoplanin were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by VEGF. Conclusions In the present work, we propose a mechanism of thrombus non-resolution demonstrating that endothelial cell-specific deletion of Kdr abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. PMID:24526692

Dietary glycemic factors, insulin resistance, and adiponectin levels in acne vulgaris.

PubMed

Çerman, Aslı Aksu; Aktaş, Ezgi; Altunay, İlknur Kıvanç; Arıcı, Janset Erkul; Tulunay, Aysın; Ozturk, Feyza Yener

2016-07-01

There is increasing evidence to support the relationship between acne vulgaris and diet. The aim of this study was to investigate possible associations among dietary glycemic index, glycemic load, milk consumption, insulin resistance, and adiponectin levels in the pathogenesis of acne vulgaris. The dietary glycemic index, glycemic load, milk consumption, fasting glucose, insulin, insulin-like growth factor)-1, insulin-like growth factor binding protein-3, adiponectin, and homeostasis model assessment of insulin resistance values of 50 patients with acne vulgaris and 36 healthy control subjects were measured. Glycemic index and glycemic load levels were significantly higher (P = .022 and P = .001, respectively) and serum adiponectin levels were significantly lower (P = .015) in patients with acne than in the control subjects. There was an inverse correlation between serum adiponectin concentration and glycemic index (P = .049, r = -0.212). This study used a cross-sectional design and the study population was limited to young, nonobese adults. A high-glycemic-index/-load diet was positively associated with acne vulgaris. Adiponectin may be a pathogenetic cofactor contributing to the development of the disease. Further research on adiponectin levels in patients with acne in terms of development of insulin resistance might be important in this possible relationship. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.

PubMed

Chiurchiù, Valerio; van der Stelt, Mario; Centonze, Diego; Maccarrone, Mauro

2018-01-01

Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although the knowledge on its underlying neurobiological mechanisms has considerably improved, there is a still unmet need for new treatment options, especially for the progressive forms of the disease. Both preclinical and clinical data suggest that cannabinoids, derived from the Cannabis sativa plant, may be used to control symptoms such as spasticity and chronic pain, whereas only preclinical data indicate that these compounds and their endogenous counterparts, i.e. the endocannabinoids, may also exert neuroprotective effects and slow down disease progression. Here, we review the preclinical and clinical studies that could explain the therapeutic action of cannabinoid-based medicines, as well as the medical potential of modulating endocannabinoid signaling in multiple sclerosis, with a link to other neuroinflammatory disorders that share common hallmarks and pathogenetic features. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features.

PubMed

McFarlane, Ian G

2002-08-01

The diagnosis of AIH depends on the finding of several suggestive features together with careful exclusion of liver diseases of other etiologies. Wherever possible, the diagnosis should be confirmed histologically by an experienced hepatopathologist. Seronegativity for the conventional autoantibodies at presentation does not exclude a diagnosis of AIH. It is important to test for anti-LKM1 antibodies to avoid missing a diagnosis of type 2 AIH, with potentially serious consequences. Although the syndrome is associated with characteristic biochemical abnormalities, and biochemical parameters are commonly used for monitoring response to therapy, it should be borne in mind that neither these nor autoantibody titers are completely reliable indices of disease activity. Although the various systems that have been promulgated for classification of the disease may identify different groups of patients on pathogenetic or clinical criteria and are useful for research purposes, none is yet sufficiently exclusive in terms of defining prognosis or planning treatment strategies to be applicable to the individual patient seen in the clinic. Clinical management should therefore continue to be individually tailored.

Multicentric Castleman Disease: Where are we now?

PubMed Central

Wang, Hao-Wei; Pittaluga, Stefania; Jaffe, Elaine S.

2016-01-01

Multicentric Castleman disease (MCD) encompasses a spectrum of conditions that give rise to overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity, which causes systemic inflammatory symptoms as well as lymphadenopathy. The histological changes in lymph nodes resemble in part the findings originally described in the unicentric forms Castleman disease, both hyaline vascular and plasma cell variants. In MCD caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV8), the cytokine over activity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In cases negative for KSHV/HHV8, so-called idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. In this article, we review the evolving concepts and definitions of the various conditions under the eponym of Castleman disease, and summarize current knowledge regarding the histopathology and pathogenesis of lesions within the MCD spectrum. PMID:27296355

Impetigo herpetiformis occurring during N-butyl-scopolammonium bromide therapy in pregnancy: case report.

PubMed

Guerriero, C; Lanza Silveri, S; Sisto, T; Rosati, D; De Simone, C; Fossati, B; Pomini, F; Rotoli, M; Amerio, P; Capizzi, R

2008-01-01

Impetigo herpetiformis (IH) is a rare dermatosis arising during the third trimester of pregnancy which is generally considered as a form of pustular psoriasis of unknown aetiology. Clinically it is characterized by erythematous plaques surrounded by sterile pustules associated with fever, diarrhea, sweating and increasing risk of stillbirth for placental insufficiency. We describe a case of developed erythematous plaques surrounded by pustules localised initially to the trunk of a 35-year-old woman at the 34th week of gestation after 5 days of treatment with N-Butyl-Scopolammonium, and which later involved the upper and lower limbs. Skin histology confirmed the diagnosis of generalised pregnancy pustular psoriasis (impetigo herpetiformis). IH is reported to be associated with hypocalcemia, hypoparathyroidism, use of oral contraceptives and bacterial infections. This is the first report suggesting the potential role of drugs other than oral contraceptives in the pathogenetic mechanism of this disease. In this case an adverse cutaneous reaction to BB could be the cause of the development of Koebner isomorphism.

Biological markers of generalized anxiety disorder

PubMed Central

Maron, Eduard; Nutt, David

2017-01-01

Generalized anxiety disorder (GAD) is a prevalent and highly disabling mental health condition; however, there is still much to learn with regard to pertinent biomarkers, as well as diagnosis, made more difficult by the marked and common overlap of GAD with affective and anxiety disorders. Recently, intensive research efforts have focused on GAD, applying neuroimaging, genetic, and blood-based approaches toward discovery of pathogenetic and treatment-related biomarkers. In this paper, we review the large amount of available data, and we focus in particular on evidence from neuroimaging, genetic, and neurochemical measurements in GAD in order to better understand potential biomarkers involved in its etiology and treatment. Overall, the majority of these studies have produced results that are solitary findings, sometimes inconsistent and not clearly replicable. For these reasons, they have not yet been translated into clinical practice. Therefore, further research efforts are needed to distinguish GAD from other mental disorders and to provide new biological insights into its pathogenesis and treatment. PMID:28867939

Beliefs about health and illness in latin-american migrants with diabetes living in sweden.

PubMed

Hjelm, Katarina; Bard, Karin

2013-01-01

The study explored beliefs about health and illness in Latin American migrants diagnosed with diabetes mellitus (DM) living in Sweden, and investigated the influence on health-related behavior including self-care and care-seeking behavior. Migrants are particularly affected in the diabetes pandemia. Beliefs about health and illness determine health-related behaviour and health but no studies have been found on Latin American migrants with DM. An explorative study design with focus-group interviews of nine persons aged 36-77 years from a diabetes clinic was used. Health was described from a pathogenetic or a salutogenetic perspective: 'freedom from disease or feeling of well-being', and being autonomous and able to work. Economic hardship due to expenses for medications and food for DM affected health. Individual factors such as diet, exercise and compliance with advice, and social factors with good social relations and avoidance of stress, often caused by having experienced severe events related to migrational experiences, were considered important for maintaining health and could cause DM. Disturbed relations to others (social factors), punishment by God or Fate (supernatural factors), intake of diuretics and imbalance between warmth and cold (natural factors) were also perceived as causes. A mix of biomedical and traditional explanations and active self-care behaviour with frequent use of herbs was found. It is important to assess the individual's beliefs, and health professionals, particularly nurses, should incorporate discussions of alternative treatments and other components of explanatory models and co-operate with social workers to consider influence of finances and migrational experiences on health.

Beliefs About Health and Illness in Latin-American Migrants with Diabetes Living in Sweden

PubMed Central

Hjelm, Katarina; Bard, Karin

2013-01-01

The study explored beliefs about health and illness in Latin American migrants diagnosed with diabetes mellitus (DM) living in Sweden, and investigated the influence on health-related behavior including self-care and care-seeking behavior. Migrants are particularly affected in the diabetes pandemia. Beliefs about health and illness determine health-related behaviour and health but no studies have been found on Latin American migrants with DM. An explorative study design with focus-group interviews of nine persons aged 36-77 years from a diabetes clinic was used. Health was described from a pathogenetic or a salutogenetic perspective: ‘freedom from disease or feeling of well-being’, and being autonomous and able to work. Economic hardship due to expenses for medications and food for DM affected health. Individual factors such as diet, exercise and compliance with advice, and social factors with good social relations and avoidance of stress, often caused by having experienced severe events related to migrational experiences, were considered important for maintaining health and could cause DM. Disturbed relations to others (social factors), punishment by God or Fate (supernatural factors), intake of diuretics and imbalance between warmth and cold (natural factors) were also perceived as causes. A mix of biomedical and traditional explanations and active self-care behaviour with frequent use of herbs was found. It is important to assess the individual’s beliefs, and health professionals, particularly nurses, should incorporate discussions of alternative treatments and other components of explanatory models and co-operate with social workers to consider influence of finances and migrational experiences on health. PMID:23802030

Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes

PubMed Central

Tuttolomondo, Antonino; Maida, Carlo; Pinto, Antonio

2015-01-01

Diabetic foot ulcerations have been extensively reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an “ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection”. Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it’s possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a “adipo-vascular” axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This “adipo-vascular axis” in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy. PMID:25621212

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia

PubMed Central

Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D. Gary; Levine, Ross L

2006-01-01

Background The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). Methods and Findings DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9–4.0 × 10 12/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Conclusions Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD. PMID:16834459

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

PubMed

Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D Gary; Levine, Ross L

2006-07-01

The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.

Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia.

PubMed

Schmidt, Martin Jürgen; Ondreka, Nele; Sauerbrey, Maren; Volk, Holger Andreas; Rummel, Christoph; Kramer, Martin

2012-09-06

Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF) between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP). Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Computed tomography (CT) scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D) models of the skull and the JF. Weight matched groups (7-10 kg) of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p < 0.0001) when compared with CKCSs with SM (median left JF: 0.0382 cm3; median right JF: 0.0434 cm3; p < 0.0001). There was no significant difference between the left and right JF within each group. Bland-Altman analysis revealed excellent reproducibility of all volume measurements. A stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed.

Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia

PubMed Central

2012-01-01

Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF) between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP). Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Results Computed tomography (CT) scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D) models of the skull and the JF. Weight matched groups (7–10 kg) of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p < 0.0001) when compared with CKCSs with SM (median left JF: 0.0382 cm3; median right JF: 0.0434 cm3; p < 0.0001). There was no significant difference between the left and right JF within each group. Bland-Altman analysis revealed excellent reproducibility of all volume measurements. Conclusion A stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed. PMID:22954070

[The potential of the non-pharmacological methods for the rehabilitation and prophylaxis in the patients suffering from with atopic dermatitis].

PubMed

Kosheleva, I V; Bitkina, O A; Klivitskaya, N A; Shadyzheva, L I

This article was designed to discuss the therapeutic potential of various non-pharmacological and physiotherapeutic methods for the treatment and rehabilitation of the patients presenting with atopic dermatitis (AD) during the inter-recurrence period of the disease. The particular emphasis is placed on the physical agents most frequently used for the purpose with special reference to the combined therapy of atopic dermatitis in the adults and children and to their rehabilitation in the inter-exacerbation periods. In addition, the data on the prospects for the use of various medications intended for tissue- and organotherapy of the patients suffering from atopic dermatitis are presented. The main traditional approaches to the management of the patients with atopic dermatitis under conditions of the spa and health resort facilities are considered based on the original experience of the authors including the application of various modes of ozone therapy regarded as a physiotherapeutic procedure for the treatment of atopic dermatitis in the children and adult patients, their rehabilitation, and the prevention of exacerbations of the pathological process based on the external and/or systemic application of the ozone-oxygen gaseous mixture. The selected modalities of ozone therapy used to treat various clinical forms and stages of the atopic dermatitis differing in severity are described in detail. The data on the influence of ozone therapy on a variety of pathogenetic factors of atopic dermatitis are presented as obtained by the investigations into dynamics of the characteristics of immunity, microcirculation, and the levels of free radical metabolites. The results of the study give evidence of the high effectiveness of ozone therapy as a method of physiotherapeutic treatment both in the capacity of a component of combined therapy during the acute phase of atopic dermatitis and as the means of secondary (post-exposure) prophylaxis of the exacerbations and relapses of this condition based at the medical and preventive treatment facilities of various specialization.

Combined treatment modalities for age related macular degeneration.

PubMed

Das, R A; Romano, A; Chiosi, F; Menzione, M; Rinaldi, M

2011-02-01

Age-related macular degeneration (AMD) is a condition that accounts for 75% of cases of legal blindness in individuals over the age of 50. The objective of this review has been to evaluate the clinical effectiveness of available combined treatments modalities in the treatment of neovascular AMD. Central and Medline were searched for original research studies (Phase I, II, III), abstracts, and review articles concerning combination therapies for the control of neovascular AMD. We included randomized controlled trials (RCTs). The results of therapeutic trials focused on the actual options in the management of neovascular AMD are discussed. Intravitreal treatment with substances targeting all isotypes of vascular endothelial growth factor (VEGF) results in a significant increase in visual acuity in patients with neovascular AMD. The combination with occlusive therapies like verteporfin photodynamic therapy (V-PDT) potentially offers a reduction of re-treatment frequency rate and long-term maintenance of the benefit reached. Despite the promise from combining anti-VEGF therapies with V-PDT, other combinations to improve outcomes with V-PDT deserve attention. Corticosteroids demonstrated an antiangiogenic effect and targeted the extravascular components of CNV, such as inflammatory cells and fibrocytes. Nevertheless, the study on the clinical application of corticosteroids will require a better understanding of the potential complications. Further developments interacting with various steps in the angiogenic cascade are under clinical or preclinical evaluation and may soon become available. In AMD the goal of a combination regimen is to address the therapy toward neovascular, inflammatory, and proliferative components of the disease. Combined treatments strategies are an obvious step providing disease control when it is not achieved with a single therapeutic approach. One risk of using a single therapy to control AMD is a rebound induced by compensatory stimulation of other pathogenetic pathways. Combination therapy is a logical approach to address mechanisms of disease progression that appear to be self-sustaining once initiated.

Characterization of ovarian clear cell carcinoma using target drug-based molecular biomarkers: implications for personalized cancer therapy.

PubMed

Li, Mengjiao; Li, Haoran; Liu, Fei; Bi, Rui; Tu, Xiaoyu; Chen, Lihua; Ye, Shuang; Cheng, Xi

2017-02-10

It has long been appreciated that different subtypes (serous, clear cell, endometrioid and mucinous) of epithelial ovarian carcinoma (EOC) have distinct pathogenetic pathways. However, clinical management, especially chemotherapeutic regimens, for EOC patients is not subtype specific. Ovarian clear cell carcinoma (CCC) is a rare histological subtype of EOC, which exhibits high rates of recurrence and low chemosensitivity. We assessed potential therapeutic targets for ovarian CCC patients through analyzing the variation of drug-based molecular biomarkers expression between ovarian CCC and high-grade serous carcinoma (HGSC). Seven candidate drug-based molecular biomarkers, human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), phosphatase and tensin homolog deleted on chromosome ten (PTEN), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2) and programmed death-ligand 1 (PD-L1) were measured in 96 ovarian CCC and 113 HGSC by immunohistochemistry in paraffin embedded tissues. The relationship between these biomarkers and clinicopathological factors were explored. The expression level of four of the seven drug-based molecular biomarkers was markedly different between HGSC and CCC. High expression levels of HER2 and PD-L1 were more commonly observed in CCC patients (12.6% vs 2.7%, 21.1% vs 11.6%, P = 0.006, 0.064, respectively), while loss of BRCA1 and BRCA2 expression were more frequently occurred in HGSC patients (72.6% vs 54.3%, 89.4% vs 79.8%, P = 0.007, 0.054, respectively). Survival analysis showed that five of seven biomarkers had prognostic values but varied between subtypes. Furthermore, EGFR expressed frequently in CCC patients with endometriosis than in HGSC patients (44.4% vs 8.3%, P = 0.049). AURKA and PD-L1 correlated with the resistance to platinum-based chemotherapy in CCC patients (P = 0.043, 0.028, respectively) while no similar results were observed in HGSC patients. Ovarian CCC showed a markedly different expression map of drug-based molecular biomarkers from HGSC, which suggested a new personalized target therapy in this rare subtype.

[Long-term consequences of polycystic ovary syndrome].

PubMed

Grigoryan, O R; Zhemaite, N S; Volevodz, N N; Andreeva, E N; Melnichenko, G A; Dedov, I I

Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disease in women. The prevailing complaints at a young age are menstrual irregularities, infertility, and hyperandrogenism-related problems. However, metabolic disorder-induced complications have been in the foreground over years. The review gives the current ideas on a change of clinical manifestations in the natural course of PCOS, as well as the pathogenetically grounded prevention of complications in patients.

[Clinical laboratory approaches to parodontitis treatment optimization].

PubMed

Soboleva, L A; Shul'diakov, A A; Oseeva, A O; Aleksandrova, E A

2010-01-01

In order to determine cycloferon liniment clinical-pathogenetic efficacy in comprehensive parodontitis therapy examination and treatment of 80 patients was done. It was determined that the cycloferon liniment use in comprehensive treatment of patients with parodontitis let to reduce infectious load in parodontal pockets and local inflammation intensity, to normalize the secretory immunoglobulin level and immune status indices that provided speed up of healing process and reduction relapse frequency.

Conversion of pemphigoid gestationis to bullous pemphigoid--two refractory cases highlighting this association.

PubMed

Jenkins, R E; Jones, S A; Black, M M

1996-10-01

Pemphigoid gestationis and bullous pemphigoid are autoimmune diseases characterized by subepidermal blisters and antibodies against the hemidesmosomal antigens: BPAG1 and BPAG2. Clinical histological and immunological similarities between pemphigoid gestationis and bullous pemphigoid suggest that they may have common pathogenetic determinants. We report two patients who presented initially with clinico-pathological features characteristic of pemphigoid gestationis but who subsequently evolved into bullous pemphigoid.

Aromatic L-Amino Acid Decarboxylase (AADC) Is Crucial for Brain Development and Motor Functions

PubMed Central

Shih, De-Fen; Hsiao, Chung-Der; Min, Ming-Yuan; Lai, Wen-Sung; Yang, Chianne-Wen; Lee, Wang-Tso; Lee, Shyh-Jye

2013-01-01

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children. PMID:23940784

Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.

PubMed

Shih, De-Fen; Hsiao, Chung-Der; Min, Ming-Yuan; Lai, Wen-Sung; Yang, Chianne-Wen; Lee, Wang-Tso; Lee, Shyh-Jye

2013-01-01

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children.

Biopsy in idiopathic pulmonary fibrosis: back to the future.

PubMed

Rossi, Giulio; Spagnolo, Paolo

2017-09-01

Idiopathic Pulmonary Fibrosis (IPF) is a relentlessly progressive, fibrosing interstitial pneumonia characterized by a radiologic and/or histologic pattern of usual interstitial pneumonia (UIP). The availability of two effective anti-fibrotic drugs in IPF has encouraged the identification and treatment of patients in early stages in order to maximize clinical benefit. The ability of high-resolution computed tomography (HRCT) to identify a 'definite' UIP pattern is suboptimal, particularly in the absence of honeycombing. Therefore, radiologic criteria for UIP are currently being redefined. Histology represents the major source of information to define a UIP pattern. Novel and less invasive approaches (particularly cryobiopsy) to sample interstitial lung diseases have demonstrated high sensitivity and specificity. In parallel, researchers are focusing on molecular mechanisms underlying IPF with the aim to identify more specific druggable targets. Lung tissue is therefore essential for diagnostic, pathogenetic and therapeutic purposes. Areas covered: We identified and critically reviewed the most relevant recent literature related to the limitations of current radiologic criteria, new lung sampling procedures, and molecular pathways in support of the need of lung tissue to better understand IPF. Expert commentary: The development of truly effective treatments for IPF requires the identification of key pathogenetic molecules and pathways. To this end, the availability of lung tissue is vital.

What's in a name? That which we call IPF, by any other name would act the same.

PubMed

Wells, Athol U; Brown, Kevin K; Flaherty, Kevin R; Kolb, Martin; Thannickal, Victor J

2018-05-01

Idiopathic pulmonary fibrosis (IPF) remains a truly idiopathic fibrotic disease, with a modest genetic predilection and candidate triggers but no overall explanation for the development of disease in non-familial cases. Agreement on terminology has contributed to major clinical and translational advances since the millennium. It is likely that the entity currently captured by the term "IPF" will be radically reclassified over the next decade, either through "splitting" (into IPF subgroups responding selectively to individual disease-modifying agents) or through "lumping" of IPF with other forms of progressive fibrotic lung disease (with shared pathogenetic mechanisms and IPF-like disease behaviour). In this perspective, we summarise the clinical and pathogenetic justification for a focus on "the progressive fibrotic phenotype" in future clinical and translational research. By this means, we can hope to address the needs of non-IPF patients with inexorably progressive fibrotic disease, currently disenfranchised by lack of access to agents that are efficacious in IPF. In this regard, ongoing trials of anti-fibrotic therapies in non-IPF patients with progressive fibrosis may be highly influential. Future revision of IPF nomenclature may be warranted if there are major conceptual changes but without compelling justification, the benefits of renaming IPF are likely to be outweighed by the resulting confusion. Copyright ©ERS 2018.

OSTEOLYSIS AROUND TOTAL KNEE ARTHOPLASTY: A REVIEW OF PATHOGENETIC MECHANISMS

PubMed Central

Gallo, Jiri; Goodman, Stuart B.; Konttinen, Yrjö T.; Wimmer, Markus A.; Holinka, Martin

2014-01-01

Aseptic loosening and other wear-related complications are one of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) predates aseptic loosening in many cases indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery-, and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL due to changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality, and muscle coordination/strength. Later large numbers of wear particles detached from TKAs trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, an impairment of osteoblast function, mechanical stresses, and an increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design, and material factors are the most important preventative factors because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented with pharmacological interventions. PMID:23669623

Molecular Approach to Targeted Therapy for Multiple Sclerosis.

PubMed

Sherbet, Gajanan V

2016-01-01

The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems.

Dyslipidemia in systemic lupus erythematosus: just another comorbidity?

PubMed

Tselios, Konstantinos; Koumaras, Charalambos; Gladman, Dafna D; Urowitz, Murray B

2016-04-01

Among traditional atherosclerotic risk factors, dyslipidemia is believed to decisively affect the long-term prognosis of lupus patients, not only with regard to cardiovascular events but also by influencing other manifestations, such as lupus nephritis. The aim of this study was to review the epidemiology, pathogenesis, evidence for its impact on atherosclerosis manifestations and management of dyslipidemia in lupus patients. English-restricted MEDLINE database search (Medical Subject Headings: lupus or systemic lupus erythematosus and dyslipidemia or hyperlipidemia). The prevalence of dyslipidemia in systemic lupus erythematosus (SLE) ranges from 36% at diagnosis to 60% or even higher after 3 years, depending on definition. Multiple pathogenetic mechanisms are implicated, including antibodies against lipoprotein lipase and cytokines affecting the balance between pro- and anti-atherogenic lipoproteins. Dyslipidemia has a clear impact on clinical cardiovascular disease and surrogate markers for subclinical atherosclerosis. Moreover, it negatively affects end-organ damage (kidneys and brain). Treatment with statins yielded contradictory results as per minimizing cardiovascular risk. Dyslipidemia is a significant comorbidity of lupus patients with multiple negative effects in the long term. Its treatment represents a modifiable risk factor; prompt and adequate treatment can minimize unnecessary burden in lupus patients, thus reducing hospitalizations and their overall morbidity and mortality. Copyright © 2016 Elsevier Inc. All rights reserved.

FOXOs attenuate bone formation by suppressing Wnt signaling

PubMed Central

Iyer, Srividhya; Ambrogini, Elena; Bartell, Shoshana M.; Han, Li; Roberson, Paula K.; de Cabo, Rafael; Jilka, Robert L.; Weinstein, Robert S.; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

2013-01-01

Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis. PMID:23867625

[Cyclooxygenase-2: a new therapeutic target in atherosclerosis?].

PubMed

Páramo, José A; Beloqui, Oscar; Orbe, Josune

2006-05-27

It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Systemic inflammatory markers (C reactive protein, cytokines adhesion molecules) also play a role in this process. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. Recent reports by our group have demonstrated increased monocyte COX-2 activity and the production of prostaglandin E2 in relation to cardiovascular risk factors and subclinical atherosclerosis in asymptomatic subjects. Our findings support the notion that the COX-2/prostaglandin E2 axis may have a role, raising the question as to whether its selective inhibition might be an attractive therapeutic target in atherosclerosis. COX-2 inhibitors, collectively called "coxibs" (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise as anti-inflammatory drugs without the some of the side effects of aspirin or non steroidal antiinflammatory agents. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk, and therefore coxibs should be restricted in atherosclerosis-prone patients.

