Enterocolic lymphocytic phlebitis: clinicopathologic features and review of the literature.

PubMed

Ngo, Nyethane; Chang, Fuju

2007-07-01

Enterocolic lymphocytic phlebitis (ELP) is a recently described entity and is of unknown etiology and pathogenesis. It is characterized by phlebitis of the bowel wall and mesentery, without arterial involvement or evidence of systemic vasculitis. The clinical presentation of ELP is varied, but it most commonly manifests with signs of an acute abdomen. Clinical, radiologic, and endoscopic findings are often conflicting and misdiagnosis is common as venous thrombosis is not suspected. The diagnosis of ELP is obtained histologically. There is a spectrum of histologic features associated with ELP, which includes lymphocytic phlebitis, necrotizing phlebitis, granulomatous phlebitis, and myointimal hyperplasia. Other features include venous thrombi and acute ischemic changes of the intestine. Surgical resection of the affected bowel is usually curative and recurrences are rare. The clinical and histopathologic features of ELP are reviewed.

Neurofibromatoses.

PubMed

Uhlmann, Erik J; Plotkin, Scott R

2012-01-01

The studies of familial tumor predisposition syndromes have contributed immensely to our understanding of oncogenesis. Neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis are inherited autosomal dominant neurocutaneous disorders with complete penetrance. They are clinically and genetically distinct and considerable knowledge has been gathered about their pathogenesis. In this chapter, the genetics, molecular mechanism of disease, as well as clinical features, diagnosis and treatment are discussed.

Coronary Microvascular Disease in Chronic Chagas Cardiomyopathy Including an Overview on History, Pathology, and Other Proposed Pathogenic Mechanisms

PubMed Central

Rossi, Marcos A.; Tanowitz, Herbert B.; Malvestio, Lygia M.; Celes, Mara R.; Campos, Erica C.; Blefari, Valdecir; Prado, Cibele M.

2010-01-01

This review focuses on the short and bewildered history of Brazilian scientist Carlos Chagas's discovery and subsequent developments, the anatomopathological features of chronic Chagas cardiomyopathy (CCC), an overview on the controversies surrounding theories concerning its pathogenesis, and studies that support the microvascular hypothesis to further explain the pathological features and clinical course of CCC. It is our belief that knowledge of this particular and remarkable cardiomyopathy will shed light not only on the microvascular involvement of its pathogenesis, but also on the pathogenetic processes of other cardiomyopathies, which will hopefully provide a better understanding of the various changes that may lead to an end-stage heart disease with similar features. This review is written to celebrate the 100th anniversary of the discovery of Chagas disease. PMID:20824217

Ebolavirus: An Overview of Molecular and Clinical Pathogenesis.

PubMed

Vine, Veronica; Scott, Dana P; Feldmann, Heinz

2017-01-01

Ebolaviruses cause severe, often fatal hemorrhagic fever in Central, East, and West Africa. Until recently, they have been viewed as rare but highly pathogenic infections with regional, but limited, global public health impact. This view has changed with the emergence of the first epidemic of Ebola hemorrhagic fever in West Africa. In this chapter we provide an introduction of the pathogenesis of ebolaviruses as well as a description of clinical disease features. We also describe the current animal models used in ebolavirus research, detailing each model's unique strengths and weaknesses. We focus on Ebola virus representing the type species Zaire ebolavirus of the genus Ebolavirus, as most work relates to this pathogen.

Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

PubMed Central

Tanna, Preena; Strauss, Rupert W; Fujinami, Kaoru; Michaelides, Michel

2017-01-01

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4. Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored. PMID:27491360

Gene knockout of tau expression does not contribute to the pathogenesis of prion disease.

PubMed

Lawson, Victoria A; Klemm, Helen M; Welton, Jeremy M; Masters, Colin L; Crouch, Peter; Cappai, Roberto; Ciccotosto, Giuseppe D

2011-11-01

Prion diseases or transmissible spongiform encephalopathies are a group of fatal and transmissible disorders affecting the central nervous system of humans and animals. The principal agent of prion disease transmission and pathogenesis is proposed to be an abnormal protease-resistant isoform of the normal cellular prion protein. The microtubule-associated protein tau is elevated in patients with Creutzfeldt-Jakob disease. To determine whether tau expression contributes to prion disease pathogenesis, tau knockout and control wild-type mice were infected with the M1000 strain of mouse-adapted human prions. Immunohistochemical analysis for total tau expression in prion-infected wild-type mice indicated tau aggregation in the cytoplasm of a subpopulation of neurons in regions associated with spongiform change. Western immunoblot analysis of brain homogenates revealed a decrease in total tau immunoreactivity and epitope-specific changes in tau phosphorylation. No significant difference in incubation period or other disease features were observed between tau knockout and wild-type mice with clinical prion disease. These results demonstrate that, in this model of prion disease, tau does not contribute to the pathogenesis of prion disease and that changes in the tau protein profile observed in mice with clinical prion disease occurs as a consequence of the prion-induced pathogenesis.

Protein contact dermatitis: allergens, pathogenesis, and management.

PubMed

Levin, Cheryl; Warshaw, Erin

2008-01-01

Protein contact dermatitis is an allergic skin reaction induced principally by proteins of either animal or plant origin. The clinical presentation is that of a chronic dermatitis, and it is often difficult to differentiate between allergic contact dermatitis and other eczematous dermatoses. One distinguishing clinical feature is that acute flares of pruritus, urticaria, edema, or vesiculation are noted minutes after contact with the causative substances. Additionally, the patch-test result is typically negative, and the scratch- or prick-test result is positive. The pathogenesis of protein contact dermatitis is unclear but may involve a type I (immunoglobulin E [IgE], immediate) hypersensitivity reaction, type IV (cell-mediated delayed) hypersensitivity reaction, and/or a delayed reaction due to IgE-bearing Langerhans' cells. Management involves avoidance of the allergen.

The Disturbance of Gaze in Progressive Supranuclear Palsy: Implications for Pathogenesis

PubMed Central

Chen, Athena L.; Riley, David E.; King, Susan A.; Joshi, Anand C.; Serra, Alessandro; Liao, Ke; Cohen, Mark L.; Otero-Millan, Jorge; Martinez-Conde, Susana; Strupp, Michael; Leigh, R. John

2010-01-01

Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies. PMID:21188269

Tissue tropism, pathology and pathogenesis of enterovirus infection.

PubMed

Muehlenbachs, Atis; Bhatnagar, Julu; Zaki, Sherif R

2015-01-01

Enteroviruses are very common and cause infections with a diverse array of clinical features. Enteroviruses are most frequently considered by practising pathologists in cases of aseptic meningitis, encephalitis, myocarditis and disseminated infections in neonates and infants. Congenital infections have been reported and transplacental transmission is thought to occur. Although skin biopsies during hand, foot and mouth disease are infrequently obtained, characteristic dermatopathological findings can be seen. Enteroviruses have been implicated in lower respiratory tract infections. This review highlights histopathological features of enterovirus infection and discusses diagnostic modalities for formalin-fixed paraffin-embedded tissues and their associated pitfalls. Immunohistochemistry can detect enterovirus antigen within cells of affected tissues; however, assays can be non-specific and detect other viruses. Molecular methods are increasingly relied upon but, due to the high frequency of asymptomatic enteroviral infections, clinical-pathological correlation is needed to determine significance. Of note, diagnostic assays on central nervous system or cardiac tissues from immunocompetent patients with prolonged disease courses are most often negative. Histopathological, immunohistochemical and molecular studies performed on clinical specimens also provide insight into enteroviral tissue tropism and pathogenesis. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Osteosclerosis, hyperostosis, and related disorders

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

Frame, B.; Honasoge, M.; Kottamasu, S.R.

1987-01-01

This book will assist physicians in the evaluation of patients where osteosclerosis and hyperostosis are the predominant radiographic features. This volume also covers disorders with lesser degrees of osteosclerosis and hyperostosis, and those which exhibit ligamentous calcifications and/or ossifications such as: fluorosis, hypervitaminosis, hypoparathyroidism, and hypophosphatemic rickets. Discussed and reviewed are the salient clinical and radiographic features as well as the pathophysiology of these conditions. In addition, many chapters contain experimental data that facilitates understanding of the pathogenesis of the disease.

A typical band-shaped calcific keratopathy with keratocyte changes.

PubMed Central

Dark, A J; Proctor, J

1982-01-01

The clinical features of a patient with atypical band keratopathy are described. Histochemical and electron probe analyses indicate that the granular deposits in Bowman's layer contain calcium and phosphate. An unusual feature in this patient was the presence of severe keratocyte degeneration; its possible role in the pathogenesis of this condition is discussed. Exfoliation of the calcified Bowman's layer appears to have been the basis for severe attacks of recurrent ocular pain. Images PMID:7074004

M-protein-positive chronic active Epstein-Barr virus infection: features mimicking HIV-1 infection.

PubMed

Imashuku, Shinsaku; Azuma, Naoto; Kanegane, Hirokazu; Kasahara, Yoshihito

2009-09-01

Chronic active Epstein-Barr virus infection (CAEBV) is a unique and fatal lymphoproliferative disease (LPD), which often shows high serum IgG and/or IgE. The significance of such immunoglobulin abnormalities in CAEBV has not been fully evaluated and discussed. In addition, such clinical features mimic HIV-1 infection. We report here a case of CAEBV with M-protein detected which may shed a new light on the pathogenesis of this disease.

Pituitary carcinoma diagnosed on fine needle aspiration: Report of a case and review of pathogenesis

PubMed Central

Yakoushina, Tatiana V.; Lavi, Ehud; Hoda, R. S.

2010-01-01

Pituitary carcinoma (PC) is a very rare entity (0.2% of all pituitary tumors), with only about 140 cases reported in English literature. There are no reliable histological, immunohistochemical or ultrastructural features distinguishing pituitary adenoma (PA) from PC. By definition, a diagnosis of PC is made after a patient with PA develops non-contiguous central nervous system (CNS) or systemic metastases. To date, only three cases of PC have been reportedly diagnosed on fine needle aspiration (FNA). Two of the reported cases were diagnosed on FNA of the cervical lymph nodes and one on FNA of the vertebral bone lesion. Herein, we present a case of PC, diagnosed on FNA of the liver lesion. In this case, we describe cytologic features of PC and compare them to histologic features of the tumor in the pituitary. Clinical behavior of tumor, pathogenesis of metastasis and immunochemical and prognostic markers will also be described. PMID:20806088

One year in review 2016: Behçet's syndrome.

PubMed

Hatemi, Gulen; Seyahi, Emire; Fresko, Izzet; Talarico, Rosaria; Hamuryudan, Vedat

2016-01-01

Several articles highlighting the epidemiology, pathogenesis, clinical features, treatment modalities and disease assessment of Behçet's syndrome (BS) have been published during the last year. Clinical and radiological features of lower extremity deep vein thrombosis due to BS can be quite different than those found in thrombosis due to other causes; additionally, frequency of post-thrombotic syndrome is significantly increased in BS. Some clinical and colonoscopic features are useful in differentiating BS from Crohn's disease. Barkhof criteria may be helpful in differentiating neurologic involvement due to BS from multiple sclerosis. Anatomical localization of papulopustular lesions but not histology has been found to be helpful in differentiating papulopustular lesions of BS from those found in acne vulgaris. Several studies looked at the ovarian reserve with contradicting results. A population-based cohort study found higher risk of hematological malignancies only among female BS patients living in Taiwan. The role of genetic factors and environment is discussed and both autoimmune and autoinflammatory features are underlined in the pathogenesis of BS. New data on the epistatic interactions between ERAP and HLA B51 is available and information on the microbiome have started to appear. New uncontrolled data suggest beneficial effects of anti-TNFs for refractory extra-ocular complications of BS such as pulmonary artery, gastrointestinal and central nervous system involvement. Uncontrolled studies suggest promising results with interleukin-1 inhibition but gevokizumab, a humanised anti IL-1β antibody, failed to meet the primary endpoint of time to first ocular exacerbation in a phase III trial. The debate on anticoagulation continues with new observational data.

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

PubMed Central

2017-01-01

ABSTRACT Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis. PMID:28148798

Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia.

PubMed

Li, Bing; Gale, Robert Peter; Xiao, Zhijian

2014-12-12

According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.

Pancreatitis and agenesis of the dorsal pancreas.

PubMed

Oldenburg, B; van Leeuwen, M S; van Berge Henegouwen, G P; Koningsberger, J C

1998-10-01

We report a case of agenesis of the dorsal pancreas, complicated by pancreatitis and diabetes mellitus. A 39-year-old woman was referred for evaluation of a chronic pancreatitis. Abdominal spiral CT and ERP and MRCP demonstrated agenesis of the dorsal pancreas. The pathogenesis, clinical features and diagnosis of this very rarely reported disease are discussed.

Vulvovaginitis and diabetes.

PubMed

Kalra, Bharti; Kalra, Sanjay

2017-01-01

Vulvovaginitis is a commonly encountered comorbid condition of diabetes, and is linked to poor glycaemic control. Proper, timely diagnosis and management is necessary to ensure optimal perineal/genital and metabolic health. Knowledge of current guidelines and recommendations helps in achieving this goal. This review describes the etiology, pathogenesis, clinical features, differential diagnosis, management and prevention of VV in diabetes.

Molecular pathogenesis and clinical management of Fanconi anemia

PubMed Central

Kee, Younghoon; D’Andrea, Alan D.

2012-01-01

Fanconi anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease. PMID:23114602

Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features

PubMed Central

Maggi, Lorenzo; Carboni, Nicola; Bernasconi, Pia

2016-01-01

LMNA-related disorders are caused by mutations in the LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C, via alternative splicing. Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes. The most frequent diseases associated with mutations in the LMNA gene are characterized by skeletal and cardiac muscle involvement. This review will focus on genetics and clinical features of laminopathies affecting primarily skeletal muscle. Although only symptomatic treatment is available for these patients, many achievements have been made in clarifying the pathogenesis and improving the management of these diseases. PMID:27529282

Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features.

PubMed

Maggi, Lorenzo; Carboni, Nicola; Bernasconi, Pia

2016-08-11

LMNA-related disorders are caused by mutations in the LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C, via alternative splicing. Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes. The most frequent diseases associated with mutations in the LMNA gene are characterized by skeletal and cardiac muscle involvement. This review will focus on genetics and clinical features of laminopathies affecting primarily skeletal muscle. Although only symptomatic treatment is available for these patients, many achievements have been made in clarifying the pathogenesis and improving the management of these diseases.

Inclusion body myositis – pathomechanism and lessons from genetics

PubMed Central

Murnyák, Balázs; Bodoki, Levente; Vincze, Melinda; Griger, Zoltán; Csonka, Tamás; Szepesi, Rita; Kurucz, Andrea; Dankó, Katalin

2015-01-01

Inclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease. PMID:28352694

Diagnosis, pathogenesis and treatment of myositis: recent advances

PubMed Central

Carstens, P-O; Schmidt, J

2014-01-01

Dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM) and inclusion body myositis (IBM) are four distinct subtypes of idiopathic inflammatory myopathies – in short myositis. Recent studies have shed some light on the unique pathogenesis of each entity. Some of the clinical features are distinct, but muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis-specific autoantibodies have become useful additions to our diagnostic repertoire. Only few controlled trials are available to substantiate current treatment approaches for myositis and hopes are high that novel modalities will become available within the next few years. In this review we provide an up-to-date overview of the pathogenesis and diagnostic approach of myositis. We aim to present a guide towards therapeutic and general management. PMID:23981102

Diagnosis, pathogenesis and treatment of myositis: recent advances.

PubMed

Carstens, P-O; Schmidt, J

2014-03-01

Dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM) and inclusion body myositis (IBM) are four distinct subtypes of idiopathic inflammatory myopathies - in short myositis. Recent studies have shed some light on the unique pathogenesis of each entity. Some of the clinical features are distinct, but muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis-specific autoantibodies have become useful additions to our diagnostic repertoire. Only few controlled trials are available to substantiate current treatment approaches for myositis and hopes are high that novel modalities will become available within the next few years. In this review we provide an up-to-date overview of the pathogenesis and diagnostic approach of myositis. We aim to present a guide towards therapeutic and general management. © 2013 British Society for Immunology.

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity.

PubMed

Morrison, Thomas E; Diamond, Michael S

2017-04-15

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis. Copyright © 2017 American Society for Microbiology.

Central nervous system manifestations of Angiostrongylus cantonensis infection.

PubMed

Martins, Yuri C; Tanowitz, Herbert B; Kazacos, Kevin R

2015-01-01

Over 20 species of Angiostrongylus have been described from around the world, but only Angiostrongylus cantonensis has been confirmed to cause central nervous system disease in humans. A neurotropic parasite that matures in the pulmonary arteries of rats, A. cantonensis is the most common cause of eosinophilic meningitis in southern Asia and the Pacific and Caribbean islands. The parasite can also cause encephalitis/encephalomyelitis and rarely ocular angiostrongyliasis. The present paper reviews the life cycle, epidemiology, pathogenesis, clinical features, diagnosis, treatment, prevention and prognosis of A. cantonesis infection. Emphasis is given on the spectrum of central nervous system manifestations and disease pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

Pathogenesis, imaging and clinical characteristics of CF and non-CF bronchiectasis.

PubMed

Schäfer, Jürgen; Griese, Matthias; Chandrasekaran, Ravishankar; Chotirmall, Sanjay H; Hartl, Dominik

2018-05-22

Bronchiectasis is a common feature of severe inherited and acquired pulmonary disease conditions. Among inherited diseases, cystic fibrosis (CF) is the major disorder associated with bronchiectasis, while acquired conditions frequently featuring bronchiectasis include post-infective bronchiectasis and chronic obstructive pulmonary disease (COPD). Mechanistically, bronchiectasis is driven by a complex interplay of inflammation and infection with neutrophilic inflammation playing a predominant role. The clinical characterization and management of bronchiectasis should involve a precise diagnostic workup, tailored therapeutic strategies and pulmonary imaging that has become an essential tool for the diagnosis and follow-up of bronchiectasis. Prospective future studies are required to optimize the diagnostic and therapeutic management of bronchiectasis, particularly in heterogeneous non-CF bronchiectasis populations.

Precursor Lesions of Urologic Malignancies.

PubMed

Khani, Francesca; Robinson, Brian D

2017-12-01

- Precursor lesions of urologic malignancies are established histopathologic entities, which are important not only to recognize for clinical purposes, but also to further investigate at the molecular level in order to gain a better understanding of the pathogenesis of these malignancies. - To provide a brief overview of precursor lesions to the most common malignancies that develop within the genitourinary tract with a focus on their clinical implications, histologic features, and molecular characteristics. - Literature review from PubMed, urologic pathology textbooks, and the 4th edition of the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. All photomicrographs were taken from cases seen at Weill Cornell Medicine or from the authors' personal slide collections. - The clinical importance and histologic criteria are well established for the known precursor lesions of the most common malignancies throughout the genitourinary tract, but further investigation is warranted at the molecular level to better understand the pathogenesis of these lesions. Such investigation may lead to better risk stratification of patients and potentially novel treatments.

Cystic pulmonary hydatidosis

PubMed Central

Sarkar, Malay; Pathania, Rajnish; Jhobta, Anupam; Thakur, Babu Ram; Chopra, Rajesh

2016-01-01

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by the larval stages of the cestode Echinococcus granulosus. Worldwide, pulmonary hydatid cyst is a significant problem medically, socially, and economically. Surgery is the definitive therapy of pulmonary hydatidosis. Benzimidazoles may be considered in patients with a surgical contraindication. This review will focus on pathogenesis, lifecycle, clinical features, and management of pulmonary hydatid disease. PMID:27051107

Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis.

PubMed Central

Justrabo, E; Genin, R; Rifle, G

1979-01-01

A uraemic patient undergoing chronic haemodialysis developed diffuse metastatic pulmonary calcification and died from acute respiratory insufficiency after renal transplantation. Thirteen similar cases previously published are reviewed, with emphasis on the clinical and anatomical features of such calcinosis. The pathogenesis of this calcification in patients on maintenance haemodialysis and some rules for its prevention are discussed. Images PMID:483215

[Skin vessel lesions in aluminum potroom workers].

PubMed

Siurin, S A; Nikanov, A N; Shilov, V V

2012-01-01

The features of development of the skin vessels lesions in 550 aluminum production workers have been investigated. The high prevalence of these disorders have been revealed in anode-operators and cell-operators, 49, 3 and 26.0% of workers, respectively. The regularity and staging of the development of this abnormity have been established, etiology, pathogenesis and clinical significance of those remain unknown.

[Dandy-Walker complex: a clinicopathologic study of 9 cases].

PubMed

Zhang, Xiao-bo; Gu, Yi-qun; Sun, Xiao-fei; Wang, Ying-nan; Wang, Ai-chun

2013-12-01

To investigate the etiology, pathogenesis, clinicopathologic characteristics, clinical prognosis and treatment of Dandy-Walker syndrome. Nine cases of Dandy-Walker syndrome were included in the study. The autopsy findings and clinical history were evaluated along with review of the literature. The causes, pathogenetic mechanism, pathologic features and prognosis of Dandy-Walker syndrome were analyzed. Among 9 Dandy-Walker syndrome cases, six patients presented with variants of Dandy-Walker complex and 3 cases had classic Dandy-Walker malformation. In addition, 4 patients presented with combined lateral ventricle expansion and multiple malformations were seen in 7 cases. Combined umbilical cord abnormality was noted in 4 patients with variant of Dandy-Walker complex and combined placental abnormality was seen in one classic Dandy-Walker syndrome. Dandy-Walker syndrome is a rare disease. In addition to complex pathogenesis with possible genetic and environmental antigenic etiologies, placental and umbilical cord abnormality may be also related to its development.

Hypersensitivity pneumonitis: an immunopathology review.