Hormone therapy in acne.

PubMed

Lakshmi, Chembolli

2013-01-01

Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

[Pathophysiology of prolonged hypokinesia].

PubMed

Kovalenko, E A

1976-01-01

Hypokinesia is an important problem in modern medicine. In the pathogenetic effect of prolonged hypokinesia the main etiological factor is diminished motor activity; of major importance are disorders in the energy and plastic metabolism which affect the muscle system; the contributing factors are cardiovascular deconditioning and orthostatic intolerance. This is attributed to a decreased oxygen supply and eliminated hydrostatic influences during a prolonged recumbency. Blood redistribution in the vascular bed is related to the Gauer-Henry reflex and subsequent changes in the fluid-electrolyte balance. Decreased load on the bone system induces changes in the protein-phosphate-calcium metabolism, diminished bone density and increased calcium content in the blood and urine. Changes in the calcium metabolism are systemic. The activity of the higher nervous system and reflex functions is lowered. Changes in the function of the autonomic nervous system which include a noticeable decline of its adaptive-trophic role as a result of the decrease of afferent and efferent impulsation are of great importance. Changes in the hormonal function involve a peculiar stress-reaction which develops at an early stage of hypokinesia as a response to an unusual situation. Prolonged hypokinesia may result in a disturbed function of the pituitary-adrenal system. It is assumed that prolonged hypokinesia may induce a specific disease of hypokinesia during which man cannot lead a normal mode of life and work.

[Psychogenic Disorders in German soldiers during World War I and II].

PubMed

Zimmermann, P; Hahne, H-H; Biesold, K-H; Lanczik, M

2005-02-01

In the First and Second World War German soldiers frequently suffered from psychogenic disorders. By comparison a change in the prevalences can be noted: in the First World War dissociative disorders dominated the clinical impression ("shell shock"), in the Second World War they could rarely be seen but were replaced by somatoform and psychosomatic diseases. The discussion about numerous reasons for this development has not been completed yet and is still not free from political attitudes. To achieve a more scientific point of view, the perspective of psychotraumatology might be helpful. According to psychotraumatic research, dissociative and somatoform disorders can emerge in a close relation to a Posttraumatic Stress Disorder. The choice of symptoms depends on personality traits of the victim, but also on specific factors that characterise the situation in which the trauma appears. The mixture of pathogenetic and protective influences includes e. g. the possibility of flight- or fight reactions, feelings of trauma-associated guilt and group cohesion in the military unit. These factors can be useful to help explain the change of symptoms between both wars. In addition the analysis of situational conditions in former wars can give hints to actual planning and prophylaxis strategies in modern military psychiatry, that has to adjust to very different military operation fields.

Parainfectious meningo-encephalo-radiculo-myelitis (cat scratch disease, Lyme borreliosis, brucellosis, botulism, legionellosis, pertussis, mycoplasma).

PubMed

Greenblatt, Daniel; Krupp, Lauren B; Belman, Anita L

2013-01-01

Parainfectious disorders of the nervous system encompass those meningo-encephalo-radiculomyelitic conditions that are temporally associated with a systemic infection, antigenic stimuli, or toxin exposure, in the absence of evidence of direct neuronal infection or invasion of the central nervous system (CNS) or peripheral nervous system (PNS). Pathogenetic mechanisms can be due to immune-mediated processes (such as bystander activation, molecular mimicy) or the inciting insult can be due to toxic factors, as in the case of botulism. A myriad of clinical manifestations can occur including headache, seizures, and mental status changes, ranging from mood and behavioral disturbances to varying levels of alteration in consciousness. Focal neurological deficits can include aphasia, hemiparesis, or paraparesis. The PNS can also be affected leading to cranial nerve involvement, focal or multifocal neuropathies, and dysfunction of the autonomic nervous system. Diagnosis is based not only on the history, examination, laboratory, and neuroimaging data but also on epidemiological factors. The parainfectious disorders covered in this review are cat scratch disease, Lyme borreliosis, legionellosis, brucellosis, botulism, pertussis, and mycoplasma. Each is associated with a distinct organism, has both systemic and neurological manifestations, and has a different epidemiological profile. Copyright © 2013 Elsevier B.V. All rights reserved.

Cytokine pattern in blister fluid and serum of patients with bullous pemphigoid: relationships with disease intensity.

PubMed

Ameglio, F; D'Auria, L; Bonifati, C; Ferraro, C; Mastroianni, A; Giacalone, B

1998-04-01

Few and contrasting data are available in the literature concerning the levels of various cytokines in blister fluid (BF) and in the serum of patients affected with bullous pemphigoid (BP). Using commercially available ELISA kits, this study reports the levels of 11 cytokines detected both in BF and sera of 15 BP patients and compares them with those of 15 control subjects' sera. Generally, no significant differences were observed in BP and control sera. In contrast, interleukin (IL) 1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) showed increased BF levels as compared with BP sera. Two cytokines, IL-11 and IL-12 did not show significant differences between BP BF and sera, while an opposite behaviour was observed for transforming growth factor beta 1 (TGF-beta 1), whose serum levels were higher than the concentrations in BF. Using the number of lesions of the patients as a possible disease intensity marker, significant correlations were found with the BF levels of IL-1 beta, IL-8, TNF-alpha and, most closely, IL-5. These data may have pathogenetic relevance and suggest the possibility that these biological modulators may be used as a quantitative marker of disease intensity.

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

Multi-therapies in androgenetic alopecia: review and clinical experiences.

PubMed

Rossi, Alfredo; Anzalone, Alessia; Fortuna, Maria Caterina; Caro, Gemma; Garelli, Valentina; Pranteda, Giulia; Carlesimo, Marta

2016-11-01

Androgenetic alopecia (AGA) is a genetically determined progressive hair-loss condition which represents the most common cause of hair loss in men. The use of the medical term androgenetic alopecia reflects current knowledge about the important role of androgens and genetic factors in its etiology. In addition to androgen-dependent changes in the hair cycle, sustained microscopic follicular inflammation contributes to its onset. Furthermore, Prostaglandins have been demonstrated to have the ability in modulating hair follicle cycle; in particular, PGD2 inhibits hair growth while PGE2/F2a promote growth. Due to the progressive nature of AGA, the treatment should be started early and continued indefinitely, since the benefit will not be maintained upon ceasing therapy. To date, only two therapeutic agents have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of AGA: topical minoxidil and oral finasteride. Considering the many pathogenetic mechanisms involved in AGA, various treatment options are available: topical and systemic drugs may be used and the choice depends on various factors including grading of AGA, patients' pathological conditions, practicability, costs and risks. So, the treatment for AGA should be based on personalized therapy and targeted at the different pathophysiological aspects of AGA. © 2016 Wiley Periodicals, Inc.

Mechanism of Inflammation in Age-Related Macular Degeneration

PubMed Central

Parmeggiani, Francesco; Romano, Mario R.; Costagliola, Ciro; Semeraro, Francesco; Incorvaia, Carlo; D'Angelo, Sergio; Perri, Paolo; De Palma, Paolo; De Nadai, Katia; Sebastiani, Adolfo

2012-01-01

Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50 in Europe, the United States, and Australia, accounting for up to 50% of all cases of central blindness. Risk factors of AMD are heterogeneous, mainly including increasing age and different genetic predispositions, together with several environmental/epigenetic factors, that is, cigarette smoking, dietary habits, and phototoxic exposure. In the aging retina, free radicals and oxidized lipoproteins are considered to be major causes of tissue stress resulting in local triggers for parainflammation, a chronic status which contributes to initiation and/or progression of many human neurodegenerative diseases such as AMD. Experimental and clinical evidences strongly indicate the pathogenetic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and accumulation within those structures that compose an essential area of the retina known as macula lutea. This paper reviews some attractive aspects of the literature about the mechanisms of inflammation in AMD, especially focusing on those findings or arguments more directly translatable to improve the clinical management of patients with AMD and to prevent the severe vision loss caused by this disease. PMID:23209345

Increased insulin-like growth factor-1 levels in cerebrospinal fluid of advanced subacute sclerosing panencephalitis patients.

PubMed

Yılmaz, Deniz; Yüksel, Deniz; Gökkurt, Didem; Oguz, Hava; Anlar, Banu

2016-07-01

Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients. In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG. The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

[Protecting health of workers and predictive preventive personified medicine].

PubMed

Izmerov, N F; Bukhtiiarov, I V; Prokopenko, L V; Kuz'mina, L P

2013-01-01

Industrial medicine is an integrated sphere of preventive medicine, aimed to regulate health of workers and concerned with scentific basis and practical application of means and methods to preserve and improve workers' health. The article covers major research trends in workers' health preservation, results of fundamental studies on pathogenetic mechanisms and developmental patterns of contemporary occupational and industrial pathologies, prospects of predictive personified trend development and its application in industrial medicine.

Long-term fundus changes in acquired partial lipodystrophy.

PubMed

Jansen, Joyce; Delaere, Lien; Spielberg, Leigh; Leys, Anita

2013-11-18

We describe long-term fundus changes in a patient with partial lipodystrophy (PL). Retinal pigment alterations, drusen and subretinal neovascularisation were seen without evidence for membranoproliferative glomerulonephritis. Fundus alterations similar to those seen in age-related macular degeneration can occur at an earlier age in patients with PL, even without renal disease. Dysregulation of an alternative complement pathway with low serum levels of C3 has been implicated as a pathogenetic mechanism.

Long-term fundus changes in acquired partial lipodystrophy

PubMed Central

Jansen, Joyce; Delaere, Lien; Spielberg, Leigh; Leys, Anita

2013-01-01

We describe long-term fundus changes in a patient with partial lipodystrophy (PL). Retinal pigment alterations, drusen and subretinal neovascularisation were seen without evidence for membranoproliferative glomerulonephritis. Fundus alterations similar to those seen in age-related macular degeneration can occur at an earlier age in patients with PL, even without renal disease. Dysregulation of an alternative complement pathway with low serum levels of C3 has been implicated as a pathogenetic mechanism. PMID:24248317

A Case of Localized Scleroderma in a Sculptor and His Wife

PubMed Central

Bakst, Richard; Kovarik, Carrie; Werth, Victoria P.

2011-01-01

SUMMARY The etiology of localized scleroderma is unknown, and its pathogenetic relationship to its systemic counterpart is unclear. Environmental exposures, notably to silica dust, have long been suspected in the pathogenesis of the disorder. However, its’ relationship to the localized variant has not been well described. Here we present two cases of localized scleroderma in a sculptor and his wife who have extensive exposure to silica dust. PMID:19955998

[Bad habits and dysgnathia: epidemiological study].

PubMed

Cordasco, G; Lo Giudice, G; Dolci, E; Romeo, U; Lafronte, G

1989-01-01

The authors refer about an epidemiological survey in 651 children in the school-age. The aim of study is to investigate about the frequency of the bad habits and the pathogenetic relations between these and the development of the dento-maxillo-facial deformities. They point out an incidence of these bad habits in the 35,48% with a predominance of mouth breathers (45,45%). After they discuss the necessity of an early detection of anomalous neuromuscular attitudes.

Eyelid dermatitis.

PubMed

Beltrani, V S

2001-07-01

Cosmetic alteration of a patient's orbital skin is a common reason for professional consultation. This review presents the differential diagnosis and recommended evaluation of inflamed eyelids. To better understand the diseases, each is individually addressed clinically, pathogenetically, and therapeutically. It is critical to recognize the lesions correctly and to have full knowledge of the putative clinical disease process. An algorithm for an appropriate work-up for each disease is offered. With this background, a successful therapeutic response can be anticipated.

149 HCV AND lymphoma: Genetic and epigenetic factors

PubMed Central

Zignego, AL; Gragnani, L; Fognani, E; Piluso, A

2014-01-01

Over 180 million people worldwide are chronically infected with the hepatitis C virus (HCV). HCV infection is a major cause for hepatocellular carcinoma (HCC), moreover the association with B-cell lymphoproliferative disorders (LPDs) like mixed cryoglobulinemia (MC) or B-cell non-Hodgkin lymphoma (B-NHL) is undisputed. The mechanisms by which HCV contributes to LPD development are still poorly understood. Available data suggest that the viral infection may induce LPDs through a multifactorial and multistep process that involves the sustained activation of B cells, the abnormal and prolonged B cell survival, and genetic and/or epigenetic factors. Concerning genetic factors, different authors reported an association between specific HLA clusters or B-cell activating factor promoter genotype and a higher risk of developing MC and lymphoma. In addition, the results of a large, ongoing genome wide association study (GWAS) will probably allow the identification of specific genetic profile of HCV patients with LPDs. Furthermore, microRNAs (miRNAs) can give a major contribution to the pathogenesis of several neoplastic, lymphoproliferative diseases and it is conceivable their involvement in the pathogenesis of HCV-related LPDs. We recently showed that specific miRNAs were differently modulated in PBMCs from HCV patients who developed MC and/or NHL. In addition, HCV patients who developed HCC, showed a differential miRNAs regulation. In conclusion, available data suggest that the genetic/epigenetic analysis of HCV-related cancerogenesis is of great usefulness in both the pathogenetic and clinical/translational areas possibly allowing the definition of diagnostic/prognostic markers for early detection of lymphatic or hepatic cancer.

Isotretinoin and FoxO1

PubMed Central

2011-01-01

Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, and neuronal crest cells and others. By means of translational research this paper provides substantial indirect evidence for isotretinoin's mode of action by upregulation of forkhead box class O (FoxO) transcription factors. FoxOs play a pivotal role in the regulation of androgen receptor transactivation, insulin/insulin like growth factor-1 (IGF-1)-signaling, peroxisome proliferator-activated receptor-γ (PPArγ)- and liver X receptor-α (LXrα)-mediated lipogenesis, β-catenin signaling, cell proliferation, apoptosis, reactive oxygene homeostasis, innate and acquired immunity, stem cell homeostasis, as well as anti-cancer effects. An accumulating body of evidence suggests that the therapeutic, adverse, teratogenic and chemopreventive effecs of isotretinoin are all mediated by upregulation of FoxO-mediated gene transcription. These FoxO-driven transcriptional changes of the second response of retinoic acid receptor (RAR)-mediated signaling counterbalance gene expression of acne due to increased growth factor signaling with downregulated nuclear FoxO proteins. The proposed isotretinoin→ATRA→RAR→FoxO interaction offers intriguing new insights into the mode of isotretinoin action and explains most therapeutic, adverse and teratogenic effects of isotretinoin in the treatment of acne by a common mode of FoxO-mediated transcriptional regulation. PMID:22110774

Haemostatic profile of healthy premature small for gestational age neonates.

PubMed

Mitsiakos, George; Giougi, Evaggelia; Chatziioannidis, Ilias; Karagianni, Paraskevi; Papadakis, Emmanouil; Tsakalidis, Christos; Papaioannou, Georgia; Malindretos, Pavlos; Nikolaidis, Nikolaos

2010-08-01

The pathogenetic profile of premature Small for Gestational Age (SGA) neonates is strongly related to their haemostatic equilibrium, which is inadequately understood. To evaluate coagulation and fibrinolysis in premature SGA neonates before intervening with Vitamin K administration. We performed a comparison of coagulation, natural inhibitors and fibrinolysis between SGA and Appropriate for Gestational Age (AGA) infants born prematurely [gestational age (G.A.) <37 weeks]. Study population consisted of 139 preterm newborns, 68 of whom were SGA (25 males and 43 females), while 71 were AGA (37 males and 34 females) that consisted the control group. Blood samples were obtained within 30 minutes following birth and before the administration of vitamin K. Investigation included: PT, INR, APTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, von Willebrand factor, protein C and free protein S, antithrombin (AT), APCR, tPA and PAI-1. The independent t-test and the Mann-Whitney U test were used to compare the differences between the values of haemostatic parameters. Premature SGA infants presented significantly lower levels of fibrinogen (p<0.029) and higher levels of VIIIc factor, APCR, tPA and PAI-1 (p<0.041, 0.017, 0.021 and 0.019 respectively). The two groups had similar demographic characteristics (except from birth weight), without significant differences in the values of other haemostatic parameters. Despite the statistically significant differentiation in the levels of fibrinogen, VIIIc factor, APCR, tPA and PAI-1, the rest of haemostatic parameters have similar values between SGA and AGA preterms. (c) 2010 Elsevier Ltd. All rights reserved.

Epigenetic Effects of Cadmium in Cancer: Focus on Melanoma

PubMed Central

Venza, Mario; Visalli, Maria; Biondo, Carmelo; Oteri, Rosaria; Agliano, Federica; Morabito, Silvia; Caruso, Gerardo; Caffo, Maria; Teti, Diana; Venza, Isabella

2014-01-01

Cadmium is a highly toxic heavy metal, which has a destroying impact on organs. Exposure to cadmium causes severe health problems to human beings due to its ubiquitous environmental presence and features of the pathologies associated with pro-longed exposure. Cadmium is a well-established carcinogen, although the underlying mechanisms have not been fully under-stood yet. Recently, there has been considerable interest in the impact of this environmental pollutant on the epigenome. Be-cause of the role of epigenetic alterations in regulating gene expression, there is a potential for the integration of cadmium-induced epigenetic alterations as critical elements in the cancer risk assessment process. Here, after a brief review of the ma-jor diseases related to cadmium exposure, we focus our interest on the carcinogenic potential of this heavy metal. Among the several proposed pathogenetic mechanisms, particular attention is given to epigenetic alterations, including changes in DNA methylation, histone modifications and non-coding RNA expression. We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma. DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma. A wider comprehension of mechanisms related to this common environmental contaminant would allow a better cancer risk evaluation. PMID:25646071

Epicardial adipose tissue and signs of metabolic syndrome in children.

PubMed

Barbaro, Giuseppe; Piedimonte, Alessandra; Podagrosi, Maria; Mercurio, Roberta; Mosca, Antonella; D'Avanzo, Miriam; Vania, Andrea

2016-06-01

The aim of this study was to investigate the possible correlation between epicardial adipose tissue (EAT) thickness and predictive parameters for metabolic syndrome (MS) in overweight/obese prepubertal children. 73 prepubertal children, average age of 8.22 years, with no endocrine or syndromic causes of obesity or under drug therapy for chronic disease were enrolled. Weight, height, body circumferences and skinfolds' thickness were measured. BMI, BMI z score (z-BMI) and waist-to-height ratio (WtHR) were calculated. Standard MS-related laboratory parameters were assessed. Finally, all children underwent echocardiographic measurement of EAT. A positive correlation between EAT and z-BMI was found only among overweight/obese children (r = 0.43, p = 0.001). In particular, data showed that 89 % of our sample had a waist (W) >90th percentile. Statistical differences in diastolic blood pressure (DBP; p < 0.01) and EAT (p = 0.02) were observed on comparing W <90th percentile vs W >90th percentile patients. Besides, in patients with W >90th percentile and family history of risk factors for MS, the value of EAT correlated positively with z-BMI, W, WtHR, triglycerides (Tg), insulin and homeostatic model assessment of insulin resistance and negatively with HDL. The EAT and the markers of MS probably share the same pathogenetic factors. Further studies might elucidate whether EAT deserves to be included among the diagnostic factors of MS.

The effect of cardioprotective diet rich with natural antioxidants on chronic inflammation and oxidized LDL during cardiac rehabilitation in patients after acute myocardial infarction.

PubMed

Mlakar, Polona; Salobir, Barbara; Čobo, Nusret; Strašek, Janja; Prezelj, Marija; Debevc, Ana; Jug, Borut; Terčelj, Marjeta; Šabovič, Mišo

2015-06-01

Chronic inflammation, the fundamental pathogenetic process of atherosclerosis, can be modified by pharmacological and non-pharmacological measures as a part of secondary prevention after acute myocardial infarction (AMI). The aim of our study was to determine the effect of diet, rich with natural antioxidants, added to physical activity (as a part of cardiac rehabilitation (CR) program) on inflammatory markers and ox-LDL, a marker of oxidative stress, closely involved in the process of chronic inflammation. 41 male patients after AMI undergoing CR were divided into a diet group (supervised cardioprotective diet throughout the CR), and control group (CR without diet). We measured hsCRP, leucocytes, neutrophils, IL-6, oxLDL, exercise capacity and classic risk factors before and after CR program. Patients from the diet group presented with a significant decline in classic risk factors (BMI, waist circumference, waist to hip ratio, systolic blood pressure, heart rate, blood glucose, total cholesterol, LDL, TAG) and inflammatory markers (hsCRP, leucocytes, neutrophils) compared to control group. Furthermore, when studying nonsmokers, we observed significant decline of oxLDL in the diet group. The addition of cardioprotective diet, rich with natural antioxidants, to physical activity as a part of a CR program, positively modifies not just classic risk factors and exercise capacity, but also diminishes chronic inflammation markers. These effects, and oxLDL decline were most prominent in nonsmoking patients.

Placenta-derived hypo-serotonin situations in the developing forebrain cause autism.

PubMed

Sato, Kohji

2013-04-01

Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests. Although there are many theories and speculations about the pathogenetic causes of autism, the disruption of the serotonergic system is one of the most consistent and well-replicated findings. Recently, it has been reported that placenta-derived serotonin is the main source in embryonic day (E) 10-15 mouse forebrain, after that period, the serotonergic fibers start to supply serotonin into the forebrain. E 10-15 is the very important developing period, when cortical neurogenesis, migration and initial axon targeting are processed. Since all these events have been considered to be involved in the pathogenesis of autism and they are highly controlled by serotonin signals, the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. I, thus, postulate a hypothesis that placenta-derived hypo-serotonin situations in the developing forebrain cause autism. The hypothesis is as follows. Various factors, such as inflammation, dysfunction of the placenta, together with genetic predispositions cause a decrease of placenta-derived serotonin levels. The decrease of placenta-derived serotonin levels leads to hypo-serotonergic situations in the forebrain of the fetus. The paucity of serotonin in the forebrain leads to mis-wiring in important regions which are responsible for the theory of mind. The paucity of serotonin in the forebrain also causes over-growth of serotonergic fibers. These disturbances result in network deficiency and aberration of the serotonergic system, leading to the autistic phenotypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Congenital ureteropelvic junction obstruction: physiopathology, decoupling of tout court pelvic dilatation-obstruction semantic connection, biomarkers to predict renal damage evolution.

PubMed

Alberti, C

2012-02-01

The widespread use of fetal ultrasonography results in a frequent antenatally observation of hydronephrosis, ureteropelvic junction obstruction (UPJO) accounting for the greatest fraction of congenital obstructive nephropathy. UPJO may be considered, in most cases, as a functional obstructive condition, depending on defective fetal smooth muscle/nerve development at this level, with lack of peristaltic wave propagation--aperistaltic segment--and, therefore, poor urine ejection from the renal pelvis into the ureter. The UPJO-related physiopathologic events are, at first, the compliant dilatation of renal pelvis that, acting as hydraulic buffer, protects the renal parenchyma from the rising intrapelvic pressure-related potential damages, and, subsequently, beyond such phase of dynamic balance, the tubular cell stretch-stress induced by increased intratubular pressure and following parenchymal inflammatory lesions: inflammatory infiltrates, fibroblast proliferation, activation of myofibroblasts, tubulo-interstitial fibrosis. Reactive oxygen species (ROS), nitric oxide (NO), several chemo- and cytokines, growth factors, prostaglandins and eicosanoids, angiotensin-II are the main pathogenetic mediators of the obstructive nephropathy. Apoptosis of tubular cells is the major cause of the tubular atrophy, together with epithelial-mesenchymal transdifferentiation. Some criticisms on tout court semantic renal pelvis dilatation-obstruction connection have been raised considering that the renal pelvis expansion isn't, in any case, linked to an ostructive condition, as it may be verified by diuretic (furosemide) renogram together with scintiscan-based evaluation of differential renal function. In this regard, rather than repetitive invasive nuclear procedures that expose the children to ionizing radiations, an intriguing noninvasive strategy, based on the evaluation of urinary biomarkers and urinary proteome, can define the UPJO-related possible progress of parenchymal lesions, thus predicting which patients must require an obstruction correcting surgery and in which patients, instead, the hydronephrosis will spontaneously resolve.

IRAK-M Is Involved in the Pathogenesis of Early-Onset Persistent Asthma

PubMed Central

Balaci, Lenuta ; Spada, Maria Cristina ; Olla, Nazario ; Sole, Gabriella ; Loddo, Laura ; Anedda, Francesca ; Naitza, Silvia ; Zuncheddu, Maria Antonietta ; Maschio, Andrea ; Altea, Daniele ; Uda, Manuela ; Pilia, Sabrina ; Sanna, Serena ; Masala, Marco ; Crisponi, Laura ; Fattori, Matilde ; Devoto, Marcella ; Doratiotto, Silvia ; Rassu, Stefania ; Mereu, Simonetta ; Giua, Enrico ; Cadeddu, Natalina Graziella ; Atzeni, Roberto ; Pelosi, Umberto ; Corrias, Adriano ; Perra, Roberto ; Torrazza, Pier Luigi ; Pirina, Pietro ; Ginesu, Francesco ; Marcias, Silvano ; Schintu, Maria Grazia ; Giacco, Gennaro Sergio Del ; Manconi, Paolo Emilio ; Malerba, Giovanni ; Bisognin, Andrea ; Trabetti, Elisabetta ; Boner, Attilio ; Pescollderungg, Lydia ; Pignatti, Pier Franco ; Schlessinger, David ; Cao, Antonio ; Pilia, Giuseppe 

2007-01-01

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-κB and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma. PMID:17503328

A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression.