PubMed

Woda, Bruce A

2008-02-01

Hypersensitivity pneumonitis (HSP) is an immunologically mediated alveolar and interstitial lung disease caused by repeated inhalation of organic dusts and some occupational agents. The pathogenesis of HSP is uncertain. A number of unexplained features of HSP remain, namely (1) why do so few exposed individuals develop clinical HSP, (2) what triggers an acute episode after prolonged periods of previous sensitization, and (3) what leads to disease progression. This article considers these issues and aims to discuss and clarify current concepts in pathogenesis. Pertinent literature review in conjunction with the author's personal interpretive opinion. Current data suggest that individuals with a T(H)1 dominant response are likely to develop clinical disease. There is also some evidence that genetic factors such as polymorphisms in the major histocompatibility complex, tumor necrosis factor alpha, and tissue inhibitor of metalloproteinase 3 are associated with the development of or resistance to the disease.

Tibetan medicine "RNSP" in treatment of Alzheimer disease.

PubMed

Shi, Jing-Ming; He, Xue; Lian, Hui-Juan; Yuan, Dong-Ya; Hu, Qun-Ying; Sun, Zheng-Qi; Li, Yan-Song; Zeng, Yu-Wen

2015-01-01

Alzheimer disease (Alzheimer Disease, AD) is one of the most common type in senile dementia. Its main pathological features were that a large number of senile plaques gathered in brain extracellular and tangles fibrosis appeared in nerve cells. Currently, the pathogenesis of AD is still uncertain, and scale investigation and combined brain CT, MRI data were analyzed mainly for clinical diagnosis. Mitigation and improvement of the nervous system activity to interfere with the subsequent behavior of the patients are the main methods for treatment. In clinical no drug can really prevent and cure AD. From the view point of Tibetan medicine studies, Tibetan medicine RNSP has effect on improving memory and repairing the neurons in the brain. In this study, we combined the characteristics of AD pathology, pathogenesis, diagnosis and treatment methods to explore the feasibility of Tibetan medicine RNSP for the treatment of AD to provide new ideas for the diagnosis and treatment of AD.

The Immune System in the Pathogenesis of Ovarian Cancer

PubMed Central

Charbonneau, Bridget; Goode, Ellen L.; Kalli, Kimberly R.; Knutson, Keith L.; DeRycke, Melissa S.

2014-01-01

Clinical outcomes in ovarian cancer are heterogeneous even when considering common features such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration into tumor and host characteristics. One compelling host characteristic is the immune response to ovarian cancer. While several studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease, recent genetic and protein analyses also suggest a role in disease incidence. Recent studies also show that anti-tumor immunity is often negated by immune suppressive cells present in the tumor microenvironment. These suppressive immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathologic network. Thus, future research into immunotherapy targeting ovarian cancer will likely become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression or by disrupting critical cytokine networks. PMID:23582060

Heart Failure: From Research to Clinical Practice.

PubMed

Islam, Md Shahidul

2018-01-01

"Heart failure: from research to clinical practice", a collection of selected reviews, which comes out also as a book, covers essentially all important aspects of heart failure, including the pathogenesis, clinical features, biomarkers, imaging techniques, medical treatment and surgical treatments, use of pacemakers and implantable cardioverter defibrillators, and palliative care. The reviews include essential background information, state of the art, critical and in-depth analysis, and directions for future researches for elucidation of the unresolved issues. Everyone interested in heart failure is expected to find this compilation helpful for a deeper understanding of some of the complex issues.

Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options.

PubMed

Tanna, Preena; Strauss, Rupert W; Fujinami, Kaoru; Michaelides, Michel

2017-01-01

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Folliculitis in prurigo pigmentosa: a proposed pathogenesis based on clinical and pathological observation.

PubMed

Kafle, Santosh U; Swe, Sai Myint; Hsiao, Pa-Fan; Tsai, Yi-Chiun; Wu, Yu-Hung

2017-01-01

Prurigo pigmentosa is a rare inflammatory dermatosis whose exact etiology is not understood yet. The purpose of this study was to provide evidence of hair follicle involvement in the pathogenesis by analyzing its clinicopathologic features. Patients who fulfilled both the clinical and histological diagnostic criteria of prurigo pigmentosa were recruited. Their histopathologic findings, clinical features and medical histories were analyzed. A total of 32 confirmed patients were enrolled from 2002 to 2013. Their ages ranged from 11 to 79 years with a female predominance. Patient lesions were primarily reddish-brown and located on the back. A total of 25 patients (78%) had pathological involvement of hair follicles, either bacterial colonies in the hair follicles (21/32, 66%), folliculitis (8/32, 25%) or perifolliculitis (15/32, 47%). There was a significantly higher proportion of patients with hair follicle involvement compared with control groups with either noninflammatory (5/43, 12%, p < 0.001) or inflammatory skin diseases (12/32, 38%, p = 0.002) on the back. Minocycline was an effective antibiotic treatment either singly or in combination with steroids. The frequent presence of bacterial colonies along with sequelae of inflammatory changes on biopsy provides new evidence to support the theory that prurigo pigmentosa is a reactive inflammation associated with bacterial folliculitis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

POLG1-related levodopa-responsive parkinsonism.

PubMed

Miguel, Rita; Gago, Miguel Fernandes; Martins, João; Barros, Pedro; Vale, José; Rosas, Maria José

2014-11-01

Parkinsonian features have been described in patients with POLG1 mutations. Notwithstanding, the clinical expression has been revealed heterogeneous and the response to dopaminergic treatment has been document in few cases. We aim to describe the longitudinal clinical features and the treatment response of three unrelated patients with neurodegenerative parkinsonism, preceded by PEO and SANDO syndromes, who harbor POLG1 mutations, including two novel mutations. It was documented a sustained response to levodopa, at 3 and 8 years of follow-up of parkinsonian syndrome, and reduced striatal dopamine uptake. We review the genotypic and phenotypic spectrum of POLG1-related parkinsonism. Our observations stimulate the debate around the role of mitochondrial DNA defects in the pathogenesis of neurodegenerative parkinsonism. Copyright © 2014 Elsevier B.V. All rights reserved.

[The role of stress-induced chronic subclinical inflammation in the pathogenesis of the chronic pelvic pain syndrome IIIB in men].

PubMed

Shormanov, I S; Mozhaev, I I; Sokolova, Kh A; Solovev, A S

2017-12-01

This literature review of recent clinical and experimental studies describes the role of oxidative stress in the multifactorial and interdisciplinary pathogenesis of non-inflammatory chronic pelvic pain syndrome IIIB (CPPS-IIIB) in men. The authors outline general biological nature of oxidative stress and its mechanisms. More detailed information is presented on cytokine-mediated chronic subclinical inflammation, one of the key mechanisms of oxidative stress, which is currently being actively studied. It is shown that the imbalance between pro- and anti-inflammatory cytokines observed in patients with CPPS-IIIB can explain some features of the clinical course (in particular, the characteristics of the pain syndrome) and the progression of this disease. In this regard, cytokine profiling of prostatic secretion can provide valuable diagnostic, prognostic and monitoring information in the management of this category of patients. Recently published evidence has demonstrated the essential role of the cytokine-mediated chronic inflammatory response as a mechanism of oxidative stress in the pathogenesis of CPPS-IIIB. Further studies in this area are warranted and in the long term may become a basis for the development of new effective pathogenetic pharmacotherapy of CPPS-IIIB.

The role of macrophages and eosinophils in reactive lesions of the oral cavity.

PubMed

Aghbali, Amir Ala; Akbarzadeh, Ayshin; Kouhsoltani, Maryam

2018-01-01

Many studies have reported that macrophages and eosinophils are involved in the pathogenesis of several diseases. To the best of our knowledge, this is the first study comparing macrophages and eosinophils in oral reactive lesions. In this study, we aimed to determine the contribution of macrophages and eosinophils to the pathogenesis of oral reactive lesions and the relationships between these biomarkers and the diverse histopathologic features. Seventy-five paraffin-embedded tissue samples were assessed in this study. Five categories (15 cases for each group), including peripheral ossifying fibroma, pyogenic granuloma, fibroma, inflammatory fibrous hyperplasia, and peripheral giant-cell granuloma, were considered. Anti-CD68 immunohistochemical and hematoxylin-eosin staining was carried out. We found that macrophages, but not eosinophils, were a significant internal component of oral reactive lesions. Macrophages were observed in high densities in all studied groups and diffusely distributed or clustered throughout these lesions. The number of macrophages was increased in peripheral giant-cell granuloma compared with other groups. Our findings suggest that macrophages are involved in the pathogenesis and the variation of microscopic features of oral reactive lesions. However, further clinical studies should be conducted to identify the biological process behind macrophages and the molecular interactions of these cells, with the ultimate aim of suggesting a new potential therapeutic target for these lesions. We found that eosinophils were not involved in the fibrotic process and the variation of microscopic features in oral reactive lesions. Our results showed that peripheral giant-cell granulomas highly demonstrated histiocytic characteristics.

[Clinicopathologic features of drug-induced vanishing bile duct syndrome].

PubMed

Ye, L H; Wang, C K; Zhang, H C; Liu, Z Q; Zheng, H W

2017-04-20

Vanishing bile duct syndrome (VBDS) manifests as progressive destruction and disappearance of the intrahepatic bile duct caused by various factors and cholestasis. VBDS associated with drug-induced liver injury (D-VBDS) is an important etiology of VBDS, and immune disorder or immune imbalance may be the main pathogenesis. According to its clinical symptoms, serological markers, and course of the disease, D-VBDS is classified into major form and minor form, and its clinical features are based on various pathomorphological findings. Its prognosis is associated various factors including regeneration of bile duct cells, number of bile duct injuries, level and range of bile duct injury, bile duct proliferation, and compensatory shunt of bile duct branches. This disease has various clinical outcomes; most patients have good prognosis after drug withdrawal, and some patients may experience cholestatic cirrhosis, liver failure, and even death. Due to the clinical manifestation and biochemical changes are similar to the primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it need to identify by clinical physician.

Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features.

PubMed

Merkel, Emily A; Gerami, Pedram

2017-06-01

In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non-UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations.

Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review

PubMed Central

van den Brand, Michiel; van Krieken, J. Han J.M.

2013-01-01

The diagnosis of nodal marginal zone lymphoma is one of the remaining problem areas in hematopathology. Because no established positive markers exist for this lymphoma, it is frequently a diagnosis of exclusion, making distinction from other low-grade B-cell lymphomas difficult or even impossible. This systematic review summarizes and discusses the current knowledge on nodal marginal zone lymphoma, including clinical features, epidemiology and etiology, histology, and cytogenetic and molecular features. In particular, recent advances in diagnostics and pathogenesis are discussed. New immunohistochemical markers have become available that could be used as positive markers for nodal marginal zone lymphoma. These markers could be used to ensure more homogeneous study groups in future research. Also, recent gene expression studies and studies describing specific gene mutations have provided clues to the pathogenesis of nodal marginal zone lymphoma, suggesting deregulation of the nuclear factor kappa B pathway. Nevertheless, nodal marginal zone lymphoma remains an enigmatic entity, requiring further study to define its pathogenesis to allow an accurate diagnosis and tailored treatment. However, recent data indicate that it is not related to splenic or extranodal lymphoma, and that it is also not related to lymphoplasmacytic lymphoma. Thus, even though the diagnosis is not always easy, it is clearly a separate entity. PMID:23813646

High-resolution copy number variation analysis of schizophrenia in Japan.

PubMed

Kushima, I; Aleksic, B; Nakatochi, M; Shimamura, T; Shiino, T; Yoshimi, A; Kimura, H; Takasaki, Y; Wang, C; Xing, J; Ishizuka, K; Oya-Ito, T; Nakamura, Y; Arioka, Y; Maeda, T; Yamamoto, M; Yoshida, M; Noma, H; Hamada, S; Morikawa, M; Uno, Y; Okada, T; Iidaka, T; Iritani, S; Yamamoto, T; Miyashita, M; Kobori, A; Arai, M; Itokawa, M; Cheng, M-C; Chuang, Y-A; Chen, C-H; Suzuki, M; Takahashi, T; Hashimoto, R; Yamamori, H; Yasuda, Y; Watanabe, Y; Nunokawa, A; Someya, T; Ikeda, M; Toyota, T; Yoshikawa, T; Numata, S; Ohmori, T; Kunimoto, S; Mori, D; Iwata, N; Ozaki, N

2017-03-01

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10 -9 , 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Joint involvement in systemic lupus erythematosus: From pathogenesis to clinical assessment.

PubMed

Ceccarelli, Fulvia; Perricone, Carlo; Cipriano, Enrica; Massaro, Laura; Natalucci, Francesco; Capalbo, Giuseppe; Leccese, Ilaria; Bogdanos, Dimitrios; Spinelli, Francesca Romana; Alessandri, Cristiano; Valesini, Guido; Conti, Fabrizio

2017-08-01

In the present review, the different phenotypes, clinimetric and imaging tools able to assess joint involvement in patients affected by Systemic Lupus Erythematosus (SLE) have been described and summarized. Furthermore, the current knowledge about the pathogenic mechanism and the potential biomarkers of this feature is reported. A literature search was done in PubMed, accessed via the National Library of Medicine PubMed interface (http://www.ncbi.nlm.nih.gov/pubmed). Firstly, PubMed was searched using the term "systemic lupus erythematosus" OR "lupus" in combination with (AND) "joint" OR "articular".Secondly, the same PubMed research was combined with other terms, such as "pathogenesis" OR "genetic" OR "antibodies" OR "biomarkers" OR "cytokines" OR "imaging" OR "ultrasonography" OR "magnetic resonance" OR "clinimetry". After a stringent selection, we evaluated in the present review 13 papers concerning clinical phenotypes of SLE joint involvement, 14 concerning clinimetric assessment, 20 concerning imaging, and finally, 28 concerning pathogenesis and biomarkers. Further relevant data were obtained from the reference lists of articles returned using these search terms and from authors own experience and knowledge of the literature. Despite the prevalence and severity of SLE joint involvement, more awareness and a deeper evaluation of the clinical heterogeneity of this manifestation are mandatory. Moreover, longitudinal studies are needed to assess the progression of this manifestation and to provide standard definitions and examination/recording protocols. Copyright © 2017 Elsevier Inc. All rights reserved.

Pathogenesis of Idiopathic Pulmonary Fibrosis

PubMed Central

Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325.

PubMed

Carew, Jennifer S; Nawrocki, Steffan T

2017-04-03

Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in vitro and in vivo studies in preclinical models of renal cell carcinoma demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy inhibition, was very well tolerated, and exhibited significant superiority with respect to autophagy inhibition and anticancer activity over hydroxychloroquine. Our findings support the clinical investigation of the safety and preliminary efficacy of ROC-325 in patients with autophagy-dependent malignancies and other disorders where aberrant autophagy contributes to disease pathogenesis.

Association of myasthenia gravis and Behçet's disease: A case report.

PubMed

Kisabay, Aysin; Sari, Ummu Serpil; Boyaci, Recep; Batum, Melike; Yilmaz, Hikmet; Selcuki, Deniz

2016-01-01

Myasthenia gravis is a disease of neuromuscular junction due to auto-immune destruction of the acetylcholine receptors. Behçet's disease, on the other hand, is a multisystemic vascular-inflammatory disease. Both conditions are not common in the general population although their association has not been reported in the literature. We wanted to present our patient who developed clinical course of myasthenia gravis following discontinuation of medications due to complications of corticosteroid for Behçet's disease. It was observed that clinical findings of myasthenia gravis recovered following restarting steroid treatment and he did not experience attacks of both conditions. Although Myasthenia gravis and Behçet's disease are distinct entities clinically as well as in terms of pathogenesis, they share common physiopathological features and their treatment is based on their common features. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Restrictive allograft syndrome and idiopathic pleuroparenchymal fibroelastosis: do they really have the same histology?

PubMed

Montero, Maria A; Osadolor, Tina; Khiroya, Reena; Salcedo, Maria Teresa; Robertus, Jan L; Rice, Alexandra; Nicholson, Andrew G; Roman, Antonio; Monforte, Victor

2017-06-01

Restrictive allograft syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation, with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. We selected four postmortem allograft lungs from patients who developed a clear clinical RAS pattern, five biopsies diagnosed as IPPFE, five UIP biopsies and five sections of normal lung. Histopathological features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibrointimal thickening, less fibroblastic foci (FF) at the advancing edge of the fibrosis (one against 14.4 FF in 2 mm 2 ) and a slight reduction of the capillary network compared to UIP (P = 0.07) and controls (P = 0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. © 2017 John Wiley & Sons Ltd.

Oral Lichen Planus: An Update on Etiology, Pathogenesis, Clinical Presentation, Diagnosis and Management

PubMed Central

Gupta, Sonia; Jawanda, Manveen Kaur

2015-01-01

The mouth is a mirror of health or disease, a sentinel or early warning system. The oral cavity might well be thought as a window to the body because oral manifestations accompany many systemic diseases. In many instances, oral involvement precedes the appearance of other symptoms or lesions at other locations. Oral lichen planus (OLP) is a chronic mucocutaneous disorder of stratified squamous epithelium of uncertain etiology that affects oral and genital mucous membranes, skin, nails, and scalp. LP is estimated to affect 0.5% to 2.0% of the general population. This disease has most often been reported in middle-aged patients with 30-60 years of age and is more common in females than in males. The disease seems to be mediated by an antigen-specific mechanism, activating cytotoxic T cells, and non-specific mechanisms like mast cell degranulation and matrix metalloproteinase activation. A proper understanding of the pathogenesis, clinical presentation, diagnosis of the disease becomes important for providing the right treatment. This article discusses the prevalence, etiology, clinical features, oral manifestations, diagnosis, complications and treatment of oral LP. PMID:26120146

Hypohidrotic and hidrotic ectodermal dysplasia: a report of two cases.

PubMed

Vasconcelos Carvalho, Marianne; Romero Souto de Sousa, José; Paiva Correa de Melo, Filipe; Fonseca Faro, Tatiane; Nunes Santos, Ana Clara; Carvalho, Silvia; Veras Sobral, Ana Paula

2013-07-14

Ectodermal dysplasias are a large group of syndromes characterized by anomalies in the structures of ectodermal origin. There are 2 major types of this disorder, based on clinical findings: hypohidrotic ectodermal dysplasia and hidrotic ectodermal dysplasia. This clinical classification is very important because clinical professionals involved with this disease need first a clear and practical method of diagnosis. The main oral manifestation of ectodermal dysplasia may be expressed as hypodontia. Thus, dental professionals may be the first to diagnose ectodermal dysplasia. The present article reports one case of each of the main types (hypohidrotic and hidrotic) of ectodermal dysplasia and the authors review the literature regarding the pathogenesis, clinical features, and therapeutic management of this condition.

[A disseminated form of Langerhans histiocytosis associated with diabetes insipidus and diabetes mellitus].

PubMed

Ben Ghorbel, I; Houman, M H; B'chir, S; Chamakhi, S; Miled, M

2001-05-01

Langerhans' cell histiocytosis is a rare disorder of unknown etiology characterized by a wide clinical spectrum and varied behavior. Diabetes insipidus is a relatively common feature in Langerhans' cell histiocytosis. The presence of both diabetes insipidus and mellitus associated with histiocytosis in an adult is rare. To our knowledge, only three previous cases have been reported. We report the clinical presentation, pathologic findings and clinical progress in an adult female who had disseminated Langerhans' cell histiocytosis (hypothalamic infiltration, multifocal bone involvement) associated with both diabetes insipidus and mellitus. The pathogenesis of diabetes mellitus in such an association will be discussed.

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance

PubMed Central

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications. PMID:29867996

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance.

PubMed

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.

The clinical maze of mitochondrial neurology

PubMed Central

DiMauro, Salvatore; Schon, Eric A.; Carelli, Valerio; Hirano, Michio

2014-01-01

Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. PMID:23835535

Polypoidal Choroidal Vasculopathy: Definition, Pathogenesis, Diagnosis, and Management.

PubMed

Cheung, Chui Ming Gemmy; Lai, Timothy Y Y; Ruamviboonsuk, Paisan; Chen, Shih-Jen; Chen, Youxin; Freund, K Bailey; Gomi, Fomi; Koh, Adrian H; Lee, Won-Ki; Wong, Tien Yin

2018-05-01

Polypoidal choroidal vasculopathy (PCV) is an age-related macular degeneration (AMD) subtype and is seen particularly in Asians. Previous studies have suggested disparity in response to intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents between PCV and typical AMD, and thus, the preferred treatment for PCV has remained unclear. Recent research has provided novel insights into the pathogenesis of PCV, and imaging studies based on OCT suggest that PCV belongs to a spectrum of conditions characterized by pachychoroid, in which disturbance in the choroidal circulation seems to be central to its pathogenesis. Advances in imaging, including enhanced depth imaging, swept-source OCT, en face OCT, and OCT angiography, have facilitated the diagnosis of PCV. Importantly, 2 large, multicenter randomized clinical trials evaluating the safety and efficacy of anti-VEGF monotherapy and combination with photodynamic therapy (PDT) recently reported initial first-year outcomes, providing level I evidence to guide clinicians in choosing the most appropriate therapy for PCV. In this review, we summarize the latest updates in the epidemiologic features, pathogenesis, and advances in imaging and treatment trials, with a focus on the most recent key clinical trials. Finally, we propose current management guidelines and recommendations to help clinicians manage patients with PCV. Remaining gaps in current understanding of PCV, such as significance of polyp closure, high recurrence rate, and heterogeneity within PCV, are highlighted where further research is needed. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Complement in Lupus Nephritis: New Perspectives.

PubMed

Bao, Lihua; Cunningham, Patrick N; Quigg, Richard J

2015-09-01

Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue. The involvement of the complement system in the pathogenesis of SLE is well accepted; yet, its exact role is still not clear. Complement plays dual roles in the pathogenesis of SLE. On the one hand, the complement system appears to have protective features in that hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE. On the other hand, IC-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathological features that are logical consequences of complement activation. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis, while treatment with recombinant protein inhibitors, such as Crry-Ig, CR2-Crry, CR2-DAF and CR2-CFH, ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor and a monoclonal anti-C5 antibody (eculizumab), have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. SLE is an autoimmune disorder which targets multiple systems. Complement is centrally involved and plays dual roles in the pathogenesis of SLE. Studies from experimental lupus models and clinical trials support the use of complement-targeted therapy in the treatment of SLE.

Vascular calcification: When should we interfere in chronic kidney disease patients and how?

PubMed Central

Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

2016-01-01

Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients. PMID:27648404

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A

PubMed Central

Amphlett, A.

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis. PMID:26819960

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A.

PubMed

Amphlett, A

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis.

Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment.

PubMed

Blavignac, Jessica; Bunimov, Natalia; Rivard, Georges E; Hayward, Catherine P M

2011-09-01

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment. Thieme Medical Publishers.

Human cytomegalovirus and Epstein-Barr virus in etiopathogenesis of apical periodontitis: a systematic review.

PubMed

Jakovljevic, Aleksandar; Andric, Miroslav

2014-01-01

During the last decade, a hypothesis has been established that human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) may be implicated in the pathogenesis of apical periodontitis. The aim of this review was to analyze the available evidence that indicates that HCMV and EBV can actually contribute to the pathogenesis of periapical lesions and to answer the following focused question: is there a relationship between HCMV and EBV DNA and/or RNA detection and the clinical features of human periapical lesions? The literature search covered MEDLINE, Science Citation Index Expanded (SCIexpanded), Scopus, and The Cochrane Library database. Quantitative statistical analysis was performed on the pooled data of HCMV and EBV messenger RNA transcripts in tissues of symptomatic and asymptomatic periapical lesions. The electronic database search yielded 48 hits from PubMed, 197 hits from Scopus, 40 hits from Web of Science, and 1 from the Cochrane Library. Seventeen cross-sectional studies have been included in the final review. The pooled results from quantitative systematic method analysis showed no statistically significant relationship between the presence of HCMV and EBV messenger RNA transcripts (P = .083 and P = .306, respectively) and the clinical features of apical periodontitis. The findings of HCMV and EBV transcripts in apical periodontitis were controversial among the included studies. Herpesviruses were common in symptomatic and large-size periapical lesions, but such results failed to reach statistical significance. Further studies, including those based on an experimental animal model, should provide more data on herpesviruses as a factor in the pathogenesis of periapical inflammation. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Hyperhidrosis in naïve purpose-bred beagle dogs (Canis familiaris).

PubMed

Carrier, Catherine A; Seeman, Jennifer L; Hoffmann, Guenther

2011-05-01

This case study details the unusual clinical findings in a unique paw-pad disorder that recently emerged among 2 male and 1 female naïve purpose-bred beagle dogs (Canis familiaris) newly received into our facility. During acclimation period physical examinations, the affected dogs demonstrated constantly moist, soft paw pads on all 4 feet. No information was available regarding the epidemiology and pathogenesis of this pad condition in beagle dogs. Here, we report the results of physical examination, clinical chemistry analysis, hematology, histopathology, detailed observations, and novel testing techniques performed during the acclimation period. Histopathology of several sections of affected footpads was compared with that of an age-matched dog with clinically normal paw pads. We describe the morphologic features of a distinctive cutaneous canine footpad condition and discuss the possible differential diagnoses. The histologic and clinical features were most consistent with those of hyperhidrosis; to our knowledge, this report is the first description of hyperhidrosis as a distinct condition in purpose-bred beagle dogs.

Hyperhidrosis in Naïve Purpose-Bred Beagle Dogs (Canis familiaris)

PubMed Central

Carrier, Catherine A; Seeman, Jennifer L; Hoffmann, Guenther

2011-01-01

This case study details the unusual clinical findings in a unique paw-pad disorder that recently emerged among 2 male and 1 female naïve purpose-bred beagle dogs (Canis familiaris) newly received into our facility. During acclimation period physical examinations, the affected dogs demonstrated constantly moist, soft paw pads on all 4 feet. No information was available regarding the epidemiology and pathogenesis of this pad condition in beagle dogs. Here, we report the results of physical examination, clinical chemistry analysis, hematology, histopathology, detailed observations, and novel testing techniques performed during the acclimation period. Histopathology of several sections of affected footpads was compared with that of an age-matched dog with clinically normal paw pads. We describe the morphologic features of a distinctive cutaneous canine footpad condition and discuss the possible differential diagnoses. The histologic and clinical features were most consistent with those of hyperhidrosis; to our knowledge, this report is the first description of hyperhidrosis as a distinct condition in purpose-bred beagle dogs. PMID:21640037

Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

PubMed

Milo, Ron

2015-04-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of a putative autoimmune origin characterized by neurologic dysfunction disseminated in space and time due to demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of the disease resulted in the introduction of numerous effective immunomodulatoty drugs having diverse mechanisms of action, modes of administration and risk-benefit profiles. This results in more complex albeit more promising treatment selection and choices. The epidemiology, clinical features, pathogenesis and diagnosis of the disease are discussed. The mode of action and main characteristics of current immunomodulatory drugs for MS and their place in the therapeutic algorithm of the disease based on evidence from clinical trials are described. Speculation on new paradigms, treatment goals and outcome measures aimed at improving the landscape of MS treatment is presented. Multiple disease, drug and patient-related factors should be taken into consideration when selecting the appropriate drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

Post-Polio Syndrome and the Late Effects of Poliomyelitis: Part 1. Pathogenesis, Biomechanical Considerations, Diagnosis, and Investigations.

PubMed

Lo, Julian K; Robinson, Lawrence R

2018-05-12

Post-Polio Syndrome (PPS) is characterized by new muscle weakness and/or muscle fatigability that occurs many years following the initial poliomyelitis illness. There are many theories that exist on the pathogenesis of PPS, which remains incompletely understood. In contrast, the Late Effects of Poliomyelitis are often a consequence of biomechanical alterations that occur as a result of polio-related surgeries, musculoskeletal deformities or weakness. Osteoporosis and fractures of the polio-involved limbs are common. A comprehensive clinical evaluation with appropriate investigations is essential to fulfilling the established PPS diagnostic criteria. PPS is a diagnosis of exclusion, in which a key clinical feature required for the diagnosis is new muscle weakness and/or muscle fatigability that is persistent for at least one year. Electromyographic and muscle biopsy findings including evidence of ongoing denervation cannot reliably distinguish between patients with or without PPS. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Fibromyalgia Pathogenesis and Treatment Options Update.

PubMed

Chinn, Steven; Caldwell, William; Gritsenko, Karina

2016-04-01

This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.

Airway smooth muscle in asthma: linking contraction and mechanotransduction to disease pathogenesis and remodelling.

PubMed

Noble, Peter B; Pascoe, Chris D; Lan, Bo; Ito, Satoru; Kistemaker, Loes E M; Tatler, Amanda L; Pera, Tonio; Brook, Bindi S; Gosens, Reinoud; West, Adrian R

2014-12-01

Asthma is an obstructive airway disease, with a heterogeneous and multifactorial pathogenesis. Although generally considered to be a disease principally driven by chronic inflammation, it is becoming increasingly recognised that the immune component of the pathology poorly correlates with the clinical symptoms of asthma, thus highlighting a potentially central role for non-immune cells. In this context airway smooth muscle (ASM) may be a key player, as it comprises a significant proportion of the airway wall and is the ultimate effector of acute airway narrowing. Historically, the contribution of ASM to asthma pathogenesis has been contentious, yet emerging evidence suggests that ASM contractile activation imparts chronic effects that extend well beyond the temporary effects of bronchoconstriction. In this review article we describe the effects that ASM contraction, in combination with cellular mechanotransduction and novel contraction-inflammation synergies, contribute to asthma pathogenesis. Specific emphasis will be placed on the effects that ASM contraction exerts on the mechanical properties of the airway wall, as well as novel mechanisms by which ASM contraction may contribute to more established features of asthma such as airway wall remodelling. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Paraneoplastic syndromes. Associated with lung cancer].

PubMed

Ochoa-Carrillo, Francisco Javier; Chávez-Mac Gregor, Mariana; Green-Renner, Dan; Green-Schneeweiss, León

2003-01-01

Paraneoplastic syndromes are disorders of host organ function occurring at a site remote from the primary tumor and its metastases. Paraneoplastic syndromes associated with primary lung cancer are not uncommon, have diverse initial manifestations, and epitomize the systemic nature of human malignant disease. The spectrum of clinical features in patients with paraneoplastic syndromes is very wide. Although diagnosis is often one of exclusion, improved understanding of the pathogenesis involved in some of these syndromes has provided another means of recognizing these disorders and perhaps treating affected patients. In this update, we review paraneoplastic syndromes associated with lung cancer, potential mechanisms, clinical manifestations, diagnosis, and treatment.

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy

PubMed Central

Chua, Jason P.; Lieberman, Andrew P.

2014-01-01

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work. PMID:24040817

Oxidative Stress and Erythrocyte Membrane Alterations in Children with Autism: Correlation with Clinical Features.

PubMed

Ghezzo, Alessandro; Visconti, Paola; Abruzzo, Provvidenza M; Bolotta, Alessandra; Ferreri, Carla; Gobbi, Giuseppe; Malisardi, Gemma; Manfredini, Stefano; Marini, Marina; Nanetti, Laura; Pipitone, Emanuela; Raffaelli, Francesca; Resca, Federica; Vignini, Arianna; Mazzanti, Laura

2013-01-01

It has been suggested that oxidative stress may play a role in the pathogenesis of Autism Spectrum Disorders (ASD), but the literature reports somewhat contradictory results. To further investigate the issue, we evaluated a high number of peripheral oxidative stress parameters, and some related issues such as erythrocyte membrane functional features and lipid composition. Twenty-one autistic children (Au) aged 5 to 12 years, were gender and age-matched with 20 typically developing children (TD). Erythrocyte thiobarbituric acid reactive substances, urinary isoprostane and hexanoyl-lysine adduct levels were elevated in Au, thus confirming the occurrence of an imbalance of the redox status of Au, whilst other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma radical absorbance capacity and carbonyl groups, erythrocyte superoxide dismutase and catalase activities) were unchanged. A very significant reduction of Na(+)/K(+)-ATPase activity (-66%, p<0.0001), a reduction of erythrocyte membrane fluidity and alteration in erythrocyte fatty acid membrane profile (increase in monounsaturated fatty acids, decrease in EPA and DHA-ω3 with a consequent increase in ω6/ω3 ratio) were found in Au compared to TD, without change in membrane sialic acid content. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity. Oxidative stress and erythrocyte membrane alterations may play a role in the pathogenesis of ASD and prompt the development of palliative therapeutic protocols. Moreover, the marked decrease in NKA could be potentially utilized as a peripheral biomarker of ASD.

ACUTE RETINAL ARTERIAL OCCLUSIVE DISORDERS

PubMed Central

Hayreh, Sohan Singh

2011-01-01

The initial section deals with basic sciences; among the various topics briefly discussed are the anatomical features of ophthalmic, central retinal and cilioretinal arteries which may play a role in acute retinal arterial ischemic disorders. Crucial information required in the management of central retinal artery occlusion (CRAO) is the length of time the retina can survive following that. An experimental study shows that CRAO for 97 minutes produces no detectable permanent retinal damage but there is a progressive ischemic damage thereafter, and by 4 hours the retina has suffered irreversible damage. In the clinical section, I discuss at length various controversies on acute retinal arterial ischemic disorders. Classification of acute retinal arterial ischemic disorders These are of 4 types: CRAO, branch retinal artery occlusion (BRAO), cotton wools spots and amaurosis fugax. Both CRAO and BRAO further comprise multiple clinical entities. Contrary to the universal belief, pathogenetically, clinically and for management, CRAO is not one clinical entity but 4 distinct clinical entities – non-arteritic CRAO, non-arteritic CRAO with cilioretinal artery sparing, arteritic CRAO associated with giant cell arteritis (GCA) and transient non-arteritic CRAO. Similarly, BRAO comprises permanent BRAO, transient BRAO and cilioretinal artery occlusion (CLRAO), and the latter further consists of 3 distinct clinical entities - non-arteritic CLRAO alone, non-arteritic CLRAO associated with central retinal vein occlusion and arteritic CLRAO associated with GCA. Understanding these classifications is essential to comprehend fully various aspects of these disorders. Central retinal artery occlusion The pathogeneses, clinical features and management of the various types of CRAO are discussed in detail. Contrary to the prevalent belief, spontaneous improvement in both visual acuity and visual fields does occur, mainly during the first 7 days. The incidence of spontaneous visual acuity improvement during the first 7 days differs significantly (p<0.001) among the 4 types of CRAO; among them, in eyes with initial visual acuity of counting finger or worse, visual acuity improved, remained stable or deteriorated in nonarteritic CRAO in 22%, 66% and 12% respectively; in nonarteritic CRAO with cilioretinal artery sparing in 67%, 33% and none respectively; and in transient nonarteritic CRAO in 82%, 18% and none respectively. Arteritic CRAO shows no change. Recent studies have shown that administration of local intra-arterial thrombolytic agent not only has no beneficial effect but also can be harmful. Prevalent multiple misconceptions on CRAO are discussed. Branch retinal artery occlusion Pathogeneses, clinical features and management of various types of BRAO are discussed at length. The natural history of visual acuity outcome shows a final visual acuity of 20/40 or better in 89% of permanent BRAO cases, 100% of transient BRAO and 100% of nonarteritic CLRAO alone. Cotton wools spots These are common, non-specific acute focal retinal ischemic lesions, seen in many retinopathies. Their pathogenesis and clinical features are discussed in detail. Amaurosis fugax Its pathogenesis, clinical features and management are described. PMID:21620994

The juvenile idiopathic inflammatory myopathies: pathogenesis, clinical and autoantibody phenotypes, and outcomes

PubMed Central

Rider, Lisa G.; Nistala, Kiran

2015-01-01

The aim of this review is to summarize recent advances in the understanding of the clinical and autoantibody phenotypes, their associated outcomes, and the pathogenesis of the juvenile idiopathic inflammatory myopathies (JIIMs). The major clinical and autoantibody phenotypes in children have many features similar to those in adults, and each has distinct demographic and clinical features and associated outcomes. The most common myositis autoantibodies in JIIM patients are anti-p155/140, anti-MJ, and anti-MDA5. Higher mortality has been associated with overlap myositis as well as with the presence of anti-synthetase and anti-MDA5 autoantibodies; a chronic illness course and lipodystrophy have been associated with anti-p155/140 autoantibodies; and calcinosis has been associated with anti-MJ autoantibodies. Histologic abnormalities of JIIMs detectable on muscle biopsy have also been correlated with myositis-specific autoantibodies; for example, patients with anti-MDA5 show low levels of inflammatory infiltrate and muscle damage on biopsy. The first genome-wide association study of adult and juvenile dermatomyositis revealed three novel genetic associations, BLK, PLCL1, and CCL21, and confirmed that the human leukocyte antigen region is the primary risk region for juvenile dermatomyositis. Here we review the well-established pathogenic processes in JIIMs, including the type 1 interferon and endoplasmic reticulum stress pathways. Several novel JIIM-associated inflammatory mediators, such as the innate immune system proteins, myeloid-related peptide 8/14, galectin 9, and eotaxin, have emerged as promising biomarkers of disease. Advances in our understanding of the phenotypes and pathophysiology of the JIIMs are leading to better tools to help clinicians stratify and treat these heterogeneous disorders. PMID:27028907

Multiproteinopathy, neurodegeneration and old age: a case study.

PubMed

Rojas, Julio C; Stephens, Melanie L; Rabinovici, Gil D; Kramer, Joel H; Miller, Bruce L; Seeley, William W

2018-02-01

A complex spectrum of mixed brain pathologies is common in older people. This clinical pathologic conference case study illustrates the challenges of formulating clinicopathologic correlations in late-onset neurodegenerative diseases featuring cognitive-behavioral syndromes with underlying multiple proteinopathy. Studies on the co-existence and interactions of Alzheimer's disease (AD) with neurodegenerative non-AD pathologies in the aging brain are needed to understand the pathogenesis of neurodegeneration and to support the development of diagnostic biomarkers and therapies.

Multiproteinopathy, neurodegeneration and old age: a case study

PubMed Central

Rojas, Julio C.; Stephens, Melanie L.; Rabinovici, Gil D.; Kramer, Joel H.; Miller, Bruce L.; Seeley, William W.

2018-01-01

A complex spectrum of mixed brain pathologies is common in older people. This clinical pathologic conference case study illustrates the challenges of formulating clinicopathologic correlations in late-onset neurodegenerative diseases featuring cognitive-behavioral syndromes with underlying multiple proteinopathy. Studies on the co-existence and interactions of Alzheimer’s disease (AD) with neurodegenerative non-AD pathologies in the aging brain are needed to understand the pathogenesis of neurodegeneration and to support the development of diagnostic biomarkers and therapies. PMID:29307276

Understanding the molecular pathogenesis of acute promyelocytic leukemia.

PubMed

Lo-Coco, Francesco; Hasan, Syed Khizer

2014-03-01

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e. PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of Therapy-related APL (t-APL). Copyright © 2014 Elsevier Ltd. All rights reserved.

Human Rhinoviruses

PubMed Central

Lamson, Daryl M.; St. George, Kirsten; Walsh, Thomas J.

2013-01-01

Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs. PMID:23297263

[Systemic lupus erythematosus and pregnancy].

PubMed

Basheva, S; Nikolov, A; Stoilov, R; Stoilov, N

2012-01-01

Connective-tissue disorders, also referred to as collagen-vascular disorders, are characterized by autoantibody-mediated connective-tissue abnormalities. These are also called immune-complex diseases because many involve deposition of immune complexes in specific organ or tissue sites. Some of these disorders are characterized by sterile inflammation, especially of the skin, joints, blood vessels, and kidneys, and are referred to as rheumatic diseases. For inexplicable reasons, many rheumatic diseases primarily affect women. Another major category of connective-tissue diseases includes inherited disorders of bone, skin, cartilage, blood vessels. Examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome. Lupus erythematosus (LE) is the main and most important disease in the group of systemic connective tissue diseases. It is heterogeneous, multiple organs autoimmune inflammatory disease with complex pathogenesis, which is the result of interaction between the susceptible genes and environmental factors that lead to abnormal immune response. In this review will consider: its incidence, pathogenesis, clinical forms and clinical features and diagnosis set based on generally accepted clinical criteria developed by the American College of Rheumatology (ACR), the course of pregnancy in patients suffering from LE, the most common complications of LE during pregnancy and antiphospholipid syndrome as part of LE.

Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review.

PubMed

Atzeni, Fabiola; Gerardi, Maria Chiara; Barilaro, Giuseppe; Masala, Ignazio Francesco; Benucci, Maurizio; Sarzi-Puttini, Piercarlo

2018-01-01

Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD-ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.

The controversial role of food allergy in infantile colic: evidence and clinical management.

PubMed

Nocerino, Rita; Pezzella, Vincenza; Cosenza, Linda; Amoroso, Antonio; Di Scala, Carmen; Amato, Francesco; Iacono, Giuseppe; Canani, Roberto Berni

2015-03-19

Food allergies (FAs) are an increasing problem in Western countries, affecting up to 10% of young children. FAs are frequently associated with gastrointestinal manifestations. The role of FAs as a potential causative factor for infantile colic (IC) is still controversial. We report the most recent evidence on the pathogenesis, clinical and diagnostic aspects of FA-induced infantile colic (IC) and suggest a stepwise diagnostic approach. We selected articles on clinical and immunologic features, pathogenesis and management of FAs and IC from of 1981 to 2015. Original and review articles were identified through selective searches performed on PubMed, using the following terms: colic, infantile colic, food allergy and infantile colic, infantile colic treatment. The possible relationship between FAs and IC derives from the presence of dysmotility with visceral hypersensitivity and dysbiosis, demonstrated in both conditions, and the clinical response to dietary interventions. Unfortunately, the design of the studies, poor characterization of atopy and different dietary approaches limit the understanding of the importance of FAs in subjects with IC. The role of FAs in IC subjects without other symptoms of atopy remains controversial. However, where there is a suspicion of FAs, a short trial with an extensively hydrolyzed cow's proteins formula or, if breast fed, with maternal elimination diet may be considered a reasonable option.

A Case of Churg-Strauss Syndrome Associated with Antiphospholipid Antibodies

PubMed Central

Ferenczi, Katalin; Chang, Timothy; Camouse, Melissa; Han, Rujing; Stern, Robert; Willis, Joseph; Cooper, Kevin D.; Gilliam, Anita C.

2008-01-01

BACKGROUND Churg-Strauss syndrome (CSS) is a systemic vasculitis affecting small and medium-sized blood vessels, almost invariably affecting the lung and frequently associated with cutaneous involvement. Microvascular vaso-occlusion leading to digital gangrene is not a feature of CSS. OBSERVATIONS We report an unusual case of a patient with Churg Strauss Syndrome with antiphospholipid antibodies who developed severe digital gangrene in addition to cutaneous vasculitis. CONCLUSION The presence of antiphospholipid antibodies is not a feature usually seen in association with Churg-Strauss syndrome. While the full clinical spectrum of Churg Strauss Syndrome is still being defined, identification of additional features associated with this syndrome might help to better understand the pathogenesis of the disease and to have an impact on management and prognosis. PMID:17175066

Network Analysis of Associations between Serum Interferon Alpha Activity, Autoantibodies, and Clinical Features in Systemic Lupus Erythematosus

PubMed Central

Weckerle, Corinna E.; Franek, Beverly S.; Kelly, Jennifer A.; Kumabe, Marissa; Mikolaitis, Rachel A.; Green, Stephanie L.; Utset, Tammy O.; Jolly, Meenakshi; James, Judith A.; Harley, John B.; Niewold, Timothy B.