PubMed

Kuhl, U; Lassner, D; Dorner, A; Rohde, M; Escher, F; Seeberg, B; Hertel, E; Tschope, C; Skurk, C; Gross, U M; Schultheiss, H-P; Poller, W

2013-09-01

Recent studies have detected erythrovirus genomes in the hearts of cardiomyopathy and cardiac transplant patients. Assessment of the functional status of viruses may provide clinically important information beyond detection of the viral genomes. Here, we report transcriptional activation of cardiotropic erythrovirus to be associated with strongly altered myocardial gene expression in a distinct subgroup of cardiomyopathy patients. Endomyocardial biopsies (EMBs) from 415 consecutive cardiac erythrovirus (B19V)-positive patients with clinically suspected cardiomyopathy were screened for virus-encoded VP1/VP2 mRNA indicating transcriptional activation of the virus, and correlated with cardiac host gene expression patterns in transcriptionally active versus latent infections, and in virus-free control hearts. Transcriptional activity was detected in baseline biopsies of only 66/415 patients (15.9 %) harbouring erythrovirus. At the molecular level, significant differences between cardiac B19V-positive patients with transcriptionally active versus latent virus were revealed by expression profiling of EMBs. Importantly, latent B19V infection was indistinguishable from controls. Genes involved encode proteins of antiviral immune response, B19V receptor complex, and mitochondrial energy metabolism. Thus, functional mapping of erythrovirus allows definition of a subgroup of B19V-infected cardiomyopathy patients characterized by virus-encoded VP1/VP2 transcripts and anomalous host myocardial transcriptomes. Cardiac B19V reactivation from latency, as reported here for the first time, is a key factor required for erythrovirus to induce altered cardiac gene expression in a subgroup of cardiomyopathy patients. Virus genome detection is insufficient to assess pathogenic potential, but additional transcriptional mapping should be incorporated into future pathogenetic and therapeutic studies both in cardiology and transplantation medicine.

[Vascular thrombosis and pulmonary thrombo-embolism due to harness suspension].

PubMed

Pisati, G; Cerri, S; Achille, G; Rossi, G; Lorenzi, G

2007-01-01

In many sports (such as rock-climbing and caving) and working activities (e.g., construction and maintenance of buildings, pruning of lung-trunked trees, abseiling in wells) people run the risk of falling from a height. To prevent the effects of any potential fall, personalprotection devices consisting of at least a body holding device (i.e. a harness of some type), a lanyard and a reliable anchor are used. Reporting on the occurrence of vascular thrombosis in subjects undergoing prolonged hanging in a harness, either for work or recreation. We investigated patients treated for vascular thrombosis in our hospital in the last 5 years to identify subjects with frequent use of a harness. We identified a 36-year-old rock-climber who developed pulmonary thrombo-embolism and infarction 5 days after he had been wearing a harness for 12 hours consecutively, and a 32 year-old worker who often used a harness to fix wire-nettings to prevent rocks falling from steep places and suffered thrombosis of the left superficial femoral artery. A feature of both cases was the considerable length of time spent hanging in the harness and the absence of alternative risk factors for thrombosis. Prolonged hanging in a harness can be dangerous in itself because it can produce vascular thrombosis. Reduction of intravascular blood flow (stasis) and compression of the femoral veins by harness groin straps were the likely pathogenetic mechanisms of the described diseases. The importance is stressed of prevention, which must be based on planned regular breaks in the hanging position, checking on the fit and comfort level of the harness before it is first used, as well as medical surveillance of the subjects who spend prolonged periods in a harness for work or recreation.

Perineural invasion in carcinoma of the cervix uteri--prognostic impact.

PubMed

Horn, Lars-Christian; Meinel, Alexandra; Fischer, Uta; Bilek, Karl; Hentschel, Bettina

2010-10-01

Limited information exists about the occurrence and the impact of perineural invasion (PNI) in patients with cervical carcinoma (CX). The original histologic slides from patients primarily treated by radical hysterectomy and systematic pelvic lymphadenectomy were re-examined regarding the occurrence of PNI. PNI was correlated to recurrence free (RFS) and overall survival (OS). 35.1% of all patients (68/194) represented perineural invasion (=PNI). The 5-year-overall-survival-rate was significantly decreased in patients representing PNI, when they were compared with those without PNI (51.1% [95% CI 38.0-64.2] vs. 75.6% [95% CI 67.8-83.4]; p = 0.001). In a separate analysis the prognostic impact persisted in the node negative, but disappeared in the node-positive cases. In multivariate analysis, pelvic lymph node involvement and PNI were independent prognostic factors for overall survival. Perineural invasion is seen in about one-third of patients with cervical carcinoma. Patients affected by PNI represented a decreased overall survival. Further studies are required to get a deeper insight into the clinical impact and the pathogenetic mechanisms of PNI in CX.

[Uveitic Secondary Glaucoma].

PubMed

Lommatzsch, Claudia; Heinz, Carsten

2018-05-01

An intraocular pressure increase with development of glaucomatous damage is a common complication of uveitis. The prevalence has a wide range depending on various factors such as the underlying uveitis type and the duration of the disease. Pathogenetically, a distinction must be made between a secondary angle closure component and the more frequently occurring open-angle glaucoma. In diagnostics, in addition to the clinical optic nerve head assessment, perimetry and tonometry, the use of imaging examination equipment, such as OCT and HRT, are recommended. In the context of uveitic glaucoma, it must be considered in the evaluation, because the glaucoma-typical changes are generally less pronounced or can be concealed by retinal swelling in comparison with other forms of glaucoma. Therapeutically, drug therapy in the form of eye drops continues to be a first-line recommendation, with the use of topical carbonic anhydrase inhibitors or beta-blockers primarily preferred, depending on the contraindications. An operative therapy follows after unsuccessful or inadequate conservative therapy: the adequate surgical technique depends on the respective finding and includes actually techniques such as filtering procedures and glaucoma drainage devices. Georg Thieme Verlag KG Stuttgart · New York.

Early Developmental Disturbances of Cortical Inhibitory Neurons: Contribution to Cognitive Deficits in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2014-01-01

Cognitive dysfunction is a disabling and core feature of schizophrenia. Cognitive impairments have been linked to disturbances in inhibitory (gamma-aminobutyric acid [GABA]) neurons in the prefrontal cortex. Cognitive deficits are present well before the onset of psychotic symptoms and have been detected in early childhood with developmental delays reported during the first year of life. These data suggest that the pathogenetic process that produces dysfunction of prefrontal GABA neurons in schizophrenia may be related to altered prenatal development. Interestingly, adult postmortem schizophrenia brain tissue studies have provided evidence consistent with a disease process that affects different stages of prenatal development of specific subpopulations of prefrontal GABA neurons. Prenatal ontogeny (ie, birth, proliferation, migration, and phenotypic specification) of distinct subpopulations of cortical GABA neurons is differentially regulated by a host of transcription factors, chemokine receptors, and other molecular markers. In this review article, we propose a strategy to investigate how alterations in the expression of these developmental regulators of subpopulations of cortical GABA neurons may contribute to the pathogenesis of cortical GABA neuron dysfunction and consequently cognitive impairments in schizophrenia. PMID:25053651

Clinical determinants and consequences of left ventricular hypertrophy.

PubMed

Messerli, F H

1983-09-26

The left ventricle adapts to an increased afterload such as that produced by arterial hypertension with concentric left ventricular hypertrophy. However, this adaptive process can be modified by a variety of physiologic and pathophysiologic states. Progressive aging, black race, and perhaps disorders with an increased sympathetic outflow seem to accelerate left ventricular hypertrophy. Obesity and other high cardiac output states predominantly produce dilatation of the left ventricle, and their combination with arterial hypertension results in eccentric left ventricular hypertrophy. Similarly, endurance exercise increases left ventricular volume more than wall thickness, whereas isometric exercise produces an increase in wall thickness only. The presence or absence of some physiologic and pathogenetic factors has direct implication on the assessment of what constitutes a "normal" left ventricular structure and function. Left ventricular hypertrophy has been shown to increase ventricular ectopic impulse generation and to put patients at a high risk of sudden death. Moreover, the increase in myocardial mass lowers coronary reserve and enhances cardiac oxygen requirements. Thus, the presence of left ventricular hypertrophy has to be considered as an ominous sign rather than as a benign adaptive process.

[Chemically-induced scleroderma].

PubMed

Haustein, U F; Ziegler, V; Herrmann, K

1992-08-01

Scleroderma-like diseases can be induced by a number of chemical compounds, such as plastics, solvents and drugs. Contaminated rapeseed oil was the cause of the toxic oil syndrome and L-tryptophan induces the so-called eosinophilia-myalgia-syndrome. On the other hand, paraffin and silicon can trigger so-called adjuvant disease, while long-term exposure to silica can lead to idiopathic scleroderma (associated with silicosis in some cases). In addition to the clinical features, some pathogenetic data in the literature, such as genetic factors (HLA, chromosomal anomalies, enzyme deficiencies) and the metabolism of chlorinated ethylenes via reactive epoxide intermediate products, and our own findings are reported. Silica-induced scleroderma cannot be distinguished from the idiopathic form by epidemiological, clinical or immunological studies or by parameters referring to the blood vessels or collagen metabolism. In cell culture studies it has been shown that macrophages/monocytes release IL1, IL6 and TNF after ingestion of silica, which affects fibroblasts, T-helper cells and endothelial cells. Comparative results from the silicosis literature are reported. Finally, the possibly stimulating role of ionizing irradiation (uranium mining) in favouring the development of scleroderma is discussed.

Reduced heart rate variability and vagal tone in anxiety: trait versus state, and the effects of autogenic training.

PubMed

Miu, Andrei C; Heilman, Renata M; Miclea, Mircea

2009-01-28

This study investigated heart rate variability (HRV) in healthy volunteers that were selected for extreme scores of trait anxiety (TA), during two opposite psychophysiological conditions of mental stress, and relaxation induced by autogenic training. R-R intervals, HF and LF powers, and LF/HF ratios were derived from short-term electrocardiographic recordings made during mental stress and relaxation by autogenic training, with respiratory rate and skin conductance being controlled for in all the analyses. The main finding was that high TA was associated with reduced R-R intervals and HF power across conditions. In comparison to mental stress, autogenic training increased HRV and facilitated the vagal control of the heart. There were no significant effects of TA or the psychophysiological conditions on LF power, or LF/HF ratio. These results support the view that TA, which is an important risk factor for anxiety disorders and predictor of cardiovascular morbidity and mortality, is associated with autonomic dysfunction that seems likely to play a pathogenetic role in the long term.

[New insights of myositis-specific and -associated autoantibodies in juvenile and adult type myositis].

PubMed

Váncsa, Andrea; Dankó, Katalin

2016-07-01

Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis-specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184.

Indirect choroidal ruptures: aetiological factors, patterns of ocular damage, and final visual outcome.

PubMed Central

Wood, C M; Richardson, J

1990-01-01

Indirect choroidal ruptures result from blunt ocular trauma and have a pathognomonic fundal appearance. We analysed a group of 30 patients with indirect choroidal ruptures with specific reference to the circumstances of the injury, the pattern of ocular damage, the cause of any visual loss, and the final visual outcome. Using this analysis we deduce a pathogenetic explanation for the characteristic fundus signs in patients with indirect choroidal ruptures. The majority of cases were young males injured during sport or by an assault, a minority were injured at work. Diffuse nonfocal impact injuries due to punches were associated with ruptures concentric with and adjacent to the optic disc. Focal impact injuries, due to projectiles, showed more extensive ocular damage. Seventeen of 30 patients regained 6/12 vision after injury. Injuries due to projectiles and temporally situated ruptures were associated with a poorer visual outcome than others. Macular damage was the commonest cause of visual loss, principally due to pigmentary maculopathy, traumatic inner retinal damage, and choroidal neovascular membranes rather than direct focal damage by the rupture. Images PMID:2337545

Serum antibodies against gangliosides and Campylobacter jejuni lipopolysaccharides in Miller Fisher syndrome.

PubMed Central

Neisser, A; Bernheimer, H; Berger, T; Moran, A P; Schwerer, B

1997-01-01

Seven patients with Miller Fisher syndrome (MFS), six in the acute phase and one in the recovery phase, were investigated for serum antibodies against gangliosides and purified lipopolysaccharides (LPS) from different strains of Campylobacter jejuni, including the MFS-associated serotypes O:2 and O:23. Immunoglobulin G antibodies against gangliosides GT1a and GQ1b were found in five of six patients in the acute phase of disease. Three of these patients also displayed antibodies to ganglioside GD2, a finding not previously reported for MFS. All anti-GT1a- and anti-GQ1b-seropositive patients showed antibody binding to C. jejuni LPS, predominantly to O:2 and O:23 LPS. Antibody cross-reactivity between gangliosides GT1a and GQ1b and O:2 and O:23 LPS was demonstrated by adsorption studies. This cross-reactivity between gangliosides and C.jejuni LPS, which is obviously due to oligosaccharide homologies, may be an important pathogenetic factor in the development of MFS after C. jejuni infection. PMID:9317004

More than 60 years later: the mediating role of trauma and posttraumatic stress disorder for the association of forced displacement in world war II with somatization in old age.

PubMed

Kuwert, Philipp; Braehler, Elmar; Freyberger, Harald J; Glaesmer, Heide

2012-10-01

Up to now, it has remained unclear whether displacement itself is the pathogenetic factor for the impairment of mental health in uprooted individuals or whether the effect is mediated by the amount of traumatic events experienced during forced displacement and/or by the development of posttraumatic stress disorder (PTSD). A total of 1657 participants were included in this population-based study, who were then administered with the Patient Health Questionnaire, a modified trauma list of the PTSD module of the Munich Composite International Diagnostic Interview, and the Posttraumatic Diagnostic Scale. Displacement was associated with increased rates of traumatic events. The displaced participants were significantly more affected by somatoform symptoms and PTSD than the nondisplaced population. It was not displacement itself but the amount of trauma experienced during displacement that predicts current somatization in the population-based sample. The results highlight the necessity for prevention and treatment of posttraumatic conditions in displaced individuals and underpin the importance to understand somatization as one condition of the posttraumatic symptoms spectrum in the elderly.

Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism.

PubMed

Feyles, Francesca; Mussa, Alessandro; Peiretti, Valentina; Tessaris, Daniele; Santanera, Arianna; Corrias, Andrea; de Sanctis, Luisa; Calvo, Luigi

2014-01-01

Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease.

Female pseudohermaphroditism with multiple caudal anomalies: Absence of Y-specific DNA sequences as pathogenetic factors

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

Seaver, L.H.; Grimes, J.; Erickson, R.P.

1994-05-15

46,XX female pseudohermaphrodites have been previously described with nearly complete masculinization of the external genitalia and no apparent source of testosterone. Multiple malformations of internal genital, urinary, and gastrointestinal tracts are associated. We have evaluated four such infants with female pseudohermaphroditism and multiple caudal anomalies. Three cases had apparently normal chromosome (46,XX); one had a 46,XX,del(10)(q25.3{yields}qter) chromosome constitution. The chromosome breakpoint is in the region of PAX2, a developmentally important paired box gene which is expressed in urogenital tissue. Using the polymerase chain reaction, we screened for the presence of multiple Y specific sequences, including SRY (sex determining region, Ymore » chromosome), that could explain masculinization of the external genitalia. All were negative for Y centromeric sequences, ZFY (Zinc finger Y), and SRY. Furthermore, there was no evidence for adrenal or other sources of testosterone. We suggest that the masculinization in these cases is the result of abnormal expression of genes which would normally be regulated by testosterone. 32 refs., 1 fig., 2 tabs.« less

Classification matters for catatonia and autism in children.

PubMed

Neumärker, Klaus-Jürgen

2006-01-01

Despite its chequered history, Kahlbaum's 1874 description of catatonia (tension insanity) and its categorization as a clinical illness is in outline still valid. Kahlbaum also acknowledged the existence of catatonia in children. Corresponding case studies have also been analyzed. The originators and disciples of the Wernicke-Kleist-Leonhard school proved catatonia in early childhood as a discrete entity with specific psychopathology. This does not mean that catatonic symptoms do not occur in other illnesses and in particular in organic psychoses. These are, however, of a totally different nature. Autism, as first described in connection with schizophrenic negativism by Bleuler in 1910, is one of the key symptoms of schizophrenia. As identified by Kanner in 1943, abnormal social interaction and communication, together with retarded development, are the main characteristics of autism in early childhood. Asperger's concept of autistic disorder (1944), although based on psychopathological theory, did not include retardation in development as an aspect. Consequently, autistic behavior can occur in a variety of mental disorders. Research into possible etiological and pathogenetic factors has been undertaken, but no clear link found as yet.

Hoigne Syndrome Caused by Intralesional Meglumine Antimoniate

PubMed Central

Guarneri, Claudio; Tchernev, Georgi; Wollina, Uwe; Lotti, Torello

2017-01-01

Hoigne syndrome (HS) is the term coined to describe an acute, non-allergic, psychiatrically based reaction occurring with a wide list of medications, mainly antibiotics. Since its first description by Hoigne and Schoch in 1959, few cases have been reported in medical literature and, although antimicrobials are commonly used, very rarely in dermatology. The authors describe the first case occurred after intralesional administration of meglumine antimoniate and briefly discuss the pathogenetic hypotheses on this atypical adverse drug reaction. PMID:28785339

[Current treatment options in acute myeloid leukemia].

PubMed

Heuser, M; Schlenk, R F; Ganser, A

2011-12-01

Genetic aberrations form the basis for diagnostic classification of patients with acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification. Moreover, these aberrations predict response to induction chemotherapy, relapse-free survival, and overall survival of patients with AML. Understanding the pathogenetic role of cytogenetic and molecular changes has led to the development of targeted treatment strategies that require rapid diagnostic assessment of the genetic profile of each patient to select the best treatment available.

[Pathogenetic grounds of trophological impact of chronic pancreatitis complex therapy].

PubMed

Babinets', L S; Halabits'ka, I M; Botsiuk, N Ie; Riabokon', S S

2014-11-01

In chronic pancreatitis patients was found persistent state of oxidative stress on the level of malonic aldehyde, which ran against the lowered levels of antioxidant enzymatic and non-enzymatic composition, and it has been found in the state of hypoproteinemia proteinogram indices (P < 0.05). The use of complex treatment of patients with chronic pancreatitis multivitamin-aminoacid drug Moriamin forte contributes to a significant regression effects oxidative stress and reduces the effects of hypoproteinemia (P < 0.05).

The "Bermuda triangle" of neonatal neurology: cerebral palsy, neonatal encephalopathy, and intrapartum asphyxia.

PubMed

Shevell, Michael I

2004-03-01

The terms "cerebral palsy," "neonatal encephalopathy," and "intrapartum asphyxia" are frequently used in pediatric neurology. This article presents concise, verifiable definitions for each of these entities based on our current understanding and formulates the nature of the interrelationships between them. The aim is to provide a level of clarity that will enhance diagnostic and pathogenetic precision and minimize conceptual misunderstanding. This should aid future therapeutic and research efforts in this important area.

Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

PubMed Central

Pierce, Christopher G.; Lopez-Ribot, Jose L.

2014-01-01

Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751

Pathogenetic role of the deafness-related M34T mutation of Cx26

PubMed Central

Bicego, Massimiliano; Beltramello, Martina; Melchionda, Salvatore; Carella, Massimo; Piazza, Valeria; Zelante, Leopoldo; Bukauskas, Feliksas F.; Arslan, Edoardo; Cama, Elona; Pantano, Sergio; Bruzzone, Roberto; D’Andrea, Paola; Mammano, Fabio

2010-01-01

Mutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic non-syndromic hearing loss. The role of the allelic variant M34T in causing hereditary deafness remains controversial. By combining genetic, clinical, biochemical, electrophysiological and structural modeling studies, we have re-assessed the pathogenetic role of the M34T mutation. Genetic and audiological data indicate that the majority of heterozygous carriers and all five compound heterozygotes exhibited an impaired auditory function. Functional expression in transiently transfected HeLa cells showed that, although M34T was correctly synthesized and targeted to the plasma membrane, it inefficiently formed intercellular channels that displayed an abnormal electrical behavior and retained only 11% of the unitary conductance of the wild-type protein (HCx26wt). Moreover, M34T channels failed to support the intercellular diffusion of Lucifer Yellow and the spreading of mechanically induced intercellular Ca2+ waves. When co-expressed together with HCx26wt, M34T exerted dominant-negative effects on cell–cell coupling. Our findings are consistent with a structural model, predicting that the mutation leads to a constriction of the channel pore. These data support the view that M34T is a pathological variant of Cx26 associated with hearing impairment. PMID:16849369

Necrotizing infundibular crystalline folliculitis: a clinicopathological study.

PubMed

Denisjuk, Natalja; Hilty, Norbert; Pfaltz, Madeleine; Kempf, Werner

2012-05-01

Necrotizing infundibular crystalline folliculitis (NICF) is a folliculocentric disorder associated with filamentous crystalline deposits, enclosed by parakeratotic columns within the partly necrotic follicular ostium and infundibulum. There are only very few data published about this disorder of unknown origin. We sought to determine the clinicopathological features and pathogenetic aspects of NICF. Clinicopathological characterization of 9 patients with NICF and a second group of 7 patients with coincidental findings of NICF in the vicinity of epithelial skin neoplasms was conducted. Clinically, NICF is characterized by multiple waxy papules with predilection for the forehead (56%), neck, and back. Birefringent crystalline deposits were present in the follicular ostia and enclosed by parakeratotic columns in all cases. The necrosis of follicular epithelium was found in 89% and perifollicular neutrophilic infiltrate in 22% of the biopsy specimens. Both yeasts and gram-positive bacteria were identified within the affected follicles in 56% in the first group and 86% in the second group of coincidental NICF. This was a single-center retrospective study. NICF is both a distinct entity and an epiphenomenon in the context of other disorders. In regard to the common association with yeasts and gram-positive bacteria in the affected follicles, we hypothesize that NICF is pathogenetically linked to these organisms, which is supported by resolution of the lesions after topical or systemic antimycotic treatment. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Preeclampsia with and without intrauterine growth restriction-Two pathogenetically different entities?

PubMed

Milosevic-Stevanovic, Jelena; Krstic, Miljan; Radovic-Janosevic, Dragana; Stefanovic, Milan; Antic, Vladimir; Djordjevic, Ivana

2016-11-01

The objective of this study is to determine the differences in histopathological features of basal decidua and placenta in cases of preeclampsia with or without fetal intrauterine growth restriction (IUGR). A prospective case-control study included a study group consisting of 30 pregnant women with preeclampsia completed by cesarean section (CS), in 19 of whom preeclampsia was associated with IUGR, and in 11 it was not. The control group consisted of 20 healthy pregnant women delivered by elective CS. Placentas and samples of placental bed obtained during CS were histopathologically (HP) analyzed after hematoxylin-eosin staining and immunohistochemical labeling of Cytokeratin 7 (CK7) trophoblastic cells in decidua. Regarding the HP changes in the spiral arteries in preeclampsia, the most frequent features were inadequate transformation of spiral arteries with poor trophoblastic invasion (70.0%) and fibrinoid necrosis of the media (66.7%), and rarely acute atherosis (33.3%) and thrombosis (30.0%). Villous hypermaturity was more frequently found in placentas of patients with preeclampsia with IUGR (p < 0.05), while there were no differences between subgroups of preeclampsia with and without IUGR regarding some of HP alterations of placental bed. Alterations of the placental bed in terms of decidual vasculopathy are more the characteristics of the preeclampsia itself than IUGR, while changes in placental villi primarily follow the presence of IUGR, which could indicate that preeclampsia with and without IUGR are two pathogenetically different entities.

Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis.

PubMed

Makhoul, I R; Aviram-Goldring, A; Paperna, T; Sujov, P; Rienstein, S; Smolkin, T; Epelman, M; Gershoni-Baruch, R

2001-02-15

The clinical spectrum of caudal dysplasia sequence (CDS) is noted for its diversity. The origin of CDS remains unknown, though poorly controlled gestational diabetes has been implicated in some cases. Here we describe the case of a newborn with CDS associated with penile enlargement (PE). The main anomalies included anal atresia, agenesis of the kidneys and of the sacrococcygeal vertebrae, dysgenesis of lumbar vertebrae, and bilateral cryptorchidism. Penile enlargement (7 cm), a rather unusual finding, has so far not been reported in association with CDS. Chromosomal analysis failed, and the neonate died 30 min after birth. Comparative genomic hybridization analysis using stored DNA showed a balanced normal male DNA content, which negates chromosomal losses or gains as a cause of CDS and/or PE. PE due to virilizing-type adrenal hyperplasia, caused by common mutations in the genes encoding for the adrenal enzymes 21-hydroxylase and 11-hydroxylase, was ruled out. We report on a previously unpublished case of the coexistence of PE and severe CDS and propose a possible pathogenetic hypothesis of this association. Copyright Wiley-Liss. Inc.

Computer vision syndrome-A common cause of unexplained visual symptoms in the modern era.