2010-01-01

Background Interferon-alpha (IFN-α) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFN-α levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. We used multivariate and network analyses to detect associations between clinical and serologic disease manifestations and serum IFN-α activity in a large diverse SLE cohort. Methods 1089 SLE patients were studied (387 African-American, 186 Hispanic-American, and 516 European-American). Presence or absence of ACR clinical criteria for SLE, autoantibodies, and serum IFN-α activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each background separately to establish the network of associations between variables that were independently significant following Bonferroni correction. Results In all ancestral backgrounds, high IFN-α activity was associated with anti-Ro and anti-dsDNA antibodies (p-values 4.6×10−18 and 2.9 × 10−16 respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFN-α activity (p≤6.7×10−4). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared by more than one ancestral background. Associations between clinical criteria were different in different ancestral backgrounds, while autoantibody-IFN-α relationships were similar across backgrounds. IFN-α activity and autoantibodies were not associated with ACR clinical features in multivariate models. Conclusions Serum IFN-α activity was strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFN-α may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations. PMID:21162028

Adult and juvenile dermatomyositis: are the distinct clinical features explained by our current understanding of serological subgroups and pathogenic mechanisms?

PubMed Central

2013-01-01

Adult and juvenile dermatomyositis share the hallmark features of pathognomic skin rash and muscle inflammation, but are heterogeneous disorders with a range of additional disease features and complications. The frequency of important clinical features such as calcinosis, interstitial lung disease and malignancy varies markedly between adult and juvenile disease. These differences may reflect different disease triggers between children and adults, but whilst various viral and other environmental triggers have been implicated, results are so far conflicting. Myositis-specific autoantibodies can be detected in both adults and children with idiopathic inflammatory myopathies. They are associated with specific disease phenotypes and complications, and divide patients into clinically homogenous subgroups. Interestingly, whilst the same autoantibodies are found in both adults and children, the disease features remain different within autoantibody subgroups, particularly with regard to life-threatening disease associations, such as malignancy and rapidly progressive interstitial lung disease. Our understanding of the mechanisms that underlie these differences is limited by a lack of studies directly comparing adults and children. Dermatomyositis is an autoimmune disease, which is believed to develop as a result of an environmental trigger in a genetically predisposed individual. Age-specific host immune responses and muscle physiology may be additional complicating factors that have significant impact on disease presentation. Further study into this area may produce new insights into disease pathogenesis. PMID:23566358

Pathogenesis of varicelloviruses in primates.

PubMed

Ouwendijk, Werner J D; Verjans, Georges M G M

2015-01-01

Varicelloviruses in primates comprise the prototypic human varicella-zoster virus (VZV) and its non-human primate homologue, simian varicella virus (SVV). Both viruses cause varicella as a primary infection, establish latency in ganglionic neurons and reactivate later in life to cause herpes zoster in their respective hosts. VZV is endemic worldwide and, although varicella is usually a benign disease in childhood, VZV reactivation is a significant cause of neurological disease in the elderly and in immunocompromised individuals. The pathogenesis of VZV infection remains ill-defined, mostly due to the species restriction of VZV that impedes studies in experimental animal models. SVV infection of non-human primates parallels virological, clinical, pathological and immunological features of human VZV infection, thereby providing an excellent model to study the pathogenesis of varicella and herpes zoster in its natural host. In this review, we discuss recent studies that provided novel insight in both the virus and host factors involved in the three elementary stages of Varicellovirus infection in primates: primary infection, latency and reactivation. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chorea revealing systemic lupus erythematosus in a 13-year old boy: A case report and short review of the literature.

PubMed

Athanasopoulos, E; Kalaitzidou, I; Vlachaki, G; Stefanaki, S; Tzagkaraki, A; Niotakis, G; Tritou, I; Ladomenou, F

2018-03-29

Among the neurological manifestations of systemic lupus erythematosus (SLE), chorea is rare, presenting in less than 7% of the pediatric SLE patients. It can appear early in the onset of SLE, be the first or even the sole clinical feature of the illness and has strongly been associated with the presence of antiphospholipid antibodies. We report on the case of a 13-year old boy, admitted with acute onset chorea and finally diagnosed with SLE. Subsequently, we present a short review of the literature on the epidemiology, suggested pathogenesis, clinical presentation and treatment of this rare presentation of SLE.

Two cases of traumatic head injury mimicking acute encephalopathy with biphasic seizures and late reduced diffusion.

PubMed

Nishiyama, Masahiro; Fujita, Kyoko; Maruyama, Azusa; Nagase, Hiroaki

2014-11-01

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) presents a distinct clinical course of biphasic seizures and impaired consciousness. These symptoms are followed by reduced diffusion in the subcortical white matter on magnetic resonance imaging that is typically observed between 3 and 9 days after illness onset. Here, we report two cases of traumatic head injury with clinical and radiological features similar to those for AESD. The similarities between our cases and AESD may be useful in understanding the pathogenesis of AESD. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Japanese encephalitis - the prospects for new treatments.

PubMed

Turtle, Lance; Solomon, Tom

2018-04-26

Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.

Neuropathies in the setting of Neurofibromatosis tumor syndromes: Complexities and opportunities.

PubMed

Schulz, Alexander; Grafe, Peter; Hagel, Christian; Bäumer, Philipp; Morrison, Helen; Mautner, Victor-Felix; Farschtschi, Said

2018-01-01

The term 'Neurofibromatosis' (NF) comprises a group of rare diseases with related clinical presentations but distinct genetic conditions. All currently known types - NF1, NF2 and Schwannomatosis - predispose afflicted individuals to the development of glial cell-derived (gliogenic) tumors. Furthermore, the occurrence of neuropathic symptoms, which add to the overall neurologic disability of patients, has been described in all disease entities. We show that neuropathic symptoms are a common and clinically important, yet infrequently studied feature in the NF spectrum. However, the clinical relevance and respective underlying pathogenesis, varies greatly among the different NF types. In this review, we summarize and interpret the latest basic research findings, as well as clinical observations, in respect of Neurofibromatosis-associated neuropathies. Copyright © 2017 Elsevier Inc. All rights reserved.

Nonpuerperal mastitis and subareolar abscess of the breast.

PubMed

Kasales, Claudia J; Han, Bing; Smith, J Stanley; Chetlen, Alison L; Kaneda, Heather J; Shereef, Serene

2014-02-01

The purpose of this article is to show radiologists how to readily recognize nonpuerperal subareolar abscess and its complications in order to help reduce the time to definitive therapy and improve patient care. To achieve this purpose, the various theories of pathogenesis and the associated histopathologic features are reviewed; the typical clinical characteristics are detailed in contrast to those seen in lactational abscess and inflammatory breast cancer; the common imaging findings are described with emphasis on the sonographic features; correlative pathologic findings are presented to reinforce the imaging findings as they pertain to disease origins; and the various treatment options are reviewed. Nonpuerperal subareolar mastitis and abscess is a benign breast entity often associated with prolonged morbidity. Through better understanding of the underlying disease process the imaging, physical, and clinical findings of this rare process can be more readily recognized and treatment options expedited, improving patient care.

Natural history of the classical form of primary growth hormone (GH) resistance (Laron syndrome).

PubMed

Laron, Z

1999-04-01

A description of the clinical, biochemical and endocrinological features of the classical form of the syndrome of primary growth hormone (GH) resistance (Laron syndrome) is presented including the progressive changes during follow-up from infancy into adulthood. The main diagnostic features are: severe growth retardation, acromicria, small gonads and genitalia, and obesity. Serum GH levels are elevated and insulin-like growth factor-I (IGF-I) values are low and do not rise upon stimulation by exogenous hGH. The pathogenesis of this syndrome is due to various molecular defects from exon deletion to nonsense, frameshift, splice and missense mutations in the GH receptor (GH-R) gene or in its post-receptor pathways.

Granulomatous mastitis: a report of seven cases

PubMed Central

Fletcher, A; Magrath, IM; Riddell, RH; Talbot, IC

1982-01-01

The clinical history and histological features of seven cases of granulomatous mastitis are presented. The lesion occurs in young parous women as a tender extra-areolar breast lump. Histologically, non-caseating discrete granulomas are present, confined to breast lobules with, in three cases, coalescence of the granulomas and microabscess formation. Pathogenesis of the changes is discussed. It is thought that granulomatous mastitis is an entity morphologically distinct from duct ectasia/plasma cell mastitis and the commoner forms of granulomatous breast diseases. Images PMID:6889612

Occupational acroosteolysis in a guitar player.

PubMed

Baran, R; Tosti, A

1993-02-01

A case of occupational acroosteolysis in a 24-year-old classical guitar player is reported. Nail tenderness was the only manifestation of initial acroosteolysis, which was due to mechanical stress on the fingers. Radiographs showed initial resorption of the 2nd, 3rd and 4th finger of the left hand. The authors review the clinical and radiological features of acroosteolysis. The pathogenesis of acroosteolysis is discussed as well as the different diseases that may cause destructive changes of the distal phalangeal bones.

[Pathological features of myositis with myositis -specific autoantibodies].

PubMed

Shimizu, Jun; Mimori, Tsuneyo

2014-01-01

Myositis is a heterogeneous group of systemic autoimmune disorders characterized by inflammation of skeletal muscle. Historically, myositis has been defined using clinical features including muscle weakness, skin disease, internal organ involvement, and an association with cancer in adults. From a clinicopathologic approach, myositis has been classified into pathologically distinct subsets, polymyositis, dermatomyositis(DM), necrotizing autoimmune myositis, amyopathic DM, and non-specific myositis. Although the characteristic pathological changes are believed to be important in pathological mechanisms of each subset of myositis, in clinical practices, the percentages of the patients with typical pathological findings are usually not high. On the other hand, with the recent discovery of new myositis-specific autoantibodies (MSAs), it has been revealed that around 60% of patients with IIMs have been shown to have a anti-myositis-specific autoantibody, including anti-synthetase, anti-Mi-2, anti-MDA5, anti-TIF1 and anti-SRP antibodies. Because of striking association between unique MSAs and distinct clinical phenotypes, these antibodies are thought to be important not only for classifications of IIMs, but also as factors involved in the mechanism underlying their pathogenesis. This review reports recent progress in understanding of pathological features of myositis with MSAs.

Oral candidiasis: pathogenesis, clinical presentation, diagnosis and treatment strategies.

PubMed

Lalla, Rajesh V; Patton, Lauren L; Dongari-Bagtzoglou, Anna

2013-04-01

Oral candidiasis is a clinical fungal infection that is the most common opportunistic infection affecting the human oral cavity. This article reviews the pathogenesis, clinical presentations, diagnosis and treatmentstrategies for oral candidiasis.

Cholera.

PubMed Central

Kaper, J B; Morris, J G; Levine, M M

1995-01-01

Despite more than a century of study, cholera still presents challenges and surprises to us. Throughout most of the 20th century, cholera was caused by Vibrio cholerae of the O1 serogroup and the disease was largely confined to Asia and Africa. However, the last decade of the 20th century has witnessed two major developments in the history of this disease. In 1991, a massive outbreak of cholera started in South America, the one continent previously untouched by cholera in this century. In 1992, an apparently new pandemic caused by a previously unknown serogroup of V. cholerae (O139) began in India and Bangladesh. The O139 epidemic has been occurring in populations assumed to be largely immune to V. cholerae O1 and has rapidly spread to many countries including the United States. In this review, we discuss all aspects of cholera, including the clinical microbiology, epidemiology, pathogenesis, and clinical features of the disease. Special attention will be paid to the extraordinary advances that have been made in recent years in unravelling the molecular pathogenesis of this infection and in the development of new generations of vaccines to prevent it. PMID:7704895

Lupus erythematosus revisited.

PubMed

Kuhn, Annegret; Wenzel, Joerg; Bijl, Marc

2016-01-01

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity. The exact pathomechanisms and interactions resulting in the inflammatory and immunological processes of this heterogeneous disease remain elusive. Approaches in the understanding of the pathomechanisms revealed that the clinical expression of LE is predisposed by susceptibility genes and that various environmental factors are responsible for an abnormal immune response. Several studies demonstrated that ultraviolet (UV) light is one of the major factors in the pathogenesis of the disease. Standardized photoprovocation in patients with LE has been shown to be a safe and efficient model for evaluating the underlying pathomechanisms which lead to the production of autoantibodies and immune complexes. In particular, interferons were defined as important players in the early activation of the immune system and were observed to play a specific role in the immunological interface between the innate and the adaptive immune system. Abnormalities or disturbances in the different processes of cell death, such as apoptosis or necrosis, have also been recognized as crucial in the pathogenesis of LE. Although each process is different and characterized by unique features, the processes are interrelated and result in a complex disease.

Chronic Inflammatory Demyelinating Polyneuropathy

PubMed Central

Dimachkie, Mazen M.; Barohn, Richard J.

2014-01-01

Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

Exuberant juvenile hyaline fibromatosis in two patients.

PubMed

Muniz, Mariela Leão; Lobo, Alice Zoghbi Coelho; Machado, Maria Cecília da Matta Rivitti; Valente, Neusa Yuriko Sakai; Kim, Chong Ae; Lourenço, Sílvia Vanessa; Nico, Marcello Menta Simonsen

2006-01-01

Juvenile hyaline fibromatosis and infantile systemic hyalinosis are rare autosomal recessive disorders of infancy and early childhood that are histologically characterized by deposition of hyaline material. The main clinical features are papulo-nodular skin lesions, gingival hypertrophy, joint contractures, and bone abnormalities. However, infantile systemic hyalinosis has a more severe clinical presentation, including visceral involvement and premature death. Very recently, genetic studies identified mutations in the same gene in patients with both conditions, strongly suggesting that they belong to the same disease spectrum. We report two new nonrelated patients who met the criteria for the diagnosis of juvenile hyaline fibromatosis/infantile systemic hyalinosis. Clinical, histopathologic, immunohistochemical, and ultrastructural findings are presented, as well as an extensive review of the literature. Recent information regarding pathogenesis and treatment is discussed.

Oxidative Stress and Erythrocyte Membrane Alterations in Children with Autism: Correlation with Clinical Features

PubMed Central

Visconti, Paola; Bolotta, Alessandra; Ferreri, Carla; Gobbi, Giuseppe; Malisardi, Gemma; Manfredini, Stefano; Marini, Marina; Nanetti, Laura; Pipitone, Emanuela; Raffaelli, Francesca; Resca, Federica; Mazzanti, Laura

2013-01-01

It has been suggested that oxidative stress may play a role in the pathogenesis of Autism Spectrum Disorders (ASD), but the literature reports somewhat contradictory results. To further investigate the issue, we evaluated a high number of peripheral oxidative stress parameters, and some related issues such as erythrocyte membrane functional features and lipid composition. Twenty-one autistic children (Au) aged 5 to 12 years, were gender and age-matched with 20 typically developing children (TD). Erythrocyte thiobarbituric acid reactive substances, urinary isoprostane and hexanoyl-lysine adduct levels were elevated in Au, thus confirming the occurrence of an imbalance of the redox status of Au, whilst other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma radical absorbance capacity and carbonyl groups, erythrocyte superoxide dismutase and catalase activities) were unchanged. A very significant reduction of Na+/K+-ATPase activity (−66%, p<0.0001), a reduction of erythrocyte membrane fluidity and alteration in erythrocyte fatty acid membrane profile (increase in monounsaturated fatty acids, decrease in EPA and DHA-ω3 with a consequent increase in ω6/ω3 ratio) were found in Au compared to TD, without change in membrane sialic acid content. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity. Oxidative stress and erythrocyte membrane alterations may play a role in the pathogenesis of ASD and prompt the development of palliative therapeutic protocols. Moreover, the marked decrease in NKA could be potentially utilized as a peripheral biomarker of ASD. PMID:23840462

Severity of clinical disease and pathology in ferrets experimentally infected with influenza viruses is influenced by inoculum volume.

PubMed

Moore, Ian N; Lamirande, Elaine W; Paskel, Myeisha; Donahue, Danielle; Kenney, Heather; Qin, Jing; Subbarao, Kanta

2014-12-01

Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 10(6) 50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology. Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulence of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus was administered at similar doses, different investigators reported a range of clinical disease outcomes, from asymptomatic infection to severe weight loss, ocular and nasal discharge, sneezing, and lethargy. We found that a wide range of inoculum volumes was used to experimentally infect ferrets, and we sought to determine whether the variations in disease outcome were the result of the volume of inoculum administered. These data highlight some less explored features of the model, methods of experimental infection, and clinical disease outcomes in a research setting. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Severity of Clinical Disease and Pathology in Ferrets Experimentally Infected with Influenza Viruses Is Influenced by Inoculum Volume

PubMed Central

Moore, Ian N.; Lamirande, Elaine W.; Paskel, Myeisha; Donahue, Danielle; Qin, Jing

2014-01-01

ABSTRACT Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 106 50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology. IMPORTANCE Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulence of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus was administered at similar doses, different investigators reported a range of clinical disease outcomes, from asymptomatic infection to severe weight loss, ocular and nasal discharge, sneezing, and lethargy. We found that a wide range of inoculum volumes was used to experimentally infect ferrets, and we sought to determine whether the variations in disease outcome were the result of the volume of inoculum administered. These data highlight some less explored features of the model, methods of experimental infection, and clinical disease outcomes in a research setting. PMID:25187553

Severe optic neuritis in infectious mononucleosis.

PubMed

Jones, J; Gardner, W; Newman, T

1988-04-01

Because the presentation and clinical features of infectious mononucleosis can be misleading in the elderly, a significant number of infections may go unrecognized. We report an unusual case of infectious mononucleosis in a 61-year-old man in whom marked visual impairment was the presenting complaint and severe optic neuritis was the only prominent finding. Confirmation of the diagnosis was made by serologic testing for Epstein-Barr virus antibody. Recovery of visual function was near complete, but optic atrophy persisted. We reviewed the English literature and collected seven cases of well-documented optic neuritis associated with infectious mononucleosis. A clinical profile of parainfectious optic neuritis is discussed along with the likely pathogenesis for this complication.

[Raise awareness of IgG4 relative ocular disease].

PubMed

Wei, Shihui; Li, Hongyang

2015-12-01

Purpose IgG4-related ocular disease is a chronic systemic disease with lymphocyte abnormal. The lacrimal glands, extraocular muscles and infraorbital nerve were often involved which was often the first symptom of systemic disease. While ophthalmologists did not know this disease well. They usually misdiagnosed it as idiopathic inflammatory pseudotumor, thyroid-associated ophthalmopathy etc, which resulted in delayed treatments. Here pathogenesis, clinical features and treatment methods of IgG4-relative ocular disease were described in order to improve awareness of this ocular disease, reduce clinical misdiagnosis, improve disease prognosis and standardized treatment. As the incidence of this disease increased in recent years, it is very necessary to improve awareness of the disease for ophthalmologists.

Genomics of Systemic Lupus Erythematosus: Insights Gained by Studying Monogenic Young-Onset Systemic Lupus Erythematosus.

PubMed

Hiraki, Linda T; Silverman, Earl D

2017-08-01

Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuroimaging findings of extensive sphenoethmoidal dysplasia in NF1.

PubMed

Tam, Allison; Sliepka, Joseph M; Bellur, Sunil; Bray, Collin Douglas; Lincoln, Christie M; Nagamani, Sandesh C S

2018-05-16

Whereas isolated sphenoid wing dysplasia (SWD) is a well-known clinical feature in neurofibromatosis 1 (NF1), extensive cranial defects involving multiple bones have been rarely reported in this disorder. In this report, we describe the clinical course of a 20-year-old male with NF1 and an extensive cranial bone dysplasia. The large sphenoethmoidal defect was associated with transethmoidal and orbital cephalocele as well as inferolateral herniation of the frontal lobe. In spite of the large defect, the individual did not have any symptoms or complications resulting from the osteopathy. We review the current knowledge of the pathogenesis and management of cranial bone dysplasia in NF1. Copyright © 2018 Elsevier Inc. All rights reserved.

An anatomic transcriptional atlas of human glioblastoma.