PubMed

Munshi, Sunil; Varghese, Ashley; Dhar-Munshi, Sushma

2017-07-01

The aim of this study was to assess the evidence and available literature on the clinical, pathogenetic, prognostic and therapeutic aspects of Computer vision syndrome. Information was collected from Medline, Embase & National Library of Medicine over the last 30 years up to March 2016. The bibliographies of relevant articles were searched for additional references. Patients with Computer vision syndrome present to a variety of different specialists, including General Practitioners, Neurologists, Stroke physicians and Ophthalmologists. While the condition is common, there is a poor awareness in the public and among health professionals. Recognising this condition in the clinic or in emergency situations like the TIA clinic is crucial. The implications are potentially huge in view of the extensive and widespread use of computers and visual display units. Greater public awareness of Computer vision syndrome and education of health professionals is vital. Preventive strategies should form part of work place ergonomics routinely. Prompt and correct recognition is important to allow management and avoid unnecessary treatments. © 2017 John Wiley & Sons Ltd.

Unraveling the equine lymphocyte proteome: differential septin 7 expression associates with immune cells in equine recurrent uveitis.

PubMed

Degroote, Roxane L; Hauck, Stefanie M; Amann, Barbara; Hirmer, Sieglinde; Ueffing, Marius; Deeg, Cornelia A

2014-01-01

Equine recurrent uveitis is a spontaneous, lymphocyte-driven autoimmune disease. It affects horses worldwide and presents with painful remitting-relapsing inflammatory attacks of inner eye structures eventually leading to blindness. Since lymphocytes are the key players in equine recurrent uveitis, we were interested in potential changes of their protein repertoire which may be involved in disease pathogenesis. To create a reference for differential proteome analysis, we first unraveled the equine lymphocyte proteome by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subsequently identified 352 protein spots. Next, we compared lymphocytes from ERU cases and healthy horses with a two-dimensional fluorescence difference in gel electrophoresis approach. With this technique, we identified seven differentially expressed proteins between conditions. One of the significantly lower expressed candidates, septin 7, plays a role in regulation of cell shape, motility and migration. Further analyses revealed T cells as the main cell type with decreased septin 7 abundance in equine recurrent uveitis. These findings point to a possible pathogenetic role of septin 7 in this sight-threatening disease.

Pathobiologic Roles of Epstein–Barr Virus-Encoded MicroRNAs in Human Lymphomas

PubMed Central

Navari, Mohsen; Etebari, Maryam; Ibrahimi, Mostafa; Leoncini, Lorenzo

2018-01-01

Epstein–Barr virus (EBV) is a human γ-herpesvirus implicated in several human malignancies, including a wide range of lymphomas. Several molecules encoded by EBV in its latent state are believed to be related to EBV-induced lymphomagenesis, among which microRNAs—small RNAs with a posttranscriptional regulating role—are of great importance. The genome of EBV encodes 44 mature microRNAs belonging to two different classes, including BamHI-A rightward transcript (BART) and Bam HI fragment H rightward open reading frame 1 (BHRF1), with different expression levels in different EBV latency types. These microRNAs might contribute to the pathogenetic effects exerted by EBV through targeting self mRNAs and host mRNAs and interfering with several important cellular mechanisms such as immunosurveillance, cell proliferation, and apoptosis. In addition, EBV microRNAs can regulate the surrounding microenvironment of the infected cells through exosomal transportation. Moreover, these small molecules could be potentially used as molecular markers. In this review, we try to present an updated and extensive view of the role of EBV-encoded miRNAs in human lymphomas. PMID:29649101

Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

PubMed

Silbiger, Jeffrey J

2013-10-01

Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Evolutionary genetic analyses of MEF2C gene: implications for learning and memory in Homo sapiens.

PubMed

Kalmady, Sunil V; Venkatasubramanian, Ganesan; Arasappa, Rashmi; Rao, Naren P

2013-02-01

MEF2C facilitates context-dependent fear conditioning (CFC) which is a salient aspect of hippocampus-dependent learning and memory. CFC might have played a crucial role in human evolution because of its advantageous influence on survival of species. In this study, we analyzed 23 orthologous mammalian gene sequences of MEF2C gene to examine the evidence for positive selection on this gene in Homo sapiens using Phylogenetic Analysis by Maximum Likelihood (PAML) and HyPhy software. Both PAML Bayes Empirical Bayes (BEB) and HyPhy Fixed Effects Likelihood (FEL) analyses supported significant positive selection on 4 codon sites in H. sapiens. Also, haplotter analysis revealed significant ongoing positive selection on this gene in Central European population. The study findings suggest that adaptive selective pressure on this gene might have influenced human evolution. Further research on this gene might unravel the potential role of this gene in learning and memory as well as its pathogenetic effect in certain hippocampal disorders with evolutionary basis like schizophrenia. Copyright © 2012 Elsevier B.V. All rights reserved.

[Streptococcus pyogenes and the brain: living with the enemy].

PubMed

Dale, R C

Streptococcus pyogenes (or group A beta hemolytic streptococcus) is a pathogenic bacterium that can give rise to a range of invasive and autoimmune diseases, although it is more widely known as the cause of tonsillitis. It is particularly interesting to note that this germ only causes disease in humans. For many years it has been acknowledged that it can cause an autoimmune brain disease (Sydenham s chorea). Yet, the spectrum of post streptococcal brain disorders has recently been extended to include other movement disorders such as tics or dystonia. A number of systematic psychiatric studies have shown that certain emotional disorders generally accompany the movement disorder (particularly, obsessive compulsive disorder). The proposed pathogenetic mechanism is that of a neuronal dysfunction in which antibodies play a mediating role. The antibodies that are produced after the streptococcal infection cross react with neuronal proteins, and more especially so in individuals with a propensity. This represents a possible model of immunological mimicry and its potential importance with respect to certain idiopathic disorders such as Tourette syndrome and obsessive compulsive disorder.

Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer's disease.

PubMed

Cooper, Garth J S

2011-07-09

This article reviews recent evidence, much of which has been generated by my group's research programme, which has identified for the first time a previously unknown copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through copper-mediated oxidative stress. This author now considers this copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the diabetic complications. Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for Wilson's disease. TETA acts as a highly selective divalent copper (Cu(II)) chelator that prevents or reverses diabetic copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in copper metabolism that characterize this systemic copper overload state. Copper overload in diabetes mellitus differs from that in Wilson's disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper. Elevated pathogenetic tissue binding of copper occurs in diabetes. It may well be mediated by advanced-glycation endproduct (AGE) modification of susceptible amino-acid residues in long-lived fibrous proteins, for example, connective tissue collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous chelators that increase the chelatable-copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in copper regulation, and have shown that they are reversible by TETA. The drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition metal chelators, including D-penicillamine, ammonium tetrathiomolybdate and clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes. Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for Wilson's disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with Alzheimer's disease and vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to Alzheimer's disease/vascular dementia as a further therapeutic target where experimental pharmacotherapy with TETA could well find further clinical application.

[The semiotics of the pain and dyspeptic syndromes in motor disorders of the digestive organs in children and adolescents].

PubMed

Dmytriieva, S M

1999-06-01

Overall 304 children and adolescents with gastro-duodenal pathology were studied for some aspects of clinical manifestations of the pain and dyspeptic syndromes as related to the character of disordered gastroduodenal motility by making use of techniques of phase polygastroduodenometry. Pathogenetic interrelationship was disclosed of clinical manifestations of the pain and dyspeptic syndromes according to the variant of gastroduodenal dysmotility (dysphasic hyper- or hypomotile dyskinesia of the stomach and duodenum).

A current view of Alzheimer's disease.

PubMed

Hooli, Basavaraj V; Tanzi, Rudolph E

2009-07-08

Several genes that influence susceptibility to Alzheimer's disease (AD) have been known for over two decades. Recent advances have elucidated novel candidate genes and the pathogenetic mechanisms underlying neurodegeneration in AD. Here, we summarize what we have learned from studies of the known AD genes with regard to the causes of AD and emerging therapies. We also review key recent discoveries that have enhanced our understanding of the etiology and pathogenesis of this devastating disease, based on new investigations into the genes and molecular mechanisms underlying AD.

Integration of Anatomic and Pathogenetic Bases for Early Lung Cancer Diagnosis

DTIC Science & Technology

2007-03-01

transform Y(x; y), the coordinate of every pixel x = (x; y) in a uniform area (x; y) ∈A. η(xk; yk) is the surrounding curve of the area. The distance...is the labeled curve η Area A structuring element Figure 1: A fast algorithm for distance transform Figure 2: Three clustered cells (from left...Design Model”. Academic Radiology. 12(11): 1112-1123, 2006 [5]. Y.Zhang, R.Sankar and W.Qian, “Boundary Delineation in Transrectal Ultrasound

[Evaluation of various renal function indices in a group of workers in the shoe industry].

PubMed

Caudarella, R; Malavolta, N; Maccaferri, M; Raffi, G B; Boari, C

1981-05-26

The possible chronic nephrotoxicity of solvents has been investigated in a group of workers in the footwear industry. A number of indices of renal function were assessed in all subjects and a qualitative study of proteinuria carried out. The noted reduction in VFG would appear to be proportional to exposure doses. The other parameters, particularly the electrolytic balance, do not lend themselves to pathogenetic interpretations. The existence of a chronic nephrotoxicity of solvents cannot, however, be excluded.

Tinea Capitis: Current Status.

PubMed

Hay, R J

2017-02-01

Tinea capitis remains a common childhood infection in many parts of the world. Yet knowledge of the underlying pathogenetic mechanisms and the development of effective immunity have shown striking advances, and new methods of diagnosis ranging from dermoscopy to molecular laboratory tests have been developed even though they have not been assimilated into routine practice in many centres. Treatment is effective although it needs to be given for at least 1 month. What is missing, however, is a systematic approach to control through case ascertainment and therapy.

Legionnaires' disease: respiratory infections caused by Legionella bacteria.

PubMed

Davis, G S; Winn, W C

1987-09-01

This article provides a review of Legionnaire's Disease, a bacterial pneumonia caused by Legionella species, and of Pontiac Fever, the flu-like illness caused by these microorganisms. The authors draw on their personal experience with major human outbreaks of Legionnaire's Disease and with animal models of Legionella pneumonia. Emphasis is placed on the sources in nature from which legionellosis is acquired, the means of dissemination of bacteria, the epidemiology of human infections, the pathogenetic mechanisms of disease and host defense, the clinical manifestations, and the treatment.

Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

PubMed Central

Leite, Nathalie C; Villela-Nogueira, Cristiane A; Cardoso, Claudia R L; Salles, Gil F

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus. PMID:25024596

Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats.

PubMed

Kemp, William; Kompa, Andrew; Phrommintikul, Arintaya; Herath, Chandana; Zhiyuan, Jia; Angus, Peter; McLean, Catriona; Roberts, Stuart; Krum, Henry

2009-10-01

The influence of circulating urotensin II (UII) on liver disease and portal hypertension is unknown. We aimed to evaluate whether UII executes a pathogenetic role in the development of hepatic fibrosis and portal hypertension. UII was administered by continuous infusion over 4 wk in 20 healthy rats divided into three treatment groups, controls (saline, n = 7), low dose (UII, 1 nmol x kg(-1) x h(-1), n = 8), and high dose (UII, 3 nmol x kg(-1) x h(-1), n = 5). Hemodynamic parameters and morphometric quantification of fibrosis were assessed, and profibrotic cytokines and fibrosis markers were assayed in hepatic tissue. UII induced a significant dose-dependent increase in portal venous pressure (5.8 +/- 0.4, 6.4 +/- 0.3, and 7.6 +/- 0.7, respectively, P = 0.03). High-dose UII infusion was associated with an increase in hepatic transcript for transforming growth factor-beta (P < 0.05) and platelet-derived growth factor-beta (P = 0.06). Liver tissue hydroxyproline was elevated in the high-dose group (P < 0.05). No systemic hemodynamic alterations were noted. We concluded that UII infusion elevates portal pressure and induces hepatic fibrosis in normal rats. This response may be mediated via induction of fibrogenic cytokines. These findings have pathophysiological implications in human liver disease where increased plasma UII levels have been observed.

[Distressful journey for the metabolic syndrome to its position in clinical practice].

PubMed

Rybka, J

2010-07-01

MS is a major atherogenic syndrome in our population. The concept of MS has had a very positive effect on our knowledge of the most serious civilization diseases, the genotypic constellation of MS, although monogenic defects explain only a very small part of pathological defects. It is certain, however, that a crucial role played is by interactions between genetic factors and risk factors of external environment. Undoubtedly, insulin resistance, central obesity and impaired metabolism of adipose tissue play an important role in the pathogenesis of MS, and there are other pathogenetic theories. The author discusses briefly the history of MS and presents the best-known definitions starting with the 90s ofthe last century, ADA and EASD reservations towards MS, as well as the new harmonized definition from 2009. This modified definition ofMS has been adopted in practice in the Czech Republic due to the Czech Institute ofmetabolic syndrome. The author discusses in greater detail the WHO expert report from 2010, which indicates some limitations of diagnostic criteria for MS. Despite all the objections the expert report provides reasons to support the use of the term metabolic syndrome, and metabolic syndrome is considered to be a recognized concept that focuses attention on the importance of comprehensive, multifactorial health problems. Finally, the author mentions sub-problems related to MS, which will have to be resolved in collaboration with diabetologists.

Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity.

PubMed

D'Auria, L; Bonifati, C; Mussi, A; D'Agosto, G; De Simone, C; Giacalone, B; Ferraro, C; Ameglio, F

1997-12-01

Cytokine serum levels, when detectable, are currently measured in many disease states, both to evaluate a possible pathogenetic involvement of such molecules and for clinical purposes. No data are currently available on the cytokine levels in the sera of patients with pemphigus vulgaris (PV), a rare bullous disease of autoimmune origin. This study presents data concerning the levels of 13 different cytokines assayed in the sera of 25 patients affected with PV as compared with 20 healthy subjects using high sensitivity ELISA kits. Of the 13 molecules analyzed, no differences in the levels of most cytokines were observed between pemphigus and control sera, with the exception of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Serum TNF-alpha and IL-6 levels were found to be significantly higher in PV patients than in normal controls (p < 0.001). Furthermore, the levels of the two cytokines decreased after one month of corticosteroid therapy. A significant correlation was found between the serum levels of both TNF-alpha and IL-6 and the number of lesions for each patient (p < 0.001). The data presented support an involvement of at least IL-6 and TNF-alpha in the biological modifications associated with PV manifestations.

Hyaluronic Acid in Vascular and Immune Homeostasis during Normal Pregnancy and Preeclampsia

PubMed Central

Ziganshina, M. M.; Pavlovich, S. V.; Bovin, N. V.; Sukhikh, G. T.

2016-01-01

Preeclampsia (PE) is a multisystem pathologic state that clinically manifests itself after the 20th week of pregnancy. It is characterized by high maternal and perinatal morbidity and mortality. According to modern concepts, the impairment of trophoblast invasion into maternal spiral arteries, leading to the development of ischemia in placenta, is considered to be the major pathogenetic factor of PE development. Ischemic lesions initiate the development of a systemic inflammatory response (SIR) and endothelial dysfunction, which is the main cause of the multiple organ failure in PE. Some data has appear indicating the importance of a glycans-forming endothelial glycocalyx and extracellular matrix (ECM) for placenta morphogenesis, as well as their role in the regulation of vascular permeability and vascular tone in hypertension disorders and, in particular, PE. Since intact glycocalyx and ECM are considered to be the major factors that maintain the physiological vascular tone and adequate intercellular interactions, their value in PE pathogenesis is underestimated. This review is focused on hyaluronic acid (HA) as the key glycan providing the organization and stabilization of the ECM and glycocalyx, its distribution in tissues in the case of presence or absence of placental pathology, as well as on the regulatory function of hyaluronic acids of various molecular weights in different physiological and pathophysiological processes. The summarized data will provide a better understanding of the PE pathogenesis, with the main focus on glycopathology. PMID:27795844

Post-traumatic syringomyelia: CSF hydrodynamic changes following spinal cord injury are the driving force in the development of PTSM.

PubMed

Shields, Christopher B; Zhang, Yi Ping; Shields, Lisa B E

2012-01-01

Post-traumatic syringomyelia (PTSM) is a disorder that occurs infrequently following spinal cord injury (SCI), characterized by progressive neurological deterioration resulting from syrinx expansion originating in proximity to the traumatic epicenter. Several pathogenetic factors are associated with this disorder, however, the precise mechanism of the development of PTSM is controversial. Combined anatomical alterations and molecular changes following trauma to the spinal cord and arachnoid participate in the development of this condition. These factors include narrowing or obstruction of the subarachnoid space (SAS), central canal occlusion, myelomalacia, and alterations in intramedullary water permeability. If a patient sustains a SCI with delayed progressive deterioration in neurological function, in association with the MRI appearance of syringomyelia (SM), the diagnosis of PTSM is straightforward. The treatment of PTSM has not undergone any significant changes recently. The surgical treatment of PTSM consists of reconstructing the SAS or shunting fluid away from the syrinx to other locations. The advantages and disadvantages of each procedure will be discussed. With greater understanding of the mechanisms contributing to the development of SM, including advanced diagnostic methods and further advances in the development of artificial dural and shunting tubing, future therapies of PTSM will be more effective and long-lasting. Incorporation of alterations of AQP4 expression provides an intriguing possibility for future treatment of PTSM. Copyright © 2012 Elsevier B.V. All rights reserved.

Chronic cough due to occupational factors

PubMed Central

Groneberg, David A; Nowak, Dennis; Wussow, Anke; Fischer, Axel

2006-01-01

Within the large variety of subtypes of chronic cough, either defined by their clinical or pathogenetic causes, occupational chronic cough may be regarded as one of the most preventable forms of the disease. Next to obstructive airway diseases such as asthma or chronic obstructive pulmonary disease, which are sometimes concomitant with chronic cough, this chronic airway disease gains importance in the field of occupational medicine since classic fiber-related occupational airway diseases will decrease in the future. Apart from acute accidents and incidental exposures which may lead to an acute form of cough, there are numerous sources for the development of chronic cough within the workplace. Over the last years, a large number of studies has focused on occupational causes of respiratory diseases and it has emerged that chronic cough is one of the most prevalent work-related airway diseases. Best-known examples of occupations related to the development of cough are coal miners, hard-rock miners, tunnel workers, or concrete manufacturing workers. As chronic cough is often based on a variety of non-occupational factors such as tobacco smoke, a distinct separation into either occupational or personally -evoked can be difficult. However, revealing the occupational contribution to chronic cough and to the symptom cough in general, which is the commonest cause for the consultation of a physician, can significantly lead to a reduction of the socioeconomic burden of the disease. PMID:16722562

Dependence of morphological changes of the carotid arteries on essential hypertension and accompanying risk factors.

PubMed

Zizek, B; Poredos, P

2002-03-01

to evaluate morphological changes (intima-media thickness, IMT) of the carotid arteries in patients being treated for essential hypertension (EH), and to discover whether this abnormality can be detected in normotensive offspring of subjects with EH (familial trait, FT); and to investigate the interrelationship between IMT and accompanying risk factors. cross-sectional study. angiology department, university teaching hospital. the study encompassed 172 subjects, of whom 46 were treated hypertonics aged 40-55 (49) years, and 44 age matched, normotensive volunteers as controls. We also investigated 41 normotensives with FT for essential hypertension aged 20-30 (25) years and 41 age- and sex-matched controls without FT. the hypertensive subjects were being treated either with long-acting calcium-channel antagonists or ACE-inhibitors. using high resolution ultrasound, IMT of the carotid bifurcation and of the common carotid artery was measured. In the hypertensives, the mean IMT was greater than that in the controls (0.92 (0.10) mm vs 0.72 (0.07) mm; p<0.00005). The IMT was independently related to accompanying risk factors: a positive family history of hypertension, age of the patient, duration of EH and the level of systolic/diastolic blood pressure (BP), body mass index and total/LDL-cholesterol. In subjects with FT, IMT was also greater compared to the control group (0.60 (0.05) mm vs 0.55 (0.04) mm; p<0.00005). IMT was not related to BP values. In treated essential patients with the EH, the IMT was increased. Individuals with FT also had greater IMT in the absence of elevated BP. The IMT in hypertensives was related to accompanying risk factors, which could be pathogenetic determinants of EH and/or its complications.

The intrathecal expression and pathogenetic role of Th17 cytokines and CXCR2-binding chemokines in tick-borne encephalitis.

PubMed

Grygorczuk, Sambor; Świerzbińska, Renata; Kondrusik, Maciej; Dunaj, Justyna; Czupryna, Piotr; Moniuszko, Anna; Siemieniako, Agnieszka; Pancewicz, Sławomir

2018-04-20

Tick-borne encephalitis (TBE) is a clinically variable but potentially severe Flavivirus infection, with the outcome strongly dependent on secondary immunopathology. Neutrophils are present in cerebrospinal fluid (CSF) of TBE patients, but their pathogenetic role remains unknown. In animal models, neutrophils contributed both to the Flavivirus entry into central nervous system (CNS) and to the control of the encephalitis, which we attempted to evaluate in human TBE. We analyzed records of 240 patients with TBE presenting as meningitis (n = 110), meningoencephalitis (n = 114) or meningoencephalomyelitis (n = 16) assessing CSF neutrophil count on admission and at follow-up 2 weeks later, and their associations with other laboratory and clinical parameters. We measured serum and CSF concentrations of Th17-type cytokines (interleukin-17A, IL-17F, IL-22) and chemokines attracting neutrophils (IL-8, CXCL1, CXCL2) in patients with TBE (n = 36 for IL-8, n = 15 for other), with non-TBE aseptic meningitis (n = 6) and in non-meningitis controls (n = 7), using commercial ELISA assays. The results were analyzed with non-parametric tests with p < 0.05 considered as significant. On admission, neutrophils were universally present in CSF constituting 25% (median) of total pleocytosis, but on follow-up, they were absent in most of patients (58%) and scarce (< 10%) in 36%. CSF neutrophil count did not correlate with lymphocyte count and blood-brain barrier integrity, did not differ between meningitis and meningoencephalitis, but was higher in meningoencephalomyelitis patients. Prolonged presence of neutrophils in follow-up CSF was associated with encephalitis and neurologic sequelae. All the studied cytokines were expressed intrathecally, with IL-8 having the highest CSF concentration index. Additionally, IL-17A concentration was significantly increased in serum. IL-17F and CXCL1 CSF concentrations correlated with neutrophil count and CXCL1 concentration was higher in patients with encephalitis. The neutrophil CNS infiltrate does not correlate directly with TBE severity, but is associated with clinical features like myelitis, possibly being involved in its pathogenesis. Th17 cytokine response is present in TBE, especially intrathecally, and contributes to the CNS neutrophilic inflammation. IL-8 and CXCL1 may be chemokines directly responsible for the neutrophil migration.

[Acroosteolysis in PVC autoclave cleaners: history of an occupational disease].

PubMed

Zocchetti, C; Osculati, A; Colosio, C

2010-01-01

This paper examines the history of an occupational disease which has now disappeared: acroosteolysis of manual tank cleaners in the production of polyvinyl chloride (PVC), which is a rare disease characterized by destructive alterations of the distal phalanges of the hands. All the available literature on this disease was examined. The history of acroosteolysis was studied within the general framework of the history of the discovery of adverse health effects of exposure to vinyl chloride, and this history was studied up to the end of the 1960's. The disease was observed for the first time in mid-1963 in Belgium (Jemeppe) in a chemical plant operated by Solvay, and affected two workers whose job was the manual cleaning of vessels used for the polymerization of vinyl chloride; similar cases occurred in almost all PVC production plants all over the world, but not in the plants where the main activity was the production of vinyl chloride monomer (VCM). Little more than one hundred cases are described in the scientific literature, and this number increases by a few dozen if we consider known but unpublished cases. These figures confirm the rarity of the disease, which peaked at the end of the 1960's and disappeared during the 1970's, probably due to the complete elimination of manual reactor cleaning. Observation of the disease lasted no more than fifteen years and the disease was not replicated in experimental conditions on animals. The disease was clinically characterized, had a short latency (from several months to several years), was rare and unequivocally linked to the manual cleaning of PVC polymerization tanks. However many questions still remain open: the period when the disease first appeared (many years after the start of PVC production in the world), the etiology of the disease (the most accredited hypothesis considers three concomitant factors: a chemical factor--one of the many substances used during polymerization, and particularly vinyl chloride monomer, a physical factor--microtraumas of the fingers during manual cleaning, individual susceptibility), the pathogenetic mechanism (in particular: the role of skin, respiratory, or digestive system, as entrance door), a method (or test) to screen subjects potentially predisposed to the disease. In our view acroosteolysis of manual tank cleaners in PVC production is an occupational disease which is distinct from "vinyl chloride disease" as identified by Viola (1974).

Some etio-pathogenetic factors in laryngeal carcinogenesis.

PubMed

Sugár, J; Vereczkey, I; Tóth, J

1996-01-01

Chemical influences, mainly heavy tobacco smoking, chewing snuff, excessive alcohol consumption, and some occupational hazards, are known to be important etiologic factors in laryngeal carcinogenesis. The synergistic or cooperative interaction of human papilloma virus (HPV) infection with these chemical factors are serious considerations in the development of laryngeal carcinoma. With the development during the last decade of Southern blot hybridization and polymerase chain reaction (PCR), extensive and comprehensive studies have been conducted to determine the presence and biological (etiologic) significance of HPV. Developed cancer, as well as juvenile and adult multiple and single papilloma of the larynx, have been the subject of clinical and molecular-pathological investigation. Our previous study showed that cancer may develop on the basis of leukoplakia and adult-onset papilloma. Extensive kilocytes, an indication of HPV infection, can be seen by histological examination in papillomas and carcinoma. Literary data suggest that in laryngeal squamous cell carcinoma, including varicoses carcinoma, HPV 16, HPV 18, and HPV 33 DNA have been detected. Both in juvenile and adult-onset respiratory papillomatosis, patients could have either HPV type 6 or 11 DNA sequences. Molecular biological and PCR studies indicate that HPV may play an etiologic role in the development of human malignancies of the upper aerodigestive tract and uterine (cervical) origin. However, evidence that unequivocally links HPV infection with laryngeal squamous cell carcinoma is still lacking. In laryngeal cancer, p53 abnormalities are related to smoking-induced mutagenesis rather than HPV. Studies have postulated an interaction between HPV infection and chemical carcinogens and have concluded that HPV possibly are co-adjuvants during the multistage process of neoplastic transformation.

SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system.

PubMed

Watanabe, Seiji; Ageta-Ishihara, Natsumi; Nagatsu, Shinji; Takao, Keizo; Komine, Okiru; Endo, Fumito; Miyakawa, Tsuyoshi; Misawa, Hidemi; Takahashi, Ryosuke; Kinoshita, Makoto; Yamanaka, Koji

2014-08-29

Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons in a subset of inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed by protein refolding. This genetic study is aimed to test whether mutant SOD1-mediated ALS pathology recapitulated in mice could be alleviated by overexpressing a longevity-related deacetylase SIRT1 whose substrates include a transcription factor heat shock factor 1 (HSF1), the master regulator of the chaperone system. We established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. While inducible HSP70 (HSP70i) was upregulated in the spinal cord of SIRT1 transgenic mice (PrP-Sirt1), no neurological and behavioral alterations were detected. To test hypothetical benefits of SIRT1 overexpression, we crossbred PrP-Sirt1 mice with two lines of ALS model mice: A high expression line that exhibits a severe phenotype (SOD1G93A-H) or a low expression line with a milder phenotype (SOD1G93A-L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1G93A-L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1G93A-L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1G93A-L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1G93A-H transgenic mice partly because their HSP70i level had peaked out. The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the activation of the HSF1/HSP70i chaperone system. Future studies shall include testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.

[A pathogenetic hypothesis based on the use of chlorpromazine of organic disorders probably due to microcirculatory changes].

PubMed

Malossi, M

1993-01-01

In the introduction it is noted that, in the physiopathology, specific pathogenetic elements are missing concerning irritative stimulation, turbid fat pathosis, digital hippocratism of chronic affections (for example, pulmonary affections), the most frequent onset of telarche and of the swelling of the areola of the breast on the left hemithorax in the premenstrual syndrome, fibrosis, cyrrosis, certain types of insipid diabetes, etc. In the opinion of the author, the use of chloropromazine, in doses that have proved to be harmless, has contributed to the clearing up of some questions concerning a few pathologies of internal organs: the liver, the spleen, the brain-and enable us to pose some hypotheses about the swelling of the liver, the origin of scleroses and cirrhoses and some splenic and encephalic swellings. The author suggests that the fundamental reason is to be sought in changes in the microcirculation which are linked to insufficient capillary and sinusoidal circulation. Two cases of insipid diabetes are mentioned which were treated with chloropromazine and for which an improvement in the trophism of the diencephalic cells was hypothesized, due to an improvement in the local circulation. A similar physiopathological microcirculatory behaviour is attributed to digital hippocratism, the P. Marie and Bamberger syndrome (similar to those determined by cyanotic congenital cardiopathies), both due to chronic suppurative processes, and the slightly more frequent onset of telarche on the left hemithorax. It is expected that other pathologies may be explained by a similar physiopathological mechanism, malignant tumor inclusive.

Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway

PubMed Central

Wang, Huakai; Li, Yongjian; Shi, Minmin; Li, Hongwei; Yan, Jiqi

2016-01-01

Background Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. Methods Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. Results We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. Conclusions This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly. PMID:26734934

Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway.

PubMed

Chen, Yunyang; Wang, Weijie; Wang, Huakai; Li, Yongjian; Shi, Minmin; Li, Hongwei; Yan, Jiqi

2016-01-01

Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly.

Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back

PubMed Central

Coccurello, Roberto; Maccarrone, Mauro

2018-01-01

Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin), and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior. PMID:29740277

Analyzing the genes related to Alzheimer's disease via a network and pathway-based approach.

PubMed

Hu, Yan-Shi; Xin, Juncai; Hu, Ying; Zhang, Lei; Wang, Ju

2017-04-27

Our understanding of the molecular mechanisms underlying Alzheimer's disease (AD) remains incomplete. Previous studies have revealed that genetic factors provide a significant contribution to the pathogenesis and development of AD. In the past years, numerous genes implicated in this disease have been identified via genetic association studies on candidate genes or at the genome-wide level. However, in many cases, the roles of these genes and their interactions in AD are still unclear. A comprehensive and systematic analysis focusing on the biological function and interactions of these genes in the context of AD will therefore provide valuable insights to understand the molecular features of the disease. In this study, we collected genes potentially associated with AD by screening publications on genetic association studies deposited in PubMed. The major biological themes linked with these genes were then revealed by function and biochemical pathway enrichment analysis, and the relation between the pathways was explored by pathway crosstalk analysis. Furthermore, the network features of these AD-related genes were analyzed in the context of human interactome and an AD-specific network was inferred using the Steiner minimal tree algorithm. We compiled 430 human genes reported to be associated with AD from 823 publications. Biological theme analysis indicated that the biological processes and biochemical pathways related to neurodevelopment, metabolism, cell growth and/or survival, and immunology were enriched in these genes. Pathway crosstalk analysis then revealed that the significantly enriched pathways could be grouped into three interlinked modules-neuronal and metabolic module, cell growth/survival and neuroendocrine pathway module, and immune response-related module-indicating an AD-specific immune-endocrine-neuronal regulatory network. Furthermore, an AD-specific protein network was inferred and novel genes potentially associated with AD were identified. By means of network and pathway-based methodology, we explored the pathogenetic mechanism underlying AD at a systems biology level. Results from our work could provide valuable clues for understanding the molecular mechanism underlying AD. In addition, the framework proposed in this study could be used to investigate the pathological molecular network and genes relevant to other complex diseases or phenotypes.

Proteomic analysis of saliva: a unique tool to distinguish primary Sjögren's syndrome from secondary Sjögren's syndrome and other sicca syndromes

PubMed Central

2011-01-01

Introduction A growing interest has arisen in salivary proteomics as a tool for the identification of biomarkers for primary Sjögren's syndrome (pSS). Nonetheless, only a limited number of preclinical validation studies have been performed, limiting the possibility of translating proteomic results into clinical practice. The primary aim of this study was to refine the diagnostic power of a panel of candidate salivary biomarkers described in pSS with respect to both healthy volunteers and pathological controls. We also explored the pathogenetic function of the detected putative biomarkers both in the local exocrinopathy and in the systemic inflammatory processes of SS. Methods One hundred and eighty patients were included in the study overall. In the first "exploratory phase", we enrolled 40 females with pSS, 40 sex- and age-matched healthy volunteers, 10 patients with sicca non-SS and 15 secondary SS (sSS) patients. The testing cohort of the second "challenge phase" of the study was represented by 75 unselected, consecutive subjects: 19 pSS, 21 healthy volunteers, 10 sicca non-SS and 25 sSS patients. Salivary proteomic analysis was performed combining two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS). Western blot (WB) analysis and enzyme-linked immunosorbent assay (ELISA) were employed to validate 2DE results. Ingenuity Pathway Analysis (IPA) Knowledge base was adopted to associate candidate biomarkers in a signalling pathogenetic network. Results A total of 28, 6, 7 and 12 protein spots were found to be significantly different in pSS samples with respect to healthy volunteers, non-SS sicca syndrome, SSc-sSS and rheumatoid arthritis-sSS, leading to the identification of 15 differently expressed proteins. Among them, α-amylases precursor, carbonic anhydrase VI, β-2 microglobulin, glyceraldehydes-3-phosphate dehydrogenase (G3PDH), epidermal fatty acid binding protein (E-FABP) and immunoglobulin k light chain (IGK-light chain) apparently showed the most significant differences in pSS when compared to healthy volunteers and non-SS pathological controls. On the other hand, as expected, pSS and sSS salivary profiles shared a great number of similarities. Conclusions This study demonstrated that salivary fluid might represent a novel ideal milieu for the detection of a diagnostic panel of candidate biomarkers for pSS, and to gain an insight into the pathogenetic processes underlying glandular and systemic autoimmune disorders. PMID:22117835

[Pseudoallergies].

PubMed

Bernardini, R; Novembre, E; Lombardi, E; Monaco, M G; Monte, M T; Pucci, N; Rossi, M E; Vierucci, A

2001-01-01

Pseudo-allergic-reactions (PAR) are clinical manifestations including urticaria, angioedema, conjunctivitis, rhinitis, asthma, and anaphylaxis. The prevalence of PAR ranges from 0.1% to 75% according to various studies. The pathogenetic mechanism of these diseases is not immunologically mediated. Food, additives, and drugs are the main responsibilities for PAR. The diagnosis of PAR is characterized by the absence of specific IgE for the suspected products. The absence of immunological mechanisms is confirmed by in vitro and in vivo tests. The treatment of PAR is similar to that of allergic diseases (antihistamine drugs, steroids, B2 agonists, epinephrine).

Hemiconvulsion-hemiplegia-epilepsy syndrome: characteristic early magnetic resonance imaging findings.

PubMed

Freeman, Jeremy L; Coleman, Lee T; Smith, Lindsay J; Shield, Lloyd K

2002-01-01

We report three patients with hemiconvulsion-hemiplegia-epilepsy syndrome who presented acutely and were shown to have striking neuroimaging findings suggestive of diffuse cytotoxic edema confined to one hemisphere, including extensive diffusion-weighted imaging abnormalities in two cases. Two patients subsequently developed progressive and extensive atrophy of the involved hemisphere. These findings are consistent with earlier descriptions of the classic neuroradiologic features of this syndrome and are helpful in the differential diagnosis of acute infantile hemiplegia. Further, the findings support the previously proposed pathogenetic mechanism of neuronal injury caused by status epilepticus.

The management of esophageal achalasia: from diagnosis to surgical treatment.

PubMed

Dobrowolsky, Adrian; Fisichella, P Marco

2014-03-01

The goal of this review is to illustrate our approach to patients with achalasia in terms of preoperative evaluation and surgical technique. Indications, patient selection and management are herein discussed. Specifically, we illustrate the pathogenetic theories and diagnostic algorithm with current up-to-date techniques to diagnose achalasia and its manometric variants. Finally, we focus on the therapeutic approaches available today: medical and surgical. A special emphasis is given on the surgical treatment of achalasia and we provide the reader with a detailed description of our pre and postoperative management.

Developmental and benign movement disorders in childhood.

PubMed

Bonnet, Cecilia; Roubertie, Agathe; Doummar, Diane; Bahi-Buisson, Nadia; Cochen de Cock, Valérie; Roze, Emmanuel

2010-07-30

Developmental and benign movement disorders are a group of movement disorders with onset in the neonatal period, infancy, or childhood. They are characterized by the absence of associated neurological manifestations and by their favorable outcome, although developmental abnormalities can be occasionally observed. Knowledge of the clinical, neurophysiological, and pathogenetic aspects of these disorders is poor. Based on a comprehensive review of the literature and our practical experience, this article summarizes current knowledge in this area. We pay special attention to the recognition and management of these movement disorders in children. (c) 2010 Movement Disorder Society.

Antinuclear Antibodies (ANA) in Gordon Setters with Symmetrical Lupoid Onychodystrophy and Black Hair Follicular Dysplasia

PubMed Central

Bohnhorst, J Øvrebø; Hanssen, I; Moen, T

2001-01-01

Antinuclear antibodies (ANA) were demonstrated in 3 out of 10 Gordon setters with symmetrical lupoid onychodystrophy and in 5 out of 13 Gordon setters with black hair follicular dysplasia. Two dogs showed both symmetrical lupoid onychodystrophy and black hair follicular dysplasia, and one of these was ANA positive. The results suggest that symmetrical lupoid onychodystrophy and black hair follicular dysplasia in the Gordon setter might be autoimmune diseases that are pathogenetically related, which might indicate a common genetic predisposition. PMID:11887392

Kikuchi-Fujimoto disease and systemic lupus erythematosus: the EBV connection?

PubMed

Gionanlis, Lazaros; Katsounaros, Marios; Bamihas, Gerasimos; Fragidis, Stelios; Veneti, Panagiota; Sombolos, Kostas

2009-01-01

Kikuchi-Fujimoto disease (KFD) is a benign and self-limited disease of unknown etiology that affects mainly young women. It presents with localized lymphadenopathy, usually cervical, accompanied with fever, night sweats, and leucopenia. KFD has been rarely described in association with autoimmune disorders, mainly systemic lupus erythematosus (SLE). We report the case of a young patient presenting with KFD coinciding with SLE. The association of KFD and SLE is reviewed. Moreover, a possible pathogenetic role of Ebstein-Barr virus linking the two clinical entities is discussed.

[Morphological features of tissue reactions in combined treatment of experimental tuberculosis induced by xenobiotics].

PubMed

Pavlov, V A; Kazak, T I; Kleĭn, A V; Nosova, N A

1995-01-01

The trend to aggravated running and contribution of air pollution of large industrial centers with polycyclic aromatic hydrocarbons (PAH) to tuberculosis onset and progress dictate the necessity of the search for new treatment methods. The authors made an attempt to treat experimental tuberculosis with sodium glutamate and isoniazide under chronic exposure to PAH dust. Sodium glutamate especially in combination with isoniazide produces a good effect enhancing granulomatous reactions fibroplastic processes in the foci of specific inflammation. Sodium glutamate is thought an effective pathogenetic treatment of tuberculosis.

[Current views of nutritional therapy].

PubMed

Pogozheva, A V; Kaganov, B S

2009-01-01

Epidemiologic studies in the Research Institute of Nutrition showed that dietary patterns of the Russian population are on the whole at variance with the balanced feeding formula largely due to excessive consumption of animal fat, insufficient consumption of proteins, vitamins, micro- and macroelements, polyunsaturated fatty acids, and dietary fibers. It is estimated that over 70% of total lethality in this country is due to diseases directly related to improper feeding (the so-called alimentary-dependent diseases), cardiovascular disorders, some neoplasms, diabetes mellitus, etc. Dietary therapy adjusted to specific pathogenetic features, clinical picture, stage of the disease, character of metabolic disorders in individual patients is an important factor having versatile beneficial effects on the patient's health, correcting metabolic problems, and improving quality of life. Decree No 330 of August 5, 2003 "On measures to improve nutritional therapy in medical institutions of the Russian Federation" introduced a new nomenclature of standard diets based on chemical composition of separate foods and the previously used system of numbered diets. Modern dietary therapy includes not only standard and special diets but also specific products to be used in concrete clinical conditions, enteral and parenteral nutrition, biologically active food additives, etc.

Cytomegalovirus-associated cutaneous vasculopathy and scleroderma sans inclusion body change.

PubMed

Magro, Cynthia M; Crowson, A Neil; Ferri, Clodoveo

2007-01-01

Viruses have long been held to be of pathogenetic importance in the evolution of autoimmune connective tissue disease. We describe 7 adults who developed cutaneous connective tissue disease stigmata in temporal association with recent cytomegalovirus (CMV) infection but without the classic cytopathic changes of CMV infection. We examined 7 adults with clinical presentations encompassing cutaneous vasculitis in 4 and scleroderma in 3. In all 7 patients, there was either IgM seropositivity for CMV and/or CMV DNA isolation from peripheral blood. Although no CMV inclusions were seen, in situ hybridization studies revealed very focal CMV RNA transcript expression with localization mainly to the endothelium. The patients with vasculitis treated with ganciclovir had improvement or resolution of symptoms, whereas only 1 patient with scleroderma received antiviral therapy, without benefit. Another scleroderma patient responded to infliximab therapy. Abortive/partial CMV reactivation can be associated with a syndrome complex mimicking and/or triggering a primary immune-based cutaneous microvascular injury syndrome. Antiviral therapy appears to be of therapeutic value in those cases associated with active necrotizing vasculitic changes. The role of tumor necrosis factor alpha blockers in scleroderma cases temporally associated with CMV infection requires further evaluation.

[Glomerular filtration and renal volume in type II diabetes (non-insulin-dependent): study in normal and microalbuminuria patients].

PubMed

Signorini, A M; Tanganelli, I; Fondelli, C; Vattimo, A; Ferrari, F; Borgogni, P; Borgogni, L; Gragnoli, G

1991-08-01

In type 2 diabetes elevated glomerular filtration rate (GFR) and increased renal volume (RV), often accompanied to normo or microalbuminuria, were demonstrated. This condition is considered a pathogenetic factor for clinical nephropathy. As this topic is little studied in type 2 diabetes, we have investigated 73 type 2 diabetic patients (34 normo and 39 microalbuminuric), looking for a correlation between GFR, RV, hypertension, duration of diabetes and indexes of metabolic control. GFR was measured by a scintigraphy, after infusion of 99Tc-DTPA. Renal volume was determined by ultrasound scanning. Between the groups GFR and RV weren't different; elevated GFR was demonstrated in 3 patients; increased RV in 1 patient. In the hypertensive group GFR was lower than in normotensive group and in controls. Multivariate analysis in stepwise demonstrated that GFR presents a negative correlation to systolic blood pressure as in normo as in microalbuminuric patients. In the normotensive group GFR didn't correlate to the other variables. The present data suggest that in type 2 diabetes there is a little prevalence of glomerular hyperfiltration and increased renal volume and that hypertension plays a role on GFR of hypertensive diabetic patients.

[Suicide risk in somatoform disorders].

PubMed

Giupponi, Giancarlo; Maniscalco, Ignazio; Mathà, Sandra; Ficco, Carlotta; Pernther, Georg; Sanna, Livia; Pompili, Maurizio; Kapfhammer, Hans-Peter; Conca, Andreas

2018-03-01

The somatoform disorders include a group of complex disorders consist of somatic symptoms for which there are no identifiable organic cause or pathogenetic mechanisms. Given the importance of these disorders and the need to clarify the diagnosis of somatoform disorder affecting the suicide risk, we took into consideration the scientific literature to investigate the correlation between the two conditions. We performed a bibliographic search through Medline, Embase, PsycINFO, Scopus, SciELO, ORCID, Google Scholar, DOAJ using the following terms: somatoform, somatization disorder, pain disorder AND psychological factor, suicide, parasuicide, suicidality. In all studies reported in our review, the suicidal behavior risk is high. But in the majority, the data are relatively unreliable because it takes into account the category nosographic "Neurotic, stress-related and somatoform disorders", too wide to be able to identify the clinical characteristics of patients at risk of only somatoform disorder. Several studies conclude that psychiatric comorbidity increases the suicide risk: patients with two or more psychiatric disorders are more likely to commit a suicide attempt; in particular if there is a axis I diagnosis, the risk reduplicate. The somatization disorder seems to have a significant psychiatric comorbidity in particular with anxious and affective disorders spectrum.

[Modeling employee stress in psychiatric rehabilitation--effects of personal and organizational factors].

PubMed

Queri, S; Konrad, M; Keller, K

2012-08-01

Increasing stress-associated health problems in Germany often are attributed to problems on the job, in particular to rising work demands. The study includes several stress predictors from other results and from literature in one predictive model for the field of work of "psychiatric rehabilitation".A cross-sectional design was used to measure personal and organizational variables with quantitative standard questionnaires as self-ratings from n=243 pedagogically active employees from various professions. Overall stress and job stress were measured with different instruments.The sample showed above-average overall stress scores along with below-average job stress scores. The multivariate predictive model for explaining the heightened stress shows pathogenetic and salutogenetic main effects for organizational variables such as "gratification crisis" and personal variables such as "occupational self-efficacy expectations" as well as an interaction of both types of variables. There are relevant gender-specific results concerning empathy and differences between professions concerning the extent of occupational self-efficacy.The results are a matter of particular interest for the practice of workplace health promotion as well as for social work schools, the main group in our sample being social workers. © Georg Thieme Verlag KG Stuttgart · New York.

[Uterine anomalies in women with recurrent pregnancy loss].

PubMed

Galamb, Ádám; Pethő, Boglárka; Fekete, Dávid; Petrányi, Győző; Pajor, Attila

2015-07-05

One percent of couples trying to have children are affected by recurrent miscarriage. These pregnancy losses have different pathogenetic (genetic, endocrine, anatomic, immunologic, microbiologic, haematologic and andrologic) backgrounds, but recurrent miscarriage remains unexplained in more than half of the affected couples. To explore risk factors for recurrent pregnancy loss the authors studied the incidence of anatomic disorders of the uterine cavity occur in Hungarian women with recurrent miscarriage. Medical records of 152 patients with recurrent miscarriage were analyzed retrospectively. In order to explore disorders of the uterine cavity hysteroscopy or 3-dimensional sonography in 132 women, hysterosalpingography in 16 and hysterosalpingo-sonography in 4 patients were used. Incidence of anomalies in the uterine cavity was found in women with recurrent miscarriage to be 15.8%. A variety of the uterine anomalies was found including uterine septum in 6.5%, endometrial polyp in 2.6%, arcuate and bicornuate uteri both in 2% and 2%, submucosal myoma in 1.3 %, and intrauterine synechiae in 1.3%. These findings suggest that morphologic disorder of the uterine cavity is frequent in Hungarian women with recurrent miscarriage. Therefore, assessment of the uterine anatomy is recommended in such patients.

UV-B-induced damage to the lens in vitro: prevention by caffeine.

PubMed

Varma, Shambhu D; Hegde, Kavita R; Kovtun, Svitlana

2008-10-01

Ultraviolet (UV) irradiation is one of the significant risk factors in the genesis of cataracts. Pathogenetically, the process can be triggered by the intraocular generation of various reactive species of oxygen that are well known to be initiated by the penetration of light, especially of the UV frequencies. The contribution of UV exposure in the etiology of this disease is likely to increase further due to ozone depletion in the upper atmosphere. The present studies were undertaken to examine if the UV effects can be attenuated with the xanthine-based alkaloids primarily present in tea and coffee. We have examined this possibility by in vitro lens culture studies with caffeine. As expected, mice lenses incubated in Tyrode solution exposed to UV at 302 nm are physiologically damaged, as evidenced by the inhibition of the active transport of (86)Rb(+), an ion acting as a surrogate of the K(+). There was a simultaneous decrease in the levels of adenosine triphosphate and glutathione. The addition of caffeine to the medium prevented such deleterious effects. That caffeine and perhaps other xanthinoids have a protective effect against cataract formation induced by UV has hence been demonstrated for the first time.

Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

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

Becker, Argentina; Kannan, T. R.; Taylor, Alexander B.

Mycoplasma pneumoniae (Mp) infections cause tracheobronchitis and “walking” pneumonia, and are linked to asthma and other reactive airway diseases. As part of the infectious process, the bacterium expresses a 591-aa virulence factor with both mono-ADP ribosyltransferase (mART) and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). CARDS TX binds to human surfactant protein A and annexin A2 on airway epithelial cells and is internalized, leading to a range of pathogenetic events. In this paper, we present the structure of CARDS TX, a triangular molecule in which N-terminal mART and C-terminal tandem β-trefoil domains associate to form anmore » overall architecture distinct from other well-recognized ADP-ribosylating bacterial toxins. We demonstrate that CARDS TX binds phosphatidylcholine and sphingomyelin specifically over other membrane lipids, and that cell surface binding and internalization activities are housed within the C-terminal β-trefoil domain. Finally, the results enhance our understanding of Mp pathogenicity and suggest a novel avenue for the development of therapies to treat Mp-associated asthma and other acute and chronic airway diseases.« less

Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

DOE PAGES

Becker, Argentina; Kannan, T. R.; Taylor, Alexander B.; ...

2015-04-06

Mycoplasma pneumoniae (Mp) infections cause tracheobronchitis and “walking” pneumonia, and are linked to asthma and other reactive airway diseases. As part of the infectious process, the bacterium expresses a 591-aa virulence factor with both mono-ADP ribosyltransferase (mART) and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). CARDS TX binds to human surfactant protein A and annexin A2 on airway epithelial cells and is internalized, leading to a range of pathogenetic events. In this paper, we present the structure of CARDS TX, a triangular molecule in which N-terminal mART and C-terminal tandem β-trefoil domains associate to form anmore » overall architecture distinct from other well-recognized ADP-ribosylating bacterial toxins. We demonstrate that CARDS TX binds phosphatidylcholine and sphingomyelin specifically over other membrane lipids, and that cell surface binding and internalization activities are housed within the C-terminal β-trefoil domain. Finally, the results enhance our understanding of Mp pathogenicity and suggest a novel avenue for the development of therapies to treat Mp-associated asthma and other acute and chronic airway diseases.« less

Campylobacters: the most common bacterial enteropathogens in the Nordic countries.