PubMed

Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy; Dalley, Rachel; Nomura, Steve R; Yoon, Jae-Guen; Smith, Kimberly A; Lankerovich, Michael; Bertagnolli, Darren; Bickley, Kris; Boe, Andrew F; Brouner, Krissy; Butler, Stephanie; Caldejon, Shiella; Chapin, Mike; Datta, Suvro; Dee, Nick; Desta, Tsega; Dolbeare, Tim; Dotson, Nadezhda; Ebbert, Amanda; Feng, David; Feng, Xu; Fisher, Michael; Gee, Garrett; Goldy, Jeff; Gourley, Lindsey; Gregor, Benjamin W; Gu, Guangyu; Hejazinia, Nika; Hohmann, John; Hothi, Parvinder; Howard, Robert; Joines, Kevin; Kriedberg, Ali; Kuan, Leonard; Lau, Chris; Lee, Felix; Lee, Hwahyung; Lemon, Tracy; Long, Fuhui; Mastan, Naveed; Mott, Erika; Murthy, Chantal; Ngo, Kiet; Olson, Eric; Reding, Melissa; Riley, Zack; Rosen, David; Sandman, David; Shapovalova, Nadiya; Slaughterbeck, Clifford R; Sodt, Andrew; Stockdale, Graham; Szafer, Aaron; Wakeman, Wayne; Wohnoutka, Paul E; White, Steven J; Marsh, Don; Rostomily, Robert C; Ng, Lydia; Dang, Chinh; Jones, Allan; Keogh, Bart; Gittleman, Haley R; Barnholtz-Sloan, Jill S; Cimino, Patrick J; Uppin, Megha S; Keene, C Dirk; Farrokhi, Farrokh R; Lathia, Justin D; Berens, Michael E; Iavarone, Antonio; Bernard, Amy; Lein, Ed; Phillips, John W; Rostad, Steven W; Cobbs, Charles; Hawrylycz, Michael J; Foltz, Greg D

2018-05-11

Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Multiple Sub-Epidermal Calcified Nodule Mimicking Eruptive Xanthoma: A Case Report and Review of the Literature

PubMed Central

Ozuguz, Pinar; Balta, Ilknur; Bozkurt, Ozlem; Unverdi, Hatice; Dostbil, Ahmet

2013-01-01

Sub-epidermal calcified nodule (SCN) is an uncommon form of idiopathic calcinosis. It usually occurs in children, particularly in the head and neck region, presenting as a solitary, painless, yellow-white nodule with papillomatous features. These lesions occur twice as common in males compared with females. The pathogenesis is uncertain, but the clinical and histological features of this lesion are distinctive. We report a case of 22-year-old man with multiple nodules bilaterally located on the dorsum of hands simulating eruptive xanthoma. Histopathological examination of one of the excised lesion confirmed the diagnosis showing epidermal and sub-epidermal deposition of calcium. This paper presents a review of the literature and adds a new case of SCN. PMID:24082201

Heparin-induced thrombocytopenia

PubMed Central

2017-01-01

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management. PMID:28416511

Pharmacotherapeutic targets in Alzheimer's disease

PubMed Central

Biran, Yif'at; Masters, Colin L; Barnham, Kevin J; Bush, Ashley I; Adlard, Paul A

2009-01-01

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated τ-protein, the amyloid-β (Aβ) peptide and metal ion dyshomeostasis – all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category. PMID:19040415

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.

PubMed

Sethi, Sanjeev; Haas, Mark; Markowitz, Glen S; D'Agati, Vivette D; Rennke, Helmut G; Jennette, J Charles; Bajema, Ingeborg M; Alpers, Charles E; Chang, Anthony; Cornell, Lynn D; Cosio, Fernando G; Fogo, Agnes B; Glassock, Richard J; Hariharan, Sundaram; Kambham, Neeraja; Lager, Donna J; Leung, Nelson; Mengel, Michael; Nath, Karl A; Roberts, Ian S; Rovin, Brad H; Seshan, Surya V; Smith, Richard J H; Walker, Patrick D; Winearls, Christopher G; Appel, Gerald B; Alexander, Mariam P; Cattran, Daniel C; Casado, Carmen Avila; Cook, H Terence; De Vriese, An S; Radhakrishnan, Jai; Racusen, Lorraine C; Ronco, Pierre; Fervenza, Fernando C

2016-05-01

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN. Copyright © 2016 by the American Society of Nephrology.

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

PubMed Central

Zheng, Hui-Wen; Sun, Ming; Guo, Lei; Wang, Jing-Jing; Song, Jie; Li, Jia-Qi; Li, Hong-Zhe; Ning, Ruo-Tong; Yang, Ze-Ning; Fan, Hai-Tao; He, Zhan-Long; Liu, Long-Ding

2017-01-01

Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis. PMID:28489053

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo).

PubMed

Zheng, Hui-Wen; Sun, Ming; Guo, Lei; Wang, Jing-Jing; Song, Jie; Li, Jia-Qi; Li, Hong-Zhe; Ning, Ruo-Tong; Yang, Ze-Ning; Fan, Hai-Tao; He, Zhan-Long; Liu, Long-Ding

2017-05-10

Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis.

[Establishing Individualized Medicine for Intractable Cancer Based on Clinical Molecular Pathogenesis].

PubMed

Jono, Hirofumi

2018-01-01

　Although cancer treatment has dramatically improved with the development of molecular-targeted agents over the past decade, identifying eligible patients and predicting the therapeutic effects remain a major challenge. Because intratumoral heterogeneity represents genetic and molecular differences affecting patients' responses to these therapeutic agents, establishing individualized medicine based on precise molecular pathological analysis of tumors is urgently required. This review focuses on the pathogenesis of oral squamous cell carcinoma (OSCC), a common head and neck neoplasm, and introduces our approaches toward developing novel anticancer therapies particularly based on clinical molecular pathogenesis. Deeper understanding of more precise molecular pathogenesis in clinical settings may open up novel strategies for establishing individualized medicine for OSCC.

[Malassezia and its presumed association with skin diseases in dogs].

PubMed

Nagata, Masahiko

2013-01-01

Malassezia pachydermatis is the major species in Malassezia isolated from dogs, and there is a presumably Malassezia-associated skin disease,"Malassezia dermatitis" in the dog. The skin lesion is characterized by relatively demarcated erythema with some scaling at the sebum-rich areas, in which lichenification and hyperpigmentation could be involved in the chronic stage. The clinical features suggest that it corresponds to seborrheic dermatitis in humans. Hence, it might be possible to identify essential pathogenesis of the disease by clarifying its differences in humans and animals as a shared disease.

Birt-Hogg-Dubé Syndrome.

PubMed

Gupta, Nishant; Sunwoo, Bernie Y; Kotloff, Robert M

2016-09-01

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the Folliculin gene and is characterized by the formation of fibrofolliculomas, early onset renal cancers, pulmonary cysts, and spontaneous pneumothoraces. The exact pathogenesis of tumor and lung cyst formation in BHD remains unclear. There is great phenotypic variability in the clinical features of BHD, and patients can present with any combination of skin, pulmonary, or renal findings. More than 80% of adult patients with BHD have pulmonary cysts on high-resolution computed tomography scan of the chest. Published by Elsevier Inc.

Hypophosphatemic rickets associated with epidermal nevus syndrome and giant hairy nevus.

PubMed

Chou, Yen-Yin; Chao, Sheau-Chiou; Shiue, Chiou-Nan; Tsai, Wen-Hui; Lin, Shio-Jean

2005-01-01

The association of hypophosphatemic rickets and epidermal nevus or giant hairy nevus is rare. We report two patients with hypophosphatemic rickets, one associated with epidermal nevus syndrome and the other with giant hairy nevus, and describe their clinical features and variable response to treatment. The abnormal nevus tissue may have contributed to the pathogenesis of hypophosphatemic rickets. We did not find a PHEX gene mutation in these two patients, and the mechanism for their rickets may be different from that in X-linked hypophosphatemic rickets.

Eosinophilic dermatosis of hematologic malignancy.

PubMed

Martires, Kathryn; Callahan, Shields; Terushkin, Vitaly; Brinster, Nooshin; Leger, Marie; Soter, Nicholas A

2016-12-15

We report a 68-year-old woman with chroniclymphocytic leukemia, who developed numerous,pruritic, edematous, and vesicobullous skin lesionsof the face and extremities over the course of severalmonths. The diagnosis of eosinophilic dermatosis ofhematologic malignancy (EDHM) was made basedon the clinical history and histopathologic features.Owing to the possible link between EDHM and amore aggressive underlying CLL, she was startedagain on chemotherapy. This case serves as areminder that, although the precise pathogenesis ofEDHM remains unclear, the paraneoplastic disorderis the result of immune dysregulation. Patientswho develop EDHM should undergo prompthematologic/oncologic evaluation.

14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome.

PubMed

Cervera, Ricard; Rodríguez-Pintó, Ignasi; Colafrancesco, Serena; Conti, Fabrizio; Valesini, Guido; Rosário, Cristina; Agmon-Levin, Nancy; Shoenfeld, Yehuda; Ferrão, Claudia; Faria, Raquel; Vasconcelos, Carlos; Signorelli, Flavio; Espinosa, Gerard

2014-07-01

The 'Task Force on Catastrophic Antiphospholipid Syndrome (CAPS)' was developed on the occasion of the 14th International Congress on Antiphospholipid Antibodies. The objectives of this Task Force were to assess the current knowledge on pathogenesis, clinical and laboratory features, diagnosis and classification, precipitating factors and treatment of this condition in order to address recommendations for future research. This article summarizes the studies analyzed by the Task Force, its recommendations and the future research agenda. Copyright © 2014 Elsevier B.V. All rights reserved.

Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia.

PubMed

Stewart, Adam; Armstrong, Mark; Graves, Stephen; Hajkowicz, Krispin

2017-07-01

Rickettsia australis , the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia.

Age-Related Macular Degeneration: Advances in Management and Diagnosis

PubMed Central

Yonekawa, Yoshihiro; Miller, Joan W.; Kim, Ivana K.

2015-01-01

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late-onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides in our understanding of AMD pathogenesis have been made in the past several decades, which have translated into revolutionary therapeutic agents in recent years. In this review, we describe the clinical and pathologic features of AMD and present an overview of current diagnosis and treatment strategies. PMID:26239130

Molecular pathogenesis of viral hemorrhagic fever.

PubMed

Basler, Christopher F

2017-07-01

The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches.

Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.

PubMed

Yeh, Tu-Hsueh; Lin, Juei-Jueng; Lai, Szu-Chia; Wu-Chou, Yah-Huei; Chen, An-Chih; Yueh, Kuo-Chu; Chen, Rou-Shayn; Lu, Chin-Song

2012-12-15

Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder in autosomal dominant inheritance. The clinical features and genetic findings of PNKD, rarely described in the Asians, were mostly delineated from European families. The present study characterized the clinical and genetic findings of a Taiwanese PNKD family. The clinical features of our five patients in successive three generations included onset age less than 10 years, attack duration between 3 min and 4h, and a variety of aura symptoms. The attacks were provoked not by sudden action but by emotional stress, caffeine, fatigue, heavy exercise and sleep deprivation. Sleep could abolish or diminish the attack and the attacks responded well to clonazepam. Sequencing the whole coding region of PNKD/MR-1 gene identified a heterozygous c.20 C>T (p.Ala7Val) mutation which was clearly segregated in the five affected patients. Comparing our patients with previously reported 18 families with PNKD/MR-1 mutations, the majority of the patients exhibited quite similar manifestations in attack patterns and precipitating factors. The recurrent conservative mutations in different ethnicities indicate importance in the pathogenesis of PNKD. Copyright © 2012 Elsevier B.V. All rights reserved.

Quebec platelet disorder: features, pathogenesis and treatment.

PubMed

Diamandis, Maria; Veljkovic, D Kika; Maurer-Spurej, Elisabeth; Rivard, Georges E; Hayward, Catherine P M

2008-03-01

Quebec platelet disorder (QPD) is a rare, autosomal-dominant, inherited bleeding disorder that is associated with unique abnormalities in fibrinolysis. Its hallmark features are delayed-onset bleeding following hemostatic challenges that responds to fibrinolytic inhibitor therapy and increased expression and storage of the fibrinolytic enzyme urokinase plasminogen activator in platelets, without increased plasma urokinase plasminogen activator or systemic fibrinolysis. The increased urokinase plasminogen activator in QPD platelets is only partially inhibited, and, as a result, there is intraplatelet generation of plasmin, and secondary degradation of many platelet alpha-granule proteins. During clot formation, the urokinase plasminogen activator released by QPD platelets leads to platelet-dependent increased fibrinolysis, and this is postulated to be a major contributor to QPD bleeding. The focus of the present review is to summarize the current state of knowledge on QPD, including the history of this disorder, its clinical and laboratory features, and recommended approaches for its diagnosis and treatment.

Traditional Chinese medicine formula Bi-Qi capsule alleviates rheumatoid arthritis-induced inflammation, synovial hyperplasia, and cartilage destruction in rats.

PubMed

Wang, Kai; Zhang, Dongmei; Liu, Yan; Wang, Xuan; Zhao, Jiantong; Sun, Tingting; Jin, Tingting; Li, Baoli; Pathak, Janak L

2018-03-14

Traditional Chinese medicine (TCM) formula Bi-Qi capsule (Bi-Qi) is a commonly prescribed drug to treat rheumatoid arthritis (RA). However, the mechanism of Bi-Qi-mediated amelioration of RA pathogenesis is still a mystery. Collagen induced arthritis (CIA) in rats is an established model that shares many similarities with RA in humans. In this study we investigated the effect of Bi-Qi on the pathogenesis of CIA in rats. CIA was developed in Sprague-Dawley (S.D) rats (n = 60, female) and used as a model resembling RA in humans. Rats were treated with a high or moderate dose of Bi-Qi, or methotrexate (MTX). Effects of the treatment on local joint and systemic inflammation, synovial hyperplasia, cartilage destruction, and other main features in the pathogenesis of CIA were analyzed. Inflamed and swollen ankles and joints were observed in arthritic rats, while Bi-Qi or MTX treatment alleviated these symptoms. Only the Bi-Qi moderate dose decreased RA-induced serum levels of tumor necrosis factor-alpha (TNF-α). Both Bi-Qi and MTX reduced the interleukin (IL)-18 serum level. Protein levels of cartilage oligomeric matrix protein and osteopontin in serum, synovium, and cartilage were elevated in arthritic rats, while Bi-Qi alleviated these effects. Synovial hyperplasia, inflammatory cell infiltration in synovium and a high degree of cartilage degradation was observed in RA, and Bi-Qi or MTX alleviated this effect. Bi-Qi at the moderate dose was the most effective in mitigating CIA-related clinical complications. Our findings showed that Bi-Qi alleviates CIA-induced inflammation, synovial hyperplasia, cartilage destruction, and the other main features in the pathogenesis of CIA. This provides fundamental evidence for the anti-arthritic properties of Bi-Qi and corroborates the use of Bi-Qi TCM formula for the treatment of RA.

Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets

PubMed Central

Glorieux, Francis H; Pettifor, John M

2014-01-01

This review describes the pathogenesis, clinical presentation and biochemical perturbations found in privational (nutritional) rickets and pseudo-vitamin D deficiency rickets (PDDR), an autosomal recessive condition with loss of function mutations in CYP27B1. It may seem strange to combine a discussion on privational rickets and PDDR as a single topic, but privational rickets and PDDR present with similar clinical signs and symptoms and with similar perturbations in bone and mineral metabolism. Of interest is the characteristic lack of features of rickets at birth in infants with PDDR, a finding which has also been reported in infants born to vitamin D-deficient mothers. This highlights the independence of the fetus and neonate from the need for vitamin D to maintain calcium homeostasis during this period. The variable roles of vitamin D deficiency and dietary calcium deficiency in the pathogenesis of privational rickets are discussed and the associated alterations in vitamin D metabolism highlighted. Although PDDR is a rare autosomal recessive disorder, results of long-term follow-up are now available on the effect of treatment with calcitriol, and these are discussed. Areas of uncertainty, such as should affected mothers breastfeed their infants, are emphasized. PMID:24818008

Compound heterozygosity of SHOX-encompassing and downstream PAR1 deletions results in Langer mesomelic dysplasia (LMD).

PubMed

Campos-Barros, Angel; Benito-Sanz, Sara; Ross, Judith L; Zinn, Andrew R; Heath, Karen E

2007-05-01

We present the clinical and molecular characteristics of a multi-generation family in which the proband presented with clinical features of Langer mesomelic dysplasia (LMD) whilst different family members had a diagnosis of Léri-Weill dyschondrosteosis (LWD) and/or pseudoachondroplasia (PSACH). In the LMD proband two different deletions were identified in the pseudoautosomal 1 region (PAR1) of the X and Y chromosomes: a SHOX-encompassing deletion inherited from his father and a downstream PAR1 deletion, which did not include SHOX, inherited from his mother. The individuals with PSACH features presented the previously described G719D mutation in the C-terminal globular domain of the cartilage oligomeric matrix protein gene (COMP). The LMD proband described here represents the first LMD case due to compound heterozygosity for deletions of the two different PAR1 regions, SHOX-encompassing and downstream from SHOX, that have been shown to be implicated in the pathogenesis of LWD and LMD.

[Depression and epilepsy : Two clinical pictures with common causes?].

PubMed

Borgmann, M; Holtkamp, M; Adli, M; Behr, J

2016-07-01

Epilepsy and depressive disorders show a high rate of comorbidity. Thus, neurobiological similarities and a bidirectional relationship in terms of pathogenesis have been suggested. The aim of this article is to present the common neurobiological features of both disorders, to characterize the bidirectional relationship and to provide an overview of therapeutic consequences. A review of the current literature and evaluation of studies on the topics of depression and epilepsy are presented. Epilepsy and depression share common neurobiological features. In epileptic patients depression should be diagnosed early and reliably as the successful treatment has a great influence on the prognosis, quality of life and suicide risk in these individuals. In therapeutic doses, antidepressive medication with noradrenergic and specific serotonergic antidepressants (NaSSA) or selective serotonin reuptake inhibitors (SSRI) imparts no clinically relevant epileptogenic potential; however, it increases the quality of life and could have anticonvulsant effects in patients with epilepsy. Clomipramine, bupropion and maprotiline, however, should not be administered to patients with epilepsy as they are known to lower the seizure threshold.

Mesomelic skeletal dysplasias.

PubMed

Kaitila, I; Leisti, J T; Rimoin, D L

1976-01-01

Mesomelic shortening of the extremities lends itself as a useful clinical and/or radiologic sign to characterize a group of hereditary bone dysplasias. Table 1 and Figure 4 are presented to facilitate the comparison between the many different types of mesomelic dwarfism. Differential diagnosis between these types is not difficult because of the specific bone changes and extraskeletal malformations present. As in many hereditary syndromes, however, there may be wide clinical variability within a single entity, and meticulous clinical and radiologic examination must be done to arrive at the correct diagnosis. Certain other forms of chondrodystrophies, such as achondroplasia, hypochondroplasia, pseudoachondroplasia and distrophic dwarfism, can be easily differentiated from the mesomelic dysplasias by their clinical features and skeletal radiographs. Nothing is known about the pathogenesis of the various forms of mesomelic dysplasias. There is no available specific treatment, although corrective surgery has benefited selected patients. The correct diagnosis is, however, important both for prognostication and accurate genetic counseling.

Characterization of clinical and immunological features in patients coinfected with dengue virus and HIV.

PubMed

Torrentes-Carvalho, Amanda; Hottz, Eugênio Damaceno; Marinho, Cintia Ferreira; da Silva, Jéssica Badolato-Corrêa; Pinto, Luzia Maria de Oliveira; Fialho, Luciana Gomes; Bozza, Fernando Augusto; Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Kubelka, Claire Fernandes; de Azeredo, Elzinandes Leal

2016-03-01

The pathogenesis of dengue in subjects coinfected with HIV remains largely unknown. We investigate clinical and immunological parameters in coinfected DENV/HIV patients. According to the new dengue classification, most coinfected DENV/HIV patients presented mild clinical manifestations of dengue infection. Herein, we show that DENV/HIV coinfected patients had higher CD8 T cells percentages reflected as a lower CD4/CD8 ratio. Furthermore, CCR5 expression on CD4 T cells and CD107a expression on both T subsets were significantly higher in coinfected patients when compared with monoinfected DENV and HIV individuals respectively. Increased inflammatory response was observed in treated HAART coinfected patients despite undetectable HIV load. These data indicate that DENV infection may influence the clinical profile and immune response in individuals concomitantly infected with HIV. Copyright © 2016 Elsevier Inc. All rights reserved.

Noonan syndrome and clinically related disorders

PubMed Central

Tartaglia, Marco; Gelb, Bruce D.; Zenker, Martin

2010-01-01

Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. PMID:21396583

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

PubMed

Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

2017-03-01

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral Sclerosis?

PubMed Central

Xue, Yuan Chao; Feuer, Ralph; Cashman, Neil; Luo, Honglin

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily attacks motor neurons in the brain and spinal cord, leading to progressive paralysis and ultimately death. Currently there is no effective therapy. The majority of ALS cases are sporadic, with no known family history; unfortunately the etiology remains largely unknown. Contribution of Enteroviruses (EVs), a family of positive-stranded RNA viruses including poliovirus, coxsackievirus, echovirus, enterovirus-A71 and enterovirus-D68, to the development of ALS has been suspected as they can target motor neurons, and patients with prior poliomyelitis show a higher risk of motor neuron disease. Multiple efforts have been made to detect enteroviral genome in ALS patient tissues over the past two decades; however the clinical data are controversial and a causal relationship has not yet been established. Recent evidence from in vitro and animal studies suggests that enterovirus-induced pathology remarkably resembles the cellular and molecular phenotype of ALS, indicating a possible link between enteroviral infection and ALS pathogenesis. In this review, we summarize the nature of enteroviral infection, including route of infection, cells targeted, and viral persistence within the central nervous system (CNS). We review the molecular mechanisms underlying viral infection and highlight the similarity between viral pathogenesis and the molecular and pathological features of ALS, and finally, discuss the potential role of enteroviral infection in frontotemporal dementia (FTD), a disease that shares common clinical, genetic, and pathological features with ALS, and the significance of anti-viral therapy as an option for the treatment of ALS. PMID:29593492

Diffuse alveolar hemorrhage in patients with systemic lupus erythematosus. Clinical manifestations, treatment, and prognosis.

PubMed

Martínez-Martínez, Marco Ulises; Abud-Mendoza, Carlos

2014-01-01

Diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus is a rare but potentially fatal condition. Although the pathogenesis of this condition is unknown, high disease activity is the main characteristic; moreover, histopathology in some studies showed alveolar immune complex deposits and capillaritis. Clinical features of DAH include dyspnea, a drop in hemoglobin, and diffuse radiographic alveolar images, with or without hemoptysis. Factors associated with mortality include mechanical ventilation, renal failure, and infections. Bacterial infections have been reported frequently in patients with DAH, but also invasive fungal infections including aspergillosis. DAH treatment is based on high dose methylprednisolone; other accepted therapies include cyclophosphamide (controversial), plasmapheresis, immunoglobulin and rituximab. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis: A Possible Pathogenetic Role of the Parasite?

PubMed

Del Grande, Claudia; Contini, Carlo; Schiavi, Elisa; Rutigliano, Grazia; Maritati, Martina; Seraceni, Silva; Pinto, Barbara; Dell'Osso, Liliana; Bruschi, Fabrizio

2017-03-01

Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.

Mucopolysaccharidosis IVA and glycosaminoglycans

PubMed Central

Khan, Shaukat; Alméciga-Díaz, Carlos J.; Sawamoto, Kazuki; Mackenzie, William G.; Theroux, Mary C; Pizarro, Christian; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2016-01-01

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA. PMID:27979613

Inflammatory features of melasma lesions in Asian skin.

PubMed

Noh, Tai Kyung; Choi, Seok Joo; Chung, Bo Young; Kang, Jin Soo; Lee, Jong Hee; Lee, Mi Woo; Chang, Sung Eun

2014-09-01

Melasma is triggered by various factors including ultraviolet radiation and estrogen; however, its pathogenesis is unclear. To investigate the inflammatory features of melasma lesions as triggers for this disorder, 197 women with melasma who attended Asan Medical Center and Kangskin Clinic, Seoul, from June 2011 to October 2011 completed a questionnaire concerning triggering or aggravating factors. These cases were divided into "non-inflammatory" and "inflammatory" groups. Skin biopsies and immunostaining for CD68, CD117, and leukocyte common antigen (LCA) were performed in the lesional and peri-lesional skin of ten cases in the non-inflammatory group and nine cases in the inflammatory group. Among the 197 subjects (mean age, 41.5 years; mean age of melasma onset, 33.8 years), 50 patients (25.4%) were categorized into the inflammatory group. This group comprised cases that had inflammatory symptoms and events that triggered the melasma lesions. The lesional dermis contained more CD68(+) melanophages, CD117(+) mast cells, and LCA(+) leukocytes in the inflammatory group than in the non-inflammatory group. Inflammatory clinical features and an increased number of inflammatory cells in the lesion may be involved in the development of melasma in Asian skin. © 2014 Japanese Dermatological Association.

Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group.

PubMed

Vergouwen, Mervyn D I; Vermeulen, Marinus; van Gijn, Jan; Rinkel, Gabriel J E; Wijdicks, Eelco F; Muizelaar, J Paul; Mendelow, A David; Juvela, Seppo; Yonas, Howard; Terbrugge, Karel G; Macdonald, R Loch; Diringer, Michael N; Broderick, Joseph P; Dreier, Jens P; Roos, Yvo B W E M

2010-10-01

In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Immunity and Immunopathology in the Tuberculous Granuloma

PubMed Central

Pagán, Antonio J.; Ramakrishnan, Lalita

2015-01-01

Granulomas, organized aggregates of immune cells, are a defining feature of tuberculosis (TB). Granuloma formation is implicated in the pathogenesis of a variety of inflammatory disorders. However, the tuberculous granuloma has been assigned the role of a host protective structure which “walls-off” mycobacteria. Work conducted over the past decade has provided a more nuanced view of its role in pathogenesis. On the one hand, pathogenic mycobacteria accelerate and exploit granuloma formation for their expansion and dissemination by manipulating host immune responses to turn leukocyte recruitment and cell death pathways in their favor. On the other hand, granuloma macrophages can preserve granuloma integrity by exerting a microbicidal immune response, thus preventing an even more rampant expansion of infection in the extracellular milieu. Even this host-beneficial immune response required to maintain the bacteria intracellular must be tempered, as an overly vigorous immune response can also cause granuloma breakdown, thereby directly supporting bacterial growth extracellularly. This review will discuss how mycobacteria manipulate inflammatory responses to drive granuloma formation and will consider the roles of the granuloma in pathogenesis and protective immunity, drawing from clinical studies of TB in humans and from animal models—rodents, zebrafish, and nonhuman primates. A deeper understanding of TB pathogenesis and immunity in the granuloma could suggest therapeutic approaches to abrogate the host-detrimental aspects of granuloma formation to convert it into the host-beneficial structure that it has been thought to be for nearly a century. PMID:25377142

FAS/FASL gene polymorphisms in Turkish patients with chronic myeloproliferative disorders.

PubMed

Ozdemirkiran, Fusun Gediz; Nalbantoglu, Sinem; Gokgoz, Zafer; Payzin, Bahriye Kadriye; Vural, Filiz; Cagirgan, Seckin; Berdeli, Afig

2017-03-01

Chronic myeloproliferative disorders (CMPD) are chronic myeloid hematological disorders, characterized by increased myeloid cell proliferation and fibrosis. Impaired apoptotic mechanisms, increased cell proliferation, uncontrolled hematopoietic cell proliferation and myeloaccumulation may contribute to the pathogenesis of CMPD. The aim of our study was to show the possible role of FAS/FASL gene polymorphisms in CMPD pathogenesis and investigate the association with clinical parameters and susceptibility to disease. We included 101 (34 polycythemia vera (PV), 23 primary myelofibrosis (PMF), 44 essential thrombocythemia (ET)) CMPD patients diagnosed according to the WHO classification criteria and 95 healthy controls in this study. All the patients and the controls were investigated for FAS/FASL gene expression, allele frequencies and phenotype features, and also FAS mRNA levels were analyzed. Chronic myeloproliferative disorders patients showed increased FAS-670AG + GG genotype distribution compared with the control group ( p < 0.05). While the A allele was more frequent in both groups, AG genotype was more frequent in CMPD patients. There was no association between FAS-670A>G gene polymorphism and some clinical parameters such as splenomegaly and thrombosis ( p > 0.05). No statistically significant difference in FASL+843C>T genotype or allele frequency was found between groups ( p > 0.05). Moreover, no statistically significant difference was detected in FASL and JAK2V617F mutations ( p > 0.05). FAS mRNA expression was 1.5-fold reduced in patients compared to healthy subjects. According to our findings, FAS/FASL gene expression may contribute to the molecular and immunological pathogenesis of CMPD. More investigations are needed to support these data.

Is Multiple Sclerosis an Autoimmune Disease?

PubMed Central

Wootla, Bharath; Eriguchi, Makoto; Rodriguez, Moses

2012-01-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS. PMID:22666554

Childhood inflammatory brain diseases: pathogenesis, diagnosis and therapy.

PubMed

Twilt, Marinka; Benseler, Susanne M

2014-08-01

Inflammatory brain diseases (IBrainDs) are a leading cause of devastating neurological deficits or neuropsychiatric syndromes in previously healthy children. The spectrum is expanding rapidly and new disease entities have been discovered in the last decade. IBrainD can occur as a primary disease or may occur secondary to an underlying cause. This review focuses on the clinical presentation, diagnostic features, pathology and histology characteristics and treatment of the primary childhood IBrainDs. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Chronic Pancreatitis.

PubMed

Stram, Michelle; Liu, Shu; Singhi, Aatur D

2016-12-01

Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Subacute constrictive pericarditis from Serratia marcescens bacteremia.

PubMed

Khan, M Y

1983-12-01

A case report of subacute constrictive pericarditis associated with disseminated Serratia marcescens infection and bacteremia in a patient with chronic tubulointerstitial nephritis and uremia is described. Although not substantiated by clinical history, the renal pathologic features were similar to those of ethylene glycol-induced tubulointerstitial nephritis. The patient did not have a history of heroin addiction. The importance of predisposing factors such as uremia, invasive vascular procedures, tracheal intubation, peritoneal dialysis, and pericardiocentesis in Serratia infection in susceptible persons is discussed, as are possible roles of uremia, pericardiocentesis, and pericardiotomy in the pathogenesis of constrictive pericarditis in the present case.

The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis.

PubMed

Blum, Stefan; Csurhes, Peter; McCombe, Pamela

2015-08-15

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired inflammatory neuropathy, which has similar clinical and pathological features to Guillain-Barré Syndrome (GBS), but differs in time course. We investigated the frequency of genes encoding Killer immunoglobulin-like receptors and their HLA ligands in subjects with CIDP, in subjects with GBS and in healthy controls. There were no differences in KIR gene frequency among the 3 groups. The gene frequencies for HLA-B Bw4-I were significantly greater in CIDP than HC, but did not differ from GBS. The frequency of the combination of 3DL1/HLA-B Bw4I was greater in CIDP than HC, but did not differ from that of GBS. These data raise the possibility of NK cell function being an important factor in the pathogenesis of CIDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis

PubMed Central

Wang, Liang; Yu, Bin; Zhuang, Qian-yu; Wang, Yi-Peng

2015-01-01

Purpose. Adolescent idiopathic scoliosis (AIS), the most common pediatric spinal deformity, is considered a complex genetic disease. Causing genes and pathogenesis of AIS are still unclear. This study was designed to identify differentially expressed long noncoding RNAs (lncRNAs) involving the pathogenesis of AIS. Methods. We first performed comprehensive screening of lncRNA and mRNA in AIS patients and healthy children using Agilent human lncRNA + mRNA Array V3.0 microarray. LncRNAs expression in different AIS patients was further evaluated using quantitative PCR. Results. A total of 139 lncRNAs and 546 mRNAs were differentially expressed between AIS patients and healthy control. GO and Pathway analysis showed that these mRNAs might be involved in bone mineralization, neuromuscular junction, skeletal system morphogenesis, nucleotide and nucleic acid metabolism, and regulation of signal pathway. Four lncRNAs (ENST00000440778.1, ENST00000602322.1, ENST00000414894.1, and TCONS_00028768) were differentially expressed between different patients when grouped according to age, height, classification, severity of scoliosis, and Risser grade. Conclusions. This study demonstrates the abnormal expression of lncRNAs and mRNAs in AIS, and the expression of some lncRNAs was related to clinical features. This study is helpful for further understanding of lncRNAs in pathogenesis, treatment, and prognosis of AIS. PMID:26421281

Role of human papilloma virus-16 in the pathogenesis of oral lichen planus--an immunohistochemical study.

PubMed

Pol, Chetan A; Ghige, Suvarna K; Gosavi, Suchitra R

2015-02-01

Oral lichen planus (OLP) is a common chronic inflammatory immune-mediated disease with an aetiopathogenesis associated with cell-mediated immunological dysfunction. It is possible that oral mucosal viral infections, including human papilloma virus-16 (HPV-16) infection, may have a causative role in OLP pathogenesis. To assess the prevalence of HPV-16 in histopathologically diagnosed specimens of OLP and to evaluate whether any clinical features (such as the localisation of specimens) or the age or gender of patients, are correlated with the presence of this virus. This study was conducted on 30 specimens with a histopathological diagnosis of OLP, using the immunohistochemical marker HPV-16. Thirty normal oral mucosa specimens were also included as controls. Brown nuclear staining was accepted as positive for the HPV-16 antibody. The results were analysed using Fisher's exact test. P values<0.05 were considered to be significant. Significant correlation (P=0.0001) was observed between HPV-16 infection and samples with OLP. No statistical conclusions could be drawn regarding age, gender, localisation and HPV-16 positivity. Our study showed that HPV-16 may play a role in the pathogenesis of OLP. Taking into account the oncogenic potential of HPV-16, patients with OLP should be screened for the presence of this virus. © 2014 FDI World Dental Federation.

Arrestin gene mutations in autosomal recessive retinitis pigmentosa.

PubMed

Nakazawa, M; Wada, Y; Tamai, M

1998-04-01

To assess the clinical and molecular genetic studies of patients with autosomal recessive retinitis pigmentosa associated with a mutation in the arrestin gene. Results of molecular genetic screening and case reports with DNA analysis and clinical features. University medical center. One hundred twenty anamnestically unrelated patients with autosomal recessive retinitis pigmentosa. DNA analysis was performed by single strand conformation polymorphism followed by nucleotide sequencing to search for a mutation in exon 11 of the arrestin gene. Clinical features were characterized by visual acuity slitlamp biomicroscopy, fundus examinations, fluorescein angiography, kinetic visual field testing, and electroretinography. We identified 3 unrelated patients with retinitis pigmentosa associated with a homozygous 1-base-pair deletion mutation in codon 309 of the arrestin gene designated as 1147delA. All 3 patients showed pigmentary retinal degeneration in the midperipheral area with or without macular involvement. Patient 1 had a sibling with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degeneration associated with a golden-yellow reflex in the peripheral fundus. Patients 1 and 3 showed features of retinitis pigmentosa without the golden-yellow fundus reflex. Although the arrestin 1147delA has been known as a frequent cause of Oguchi disease, this mutation also may be related to the pathogenesis of autosomal recessive retinitis pigmentosa. This phenomenon may provide evidence of variable expressivity of the mutation in the arrestin gene.

Recent advances in bulbar syndromes: genetic causes and disease mechanisms.

PubMed

Manole, Andreea; Fratta, Pietro; Houlden, Henry

2014-10-01

With advances in next-generation gene sequencing, progress in deep phenotyping and a greater understanding of the pathogenesis of motor neuron disease, our knowledge of the progressive bulbar syndromes has significantly increased in recent years. This group of heterogeneous conditions, in which the primary disorder is focused around degeneration of the lower cranial nerves, can occur in children or adults and form a spectrum of severity, based around the common feature of bulbar dysfunction. Early genetic diagnosis may allow treatment in some bulbar syndromes. Brown-Vialetto-Van Laere and Fazio-Londe syndromes are the most recent childhood forms of progressive bulbar palsy to be genetically defined. The clinical phenotype of this group of childhood disorders was first reported over 120 years ago. Recently, it was demonstrated that in a third of these patients Brown-Vialetto-Van Laere is caused by mutations in the SLC52A2 and SLC52A3 genes, both of which encode riboflavin transporters. Importantly, supplementation of riboflavin can lead to significant clinical improvement if started early in the disease process. Here, we outline the clinical features, management and an update on the disease mechanisms and genetic causes of the progressive bulbar syndromes.

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

PubMed Central

Wei, Diana Yi-Ting; Yuan Ong, Jonathan Jia; Goadsby, Peter James

2018-01-01

Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts. PMID:29720812

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis.

PubMed

Wei, Diana Yi-Ting; Yuan Ong, Jonathan Jia; Goadsby, Peter James

2018-04-01

Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts.

The evolving definition of essential tremor: What are we dealing with?

PubMed

Louis, Elan D

2018-01-01

Although essential tremor (ET) is commonly encountered in clinical practice, historically, there has been considerable disagreement as how to best define it, and now with a growing sense of its clinical complexity, how to best encapsulate it. Here, I draw attention to five issues of current uncertainty. A PubMed search conducted on June 19, 2017 crossed "essential tremor" with 9 second search terms (e.g., definition, diagnosis). There are several major issues of clinical and diagnostic uncertainty. Underlying each issue is a larger question about the nature of the underlying pathophysiology of ET. Does age of onset of ET matter? How much dystonia is acceptable in ET? How much in the way of "cerebellar signs" are acceptable? Are non-motor features due to the underlying disease or merely secondary to the clinical features? Is ET a single disease entity or something else? We are learning more about ET and, as a by-product of these efforts, are struggling with its definition. Further understanding the nature of the underlying disease pathogenesis as well as the role the cerebellum and cerebellar relays play in this process will likely provide important clues to enable us to bring order to areas of uncertainty. Copyright © 2017 Elsevier Ltd. All rights reserved.

The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome.

PubMed

Lee, P; Bhansali, R; Izraeli, S; Hijiya, N; Crispino, J D

2016-09-01

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.

[Myotonic dystrophy - a new insight into a well-known disease].

PubMed

Lusakowska, Anna; Sułek-Piatkowska, Anna

2010-01-01

Myotonic dystrophy (DM), the most common dystrophy in adults, is an autosomal dominant disease characterized by a variety of multisystemic features. Two genetically distinct forms of DM are identified - type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is caused by trinucleotide expansion of CTG in the myotonic dystrophy protein kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in the zinc finger protein 9 gene was identified. Both mutations are dynamic and are located in non-coding parts of the genes. Phenotype variability of DM1 and DM2 is caused by a molecular mechanism due to mutated RNA toxicity. This paper reviews the clinical features of both types of myotonic dystrophies and summarizes current views on pathogenesis of myotonic dystrophy.

“Neuropathology of amyotrophic lateral sclerosis and its variants”

PubMed Central

Saberi, Shahram; Stauffer, Jennifer E.; Schulte, Derek J.; Ravits, John

2015-01-01

Summary Amyotrophic lateral sclerosis (ALS) is a clinical syndrome named for its neuropathological hallmark: degeneration of motor neurons in the spinal anterior horn and motor cortex and loss of axons in the lateral columns of the spinal cord. The signature neuropathological molecular signature common to almost all sporadic ALS and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathological and molecular neuropathological features of ALS variants primarly lateral sclerosis and progressive muscular atrophy are less certain, but also appear to share the primary features of ALS. A number of genetic causes including mutations in SOD1, FUS, and C9orf72 comprise a disease spectrum and all demonstrate distinctive molecular and neuropathological signatures. Neuropathology will continue to play to a key role in solving the puzzle of ALS pathogenesis. PMID:26515626

Sclerosing lymphangitis of the penis associated with marked penile oedema and skin erosions.

PubMed

Karray, Mehdi; Litaiem, Noureddine; Jones, Mariem; Zeglaoui, Faten

2017-07-27

Sclerosing lymphangitis of the penis is a benign, under-reported condition consisting of a asymptomatic firm cord-like swelling around the coronal sulcus of the penis usually affecting men in the second or third decade of life. Penile oedema and erosions are rarely reported. Clinical signs may be remarkable contrasting with the self-limited character of the disease. We report a new case of sclerosing lymphangitis of the penis occurring in a 59-year-old patient marked by penile swelling and several overlying skin erosions, and discuss the clinical features and the pathogenesis aspects of the disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Origins and molecular biology of testicular germ cell tumors.

PubMed

Reuter, Victor E

2005-02-01

Testicular germ cell tumors can be divided into three groups (infantile/prepubertal, adolescent/young adult and spermatocytic seminoma), each with its own constellation of clinical histology, molecular and clinical features. They originate from germ cells at different stages of development. The most common testicular cancers arise in postpubertal men and are characterized genetically by having one or more copies of an isochromosome of the short arm of chromosome 12 [i(12p)] or other forms of 12p amplification and by aneuploidy. The consistent gain of genetic material from chromosome 12 seen in these tumors suggests that it has a crucial role in their development. Intratubular germ cell neoplasia, unclassified type (IGCNU) is the precursor to these invasive tumors. Several factors have been associated with their pathogenesis, including cryptorchidism, elevated estrogens in utero and gonadal dysgenesis. Tumors arising in prepubertal gonads are either teratomas or yolk sac tumors, tend to be diploid and are not associated with i(12p) or with IGCNU. Spermatocytic seminoma (SS) arises in older patients. These benign tumors may be either diploid or aneuploid and have losses of chromosome 9 rather than i(12p). Intratubular SS is commonly encountered but IGCNU is not. The pathogenesis of prepubertal GCT and SS is poorly understood.

Modeling asthma: Pitfalls, promises, and the road ahead.

PubMed

Rosenberg, Helene F; Druey, Kirk M

2018-02-16

Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild-type and genetically manipulated laboratory mice (Mus musculus). Antigen sensitization and challenge strategies have reproduced numerous important features of airway inflammation characteristic of human asthma, notably the critical roles of type 2 T helper cell cytokines. Recent models of disease induction have advanced to include physiologic aeroallergens with prolonged respiratory challenge without systemic sensitization; others incorporate tobacco, respiratory viruses, or bacteria as exacerbants. Nonetheless, differences in lung size, structure, and physiologic responses limit the degree to which airway dynamics measured in mice can be compared to human subjects. Other rodent allergic airways models, including those featuring the guinea pig (Cavia porcellus) might be considered for lung function studies. Finally, domestic cats (Feline catus) and horses (Equus caballus) develop spontaneous obstructive airway disorders with clinical and pathologic features that parallel human asthma. Information on pathogenesis and treatment of these disorders is an important resource. ©2018 Society for Leukocyte Biology.

Nakalanga Syndrome: Clinical Characteristics, Potential Causes, and Its Relationship with Recently Described Nodding Syndrome

PubMed Central

Föger, Kathrin; Gora-Stahlberg, Gina; Sejvar, James; Ovuga, Emilio; Jilek-Aall, Louise; Schmutzhard, Erich

2017-01-01

Nakalanga syndrome is a condition that was described in Uganda and various other African countries decades ago. Its features include growth retardation, physical deformities, endocrine dysfunction, mental impairment, and epilepsy, amongst others. Its cause remains obscure. Nodding syndrome is a neurological disorder with some features in common with Nakalanga syndrome, which has been described mainly in Uganda, South Sudan, and Tanzania. It has been considered an encephalopathy affecting children who, besides head nodding attacks, can also present with stunted growth, delayed puberty, and mental impairment, amongst other symptoms. Despite active research over the last years on the pathogenesis of Nodding syndrome, to date, no convincing single cause of Nodding syndrome has been reported. In this review, by means of a thorough literature search, we compare features of both disorders. We conclude that Nakalanga and Nodding syndromes are closely related and may represent the same condition. Our findings may provide new directions in research on the cause underlying this neurological disorder. PMID:28182652

Diprosopia/dicephalia in calves in northern Italy: clinical and aetio-pathological features.