PubMed

Rautelin, H; Hänninen, M L

2000-10-01

Campylobacters have been known as important human pathogens since the late 1970s. Campylobacter jejuni and coli are the most common bacterial enteropathogens in the developed countries. During the past years an increasing incidence of campylobacteriosis has been reported in many developed countries. C. jejuni is the most common Campylobacter species while C. coli accounts for about 5-10% of the cases. Although the genome of C. jejuni NCTC 11168 strain was sequenced recently, the exact pathogenetic mechanisms are still not known. Furthermore, there are no reliable animal models available. The epidemiology of this common infection is not well understood; however, eating and handling poultry, contaminated drinking water, and contact with pet animals have been recognized as important risk factors. Most of the cases are sporadic although large water-borne outbreaks have also been reported. Discriminatory typing methods are helpful in tracing the sources and transmission routes. In addition to traditional serotyping, genotyping methods, such as pulsed-field gel electrophoresis, have been developed. As Campylobacter infections probably precede Guillan-Barré syndrome in many cases, a great interest has lately been focused on the possible triggering mechanisms underlying this phenomenon.

Histophilus somni host-parasite relationships.

PubMed

Corbeil, Lynette B

2007-12-01

Histophilus somni (Haemophilus somnus) is one of the key bacterial pathogens involved in the multifactorial etiology of the Bovine Respiratory Disease Complex. This Gram negative pleomorphic rod also causes bovine septicemia, thrombotic meningencephalitis, myocarditis, arthritis, abortion and infertility, as well as disease in sheep, bison and bighorn sheep. Virulence factors include lipooligosaccharide, immunoglobulin binding proteins (as a surface fibrillar network), a major outer membrane protein (MOMP), other outer membrane proteins (OMPs) and exopolysaccharide. Histamine production, biofilm formation and quorum sensing may also contribute to pathogenesis. Antibodies are very important in protection as shown in passive protection studies. The lack of long-term survival of the organism in macrophages, unlike facultative intracellular bacteria, also suggests that antibodies should be critical in protection. Of the immunoglobulin classes, IgG2 antibodies are most implicated in protection and IgE antibodies in immunopathogenesis. The immunodominant antigen recognized by IgE is the MOMP and by IgG2 is a 40 kDa OMP. Pathogenetic synergy of bovine respiratory syncytial virus (BRSV) and H. somni in calves can be attributed, in part at least, to the higher IgE anti-MOMP antibody responses in dually infected calves. Other antigens are probably involved in stimulating host defense or immunopathology as well.

Cystic dysplasia of the testis: a very rare paediatric tumor of the testis.

PubMed

Eberli, Daniel; Gretener, Heini; Dommann-Scherrer, Corina; Pestalozzi, Dietegen; Fehr, Jean-Luc

2002-01-01

To describe a case of cystic dysplasia of the testis (CDT), an uncommon cause of scrotal swelling in the pediatric patient. Clinic, therapy, fertility, and radiographic and pathologic findings are discussed and the 30 previously reported cases are reviewed. A 9-year-old boy presented with asymptomatic scrotal swelling. A scrotal ultrasound showed a multicystic scrotal mass in the rete testis and an ipsilateral renal agenesis. The growth in size of the mass forced the authors to perform an operative exploration. Intraoperative findings included a multicystic mass in the rete testis of the right testicle. Testicle-sparing total removal of the multicystic mass was performed and the pathologic examination revealed a benign, multilobulated configuration of the cysts in the region of the rete testis. These findings were similar to those found in previously reported cases of CDT. Ipsilateral renal agenesis is the most common associated anomaly. As a pathogenetic factor, mal-junction of the Wolffian duct in the 5th week of gestation is most creditable. CDT is a rare cause of pediatric scrotal mass. When feasible, a testicle-sparing approach should be considered and all patients should undergo evaluation for associated urologic anomalies.

Two cases of distal extremity swelling with pitting oedema in psoriatic arthritis: the different pathological mechanisms.

PubMed

Quarta, L; Corrado, A; d'Onofrio, F; Maruotti, N; Cantatore, Francesco Paolo

2010-08-01

In psoriatic arthritis, swelling and pitting oedema may be caused by different pathogenic mechanisms: on one hand, the involvement of tenosynovial structures; on the other hand, the involvement of lymphatic vessels, which may be rarely implicated by the inflammatory process. This different involvement is responsible for a different response to therapy and a different clinical outcome. In fact, patients with inflammation of the tenosynovial structures and normal lymphatic drainage have a more favourable clinical outcome and response to pharmacologic treatment, whilst patients affected by psoriatic arthritis with chronic lymphatic vascular damage are characterized usually by resistance of oedema to therapy. In this study, we report two cases of psoriatic arthritis with distal extremity swelling and pitting oedema. In the first patient, the swelling and pitting oedema were associated with lymphatic obstruction, as detected by lymphoscintigraphy. In the second, the predominant involvement of the tenosynovial structures, as shown by magnetic resonance, with normal lymphatic flow, may have been the cause of arthritis with oedema. These different pathogenetic mechanisms were associated with different response to therapy. Nevertheless, oedema was resistant to therapy in both patients probably because of other unknown factors, which influence therapy and clinical outcome.

Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development.

PubMed

Sagaert, Xavier; Van Cutsem, Eric; De Hertogh, Gert; Geboes, Karel; Tousseyn, Thomas

2010-06-01

Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma arising in lymphoid infiltrates that are induced by chronic inflammation in extranodal sites. The stomach is the most commonly affected organ, in which MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Gastric MALT lymphoma has attracted attention because of the involvement of genetic aberrations in the nuclear factor kappaB (NFkappaB) pathway, one of the most investigated pathways in the fields of immunology and oncology. This Review presents gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development, and describes how this information can be integrated into daily clinical practice. Gastric MALT lymphoma is considered one of the best models of how genetic events lead to oncogenesis, determine tumor biology, dictate clinical behavior and represent viable therapeutic targets. Moreover, in view of the association of gastric MALT lymphoma with dysregulation of the NFkappaB pathway, this signaling pathway will be discussed in depth in both normal and pathological conditions, highlighting strategies to identify new therapeutic targets in this lymphoma.

[Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome].

PubMed

Góth, Miklós; Hubina, Erika; Korbonits, Márta

2005-01-09

The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

PubMed Central

Tsuda, Takeshi; Fitzgerald, Kristi K.

2017-01-01

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. PMID:29367543

Clinical, cellular, microscopic, and ultrastructural studies of a case of fibrogenesis imperfecta ossium

PubMed Central

Barron, Melissa L; Rybchyn, Mark S; Ramesh, Sutharshani; Mason, Rebecca S; Fiona Bonar, S; Stalley, Paul; Khosla, Sundeep; Hudson, Bernie; Arthur, Christopher; Kim, Edward; Clifton-Bligh, Roderick J; Clifton-Bligh, Phillip B

2017-01-01

Fibrogenesis imperfecta ossium is a rare disorder of bone usually characterized by marked osteopenia and associated with variable osteoporosis and osteosclerosis, changing over time. Histological examination shows that newly formed collagen is abnormal, lacking birefringence when examined by polarized light. The case presented demonstrates these features and, in addition, a previously undocumented finding of a persistent marked reduction of the serum C3 and C4. Osteoblasts established in culture from a bone biopsy showed abnormal morphology on electron microscopy and increased proliferation when cultured with benzoylbenzoyl-ATP and 1,25-dihydroxyvitamin D, contrasting with findings in normal osteoblasts in culture. A gene microarray study showed marked upregulation of the messenger RNA (mRNA) for G-protein-coupled receptor 128 (GPR 128), an orphan receptor of unknown function and also of osteoprotegerin in the patient’s osteoblasts in culture. When normal osteoblasts were cultured with the patient’s serum, there was marked upregulation of the mRNA for aquaporin 1. A single pathogenetic factor to account for the features of this disorder has not been defined, but the unique findings described here may facilitate more definitive investigation of the abnormal bone cell function. PMID:28326223

The Challenges of Precision Medicine in COPD.

PubMed

Cazzola, Mario; Calzetta, Luigino; Rogliani, Paola; Matera, Maria Gabriella

2017-08-01

Pheno-/endotyping chronic obstructive pulmonary disease (COPD) is really important because it provides patients with precise and personalized medicine. The central concept of precision medicine is to take individual variability into account when making management decisions. Precision medicine should ensure that patients get the right treatment at the right dose at the right time, with minimum harmful consequences and maximum efficacy. Ideally, we should search for genetic and molecular biomarker-based profiles. Given the clinical complexity of COPD, it seems likely that a panel of several biomarkers will be required to characterize pathogenetic factors and their course over time. The need for biomarkers to guide the clinical care of individuals with COPD and to enhance the possibilities of success in drug development is clear and urgent, but biomarker development is tremendously challenging and expensive, and translation of research efforts to date has been largely ineffective. Furthermore, the development of personalized treatments will require a much more detailed understanding of the clinical and biological heterogeneity of COPD. Therefore, we are still far from being able to apply precision medicine in COPD and the treatable traits and FEV 1 -free approaches are attempts to precision medicine in COPD that must be considered still quite unsophisticated.

Familial subacute sclerosing panencephalitis associated with short latency.

PubMed

Sharma, Vinod; Gupta, Vineet B; Eisenhut, Michael

2008-03-01

The familial recurrence of subacute sclerosing panencephalitis is rare. The study of such cases and a comparison of intrafamilial with sporadic cases of subacute sclerosing panencephalitis may shed light on important pathogenetic factors. We report on the occurrence of subacute sclerosing panencephalitis in two brothers from rural India, who contracted measles infection simultaneously at ages 3 and 11 years. They developed subacute sclerosing panencephalitis 21 and 37 months later, respectively. A diagnosis of subacute sclerosing panencephalitis was based on history, electroencephalographic changes, and significantly raised levels of cerebrospinal-fluid anti-measles virus immunoglobulin G. A comparison of intrafamilial with sporadic cases of subacute sclerosing panencephalitis revealed that latency in familial subacute sclerosing panencephalitis involved a median of 6.4 years (range, 1.0-10.9), significantly (P < 0.05) shorter than in sporadic cases with a median of 9.7 years (range, 2.7-23.4). This difference was because of significantly later infection with measles virus and an earlier onset of encephalitis. We describe the first siblings affected by subacute sclerosing panencephalitis from the Indian subcontinent. We confirmed a more rapid manifestation of subacute sclerosing panencephalitis after measles virus infection in intrafamilial compared with sporadic subacute sclerosing panencephalitis.

['Specificity' in microbiology and immunochemistry between 1880 and 1930].

PubMed

Corbellini, Gilberto

2010-01-01

During the second half of the XIX Century, microbiological sciences acquired a set of conceptual, methodological and technological tools that radically transformed theoretical and empirical knowledge of the microorganisms, with particular regard to their biochemical properties and their etiopathological role in infectious diseases. During that period, theoretical and experimental researches in general microbiology and immunochemistry addressed the nature and empirical appearances of microbes, both pathogens and not, and the origins of chemical properties of immune sera. In other words, microbiologists tried operatively explaining the origins of the morphological, physiological, and pathogenetic differences between the microbial species. At the same time physiologists and biochemists investigated the chemical basis of the selective or specific interactions between microorganisms or their chemical components and humoral factors contained into the sera produced by the body in response to the contact with microbes. During the half a century, between 1880 and 1930, qualitative and quantitative experimental studies demonstrated that the specificity of microbiological phenomena depended on the biology of microbes and that the specificity of immune reactions hinged upon the biochemical properties of special molecules synthesized by some physiological system which can recognize and react against any foreign substance.

Hepatitis E virus and hepatitis A virus exposures in an apparently healthy high-risk population in Italy.

PubMed

Rapicetta, M; Monarca, R; Kondili, L A; Chionne, P; Madonna, E; Madeddu, G; Soddu, A; Candido, A; Carbonara, S; Mura, M S; Starnini, G; Babudieri, S

2013-02-01

The prevalence of anti-hepatitis E virus (HEV) and anti-hepatitis A virus (HAV), as well as the possible links with socio-demographic and other viral risks factors, were evaluated in an inmates population. The study population consisted of 973 consecutively recruited inmates of eight Italian prisons. The anti-HEV prevalence was 11.6 % (113/973). It increased significantly by age (χ(2) for linear trend: p = 0.001) and was significantly higher among non-Italian compared to Italian inmates (15.3 vs. 10.7 %, respectively). Age >40 years [odds ratio (OR) 2.1; 95 % confidence interval (CI) 1.4-3.1], non-Italian citizenship (OR 1.8; 95 % CI 1.1-2.9) and anti-HIV seropositivity (OR 2.2; 95 % CI 1.2-4.2) were the only factors independently associated to anti-HEV positivity by logistic regression analysis. The overall anti-HAV prevalence was 86.4 %, and was significantly higher in non-Italian compared to Italian prisoners (92.6 vs. 84.9 %, respectively; p = 0.02). Age older than 40 years (OR 3.6; 95 % CI 2.2-5.9), <5 years formal education (OR 2.1; 95 % CI 1.3-3.2) and non-Italian nationality (OR 2.7; 95 % CI 1.5-4.8) were factors independently associated to anti-HAV positivity by the logistic regression analysis. Compared to the general population, significantly higher anti-HEV and anti-HAV prevalences were observed in an inmates population in Italy. Old age and non-Italian nationality were factors independently related to both HEV and HAV exposures. This data suggest the important role of low socio-economic factors in the transmission of both infections in high-risk populations. The possible epidemiological and/or pathogenetic links between HEV and HIV exposures need to be studied further.

The Nrf2 pathway in the progression of renal disease.

PubMed

Zoja, Carlamaria; Benigni, Ariela; Remuzzi, Giuseppe

2014-02-01

The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.

Review article: Update on current and emergent data on hepatopulmonary syndrome

PubMed Central

Soulaidopoulos, Stergios; Cholongitas, Evangelos; Giannakoulas, George; Vlachou, Maria; Goulis, Ioannis

2018-01-01

Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. Its prevalence ranges from 4% to 47% in patients with cirrhosis due to the different diagnostic criteria applied among different studies. Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. A classification of HPS according to the severity of hypoxemia has been suggested. Contrast-enhanced echocardiography represents the gold standard method for the detection of intrapulmonary vascular dilatations which is required, in combination with an elevated alveolar arterial gradient to set the diagnosis. The only effective treatment which can modify the syndrome’s natural history is liver transplantation. Although it is usually asymptomatic, HPS imparts a high risk of pretransplantation mortality, independently of the severity of liver disease, while there is variable data concerning survival rates after liver transplantation. The potential of myocardial involvement in the setting of HPS has also gained increasing interest in recent research. The aim of this review is to critically approach the existing literature of HPS and emphasize unclear points that remain to be unraveled by future research. PMID:29599604

Current trends in antithyroid drug treatment of Graves' disease.

PubMed

Okosieme, Onyebuchi E; Lazarus, John H

2016-10-01

Graves' hyperthyroidism is associated with significant morbidity and mortality risk. The thionamides, methimazole, its pro-drug derivative carbimazole, and propylthiouracil, remain a cornerstone of management. Yet despite decades of use, optimal strategies for maximising treatment response and curtailing adverse effect risk remains uncertain. We reviewed the current literature on the evidence based medical management of Graves' disease. Specifically, we evaluated current approaches to the use of thionamides, adjunctive therapies, and potential novel agents for controlling Graves' hyperthyroidism. Primary medical therapy is successful in less than 50% of cases and so careful selection of patients for medical treatment based on a combination of pathological and pragmatic considerations is essential. Carbimazole or methimazole is the treatment of choice in the non-pregnant population driven by its more favourable pharmacokinetic and adverse effect profile over propylthiouracil. In pregnancy the choice of treatment is less straightforward and an approach that minimises undue fetal exposure to all thionamides should be adopted. Additional data is needed on the value of adjunctive therapies including potassium perchlorate, iodides, glucocorticoids, lithium, and cholestyramine. Novel agents directed against pathogenetic targets including TSH receptor blocking monoclonal antibodies and small molecule antagonists may hold promise for the future.

[Autism, epilepsy and tuberous sclerosis complex: a functional model linked to mTOR pathway].

PubMed

García-Peñas, Juan José; Carreras-Sááez, Inmaculada

2013-02-22

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. Brain disorders are the origin of more frequent and severe problems and include infantile spasms, intractable epilepsy, brain tumors, cognitive disabilities, and autism. TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. AIM. To review the etiopathogenic mechanisms and the natural course of the association of autism and epilepsy in TSC. Both the clinical and the neuroimaging findings of TSC, including early onset epilepsy and the localization of cortical tubers in the temporal lobes, and the molecular understanding of the mTOR signaling pathway, not only involved in cell growth, but also in synaptogenesis, synaptic plasticity and neuronal functioning, have suggested a multimodal origin of autism in these patients. A greater understanding of the pathogenetic mechanisms underlying autism in TSC could help in devising targeted and potentially more effective treatment strategies. Antagonism of the mTOR pathway with rapamycin and everolimus may provide new therapeutic options for these TSC patients.

Vaginal microbial flora and outcome of pregnancy.

PubMed

Donati, Laura; Di Vico, Augusto; Nucci, Marta; Quagliozzi, Lorena; Spagnuolo, Terryann; Labianca, Antonietta; Bracaglia, Marina; Ianniello, Francesca; Caruso, Alessandro; Paradisi, Giancarlo

2010-04-01

The vaginal microflora of a healthy asymptomatic woman consists of a wide variety of anaerobic and aerobic bacterial genera and species dominated by the facultative, microaerophilic, anaerobic genus Lactobacillus. The activity of Lactobacillus is essential to protect women from genital infections and to maintain the natural healthy balance of the vaginal flora. Increasing evidence associates abnormalities in vaginal flora during pregnancy with preterm labor and delivery with potential neonatal sequelae due to prematurity and poor perinatal outcome. Although this phenomenon is relatively common, even in populations of women at low risk for adverse events, the pathogenetic mechanism that leads to complications in pregnancy is still poorly understood. This review summarizes the current knowledge and uncertainties in defining alterations of vaginal flora in non-pregnant adult women and during pregnancy, and, in particular, investigates the issue of bacterial vaginosis and aerobic vaginitis. This could help specialists to identify women amenable to treatment during pregnancy leading to the possibility to reduce the preterm birth rate, preterm premature rupture of membranes, chorioamnionitis, neonatal, puerperal and maternal-fetal infectious diseases. Vaginal ecosystem study with the detection of pathogens is a key instrument in the prevention of preterm delivery, pPROM, chorioamnionitis, neonatal, puerperal and maternal-fetal infections.

Targeting the epigenome: Screening bioactive compounds that regulate histone deacetylase activity

PubMed Central

Godoy, Luis D.; Lucas, Julianna E.; Bender, Abigail J.; Romanick, Samantha S.; Ferguson, Bradley S.

2017-01-01

Scope Nutrigenomics is a rapidly expanding field that elucidates the link between diet-genome interactions. Recent evidence demonstrates that regulation of the epigenome, and in particular inhibition of HDACs, impact pathogenetic mechanisms involved in chronic disease. Few studies, to date, have screened libraries of bioactive compounds that act as epigenetic modifiers. This study screened a library of 131 natural compounds to determine bioactive compounds that inhibit Zn-dependent HDAC activity. Methods and results Using class-specific HDAC substrates, we screened 131 natural compounds for HDAC activity in bovine cardiac tissue. From this screen, we identified 18 bioactive compound HDAC inhibitors. Using our class-specific HDAC substrates, we next screened these 18 bioactive compounds against recombinant HDAC proteins. Consistent with inhibition of HDAC activity, these compounds were capable of inhibiting activity of individual HDAC isoforms. Lastly, we report that treatment of H9c2 cardiac myoblasts with bioactive HDAC inhibitors was sufficient to increase lysine acetylation as assessed via immunoblot. Conclusion This study provided the first step in identifying multiple bioactive compound HDAC inhibitors. Taken together, this report sets the stage for future exploration of these bioactive compounds as epigenetic regulators to potentially ameliorate chronic disease. PMID:27981795

Translating Discovery in Zebrafish Pancreatic Development to Human Pancreatic Cancer: Biomarkers, Targets, Pathogenesis, and Therapeutics

PubMed Central

Kazi, Abid A.; Yee, Rosemary K.

2013-01-01

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer. PMID:23682805

Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics.

PubMed

Yee, Nelson S; Kazi, Abid A; Yee, Rosemary K

2013-06-01

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria

PubMed Central

Jauregui, Alexandra; Mintz, Daniel H; Mundel, Peter; Fornoni, Alessia

2010-01-01

Purpose of review In diabetic nephropathy (DN), insulin resistance and hyperinsulinemia correlate with the development of albuminuria. The possibility that altered insulin signaling in glomerular cells and particularly podocytes contributes to the development of DN will be discussed. Recent findings While normal podocytes uptake glucose in response to insulin, diabetic podocytes become insulin resistant in experimental DN prior to the development of significant albuminuria. Both clinical and experimental data suggest that insulin sensitizers may be renoprotective independently of their systemic effects on the metabolic control of diabetes. Summary We will review the clinical and experimental evidence that altered insulin signaling correlates with the development of DN in both type 1 and type 2 diabetes, and that insulin sensitizers may be superior to other hypoglycemic agents in the prevention of DN. We will then review potential mechanisms by which altered podocyte insulin signaling may contribute to the development of DN. Understanding the role of podocyte in glucose metabolism is important because it may lead to the discovery of novel pathogenetic mechanisms of DN, it may affect current strategies for prevention and treatment of DN, and it may allow for the identification of novel therapeutic targets. PMID:19724224

[Use of alpha-lipoic acid and omega-3 in postpartum pain treatment].

PubMed

Costantino, D; Guaraldi, C; Costantino, M; Bounous, V E

2015-10-01

Postpartum pain is a frequent condition that negatively affects women's quality of life, interferring with everyday life. Analgesic drugs and surgery are often contraindicated in pregnancy and during breast feeding. This review of the literature aims to evaluate the rational of the association of lipoic acid and omega-3 employ in the management of postpartum pain. Lipoic acid is a cofactor essential in mitochondrial metabolism with antioxidant and anti-inflammatory activity. Lipoic acid has been shown to be effective in neuropatic pain treatment in patients with sciatica, carpal tunnel syndrome and diabetic neuropathy. Omega-3 are known for their anti-inflammatory and neurotrophic activity. The peripheral and central activity of both substances allows to act on neuroinflammation mechanisms thus reducing cronicization of pain and also determining a potential improvement of women's emotional status. The preliminary data here presented confirm the positive effect of this association on the treatment of postpartum perineal pain. The supplementation of lipoic acid in association with omega-3 seems effective and safe for the treatment of chronic postpartum pain, allowing a pathogenetic approach to neuroinflammation, thus reducing the consumption of analgesic drugs, often contraindicated during breast-feeding.

Respiratory Syncytial Virus Infection: Mechanisms of Redox Control and Novel Therapeutic Opportunities

PubMed Central

Garofalo, Roberto P.; Kolli, Deepthi

2013-01-01

Abstract Respiratory syncytial virus (RSV) is one of the most important causes of upper and lower respiratory tract infections in infants and young children, for which no effective treatment is currently available. Although the mechanisms of RSV-induced airway disease remain incompletely defined, the lung inflammatory response is thought to play a central pathogenetic role. In the past few years, we and others have provided increasing evidence of a role of reactive oxygen species (ROS) as important regulators of RSV-induced cellular signaling leading to the expression of key proinflammatory mediators, such as cytokines and chemokines. In addition, RSV-induced oxidative stress, which results from an imbalance between ROS production and airway antioxidant defenses, due to a widespread inhibition of antioxidant enzyme expression, is likely to play a fundamental role in the pathogenesis of RSV-associated lung inflammatory disease, as demonstrated by a significant increase in markers of oxidative injury, which correlate with the severity of clinical illness, in children with RSV infection. Modulation of ROS production and oxidative stress therefore represents a potential novel pharmacological approach to ameliorate RSV-induced lung inflammation and its long-term consequences. Antioxid. Redox Signal. 18, 186–217. PMID:22799599

A Review of Neuroimaging Findings in Repetitive Brain Trauma

PubMed Central

Koerte, Inga K.; Lin, Alexander P.; Willems, Anna; Muehlmann, Marc; Hufschmidt, Jakob; Coleman, Michael J.; Green, Isobel; Liao, Huijun; Tate, David F.; Wilde, Elisabeth A.; Pasternak, Ofer; Bouix, Sylvain; Rathi, Yogesh; Bigler, Erin D.; Stern, Robert A.; Shenton, Martha E.

2017-01-01

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at post-mortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically-confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma versus those who go on to develop CTE. PMID:25904047

Targeting the epigenome: Screening bioactive compounds that regulate histone deacetylase activity.