PubMed

Biasibetti, E; D'Angelo, A; Bellino, C; Gay, L; Gianella, P; Capucchio, M T

2011-12-01

Cephalic parapagia, a rare congenital anomaly caused by the fusion of two monozygotic embryos, is characterized by a single body and a spectrum of duplication of craniofacial structures. The authors describe the clinical and pathological aspects of the parapagus conjoined twin defect in nine calves referred to the Department of Animal Pathology, Turin, between 1999 and 2009. The majority of the calves (eight cases) presented two snouts that shared three or four eyes (diprosopia); one calf presented two separate skulls fused at the foramen magnum (dicephalia). Bilateral inferior brachygnathia was observed in four calves. Post-mortem examination of the skull revealed complete brain duplication with fusion at the caudal portion of the brainstem in all calves. Histological features of the cerebral hemispheres and brainstem were normal; moderate disorganization of the cerebellar cortex was noted in two cases. Cardiac malformations were observed in three calves. No aetiologic cause was determined. This article underscores the importance of diprosopia in cattle species and suggests the need for more detailed investigations to better understand its pathogenesis. © 2011 Blackwell Verlag GmbH.

Recent insights into C3 glomerulopathy

PubMed Central

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

2013-01-01

‘C3 glomerulopathy’ is a recent disease classification comprising several rare types of glomerulonephritis (GN), including dense deposit disease (DDD), C3 glomerulonephritis (C3GN) and CFHR5 nephropathy. These disorders share the key histological feature of isolated complement C3 deposits in the glomerulus. A common aetiology involving dysregulation of the alternative pathway (AP) of complement has been elucidated in the past decade, with genetic defects and/or autoantibodies able to be identified in a proportion of patients. We review the clinical and histological features of C3 glomerulopathy, relating these to underlying molecular mechanisms. The role of uncontrolled C3 activation in pathogenesis is emphasized, with important lessons from animal models. Methods, advantages and limitations of gene testing in the assessment of individuals or families with C3 glomerulopathy are discussed. While no therapy has yet been shown consistently effective, clinical evaluation of agents targeting specific components of the complement system is ongoing. However, limits to current knowledge regarding the natural history and the appropriate timing and duration of proposed therapies need to be addressed. PMID:23479095

Mucopolysaccharidosis IVA and glycosaminoglycans.

PubMed

Khan, Shaukat; Alméciga-Díaz, Carlos J; Sawamoto, Kazuki; Mackenzie, William G; Theroux, Mary C; Pizarro, Christian; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA. Copyright © 2016 Elsevier Inc. All rights reserved.

Management of refractory pityriasis rubra pilaris: challenges and solutions

PubMed Central

Moretta, Gaia; De Luca, Erika V; Di Stefani, Alessandro

2017-01-01

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous skin disease. Its clinical presentation and evolution is very variable. The most frequent clinical features are follicular papules, progressing to yellow-orange erythroderma with round small areas of normal skin and the well-demarcated palmoplantar keratoderma. Actually, six different types of PRP have been described based on clinical characteristics, age of onset, and prognosis. The pathogenesis is still unknown, and treatment can be challenging. Available treatments are mainly based on case reports or case series of clinical experience because no controlled randomized trials have never been performed because of the rarity of the condition. Traditional systemic treatment consists in retinoids, which are actually considered as first-line therapy, but refractory cases that do not respond or relapse after drug interruption do exist. In recent years, numerous reports have demonstrated the efficacy of new agents such as biological drugs. This article is an overview on available therapeutic options, in particular for refractory forms of PRP. PMID:29184428

Imaging Diagnosis of Splanchnic Venous Thrombosis

PubMed Central

Rajesh, S.; Mukund, Amar

2015-01-01

Splanchnic vein thrombosis (SVT) is a broad term that includes Budd-Chiari syndrome and occlusion of veins that constitute the portal venous system. Due to the common risk factors involved in the pathogenesis of these clinically distinct disorders, concurrent involvement of two different regions is quite common. In acute and subacute SVT, the symptoms may overlap with a variety of other abdominal emergencies while in chronic SVT, the extent of portal hypertension and its attendant complications determine the clinical course. As a result, clinical diagnosis is often difficult and is frequently reliant on imaging. Tremendous improvements in vascular imaging in recent years have ensured that this once rare entity is being increasingly detected. Treatment of acute SVT requires immediate anticoagulation. Transcatheter thrombolysis or transjugular intrahepatic portosystemic shunt is used in the event of clinical deterioration. In cases with peritonitis, immediate laparotomy and bowel resection may be required for irreversible bowel ischemia. In chronic SVT, the underlying cause should be identified and treated. The imaging manifestations of the clinical syndromes resulting from SVT are comprehensively discussed here along with a brief review of the relevant clinical features and therapeutic approach. PMID:26600801

Oral lymphoepithelial cyst: A clinicopathological study of 26 cases and review of the literature.

PubMed

Sykara, Maria; Ntovas, Panagiotis; Kalogirou, Eleni-Marina; Tosios, Konstantinos I; Sklavounou, Alexandra

2017-08-01

Τo describe the clinicopathological features of 26 oral lymphoepithelial cysts (LECs) and review the literature. Twenty-six cases of oral LECs diagnosed during a 37-year period were retrospectively collected. The patients' gender and age, as well as the main clinical features of the cysts were retrieved from the requisition forms. The main microscopic features were recorded after reevaluation of all cases. Pubmed and Google Scholar electronic databases were searched with the key word "oral LEC". Inclusion criteria were the microscopic confirmation of LEC diagnosis and the report at least two of three main clinical features (gender, age and cyst's location). The 26 oral LECs represented 0.08% of 31,564 biopsies accessioned during the study period. They affected 25 patients, 14 females and 11 males with a mean age of 33.04±9.81 years. They appeared as smooth (92%) nodules, with soft (24%) or firm (76%) consistency and normal (28%), yellow to normal (20%), yellow (32%) or white (20%) hue, in the tongue (69.23%) or the floor of mouth (30.77%). They were covered by parakeratinized squamous (92.31%) or non-keratinized (7.69%) epithelium and contained desquamated epithelial cells, amorphous eosinophilic material and/or inflammatory cells (100%). The lymphoid tissue surrounded the cystic cavity partially (34.62%) or completely (65.38%), often in a follicular pattern with prominent germinal centers (53.85%). Literature review yielded 316 cases of oral LECs derived from 25 case reports, 3 case studies/retrospective studies with detailed information for each case and 7 studies with summarized data. Oral LEC is a pathologic entity with discrete clinical presentation that is, however, commonly misdiagnosed in clinical practice as other, mostly benign, entities. Its pathogenesis remains obscure, as its clinicopathologic features are consistent with both theories suggested up to date. Key words: Oral lymphoepithelial cyst; developmental cyst; non odontogenic cyst; lymphoid tissue; oral tonsil.

Oral lymphoepithelial cyst: A clinicopathological study of 26 cases and review of the literature

PubMed Central

Sykara, Maria; Ntovas, Panagiotis; Tosios, Konstantinos I.; Sklavounou, Alexandra

2017-01-01

Introduction Τo describe the clinicopathological features of 26 oral lymphoepithelial cysts (LECs) and review the literature. Material and Methods Twenty-six cases of oral LECs diagnosed during a 37-year period were retrospectively collected. The patients’ gender and age, as well as the main clinical features of the cysts were retrieved from the requisition forms. The main microscopic features were recorded after reevaluation of all cases. Pubmed and Google Scholar electronic databases were searched with the key word “oral LEC”. Inclusion criteria were the microscopic confirmation of LEC diagnosis and the report at least two of three main clinical features (gender, age and cyst’s location). Results The 26 oral LECs represented 0.08% of 31,564 biopsies accessioned during the study period. They affected 25 patients, 14 females and 11 males with a mean age of 33.04±9.81 years. They appeared as smooth (92%) nodules, with soft (24%) or firm (76%) consistency and normal (28%), yellow to normal (20%), yellow (32%) or white (20%) hue, in the tongue (69.23%) or the floor of mouth (30.77%). They were covered by parakeratinized squamous (92.31%) or non-keratinized (7.69%) epithelium and contained desquamated epithelial cells, amorphous eosinophilic material and/or inflammatory cells (100%). The lymphoid tissue surrounded the cystic cavity partially (34.62%) or completely (65.38%), often in a follicular pattern with prominent germinal centers (53.85%). Literature review yielded 316 cases of oral LECs derived from 25 case reports, 3 case studies/retrospective studies with detailed information for each case and 7 studies with summarized data. Conclusions Oral LEC is a pathologic entity with discrete clinical presentation that is, however, commonly misdiagnosed in clinical practice as other, mostly benign, entities. Its pathogenesis remains obscure, as its clinicopathologic features are consistent with both theories suggested up to date. Key words:Oral lymphoepithelial cyst; developmental cyst; non odontogenic cyst; lymphoid tissue; oral tonsil. PMID:28936296

How Do Stress Exposure and Stress Regulation Relate to Borderline Personality Disorder?

PubMed Central

Bourvis, Nadège; Aouidad, Aveline; Cabelguen, Clémence; Cohen, David; Xavier, Jean

2017-01-01

Borderline personality disorder (BPD) is a severe and frequent disorder characterized by a pervasive pattern of instability affecting impulse control, emotional regulation, cognitive processing, self-image and interpersonal relationships. Patients’ personal histories are often marked by stressful or traumatic experiences, either unique or repeated. Moreover, while clinical signs of the disorder include both chronic and acute features, acute features are mostly triggered by acute stressful situations. Such features include transient cognitive distortion, intense anger, uncontrollable impulsivity, and self-harm behavior – including suicide – and contribute to the burden of the disease. In this paper, we review the various aspects (epidemiological, clinical, and physiological) contributing to the relationship between BDP and stress. In particular, we explore the statistical association between stress exposure and the emergence of BPD while taking into account other psychopathologies, such as post-traumatic stress disorder. Then, the different aspects of stress responses (namely, the phenomenological, behavioral, hormonal, neuro-vegetative and neural responses) are reviewed in BPD patients. Pathophysiological hypotheses are formulated to explain the differences in responses between BPD patients and healthy subjects and their relation to BPD symptoms. Although the pathogenesis remains uncertain, our conclusions seem to reflect a specific biological and neural pattern of altered stress perception and regulation in BPD. PMID:29250007

How Do Stress Exposure and Stress Regulation Relate to Borderline Personality Disorder?

PubMed

Bourvis, Nadège; Aouidad, Aveline; Cabelguen, Clémence; Cohen, David; Xavier, Jean

2017-01-01

Borderline personality disorder (BPD) is a severe and frequent disorder characterized by a pervasive pattern of instability affecting impulse control, emotional regulation, cognitive processing, self-image and interpersonal relationships. Patients' personal histories are often marked by stressful or traumatic experiences, either unique or repeated. Moreover, while clinical signs of the disorder include both chronic and acute features, acute features are mostly triggered by acute stressful situations. Such features include transient cognitive distortion, intense anger, uncontrollable impulsivity, and self-harm behavior - including suicide - and contribute to the burden of the disease. In this paper, we review the various aspects (epidemiological, clinical, and physiological) contributing to the relationship between BDP and stress. In particular, we explore the statistical association between stress exposure and the emergence of BPD while taking into account other psychopathologies, such as post-traumatic stress disorder. Then, the different aspects of stress responses (namely, the phenomenological, behavioral, hormonal, neuro-vegetative and neural responses) are reviewed in BPD patients. Pathophysiological hypotheses are formulated to explain the differences in responses between BPD patients and healthy subjects and their relation to BPD symptoms. Although the pathogenesis remains uncertain, our conclusions seem to reflect a specific biological and neural pattern of altered stress perception and regulation in BPD.

Is PIGD a legitimate motor subtype in Parkinson disease?

PubMed

Kotagal, Vikas

2016-06-01

Parkinson disease is a chronic progressive syndrome with a broad array of clinical features. Different investigators have suggested the heterogeneous motor manifestations of early Parkinson disease can be conceptualized through a taxonomy of clinical subtypes including tremor-predominant and postural instability and gait difficulty-predominant subtypes. Although it is theoretically valuable to distinguish subtypes of Parkinson disease, the reality is that few patients fit these discrete categories well and many transition from exhibiting elements of one subtype to elements of another. In the time since the initial description of the postural instability and gait difficulty-predominant subtype, Parkinson disease clinical research has blossomed in many ways - including an increased emphasis on the role of medical comorbidities and extranigral pathologies in Parkinson disease as markers of prognostic significance. By conceptualizing the pathogenesis of an expansive disease process in the limited terms of categorical motor subtypes, we run the risk of overlooking or misclassifying clinically significant pathogenic risk factors that lead to the development of motor milestones such as falls and related axial motor disability. Given its critical influence on quality of life and overall prognosis, we are in need of a model of postural instability and gait difficulty-predominant features in Parkinson disease that emphasizes the overlooked pathological influence of aging and medical comorbidities on the development of axial motor burden and postural instability and gait difficulty-predominant features. This Point of View proposes thinking of postural instability and gait difficulties in Parkinson disease not as a discrete subtype, but rather as multidimensional continuum influenced by several overlapping age-related pathologies.

[Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. Contribution of two new cases].

PubMed

Fernández Fernández, F J; de la Fuente Aguado, J; Pérez Fernández, S; Sopeña Pérez-Argüelles, B; Nodar Germiñas, A; Butrón Vila, M

2005-03-01

The autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome is characterized for clinical, biochemical, immunological, and histological features overlapping those of AIH and PBC, whose pathogenesis and more appropriate treatment are unknown at present. We describe two new patients of this entity, which made debut with cholestasic acute hepatitis accompanied of hypergammaglobulinemia. In the first patient was demonstrated the presence of AMA, ASMA, and anti-LKM1 autoantibodies; and ANA in the second one. The histological findings showed changes suggestive of AIH and PBC. After the start of immunosuppressive treatment, associated to ursodeoxycholic acid in one patient, a successful outcome was observed.

Understanding the Dengue Viruses and Progress towards Their Control

PubMed Central

Gould, Ernest A.

2013-01-01

Traditionally, the four dengue virus serotypes have been associated with fever, rash, and the more severe forms, haemorrhagic fever and shock syndrome. As our knowledge as well as understanding of these viruses increases, we now recognise not only that they are causing increasing numbers of human infections but also that they may cause neurological and other clinical complications, with sequelae or fatal consequences. In this review we attempt to highlight some of these features in the context of dengue virus pathogenesis. We also examine some of the efforts currently underway to control this “scourge” of the tropical and subtropical world. PMID:23936833

Exploiting the epigenome to control cancer promoting gene expression programs

PubMed Central

Brien, Gerard L.; Valerio, Daria G.; Armstrong, Scott A.

2016-01-01

Summary The epigenome is a key determinant of transcriptional output. Perturbations within the epigenome are thought to be a key feature of many, perhaps all cancers, and it is now clear that epigenetic changes are instrumental in cancer development. The inherent reversibility of these changes makes them attractive targets for therapeutic manipulation and a number of small molecules targeting chromatin-based mechanisms are currently in clinical trials. In this perspective we discuss how understanding the cancer epigenome is providing insights into disease pathogenesis and informing drug development. We also highlight additional opportunities to further unlock the therapeutic potential within the cancer epigenome. PMID:27070701

Radiological manifestations of radiation-induced injury to the normal upper gastrointestinal tract

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

Goldstein, H.M.; Rogers, L.F.; Fletcher, G.H.

1975-10-01

Radiation-induced injury to the normal esophagus, stomach, and duodenum in patients with advanced cervical carcinoma who received high para-aortic lymph- node irradiation to an average tumor dose of 5,000 rads is discussed. Radiation esophagitis is usually the result of mediastinal irradiation for bronchogenic carcinoma. The most consistent radiological finding is abnormal motility, with esophageal stricture and/or ulceration occurring less frequently. Radiation gastritis is usually present as pyloric ulceration or irregular contractions of the antrum, simulating gastric carcinoma. Postbulbar duodenal mucosal thickening, ulceration, and strictures may occur. Pertinent clinical features, pathogenesis, and pathological correlations are discussed. (auth)

The role of elastic fibers in pathogenesis of conjunctivochalasis

PubMed Central

Gan, Jing-Yun; Li, Qing-Song; Zhang, Zhen-Yong; Zhang, Wei; Zhang, Xing-Ru

2017-01-01

The PubMed, MEDLINE databases and China National Knowledge Infrastructure (CNKI) were searched for information regarding the etiology and pathogenesis of conjunctivochalasis (CCh) and the synthesis and degradation of elastic fibers. After analysis of the literature, we found elastic fibers was a complex protein molecule from the structure and composition; the degradation of elastic fibers was one of the histopathological features of the disease; the vast majority of the factors related to the pathogenesis of CCh ultimately pointed to abnormal elastic fibers. By reasonably speculating, we considered that abnormal elastic fibers cause the conjunctival relaxation. In conclusion, we hypothesize that elastic fibers play an important role in the pathogenesis of CCh. Studies on the mechanism of synthesis, degradation of elastic fibers are helpful to clarify the pathogenesis of the disease and to find effective treatment methods. PMID:28944209

Redefining cerebral malaria by including malaria retinopathy.

PubMed

Beare, Nicholas A V; Lewallen, Susan; Taylor, Terrie E; Molyneux, Malcolm E

2011-03-01

Accurate diagnosis of cerebral malaria (CM) is important for patient management, epidemiological and end point surveillance, and enrolling patients with CM in studies of pathogenesis or therapeutic trials. In malaria-endemic areas, where asymptomatic Plasmodium falciparum parasitemia is common, a positive blood film in a comatose individual does not prove that the coma is due to malaria. A retinopathy consisting of two unique features - patchy retinal whitening and focal changes of vessel color - is highly specific for encephalopathy of malarial etiology. White-centered retinal hemorrhages are a common but less specific feature. Either indirect or direct ophthalmoscopy can be used to identify the changes, and both procedures can be learned and practiced by nonspecialist clinicians. In view of its important contributions to both clinical care and research, examination of the retina should become a routine component of the assessment of a comatose child or adult when CM is a possible diagnosis.

Redefining cerebral malaria by including malaria retinopathy

PubMed Central

Beare, Nicholas AV; Lewallen, Susan; Taylor, Terrie E; Molyneux, Malcolm E

2011-01-01

Accurate diagnosis of cerebral malaria (CM) is important for patient management, epidemiological and end point surveillance, and enrolling patients with CM in studies of pathogenesis or therapeutic trials. In malaria-endemic areas, where asymptomatic Plasmodium falciparum parasitemia is common, a positive blood film in a comatose individual does not prove that the coma is due to malaria. A retinopathy consisting of two unique features – patchy retinal whitening and focal changes of vessel color – is highly specific for encephalopathy of malarial etiology. White-centered retinal hemorrhages are a common but less specific feature. Either indirect or direct ophthalmoscopy can be used to identify the changes, and both procedures can be learned and practiced by nonspecialist clinicians. In view of its important contributions to both clinical care and research, examination of the retina should become a routine component of the assessment of a comatose child or adult when CM is a possible diagnosis. PMID:21449844

Tremor in dystonia.

PubMed

Pandey, Sanjay; Sarma, Neelav

2016-08-01

Tremor has been recognized as an important clinical feature in dystonia. Tremor in dystonia may occur in the body part affected by dystonia known as dystonic tremor or unaffected body regions known as tremor associated with dystonia. The most common type of tremor seen in dystonia patients is postural and kinetic which may be mistaken for familial essential tremor. Similarly familial essential tremor patients may have associated dystonia leading to diagnostic uncertainties. The pathogenesis of tremor in dystonia remains speculative, but its neurophysiological features are similar to dystonia which helps in differentiating it from essential tremor patients. Treatment of tremor in dystonia depends upon the site of involvement. Dystonic hand tremor is treated with oral pharmacological therapy and dystonic head, jaw and voice tremor is treated with injection botulinum toxin. Neurosurgical interventions such as deep brain stimulation and lesion surgery should be an option in patients not responding to the pharmacological treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rheumatoid arthritis: what do MRI and ultrasound show

PubMed Central

Jans, Lennart; Teh, James

2017-01-01

Rheumatoid arthritis is the most common inflammatory arthritis, affecting approximately 1% of the world’s population. Its pathogenesis has not been completely understood. However, there is evidence that the disease may involve synovial joints, subchondral bone marrow as well as intra- and extraarticular fat tissue, and may lead to progressive joint destruction and disability. Over the last two decades, significant improvement in its prognosis has been achieved owing to new strategies for disease management, the emergence of new biologic therapies and better utilization of conventional disease-modifying antirheumatic drugs. Prompt diagnosis and appropriate therapy have been recognized as essential for improving clinical outcomes in patients with early rheumatoid arthritis. Despite the potential of ultrasonography and magnetic resonance imaging to visualize all tissues typically involved in the pathogenesis of rheumatoid arthritis, the diagnosis of early disease remains difficult due to limited specificity of findings. This paper summarizes the pathogenesis phenomena of rheumatoid arthritis and describes rheumatoid arthritis-related features of the disease within the synovium, subchondral bone marrow and articular fat tissue on MRI and ultrasound. Moreover, the paper aims to illustrate the significance of MRI and ultrasound findings in rheumatoid arthritis in the diagnosis of subclinical and early inflammation, and the importance of MRI and US in the follow-up and establishing remission. Finally, we also discuss MRI of the spine in rheumatoid arthritis, which may help assess the presence of active inflammation and complications. PMID:28439423

Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

PubMed Central

Nayak, Ramesh C.; Trump, Lisa R.; Aronow, Bruce J.; Myers, Kasiani; Mehta, Parinda; Kalfa, Theodosia; Wellendorf, Ashley M.; Valencia, C. Alexander; Paddison, Patrick J.; Horwitz, Marshall S.; Grimes, H. Leighton; Lutzko, Carolyn; Cancelas, Jose A.

2015-01-01

Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which encodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered the understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN patient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that recapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte death and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein response/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues the dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In contrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular NE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and promoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes NE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the potential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to correct NE mislocalization. PMID:26193632

Appendicitis-like clinical image elicited by Enterobius vermicularis: case report and review of the literature.