PubMed

Godoy, Luis D; Lucas, Julianna E; Bender, Abigail J; Romanick, Samantha S; Ferguson, Bradley S

2017-04-01

Nutrigenomics is a rapidly expanding field that elucidates the link between diet-genome interactions. Recent evidence demonstrates that regulation of the epigenome, and in particular inhibition of histone deacetylases (HDACs), impact pathogenetic mechanisms involved in chronic disease. Few studies, to date, have screened libraries of bioactive compounds that act as epigenetic modifiers. This study screened a library of 131 natural compounds to determine bioactive compounds that inhibit Zn-dependent HDAC activity. Using class-specific HDAC substrates, we screened 131 natural compounds for HDAC activity in bovine cardiac tissue. From this screen, we identified 18 bioactive compound HDAC inhibitors. Using our class-specific HDAC substrates, we next screened these 18 bioactive compounds against recombinant HDAC proteins. Consistent with inhibition of HDAC activity, these compounds were capable of inhibiting activity of individual HDAC isoforms. Lastly, we report that treatment of H9c2 cardiac myoblasts with bioactive HDAC inhibitors was sufficient to increase lysine acetylation as assessed via immunoblot. This study provided the first step in identifying multiple bioactive compound HDAC inhibitors. Taken together, this report sets the stage for future exploration of these bioactive compounds as epigenetic regulators to potentially ameliorate chronic disease. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

MinION Nanopore Sequencing Enables Correlation between Resistome Phenotype and Genotype of Coliform Bacteria in Municipal Sewage.

PubMed

Xia, Yu; Li, An-Dong; Deng, Yu; Jiang, Xiao-Tao; Li, Li-Guan; Zhang, Tong

2017-01-01

Wastewater treatment plants (WWTPs) functioned as the intersection between the human society and nature environment, are receiving increasingly more attention on risk assessment of the acquisition of environmental antibiotic resistance genes (ARGs) by pathogenetic populations during treatment. However, because of the general lack of robust resistome profiling methods, genotype, and resistance phenotype is still poorly correlated in human pathogens of sewage samples. Here we applied MinION sequencing to quantify the resistance genes of multiple antibiotic resistant (MAR) coliform bacteria, a common indicator for human enteric pathogens in sewage samples. Our pipeline could deliver the results within 30 h from sample collection and the resistome quantification was consistent to that based on the Illumina platform. Additionally, the long nanopore reads not only enabled a simultaneous identification of the carrier populations of ARGs detected, but also facilitated the genome reconstruction of a representative MAR strain, from which we identified an instance of chromosomal integration of environmental resistance gene obtained by plasmid exchange with a porcine pathogen. This study demonstrated the utilization of MinION sequencing in quick monitoring and simultaneous phylogenetic tracking of environmental ARGs to address potential health risk associated with them.

MinION Nanopore Sequencing Enables Correlation between Resistome Phenotype and Genotype of Coliform Bacteria in Municipal Sewage

PubMed Central

Xia, Yu; Li, An-Dong; Deng, Yu; Jiang, Xiao-Tao; Li, Li-Guan; Zhang, Tong

2017-01-01

Wastewater treatment plants (WWTPs) functioned as the intersection between the human society and nature environment, are receiving increasingly more attention on risk assessment of the acquisition of environmental antibiotic resistance genes (ARGs) by pathogenetic populations during treatment. However, because of the general lack of robust resistome profiling methods, genotype, and resistance phenotype is still poorly correlated in human pathogens of sewage samples. Here we applied MinION sequencing to quantify the resistance genes of multiple antibiotic resistant (MAR) coliform bacteria, a common indicator for human enteric pathogens in sewage samples. Our pipeline could deliver the results within 30 h from sample collection and the resistome quantification was consistent to that based on the Illumina platform. Additionally, the long nanopore reads not only enabled a simultaneous identification of the carrier populations of ARGs detected, but also facilitated the genome reconstruction of a representative MAR strain, from which we identified an instance of chromosomal integration of environmental resistance gene obtained by plasmid exchange with a porcine pathogen. This study demonstrated the utilization of MinION sequencing in quick monitoring and simultaneous phylogenetic tracking of environmental ARGs to address potential health risk associated with them. PMID:29163399

Etiological involvement of Helicobacter pylori in "reflux" gastritis after gastrectomy.

PubMed

Nagahata, Y; Kawakita, N; Azumi, Y; Numata, N; Yano, M; Saitoh, Y

1996-10-01

"Reflux" gastritis after gastrectomy is associated with various symptoms that are often detrimental to the patients' quality of life. However, prevention of the reflux does not always bring relief from the symptoms of gastritis. Helicobacter pylori (H. pylori) is now considered one of the most important pathogenetic factors in gastritis. The association between H. pylori infection and reflux gastritis after gastrectomy was investigated in the present study. In total, 115 patients who had undergone gastrectomy were entered in this study. Five biopsy specimens from the gastric remnant were taken during upper GI endoscopy. One specimen was examined pathohistologically, and the remaining four were examined for H. pylori infection. The histological degree of gastritis was determined according to the score system of Rauws et al. Forty-six patients (40%) demonstrated H. pylori infection in their stomachs. The prevalence of the infection was significantly higher in patients with conventional gastrectomy than in those with subtotal gastrectomy. The prevalence of H. pylori infection was significantly lower in patients who had undergone gastrectomy more than 4 yr ago. The histological gastritis score in patients with H. pylori infection was significantly higher than in those without H. pylori infection. Furthermore, the eradication of H. pylori in patients with both serious gastritis symptoms and no bile reflux improved the symptoms and significantly decreased the histological gastritis score. The results suggest that H. pylori is a factor in the pathogenesis of reflux gastritis after gastrectomy.

The food contaminant and nephrotoxin ochratoxin A enhances Wnt1 inducible signaling protein 1 and tumor necrosis factor-α expression in human primary proximal tubule cells.

PubMed

Hennemeier, Isabell; Humpf, Hans-Ulrich; Gekle, Michael; Schwerdt, Gerald

2012-09-01

The underlying molecular mechanisms of nanomolar ochratoxin A (OTA) concentrations, especially those on pathophysiological relevant gene expression in target tissue and underlying signaling mechanisms are unknown. qPCR arrays showed that 14 days exposure of human primary proximal tubule cells to 10 nM OTA influences the expression of genes that are related to inflammation, malignant transformation, and epithelial-to-mesenchymal transition. Wnt1 inducible signaling protein 1 (WISP1), an oncogenic, and profibrotic growth factor, turned out to be the gene with the strongest upregulation. Its expression, and that of TNF-α, an important inflammatory mediator, was further investigated in human renal cells and in primary human lung fibroblasts. OTA-induced upregulation of WISP1 and TNF-α occurs only in renal cells. Inhibition of ERK1/2 activation reverses the effect of OTA on WISP1 and TNF-α expression. Wnt or other signaling pathways were not involved. Upregulation of WISP1 and TNF-α occured independently of each other. Long-term exposure of human kidney cells with OTA concentrations expectable in renal tissue due to average dietary intake leads in an ERK1/2-dependent manner to pathogenetic alterations of gene expression, notably WISP1 and TNF-α. Renal long-term risk by OTA is actually not excludable and argues for low but rational safety levels. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enterohemorrhagic Escherichia coli O157 outer membrane vesicles induce interleukin 8 production in human intestinal epithelial cells by signaling via Toll-like receptors TLR4 and TLR5 and activation of the nuclear factor NF-κB.

PubMed

Bielaszewska, Martina; Marejková, Monika; Bauwens, Andreas; Kunsmann-Prokscha, Lisa; Mellmann, Alexander; Karch, Helge

2018-06-19

Proinflammatory cytokines play important roles in the pathogenesis of diseases caused by enterohemorrhagic Escherichia coli (EHEC) O157, but the spectrum of bacterial components involved in the proinflammatory responses is not fully understood. Here, we investigated the abilities of outer membrane vesicles (OMVs), nanoparticles released by EHEC O157 during growth, to induce production of proinflammatory cytokines in human intestinal epithelial cells. OMVs from both EHEC O157:H7 and sorbitol-fermenting (SF) EHEC O157:H - induced production of interleukin-8 (IL-8) in Caco-2, HCT-8, and HT-29 intestinal epithelial cell lines. H7 flagellin was the key IL-8-inducing component of EHEC O157:H7 OMVs, whereas cytolethal distending toxin V and O157 lipopolysaccharide (LPS) largely contributed to IL-8 production elicited by flagellin-lacking OMVs from SF EHEC O157:H - . The H7 flagellin-mediated signaling via Toll-like receptor (TLR) 5, and O157 LPS-mediated signaling via TLR4/MD-2 complex, which were followed by activation of the nuclear factor NF-κB were major pathways underlying IL-8 production induced by EHEC O157 OMVs. The proinflammatory and immunomodulatory capacities of EHEC O157 OMVs have pathogenetic implications and support the OMVs as suitable vaccine candidates. Copyright © 2018 Elsevier GmbH. All rights reserved.

Efficacy of Intravitreal Anti-vascular Endothelial Growth Factor or Steroid Injection in Diabetic Macular Edema According to Fluid Turbidity in Optical Coherence Tomography

PubMed Central

Lee, Kyungmin; Chung, Heeyoung; Park, Youngsuk

2014-01-01

Purpose To determine if short term effects of intravitreal anti-vascular endothelial growth factor or steroid injection are correlated with fluid turbidity, as detected by spectral domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME) patients. Methods A total of 583 medical records were reviewed and 104 cases were enrolled. Sixty eyes received a single intravitreal bevacizumab injection (IVB) on the first attack of DME and 44 eyes received triamcinolone acetonide treatment (IVTA). Intraretinal fluid turbidity in DME patients was estimated with initialintravitreal SD-OCT and analyzed with color histograms from a Photoshop program. Central macular thickness and visual acuity using a logarithm from the minimum angle of resolution chart, were assessed at the initial period and 2 months after injections. Results Visual acuity and central macular thickness improved after injections in both groups. In the IVB group, visual acuity and central macular thickness changed less as the intraretinal fluid became more turbid. In the IVTA group, visual acuity underwent less change while central macular thickness had a greater reduction (r = -0.675, p = 0.001) as the intraretinal fluid was more turbid. Conclusions IVB and IVTA injections were effective in reducing central macular thickness and improving visual acuity in DME patients. Further, fluid turbidity, which was detected by SD-OCT may be one of the indexes that highlight the influence of the steroid-dependent pathogenetic mechanism. PMID:25120338

Efficacy of intravitreal anti-vascular endothelial growth factor or steroid injection in diabetic macular edema according to fluid turbidity in optical coherence tomography.

PubMed

Lee, Kyungmin; Chung, Heeyoung; Park, Youngsuk; Sohn, Joonhong

2014-08-01

To determine if short term effects of intravitreal anti-vascular endothelial growth factor or steroid injection are correlated with fluid turbidity, as detected by spectral domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME) patients. A total of 583 medical records were reviewed and 104 cases were enrolled. Sixty eyes received a single intravitreal bevacizumab injection (IVB) on the first attack of DME and 44 eyes received triamcinolone acetonide treatment (IVTA). Intraretinal fluid turbidity in DME patients was estimated with initial intravitreal SD-OCT and analyzed with color histograms from a Photoshop program. Central macular thickness and visual acuity using a logarithm from the minimum angle of resolution chart, were assessed at the initial period and 2 months after injections. Visual acuity and central macular thickness improved after injections in both groups. In the IVB group, visual acuity and central macular thickness changed less as the intraretinal fluid became more turbid. In the IVTA group, visual acuity underwent less change while central macular thickness had a greater reduction (r = -0.675, p = 0.001) as the intraretinal fluid was more turbid. IVB and IVTA injections were effective in reducing central macular thickness and improving visual acuity in DME patients. Further, fluid turbidity, which was detected by SD-OCT may be one of the indexes that highlight the influence of the steroid-dependent pathogenetic mechanism.

Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia.

PubMed

Yang, Chunzhang; Zhuang, Zhengping; Fliedner, Stephanie M J; Shankavaram, Uma; Sun, Michael G; Bullova, Petra; Zhu, Roland; Elkahloun, Abdel G; Kourlas, Peter J; Merino, Maria; Kebebew, Electron; Pacak, Karel

2015-01-01

We have investigated genetic/pathogenetic factors associated with a new clinical entity in patients presenting with pheochromocytoma/paraganglioma (PHEO/PGL) and polycythemia. Two patients without hypoxia-inducible factor 2α (HIF2A) mutations, who presented with similar clinical manifestations, were analyzed for other gene mutations, including prolyl hydroxylase (PHD) mutations. We have found for the first time a germ-line mutation in PHD1 in one patient and a novel germ-line PHD2 mutation in a second patient. Both mutants exhibited reduced protein stability with substantial quantitative protein loss and thus compromised catalytic activities. Due to the unique association of patients' polycythemia with borderline or mildly elevated erythropoietin (EPO) levels, we also performed an in vitro sensitivity assay of erythroid progenitors to EPO and for EPO receptor (EPOR) expression. The results show inappropriate hypersensitivity of erythroid progenitors to EPO in these patients, indicating increased EPOR expression/activity. In addition, the present study indicates that HIF dysregulation due to PHD mutations plays an important role in the pathogenesis of these tumors and associated polycythemia. The PHD1 mutation appears to be a new member contributing to the genetic landscape of this novel clinical entity. Our results support the existence of a specific PHD1- and PHD2-associated PHEO/PGL-polycythemia disorder. • A novel germ-l i n e PHD1 mutation causing heochromocytoma/paraganglioma and polycythemia. • Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO.

The Relation Between Injury of the Spinothalamocortical Tract and Central Pain in Chronic Patients With Mild Traumatic Brain Injury.

PubMed

Kim, Jin Hyun; Ahn, Sang Ho; Cho, Yoon Woo; Kim, Seong Ho; Jang, Sung Ho

2015-01-01

Little is known about the pathogenetic etiology of central pain in patients with traumatic brain injury (TBI). We investigated the relation between injury of the spinothalamocortical tract (STT) and chronic central pain in patients with mild TBI. Retrospective survey. We recruited 40 consecutive chronic patients with mild TBI and 21 normal control subjects: 8 patients were excluded by the inclusion criteria and the remaining 32 patients were finally recruited. The patients were classified according to 2 groups based on the presence of central pain: the pain group (22 patients) and the nonpain group (10 patients). Diffusion tensor tractography for the STT was performed using the Functional Magnetic Resonance Imaging of the Brain Software Library. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each STT were measured. Lower FA value and tract volume were observed in the pain group than in the nonpain group and the control group (P < .05). By contrast, higher MD value was observed in the pain group than in the nonpain group and the control group (P < .05). However, no significant differences in all diffusion tensor imaging parameters were observed between the nonpain group and the control group (P > .05). Decreased FA and tract volume and increased MD of the STTs in the pain group appeared to indicate injury of the STT. As a result, we found that injury of the STT is related to the occurrence of central pain in patients with mild TBI. We believe that injury of the STT is a pathogenetic etiology of central pain following mild TBI.

Natural history of small gallbladder polyps is benign: evidence from a clinical and pathogenetic study.

PubMed

Colecchia, Antonio; Larocca, Anna; Scaioli, Eleonora; Bacchi-Reggiani, Maria Letizia; Di Biase, Anna Rita; Azzaroli, Francesco; Gualandi, Roberta; Simoni, Patrizia; Vestito, Amanda; Festi, Davide

2009-03-01

Little is known about the natural history and pathogenesis of small gallbladder polyps (<10 mm, usually of the cholesterol type), particularly in Western populations. It is unclear if these polyps and gallstones represent different aspects of the same disease. The aim of this study was to characterize the natural history and pathogenesis of small gallbladder polyps. Fifty-six Caucasian patients with small gallbladder polyps, 30 matched gallstone patients, and 30 controls were enrolled in this 5-year prospective study. Patients underwent a symptomatic questionnaire, abdominal ultrasonography, and ultrasonographic evaluation of gallbladder motility at baseline and yearly intervals for 5 years. Cholesterol saturation index, cholesterol crystals in bile, and apolipoprotein E genotype were also determined. Most patients with polyps (mean size: 5.3 mm) were men (61%), asymptomatic, and had multiple polyps (57%). Polyps did not change in 91% of patients during follow-up. No subject experienced biliary pain or underwent cholecystectomy; four developed gallstones. Cholesterol saturation index was higher in patients with polyps or gallstones than in controls (P<0.05). Cholesterol crystals were more frequent in patients with polyps than in controls (P<0.0001) but less common than in gallstone patients (P<0.0001). Polyps and gallstones were associated with nonapolipoprotein E4 phenotypes. The natural history of small gallbladder polyps was benign, as no patient developed specific symptoms and/or morphological changes in polyps. Consequently, a "wait and see" policy is advisable in these patients. Polyps have some pathogenetic mechanisms in common with gallstones, but few patients developed gallstones.

Histopathology of tumour associated sarcoid-like stromal reaction in breast cancer. An analysis of 5 cases with immunohistochemical investigations.

PubMed

Bässler, R; Birke, F

1988-01-01

In 5 cases of invasive ductal and lobular carcinoma of the breast multiple epithelioid and giant cell containing granulomas were detected, localized mainly in circumferential regions, but also in the center of the carcinomas. These granulomas were interpreted as sarcoid-like stromal reactions, occurring as sarcoid-like lesions in uni- and bilateral primaries, in a recurrent tumour, and also in axillary lymph nodes. Histopathologically, these granulomas were not quite uniform, some of them corresponding to typical sarcoidosis, others showing marked proliferations of epithelioid or giant cells or containing fibrinoid exudate or necroses. The granulomas were surrounded by dense infiltrates of mononuclear cells. Tuberculosis and mycosis was excluded. There were no hints of generalized sarcoidosis. Pathogenetically, these are reactions in the tumour stroma of varying intensity, and are not caused by necroses of the tumour tissue nor by microbial infections. Such tumour-associated sarcoid-like stroma reactions are interpreted as a T-cell mediated immune response to an antigen expression of the carcinoma acting as the local trigger; in 2 cases they were connected with sarcoid-like lesions of the axillary lymph nodes. Their occurrence in bilateral carcinoma of the breast points to an immunological disposition for this special kind of host-versus-tumour response. The intensity of these changes in a recurrent tumour reflects an immunological hypersensitivity reaction. The pathogenetic and differential diagnostic aspects of epithelioid granulomas of the female breast in chronic granulomatous mastitis, panniculitis, foreign body reaction, rare infections, and in therapeutically induced sarcoidosis are described and discussed.

[Studies on the mycotic and bacterial risk of contamination and the use of nipagin in the artificial insemination of cryosperm].

PubMed

Glander, H G; Rytter, M; Schönborn, C

1984-01-01

Primary bacterial and mycological contamination was studied in random human ejaculates. After various phases of cryopreservation secondary microbiological contamination was investigated. Furthermore, semen samples of several donors were inoculated with suspension of different concentrations of yeasts and with the test bacteria Escherichia coli K12 and Staphylococcus aureus SG 511. Microbiological results were then compared before an after cryopreservation. The cryopreserving process was carried out with and without antibiotics to test the antibacterial effectiveness of antibiotics under these conditions. Moreover, we investigated the usability of a chemical preservative (Nipagin) at cryopreservation. The following results were obtained: 9.8 per cent of samples showed primary mycological contamination (1.9 per cent with Candida albicans). Cryopreservation reduced the concentration of fungi by more than 90 per cent on average. The bacteriological investigations have shown, that with one exception the semen was without pathogenetic bacteria. This situation was altered scarcely during the cryopreserving process (also by use of cryoprotective medium without antibiotics). Out of 25 ejaculates 11 had primary non-pathogenetic bacteria. Test bacteria inoculated into semen were not influenced by the addition of antibiotics to the cryoprotective medium (CPM). Nipagin prevented respectively reduced a bacterial or a mycological contamination of the CPM during a storage of 14 days dependent of nipagin concentration but reduced the motility of human spermatozoa after cryopreservation. The results suggest the conclusion to prefer a portionate storage without nipagin at a temperature of nearly + 1 degree C, thereby the microbiological contamination may be neglected.

Correction of biochemical and functional disorders in brain ischaemia with laser therapy

NASA Astrophysics Data System (ADS)

Musienko, Julia I.; Nechipurenko, Natalia I.; Vasilevskaya, Ludmila A.

2005-08-01

Application of intravenous laser irradiation of blood (ILIB) is considered to be the most effective method of laser therapy and its application is expedient pathogenetically in the ischemic disturbances. The aim of this study is to investigate ILIB influence with red helium-neon laser (HNL) with 630 nm wavelength and different powers on blood oxygen transport (BOT), cerebral and dermal microhaemodynamics (MGD), hydro-ion balance in normal rabbits and after modeling of local ischemia of brain (LIB). Experimental cerebral ischemia is characterized by development of BOT disturbance, ionic disbalance and edema in the ischemic brain region. Microcirculation disturbances with worsening of the cerebral and dermal MHD were revealed. ILIB with HNL radiation of 2.5 and 4.5 mW powers provokes dehydratation of brain structure alone with the K+, Na+ concentration decreasing and hemoglobin-oxygen affinity increasing in intact group of animals. There was not revealed marked changes of cerebral MHD condition here. Using of ILIB in rabbits after LIB contributes for improving function of BOT, normalizing of water content in all cerebral structures compared to operated animals. Preventive ILIB provoked improvement of speckl-optical parameters and marked protective effect on microhaemodynamics processes in superficial brain structures. HNL radiation with 1.0 mW power results in worsening of oxygen transport, cerebral and skin MHD, hydro-ion homeostasis in animals with LIB modeling. Thus, laser haemotherapy contributes for improving of hydro-ion status, blood oxygen transport and cerebral microcirculation in brain ischemia, what allows considering that helium-neon radiation with the pointed regimen is substantiated pathogenetically in brain ischaemia.

Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates

PubMed Central

Costanza, Alessandra; Weber, Kerstin; Gandy, Samuel; Bouras, Constantin; Hof, Patrick R.; Canuto, Alessandra

2011-01-01

Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal, and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging (MRI) usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum (CSP), signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces, and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology, and pathogenesis of CTE and Alzheimer’s disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP, and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia. PMID:21696410

E. coli invasion of brain microvascular endothelial cells as a pathogenetic basis of meningitis.

PubMed

Kim, K S

2000-01-01

A major limitation to advances in prevention and therapy of bacterial meningitis is our incomplete understanding of the pathogenesis of this disease. Successful isolation and cultivation of BMEC, which constitute the blood brain barrier, and the development of experimental hematogenous meningitis animal model, which mimics closely the pathogenesis of human meningitis, enabled us to dissect the pathogenetic mechanisms of bacterial meningitis. We have shown for the first time using E. coli as a paradigm the mechanisms of bacterial crossing of the blood-brain barrier into the central nervous system. We have shown that invasion of BMEC is a requirement for E. coli K1 crossing of the blood-brain barrier in vivo (Prasadarao et al., 1996b; Huang et al., 1995). We have identified several novel E. coli proteins (i.e., Ibe10, Ibe7, and Ibe23) contributing to invasion of BMEC. We have also established a novel phenotype, i.e., invasion of BMEC, of a well known major E. coli protein, OmpA. In addition, we have shown that some of these E. coli proteins (i.e., OmpA, Ibe10) interact with novel endothelial receptors present on BMEC, not on systemic vascular endothelial cells. Further understanding and characterization of these E. coli-BMEC interactions should allow us to develop novel strategies to prevent this serious infection. In addition, the in vitro and in vivo models of the blood-brain barrier and the information derived from our study should be beneficial to investigating the pathogenesis of meningitis due to other organisms such as group B streptococci, Listeria monocytogenes, Streptococcus pneumoniae and Citrobacter.

Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats

PubMed Central

Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

2016-01-01

Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti-inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)-induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN-induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor-α, interferon-γ and granulocyte/macrophage colony-stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN-induced liver injury. Therefore, Centella asiatica may be useful in preventing liver damage. PMID:27748812

Paraduodenal Pancreatitis: Imaging and Pathologic Correlation of 47 Cases Elucidates Distinct Subtypes and the Factors Involved in its Etiopathogenesis.

PubMed

Muraki, Takashi; Kim, Grace E; Reid, Michelle D; Mittal, Pardeep; Bedolla, Gabriela; Memis, Bahar; Pehlivanoglu, Burcin; Freedman, Alexa; Erbarut Seven, Ipek; Choi, Hyejeong; Kooby, David; Maithel, Shishir K; Sarmiento, Juan M; Krasinskas, Alyssa; Adsay, Volkan

2017-10-01

Clinicopathologic characteristics of paraduodenal (groove) pancreatitis (PDP) remain to be fully unraveled. In this study, 47 PDPs with preoperative enhanced images available were subjected to detailed comparative analysis in conjunction with pathologic findings. PDP were predominantly in males (3:1) with a mean age of 50 years, and 60% had a preoperative diagnosis of cancer. Mean lesional size was 3.1 cm. Three distinct subtypes were identified by imaging. Solid-tumoral (type-1) with groove-predominant (type-1A, 36%) forming a distinct solid band between the duodenum and pancreas often with histologic microabscesses (69% vs. 33% in others), and pancreas-involving (type-1B, 19%) forming a pseudotumoral mass spanning into the head-groove area, always diagnosed preoperatively as "cancer," but often lacked parenchymal atrophy of the body (44% vs. 92%). Cyst-forming (type-2) had groove-predominant (type-2A, 15%), often accompanied by Brunner gland hyperplasia, and pancreas-predominant (type-2B, 15%) were in younger (mean: 44 y) females (57% vs. 18%) and had less alcohol/tobacco abuse (50/33% vs. 81/69%). Ill-defined (type-3; 15%) often had main pancreatic duct dilatation (mean: 5.6 vs. 2.8 mm). The capricious presentations of PDP could be attributed to variable effects of different mechanistic and precipitative etiopathogenetic factors such as disturbed accessory duct outflow (dilated Santorini duct, 87%), aggravated by alcohol (77%) with superimposed stasis in the main ampulla (previous cholecystectomy, 47%; choledocholithiasis, 9%), strictured Wirsung duct (68%), and some likely exacerbated by ischemia (hypertension [59%], tobacco abuse [64%], arteriosclerosis in the tissue [23%]). In conclusion, our study identified 3 distinct types of PDP and each may reflect different pathogenetic contributing factors.

Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece.

PubMed

Dessinioti, Clio; Tzannis, Kimon; Sypsa, Vana; Nikolaou, Vasiliki; Kypreou, Katerina; Antoniou, Christina; Katsambas, Andreas; Stratigos, Alexander J

2011-08-01

Basal cell carcinoma (BCC) is the most common form of skin cancer with increasing incidence rates worldwide. To assess the association of BCC with epidemiologic risk factors in a Southern European population from Greece, we conducted a hospital-based case-control study of 199 patients with BCC and 200 controls. In the multivariate analysis, fair skin colour was associated with increased risk of BCC (OR: 4.9, 95% CI: 2.4-10.0). However, darker skin phototypes III/IV (patient's reported sun sensitivity/tanning ability) showed a higher BCC risk (OR: 3.9, 95% CI: 1.8-8.5). Persons with occupational UV exposure of 5 years or more had a 2.7-fold increased risk (95% CI:1.4-5.3). There was an increased risk of BCC related to the number of sunburns after the age of 20 years (OR: 3.2, 95% CI: 1.4-7.3) and solar lentigines (OR: 6.8, 95% CI: 3.6-12.8). Subgroup analysis showed that different risk factors are associated with early onset BCC including the presence of dysplastic nevi (OR: 6.4, 95% CI: 1.5-27.2), the number of weeks per year spent at the beach during childhood (OR: 8.9, 95% CI: 3.3-24.1) and the history of sunburns during childhood (OR:5.0, 95% CI: 1.3-19.1). Fair skin colour was significantly associated with BCC risk. The relation of sunburns during adulthood with BCC underlies the importance of sunburn prevention throughout life time. Early onset BCCs seem to have a different pathogenetic background and were associated with dysplastic nevi as well as intermittent sun exposure and sunburns during the early years of life. © 2011 John Wiley & Sons A/S.

Descriptive Epidemiology of Idiopathic Clubfoot

PubMed Central

Werler, Martha M.; Yazdy, Mahsa M.; Mitchell, Allen A.; Meyer, Robert E.; Druschel, Charlotte M.; Anderka, Marlene; Kasser, James R.; Mahan, Susan T.

2013-01-01

Clubfoot is a common structural malformation, occurring in approximately 1/1000 live births. Previous studies of sociodemographic and pregnancy-related risk factors have been inconsistent, with the exception of the strong male preponderance and association with primiparity. Hypotheses for clubfoot pathogenesis include fetal constraint, Mendelian-inheritance, and vascular disruption, but its etiology remains elusive. We conducted a population-based case-control study of clubfoot in North Carolina, Massachusetts, and New York from 2007 to 2011. Mothers of 677 clubfoot cases and 2,037 non-malformed controls were interviewed within one year of delivery about socio-demographic and reproductive factors. Cases and controls were compared for child’s sex, maternal age, education, cohabitation status, race/ethnicity, state, gravidity, parity, body mass index (BMI), and these pregnancy-related conditions: oligohydramnios, breech delivery, bicornuate uterus, plural birth, early amniocentesis (<16 weeks), chorionic villous sampling (CVS), and plural gestation with fetal loss. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for state. Cases were more likely to be male (OR: 2.7; 2.2–3.3) and born to primiparous mothers (1.4; 1.2–1.7) and mothers with BMI ≥30 kg/m2 (1.4; 1.1–1.8). These associations were greatest in isolated and bilateral cases. ORs for the pregnancy-related conditions ranged from 1.3 (breech delivery) to 5.6 (early amniocentesis). Positive associations with high BMI were confined to cases with a marker of fetal constraint (oligohydramnios, breech delivery, bicornuate uterus, plural birth), inheritance (family history in 1st degree relative), or vascular disruption (early amniocentesis, CVS, plural gestation with fetal loss). Pathogenetic factors associated with obesity may be in the causal pathway for clubfoot. PMID:23686911

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis

PubMed Central

Bridgewood, Charlie; Fearnley, Gareth W.; Berekmeri, Anna; Laws, Philip; Macleod, Tom; Ponnambalam, Sreenivasan; Stacey, Martin; Graham, Anne; Wittmann, Miriam

2018-01-01

The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence. PMID:29535706

Cochlear implantation for severe sensorineural hearing loss caused by lightning.

PubMed

Myung, Nam-Suk; Lee, Il-Woo; Goh, Eui-Kyung; Kong, Soo-Keun

2012-01-01

Lightning strike can produce an array of clinical symptoms and injuries. It may damage multiple organs and cause auditory injuries ranging from transient hearing loss and vertigo to complete disruption of the auditory system. Tympanic-membrane rupture is relatively common in patients with lightning injury. The exact pathogenetic mechanisms of auditory lesions in lightning survivors have not been fully elucidated. We report the case of a 45-year-old woman with bilateral profound sensorineural hearing loss caused by a lightning strike, who was successfully rehabilitated after a cochlear implantation. Copyright © 2012 Elsevier Inc. All rights reserved.

Seronegative rheumatoid arthritis: pathogenetic and therapeutic aspects.

PubMed

Pratt, Arthur G; Isaacs, John D

2014-08-01

Rheumatoid arthritis (RA) has long been recognised as a highly heterogeneous disease of immune dysregulation. Despite an ever-growing appreciation of the role of circulating autoantibodies in the development of 'seropositive' disease, the pathogenesis of seronegative RA remains poorly understood. Accumulating evidence suggests that RA 'serotypes', in fact, reflect distinct disease entities that, despite their clinical overlap, diverge in respect of genetic architecture, cellular pathology and even therapeutic responsiveness. Focussing on seronegative RA, this review considers these concepts and their implications for the management of patients with this challenging, though sometimes overlooked, condition. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Cutaneous Manifestations of Crohn Disease.

PubMed

Hagen, Joshua W; Swoger, Jason M; Grandinetti, Lisa M

2015-07-01

Awareness of the extraintestinal manifestations of Crohn disease is increasing in dermatology and gastroenterology, with enhanced identification of entities that range from granulomatous diseases recapitulating the underlying inflammatory bowel disease to reactive conditions and associated dermatoses. In this review, the underlying etiopathology of Crohn disease is discussed, and how this mirrors certain skin manifestations that present in a subset of patients is explored. The array of extraintestinal manifestations that do not share a similar pathology, but which are often seen in association with inflammatory bowel disease, is also discussed. Treatment and pathogenetic mechanisms, where available, are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Ab initio molecular simulations on specific interactions between amyloid beta and monosaccharides

NASA Astrophysics Data System (ADS)

Nomura, Kazuya; Okamoto, Akisumi; Yano, Atsushi; Higai, Shin'ichi; Kondo, Takashi; Kamba, Seiji; Kurita, Noriyuki

2012-09-01

Aggregation of amyloid β (Aβ) peptides, which is a key pathogenetic event in Alzheimer's disease, can be caused by cell-surface saccharides. We here investigated stable structures of the solvated complexes of Aβ with some types of monosaccharides using molecular simulations based on protein-ligand docking and classical molecular mechanics methods. Moreover, the specific interactions between Aβ and the monosaccharides were elucidated at an electronic level by ab initio fragment molecular orbital calculations. Based on the results, we proposed which type of monosaccharide prefers to have large binding affinity to Aβ and inhibit the Aβ aggregation.

Recurrent adult onset Henoch-Schonlein Purpura: a case report.

PubMed

Gaskill, Neil; Guido, Bruce; Magro, Cynthia

2016-08-15

Henoch-Schonlein purpura is an immunoglobulin A (IgA)-immune complex mediated leukocytoclastic vasculitis that classically manifests with palpable purpura, abdominal pain, arthritis, and hematuria or proteinuria. The condition is much more predominant in children (90% of cases) and commonly follows an upper respiratory infection. We present a case of recurrent Henoch-Schonlein purpura (HSP) complicated by nephritis in an adult female initially categorized as IgA nephropathy (IgAN). We review the pathophysiologic basis of HSP nephritis as the variant of HSP accompanied by renal involvement and its pathogenetic commonality with IgA nephropathy.

Tufted hair folliculitis: a case report and literature review.

PubMed

Broshtilova, V; Bardarov, E; Kazandjieva, J; Marina, S

2011-01-01

Tufted hair folliculitis is a rare folliculitis of the scalp that resolves with patches of scarring alopecia within multiple hair tufts emerging from dilated follicular orifices. Tufting of hair is caused by clustering of adjacent follicular units due to a fibrosing process and to retention of telogen hairs within a dilated follicular orifice. Various pathogenetic mechanisms have been proposed including nevoid abnormalities, recurrent infections of the follicles, and retention of telogen hair in the tufts. We present a patient with tufted hair folliculitis who was effectively treated with antibacterial medications, verifying the infectious nature of the disease.

Comparative estimation of the effectiveness of laser and other methods of stomatological disease treatment

NASA Astrophysics Data System (ADS)

Kunin, Anatoly A.; Erina, Stanislava V.; Pankova, Svetlana N.; Buerger, Friedhelm R.; Baumert, R.; Stepanov, Nicolay N.; Malinovskaya, L. A.; Sokolova, Irina A.; Podolskaya, Elana E.; Kazmina, Svetlana G.; Dergunova, Elvira I.; Mozhaev, N. N.

1996-11-01

A perspective trend in the perfection of laser methods of stomatological diseases treatment is the application of low intensity laser radiation having a wide range of the therapeutic effect. Thus, laser radiation has various, pathogenetic effect. Patients with carries, pulpits, periodontitis, diseases of parodontium and oral mucous membranes were treated. Traditional examination methods were used, i.e. biochemical, visual pulp examination, immunological and macrohistological ones. The obtained results prove high effectiveness of laser therapy in the treatment of a number of stomatological disease in comparison with traditional methods and can be recommended to be used in practice.

Pathogenetic validation of the use of biological protective agents and early treatment in cases of radiation injury simulating radiation effects under space flight conditions

NASA Technical Reports Server (NTRS)

Rogozkin, V. D.; Varteres, V.; Sabo, L.; Groza, N.; Nikolov, I.

1974-01-01

In considering a radiation safety system for space flights, the various measures to protect man against radiation include drug prophylaxis. At the present time a great deal of experimental material has been accumulated on the prevention and treatment of radiation injuries. Antiradiation effectiveness has been established for sulfur- and nitrogen-containing substances, auxins, cyanides, polynucleotides, mucopolysaccharides, lipopolysaccharides, aminosaccharides, synthetic polymers, vitamins, hormones, amino acids and other compounds which can be divided into two basic groups - biological and chemical protective agents.

Acantholysis revisited: back to basics.

PubMed

Seshadri, Divya; Kumaran, M Sendhil; Kanwar, Amrinder J

2013-01-01

Acantholysis means loss of coherence between epidermal cells due to the breakdown of intercellular bridges. It is an important pathogenetic mechanism underlying various bullous disorders, particularly the pemphigus group, as well as many non-blistering disorders. Although a well-known concept, the student often has to refer to many sources to comprehend acantholysis completely. Thorough knowledge of this topic helps in clinching many diagnoses. The etiopathogenesis, classification, clinical signs, and laboratory demonstration of acantholysis are discussed in detail to help students build clear concepts. We have focused on various distinguishing points in different disorders for an easy grasp of the topic.

Methodology and potential pitfalls in allergic diseases study designs: measurements for the assessment of the overall severity of atopic dermatitis--the four step severity score (FSSS), SCORAD-related, electronic system, for the simple and rapid evaluation of the skin and mucosal allergic inflammation.

PubMed

Mastrandrea, F; Pecora, S; Scatena, C; Cadario, G

2005-11-01

Medical statistics may contribute to ameliorate research by improving the design of studies and identifying the optimal method for the analysis of results. Sometimes, nevertheless, it could be misemployed flawing the benefit potential. Allergic diseases pathogenesis is recognized to be systemic but global initiatives such as GINA and ARIA documents define allergic asthma and rhinitis as organ diseases; such an asymmetrical view raises a set of known and unknown confounding that could influence the quality of the process of evidence-based decision-making (topic symptomatic therapeutic interventions versus systemic pathogenetic interventions). This article shows the first scoring system for the assessment of atopic dermatitis lesions developed in the allergy-area. A four-step severity score (FSSS) was chosen in agreement with those developed for asthma and rhinitis in global initiatives, to avoid any further differences in evaluating the severity of allergic diseases. FSSS relates each step with the objective signs of the SCORAD and rates the disease course as intermittent or persistent. A devoted electronic program has been also framed to allow a quick and simple contemporary evaluation of the SCORAD Index (Section I) and of the FSSS (Section II); the program furthermore foresees a third section named ESAS (Extra Skin Allergic Signs) (Section III) in which it is possible to check whether organs other than the skin are involved by the allergic inflammation. The limitations potential generated by a misemployment of medical statistics for clinical trials designed to establish benefits rising from specific immunotherapy for allergic diseases have been also discussed extensively.

Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms.

PubMed

Tonacchera, M; Vitti, P; Agretti, P; Ceccarini, G; Perri, A; Cavaliere, R; Mazzi, B; Naccarato, A G; Viacava, P; Miccoli, P; Pinchera, A; Chiovato, L

1999-11-01

The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gs alpha genes may confer TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and nonfunctioning follicular thyroid adenomas specifically selected for their homogeneous gross anatomy (single nodule in an otherwise normal thyroid gland). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codons 201 and 227 of the Gs alpha gene were also analyzed. At histology, all hyperfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed as follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features indicating malignant transformation (a minimally invasive follicular carcinoma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyperfunctioning follicular thyroid adenomas. In one hyperfunctioning adenoma, which was negative for TShR mutations, a mutation in codon 227 of the Gs alpha gene was identified. At variance with hyperfunctioning thyroid adenomas, no mutation of the TShR or Gs alpha genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings clearly define a different molecular pathogenetic mechanism in hyperfunctioning and nonfunctioning follicular thyroid adenomas. Activation of the cAMP cascade, which leads to proliferation but maintains differentiation of follicular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gs alpha genes are probably involved in nonfunctioning follicular adenomas.

[Arthur Vick Prize 2017 of the German Society of Orthopaedic Rheumatology].

PubMed

Bause, L; Niemeier, A; Krenn, V

2018-03-01

The German Society of Orthopaedic Rheumatology (DGORh) honored Prof. Dr. med. Veit Krenn (MVZ-ZHZMD-Trier) with the Arthur Vick Prize 2017. With this award, scientific results with high impact on the diagnosis, therapy and pathogenetic understanding of rheumatic diseases are honored. In cooperation with pathologists and colleagues from various clinical disciplines Prof. Dr. med. Veit Krenn developed several histopathologic scoring systems which contribute to the diagnosis and pathogenetic understanding of degenerative and rheumatic diseases. These scores include the synovitis score, the meniscal degeneration score, the classification of periprosthetic tissues (SLIM classification), the arthrofibrosis score, the particle score and the CD15 focus score. Of highest relevance for orthopedic rheumatology is the synovitis score which is a semiquantitative score for evaluating immunological and inflammatory changes of synovitis in a graded manner. Based on this score, it is possible to divide results into low-grade synovitis and high-grade synovitis: a synovitis score of 1-4 is called low-grade synovitis and occurs for example in association with osteoarthritis (OA), post-trauma, with meniscal lesions and hemochromatosis. A synovitis score of 5-9 is called high-grade synovitis, e.g. rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection and reactive arthritis as well as peripheral arthritis with Bechterew's disease (sensitivity 61.7%, specificity 96.1%). The first publication (2002) and an associated subsequent publication (2006) of the synovitis score has led to national and international acceptance of this score as the standard for histopathological assessment of synovitis. The synovitis score provides a diagnostic, standardized and reproducible histopathological evaluation method for joint diseases, particularly when this score is applied in the context with the joint pathology algorithm.

[Analysis of mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes in patients with nonsyndromic sensorineural hearing loss from various regions of Russia].

PubMed

Dzhemileva, L U; Posukh, O L; Tazetdinov, A M; Barashkov, N A; Zhuravskiĭ, S G; Ponidelko, S N; Markova, T G; Tadinova, V N; Fedorova, S A; Maksimova, N R; Khusnutdinova, E K

2009-07-01

Mitochondrial DNA (mtDNA) mutations play an important role in etiology of hereditary hearing loss. In various regions of the world, patients suffer from nonsyndromic sensorineural hearing loss initiated by aminoglycoside antibiotics. Mutations that had been shown as pathogenetically important for hearing function disturbance were identified in mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes while pathogenic role of several DNA sequences requires additional studies. This work presents the results of studying the spectrum of mutations and polymorphic variations in mtDNA genes 12S rRNA and tRNA(Ser(UGN)) in 410 patients with nonsyndromal sensoneural hearing impairment/loss from the Volga Ural region, St Petersburg, Yakutia, and Altai and in 520 individuals with normal hearing, which represent several ethnic groups (Russians, Tatars, Bashkirs, Yakuts, Altaians) residing in the Russian Federation. Pathogenetically significant mutation A1555G (12S rRNA) was found in two families (from Yakutia and St Peresburg) with hearing loss, probably caused by treatment with aminoglucosides, and in the population sample of Yakuts with a frequency of 0.83%. Further research is needed to confirm the role in hearing impairment of mutations 961insC, 961insC(n), 961delTinsC(n), T961G, T1095C (12S rRNA) and G7444A, A7445C (tRNA(Ser(UGN revealed in the patients. In addition, in the patients and the population groups, polymorphic mt DNA variants were detected, which are characteristic also of other Eurasian populations both in spectrum and frequency.

Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ.

PubMed

Ferri, Lorenzo; Malesci, Duccio; Fioravanti, Antonella; Bagordo, Gaia; Filippini, Armando; Ficcadenti, Anna; Manna, Raffaele; Antuzzi, Daniela; Verrecchia, Elena; Donati, Ilaria; Mignani, Renzo; Cavicchi, Catia; Guerrini, Renzo; Morrone, Amelia

2018-06-01

Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants (e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic (e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN.

PubMed

Iatropoulos, Paraskevas; Daina, Erica; Curreri, Manuela; Piras, Rossella; Valoti, Elisabetta; Mele, Caterina; Bresin, Elena; Gamba, Sara; Alberti, Marta; Breno, Matteo; Perna, Annalisa; Bettoni, Serena; Sabadini, Ettore; Murer, Luisa; Vivarelli, Marina; Noris, Marina; Remuzzi, Giuseppe

2018-01-01

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment. Copyright © 2018 by the American Society of Nephrology.

Current surgical treatment for chronic pancreatitis.

PubMed

Aimoto, Takayuki; Uchida, Eiji; Nakamura, Yoshiharu; Yamahatsu, Kazuya; Matsushita, Akira; Katsuno, Akira; Cho, Kazumitsu; Kawamoto, Masao

2011-01-01

Chronic pancreatitis (CP) is a painful, yet benign inflammatory process of the pancreas. Surgical management should be individualized because the pain is multifactorial and its mechanisms vary from patient to patient. Two main pathogenetic theories for the mechanisms of pain in CP have been proposed: the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. The latter theory is strongly supported by the good results of drainage procedures in the surgical management of CP. Other possible contributing factors include pancreatic ischemia; a centrally sensitized pain state; and the development of complications, such as pseudocysts and stenosis of the duodenum or common bile duct. Common indications for surgery include intractable pain, suspicion of neoplasm, and complications that cannot be resolved with radiological or endoscopic treatments. Operative procedures have been historically classified into 4 categories: decompression procedures for diseased and obstructed pancreatic ducts; resection procedures for the proximal, distal, or total pancreas; denervation procedures of the pancreas; and hybrid procedures. Pancreaticoduodenectomy and pylorus-preserving pancreaticoduodenectomy, once the standard operations for patients with CP, have been replaced by hybrid procedures, such as duodenum-preserving pancreatic head resection, the Frey procedure, and their variants. These procedures are safe and effective in providing long-term pain relief and in treating CP-related complications. Hybrid procedures should be the operations of choice for patients with CP.

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques

PubMed Central

Geisbert, Thomas W.; Hensley, Lisa E.; Larsen, Tom; Young, Howard A.; Reed, Douglas S.; Geisbert, Joan B.; Scott, Dana P.; Kagan, Elliott; Jahrling, Peter B.; Davis, Kelly J.

2003-01-01

Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions. PMID:14633608

Malassezia species and their associated skin diseases.

PubMed

Harada, Kazutoshi; Saito, Mami; Sugita, Takashi; Tsuboi, Ryoji

2015-03-01

Malassezia spp. are lipophilic fungi that occur on all skin surfaces of humans and animals as commensal and pathogenic organisms. In the 2000s, several new species were added to the Malassezia genus by Japanese researchers. The genus Malassezia now includes 14 species of basidiomycetous yeast. Culture-independent molecular analysis clearly demonstrated that the DNA of Malassezia spp. was predominantly detected in core body and arm sites, suggesting that they are the dominant fungal flora of the human body. Malassezia spp. have been implicated in skin diseases including pityriasis versicolor (PV), Malassezia folliculitis (MF), seborrheic dermatitis (SD) and atopic dermatitis (AD). While Malassezia spp. are directly responsible for the infectious diseases, PV and MF, they act as an exacerbating factor in AD and SD. The fatty acids generated by Malassezia lipase can induce inflammation of the skin, resulting in development of SD. Patch and serum immunoglobulin E tests revealed that AD patients were hypersensitive to Malassezia. However, these findings only partially elucidated the mechanism by which Malassezia spp. induce inflammation in the skin; understanding of the pathogenetic role of Malassezia spp. in SD or AD remains incomplete. In this article, the latest findings of Malassezia research are reviewed with special attention to skin diseases. © 2015 Japanese Dermatological Association.

Sonographic alteration of lenticular nucleus in focal task-specific dystonia of musicians.

PubMed

Walter, Uwe; Buttkus, Franziska; Benecke, Reiner; Grossmann, Annette; Dressler, Dirk; Altenmüller, Eckart

2012-01-01

In distinct movement disorders, transcranial sonography detects alterations of deep brain structures with higher sensitivity than other neuroimaging methods. Lenticular nucleus hyperechogenicity on transcranial sonography, thought to be caused by increased local copper content, has been reported as a characteristic finding in primary spontaneous dystonia. Here, we wanted to find out whether deep brain structures are altered in task-specific dystonia. The frequency of sonographic brainstem and basal ganglia changes was studied in an investigator-blinded setting in 15 musicians with focal task-specific hand dystonia, 15 musicians without dystonia, and 15 age- and sex-matched nonmusicians without dystonia. Lenticular nucleus hyperechogenicity was found in 12 musicians with task-specific dystonia, but only in 3 nondystonic musicians (Fisher's exact test, p = 0.001) and 2 nonmusicians (p < 0.001). The degree of lenticular nucleus hyperechogenicity in affected musicians correlated with age, but not with duration of music practice or duration of dystonia. In 2 of 3 affected musicians with normal echogenic lenticular nucleus, substantia nigra hyperechogenicity was found. Our findings support the idea of a pathogenetic link between primary spontaneous and task-specific dystonia. Sonographic basal ganglia alteration might indicate a risk factor that in combination with extensive fine motor training promotes the manifestation of task-specific dystonia. Copyright © 2011 S. Karger AG, Basel.

A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease.

PubMed

Tovoli, Francesco; Napoli, Lucia; Negrini, Giulia; D'Addato, Sergio; Tozzi, Giulia; D'Amico, Jessica; Piscaglia, Fabio; Bolondi, Luigi

2017-05-25

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)-however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors.

Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

PubMed

Hossain, Mohammad Zakir; Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-09-26

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

PubMed Central

Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-01-01

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP. PMID:28954391

Type 2 diabetes: epidemiologic trends, evolving pathogenetic [corrected] concepts, and recent changes in therapeutic approach.

PubMed

Rizvi, Ali A

2004-11-01

The prevalence of type 2 diabetes has assumed epidemic dimensions. Children are now vulnerable to a disease that was once the exclusive domain of adulthood. Increased body weight and sedentary behavior accelerate insulin resistance and beta-cell dysfunction, leading to the clinical manifestation of hyperglycemia. Other cardiovascular risk factors tend to cluster in this milieu, setting the stage for vastly increased macrovascular morbidity. Many more people have impaired glucose tolerance ('prediabetes'). They are not only at risk for frank diabetes but also for the recently recognized entity of 'metabolic syndrome,' which is further characterized by hypertension, dyslipidemia, and central adiposity. A multifactorial approach addressing these aspects in addition to intensive glycemic control is the most efficacious therapy, optimally achieved through a team effort comprising the clinician, diabetes nurse, dietitian, and other professionals. Early use of oral-agent combinations is gaining favor. Insulin is best utilized in a basal-bolus fashion to manage both fasting and postprandial glycemia, delivered with multiple-dose injections or continuously via the pump. In hospitalized patients, good diabetic control reduces mortality. Finally, recent trials show that optimal weight maintenance and regular exercise can prevent or delay type 2 diabetes. Such information can serve as the foundation for large-scale preventive endeavors at the community level.