PubMed

Vleeschouwers, W; Hofman, Ph; Gillardin, J P; Meert, V; Van Slycke, S

2013-01-01

A 17-year-old female patient presented with the clinical features of an acute appendicitis. During laparoscopic exploration a macroscopically normal appendix was found. Since there were no intra-abdominal abnormalities found, the appendix was resected. Anatomopathology demonstrated Enterobius vermicularis, a pinworm infecting only humans, and mostly living in the caecum. This parasite is responsible for possibly the most common helminthic infection in the developed world. Its role in the pathogenesis of acute appendicitis is controversial, but more recent studies indicate a stronger association between enterobiasis and appendicitis. Often, enterobius mimics appendicitis by obstructing the lumen of the appendix, thereby causing appendiceal colic. This case report stresses the importance of microscopic examination of all appendectomy resection specimens. In case of enterobius infestation, systemic therapy of patient and family is necessary.

Urticarial vasculitis.

PubMed

Chang, Suyoung; Carr, Warner

2007-01-01

A case of urticarial vasculitis (UV) is presented. The pathogenesis, clinical characteristics, diagnosis, and management of this disease are reviewed, followed by clinical pearls and pitfalls for the practicing allergist (Venzor J, et al., Urticarial vasculitis, Clin Rev Allergy Immunol 23:201-216, 2002). The lesions in UV typically lasts > 24 hours in a fixed location, resolves with residual hyperpigmentation, and may or may not be pruritic. In contrast, standard urticaria lesions persist < 24 hours, leave no trace, and is always pruritic (Black AK, Urticarial vasculitis, Clin Dermatol 17:565-569, 1999). Since urticarial vasculitis is characterized by a variety of cutaneous, systemic, and serological features, different names of this disorder exist in the literature (Wisnieski JJ, Urticarial vasculitis, Curr Opin Rheumatol 12:24-31, 2000). A biopsy of an active lesion remains the gold standard for the diagnosis of urticarial vasculitis.

Oral varix: a review.

PubMed

Lazos, Jerónimo P; Piemonte, Eduardo D; Panico, René L

2015-06-01

Ageing produces several changes on the oral cavity, and oral varix (OV) is among the most common, and they are related with some medical diseases; however, this association is not clear. The aim of this article is to offer a review of OV, regarding aetiology, clinical and histological features, associated factors, treatment and its clinical significance. Except for a higher incidence of OV in elder individuals, there is limited evidence that supports its relationship with medical conditions such us cardiovascular diseases or portal hypertension. Also, there is no consensus regarding its pathogenesis, but the hemodynamic theory embodies the most comprehensive approach. The high prevalence in elderly people stresses the need for regular oral examination, but more detailed studies regarding OV in relation to systemic diseases are needed. © 2013 John Wiley & Sons A/S and The Gerodontology Society. Published by John Wiley & Sons Ltd.

Toxic shock syndrome: clinical and laboratory features in 15 patients.

PubMed

Tofte, R W; Williams, D N

1981-02-01

Toxic shock syndrome is a recently recognized illness with serious morbidity and mortality that occurs primarily in healthy menstruating women who use tampons. Thirteen women and two men were evaluated; two of the women died in spite of seemingly appropriate therapy. All patients had a temperature of 38.9 degrees C or greater, hypotension of syncope, a skin rash with subsequent desquamation, mucous membrane inflammation, and laboratory evidence of multiple organ dysfunction. Staphylococcus aureus was isolated from the cervix or vagina in eight women and from soft-tissue infections in both men. Two patients were bacteremic. The significant heterogeneity in the clinical manifestations, laboratory abnormalities, and therapeutic requirements among patients may result in diagnostic confusion and inappropriate therapy. Although toxic shock syndrome appears to be associated with tampon usage and S. aureus, the pathogenesis remains unknown.

Gastric biomarkers: a global review.

PubMed

Baniak, Nick; Senger, Jenna-Lynn; Ahmed, Shahid; Kanthan, S C; Kanthan, Rani

2016-08-11

Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.

Gallbladder Cancer in the 21st Century

PubMed Central

Kanthan, Rani; Senger, Jenna-Lynn; Ahmed, Shahid; Kanthan, Selliah Chandra

2015-01-01

Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC. PMID:26421012

Osteogenesis imperfecta types I-XI: implications for the neonatal nurse.

PubMed

Womack, Jody

2014-10-01

Osteogenesis imperfecta (OI), also called "brittle bone disease," is a rare heterozygous connective tissue disorder that is caused by mutations of genes that affect collagen. Osteogenesis imperfecta is characterized by decreased bone mass, bone fragility, and skin hyperlaxity. The phenotype present is determined according to the mutation on the affected gene as well as the type and location of the mutation. Osteogenesis imperfecta is neither preventable nor treatable. Osteogenesis imperfecta is classified into 11 types to date, on the basis of their clinical symptoms and genetic components. This article discusses the definition of the disease, the classifications on the basis of its clinical features, incidence, etiology, and pathogenesis. In addition, phenotype, natural history, diagnosis and management of this disease, recurrence risk, and, most importantly, the implications for the neonatal nurse and management for the family are discussed.

Age-associated Pro-inflammatory Remodeling and Functional Phenotype in the Heart and Large Arteries

PubMed Central

Wang, Mingyi; Shah, Ajay M

2015-01-01

The aging population is increasing dramatically. Aging–associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure. PMID:25665458

Therapy development for diffuse axonal injury.

PubMed

Smith, Douglas H; Hicks, Ramona; Povlishock, John T

2013-03-01

Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

PubMed

Shinohara, Mitsuru; Sato, Naoyuki; Shimamura, Munehisa; Kurinami, Hitomi; Hamasaki, Toshimitsu; Chatterjee, Amarnath; Rakugi, Hiromi; Morishita, Ryuichi

2014-01-01

The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

Idiopathic Juxtafoveolar Retinal Telangiectasis: A Current Review

PubMed Central

Nowilaty, Sawsan R.; Al-Shamsi, Hanan N.; Al-Khars, Wajeeha

2010-01-01

Idiopathic juxtafoveolar retinal telangiectasis (IJFT), also known as parafoveal telangiectasis or idiopathic macular telangiectasia, refers to a heterogeneous group of well-recognized clinical entities characterized by telangiectatic alterations of the juxtafoveolar capillary network of one or both eyes, but which differ in appearance, presumed pathogenesis, and management strategies. Classically, three groups of IJFT are identified. Group I is unilateral easily visible telangiectasis occurring predominantly in males, and causing visual loss as a result of macular edema. Group II, the most common, is bilateral occurring in both middle-aged men and women, and presenting with telangiectasis that is more difficult to detect on biomicroscopy, but with characteristic and diagnostic angiographic and optical coherence tomography features. Vision loss is due to retinal atrophy, not exudation, and subretinal neovascularization is common. Group III is very rare characterized predominantly by progressive obliteration of the perifoveal capillary network, occurring usually in association with a medical or neurologic disease. This paper presents a current review of juxtafoveolar retinal telangiectasis, reviewing the classification of these entities and focusing primarily on the two most common types encountered in clinical practice, i.e., groups I and II, describing their clinical features, histopathology, natural history, complications, latest results from imaging modalities and functional studies, differential diagnosis, and treatment modalities. PMID:20844678

Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome.

PubMed

Sproule, Douglas M; Kaufmann, Petra

2008-10-01

Since the initial description almost 25 years ago, the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) has been a useful model to study the complex interplay of factors that define mitochondrial disease. This syndrome, most commonly caused by an A-to-G transition mutation at position 3243 of the mitochondrial genome, is typified by characteristic neurological manifestations including seizures, encephalopathy, and strokelike episodes, as well as other frequent secondary manifestations including short stature, cognitive impairment, migraines, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus. In this review, we discuss the history, pathogenesis, clinical features, and diagnostic and management strategies of mitochondrial disease in general and of MELAS in particular. We explore features of mitochondrial genetics, including the concepts of heteroplasmy, mitotic segregation, and threshold effect, as a basis for understanding the variability and complicated inheritance patterns seen with this group of diseases. We also describe systemic manifestations of MELAS-associated mutations, including cardiac, renal, endocrine, gastrointestinal, and endothelial abnormalities and pathology, as well as the hypothetical role of derangements to COX enzymatic function in driving the unique pathology and clinical manifestations of MELAS. Although therapeutic options for MELAS and other mitochondrial diseases remain limited, and recent trials have been disappointing, we also consider current and potential therapeutic modalities.

Pleuroparenchymal fibroelastosis: is it also an idiopathic entity?

PubMed

Portillo, Karina; Guasch Arriaga, Ignasi; Ruiz-Manzano, Juan

2015-10-01

Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that has been recently included in the updated consensus on idiopathic interstitial pneumonias. It shares some clinical features with other chronic interstitial pneumonias (dyspnea, dry cough), and is radiologically characterized by pleural and subpleural parenchymal fibrosis and elastosis, mainly in the upper lobes. The main histological findings include pleural fibrosis and prominent subpleural and parenchymal fibroelastosis. Its characterization is based on the increasing number of cases reported in the literature, so several aspects of the etiology, pathogenesis and natural history are still unknown. Although some cases have been described as idiopathic, PPFE has been reported as a complication after bone marrow transplantation, lung transplantation and chemotherapy, especially with alkylating agents.Spontaneous or iatrogenic pneumothorax is a frequently reported complication of invasive diagnostic tests for identifying PPFE. The disease course is variable, ranging from slow progression to rapid clinical deterioration. No treatment has shown evidence of efficacy, and lung transplantation remains the only option for patients who fulfill the diagnostic criteria for this option. Recognizing and disseminating the specific features of PPFE is essential to raise the level of clinical suspicion for this entity, and to implement appropriate multidisciplinary diagnostic management. Copyright © 2015 SEPAR. Published by Elsevier Espana. All rights reserved.

Autoantibodies Associated With Connective Tissue Diseases: What Meaning for Clinicians?

PubMed Central

Didier, Kevin; Bolko, Loïs; Giusti, Delphine; Toquet, Segolene; Robbins, Ailsa; Antonicelli, Frank; Servettaz, Amelie

2018-01-01

Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjögren’s syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient’s management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs. PMID:29632529

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

PubMed Central

Abraham, Clara; Dulai, Parambir S.; Vermeire, Séverine; Sandborn, William J.

2016-01-01

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID:27780712

A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some β3GalT6-pathy mutations.

PubMed

Ben-Mahmoud, A; Ben-Salem, S; Al-Sorkhy, M; John, A; Ali, B R; Al-Gazali, L

2018-06-01

Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (β3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondyloepimetaphyseal dysplasia with joint laxity type I (SEMD-JL1). In 2017, a new international classification of EDS included these 2 conditions together with the child reported to have features similar to Al-Gazali syndrome under spondylodysplastic EDS (spEDS). We report a disease-causing variant c.618C > G, p.(Cys206Trp) in 1 patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the endoplasmic reticulum-associated protein degradation, in the pathogenesis of 13 B3GALT6 variants. Retention in endoplasmic reticulum was evident in 6 of them while the c.618C > G, p.(Cys206Trp) and the other 6 variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic variants in this gene. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions.

PubMed

Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

2017-09-01

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Non-scarring patchy alopecia in patients with systemic lupus erythematosus differs from that of alopecia areata.

PubMed

Ye, Y; Zhao, Y; Gong, Y; Zhang, X; Caulloo, S; Zhang, B; Cai, Z; Yang, J; McElwee, K J; Zhang, X

2013-12-01

Non-scaring patchy alopecia associated with systematic lupus erythematosus (SLE) is sometimes mis-diagnosed as alopecia areata (AA). Our aim was to differentiate non-scarring patchy SLE alopecia features from patchy AA. Clinical, dermatoscopic and histopathological data from 21 SLE patients with patchy alopecia were compared with data from 21 patients with patchy AA. Incomplete alopecia was common in SLE alopecia patches, while AA patches exhibited complete alopecia. Exclamation-mark hairs, black dots, broken hair and yellow dots were common to AA, while hair shaft thinning and hypopigmentation, angiotelectasis, peripilar sign, perifollicular red dots, white dots and honeycomb pigment patterns were more common in SLE. Interfollicular polymorphous vessels were the most common angiotelectasis presentation in the SLE alopecia patches, but interfollicular arborizing vessels were significantly more common in non-hair-loss-affected SLE regions and in AA hair-loss regions. During follow-up, increased vellus hair was the earliest feature that emerged after treatment both in SLE and AA, while the earliest feature that disappeared was hair shaft hypopigmentation in SLE and broken hair in AA. After treatment, no SLE patients had relapse of alopecia, while 41.7% of AA patients did. Distinct clinical, dermatoscopic and histopathological features were found in SLE-associated alopecia regions, which were different from those of AA. Serological autoantibody tests are of value to confirm the differential diagnosis. Local angiotelectasis and vasculitis close to hair follicles may be involved in the pathogenesis of alopecia in SLE.

Generalized pustular psoriasis - A model disease for specific targeted immunotherapy, systematic review.

PubMed

Boehner, Alexander; Navarini, Alexander A; Eyerich, Kilian

2018-05-31

Generalized pustular psoriasis (GPP) psoriasis is a rare, multisystemic skin disease characterized by recurrent episodes of pustulation. GPP can be life-threatening and is often difficult to treat. In the era of precision medicine in dermatology, GPP stands exemplary for both challenges and chances - while new treatments offer great hope, there is urgent need for better definition and stratification of this severe and heterogeneous disease. Our objective was to systematically review the literature for evidence of efficacy of targeted immunotherapy and their mode of action in the context of clinical phenotype, classification and pathogenesis of adult GPP. Classifying GPP is challenging since clinical criteria for description and diagnosis are not consistent between expert centers. We therefore defined diagnostic feasibility of the reviewed cases by assessing four criteria: compatible clinical history, typical dermatological features and/or diagnostic histopathology, consistent clinical pictures and the DITRA status. Pathogenesis of GPP is mediated by pathways that partly overlap plaque type psoriasis, with a more pronounced activity of the innate immune system. Both IL-1 and IL-36 but also IL-17 play a major role in disease formation. We ascertained a total of 101 published cases according to our predefined criteria and identified TNF-α, IL-12/23, IL-17 and IL-1β as targets for immunotherapy for the treatment of GPP. Of those cases, 61% showed complete response and 27% partial response to targeted immunotherapy. Only 12% experienced weak or no response. These data indicate that specific immunotherapy can be used to effectively treat GPP, with most evidence existing for anti-IL-17 agents. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Self-healing juvenile cutaneous mucinosis: Clinical and histopathologic findings of 9 patients: The relevance of long-term follow-up.

PubMed

Luchsinger, Isabelle; Coulombe, Jérôme; Rongioletti, Franco; Haspeslagh, Marc; Dompmartin, Anne; Melki, Isabelle; Dagher, Rawane; Bader-Meunier, Brigitte; Fraitag, Sylvie; Bodemer, Christine

2018-06-01

Self-healing juvenile cutaneous mucinosis (SHJCM) is a rare disorder, and its pathogenesis and long-term prognosis are unknown. To elucidate the clinical and histopathologic characteristics, pathogenesis, and outcome in patients with SHJCM. Retrospective study of 9 patients with SHCJM. To complement initial findings, data collection forms were sent to the referring physicians. All patients had an acute onset of firm nodules. Of the 9 patients, 6 presented initially with waxy papules on the dorsum of the hands; 5 suffered from periorbital edema, and 6 had a febrile prodrome. Histopathologic assessment of the papules revealed dermal mucin deposition, whereas the nodules showed proliferative fasciitis-like features or nonspecific chronic lobular panniculitis. Laboratory studies elicited evidence of active viral infection in 2 patients (human herpes virus 6 and rotavirus). Seven cases had spontaneous resolution within 6 months, and 2 patients with incomplete resolution showed subsequent transition to fibroblastic rheumatism and an autoinflammatory rheumatologic disease, respectively. This was a retrospective study with incomplete data from referring physicians. Although spontaneous complete regression is expected, patients with SHJCM need long-term follow-up because of the possible development of dematorheumatolgic conditions. The pathogenetic role of microbial agents deserves further investigation. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

What causes alopecia areata?

PubMed Central

McElwee, K. J.; Gilhar, A.; Tobin, D. J.; Ramot, Y.; Sundberg, J. P.; Nakamura, M.; Bertolini, M.; Inui, S.; Tokura, Y.; Jr, L. E. King; Duque-Estrada, B.; Tosti, A; Keren, A.; Itami, S.; Shoenfeld, Y.; Zlotogorski, A.; Paus, R.

2014-01-01

The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8+ T cells, CD4+ T cells and NKGD2+ NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA-related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re-evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease. PMID:23947678

α-Synuclein oligomers and clinical implications for Parkinson disease

PubMed Central

Kalia, Lorraine V.; Kalia, Suneil K.; McLean, Pamela J.; Lozano, Andres M.; Lang, Anthony E.

2012-01-01

Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long-held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent suggesting another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α-synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α-synuclein also forms oligomeric species with certain conformations being toxic to cells. The mechanisms by which these α-synuclein oligomers cause cell death are being actively investigated as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α-synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications. PMID:23225525

Prioritizing causal disease genes using unbiased genomic features.

PubMed

Deo, Rahul C; Musso, Gabriel; Tasan, Murat; Tang, Paul; Poon, Annie; Yuan, Christiana; Felix, Janine F; Vasan, Ramachandran S; Beroukhim, Rameen; De Marco, Teresa; Kwok, Pui-Yan; MacRae, Calum A; Roth, Frederick P

2014-12-03

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits. To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM. Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature.

Phosphodiesterase type 5 and cancers: progress and challenges

PubMed Central

Barone, Ines; Giordano, Cinzia; Bonofiglio, Daniela; Andò, Sebastiano; Catalano, Stefania

2017-01-01

Cancers are an extraordinarily heterogeneous collection of diseases with distinct genetic profiles and biological features that directly influence response patterns to various treatment strategies as well as clinical outcomes. Nevertheless, our growing understanding of cancer cell biology and tumor progression is gradually leading towards rational, tailored medical treatments designed to destroy cancer cells by exploiting the unique cellular pathways that distinguish them from normal healthy counterparts. Recently, inhibition of the activity of phosphodiesterase type 5 (PDE5) is emerging as a promising approach to restore normal intracellular cyclic guanosine monophosphate (cGMP) signalling, and thereby resulting into the activation of various downstream molecules to inhibit proliferation, motility and invasion of certain cancer cells. In this review, we present an overview of the experimental and clinical evidences highlighting the role of PDE5 in the pathogenesis and prevention of various malignancies. Current data are still not sufficient to draw conclusive statements for cancer patient management, but could provide further rational for testing PDE5-targeting drugs as anticancer agents in clinical settings. PMID:29228762

Present status of yellow fever: memorandum from a PAHO meeting.

PubMed

1986-01-01

An international seminar on the treatment and laboratory diagnosis of yellow fever, sponsored by the Pan American Health Organization (PAHO) and held in 1984, differed from previous meetings on yellow fever because of its emphasis on the care and management of patients and because the participants included specialists from several branches of medicine, such as hepatology, haematology, cardiology, infectious diseases, pathology and nephrology. The meeting reviewed the current status of yellow fever and problems associated with case-finding and notification; features of yellow fever in individual countries of Latin America; health services and facilities for medical care as they relate to diagnosis and management of cases; prevention strategies for and current status of immunization programmes; clinical and pathological aspects of yellow fever in humans; pathogenesis and pathophysiology of yellow fever in experimental animal models; clinical and specific laboratory diagnosis; treatment of the disease and of complications in the functioning of individual organ systems; prognosis and prognostic indicators; and directions for future clinical and experimental research on pathophysiology and treatment.

Pigmented well-differentiated hepatocellular neoplasm with beta-catenin mutation.

PubMed

Souza, Lara Neves; de Martino, Rodrigo Bronze; Thompson, Richard; Strautnieks, Sandra; Heaton, Nigel D; Quaglia, Alberto

2015-12-01

According to the most recent WHO classification of hepatocellular adenomas, a small percentage of inflammatory hepatocellular adenomas presents with mutation in the beta-catenin gene and are at higher risk of malignant transformation. It has been recognized that adenoma-like hepatocellular neoplasms with focal atypia, or in unusual clinical context present with similar cytogenetic and immunohistochemistry characteristics to well-differentiated hepatocellular carcinomas. We report a case of a well-differentiated hepatocellular neoplasm with Dubin-Johnson-like pigment displaying histological features overlapping with a beta-catenin mutated inflammatory adenoma and a well-differentiated hepatocellular carcinoma in a non-cirrhotic liver. The patient was a 48-year-old woman, who was asymptomatic, and had a clinical history of intra-uterine exposure to diethylstilbestrol, previous cancers and past oral contraceptive use. The recently proposed term "well-differentiated hepatocellular neoplasm of uncertain malignant potential" should be applied in such cases to highlight the different pathogenesis and risk of malignancy compared to the typical adenomas, and to suggest a careful and customized clinical management.

R1 autonomic nervous system in acute kidney injury.

PubMed

Hering, Dagmara; Winklewski, Pawel J

2017-02-01

Acute kidney injury (AKI) is a rapid loss of kidney function resulting in accumulation of end metabolic products and associated abnormalities in fluid, electrolyte and acid-base homeostasis. The pathophysiology of AKI is complex and multifactorial involving numerous vascular, tubular and inflammatory pathways. Neurohumoral activation with heightened activity of the sympathetic nervous system and renin-angiotensin-aldosterone system play a critical role in this scenario. Inflammation and/or local renal ischaemia are underlying mechanisms triggering renal tissue hypoxia and resultant renal microcirculation dysfunction; a common feature of AKI occurring in numerous clinical conditions leading to a high morbidity and mortality rate. The contribution of renal nerves to the pathogenesis of AKI has been extensively demonstrated in a series of experimental models over the past decades. While this has led to better knowledge of the pathogenesis of human AKI, therapeutic approaches to improve patient outcomes are scarce. Restoration of autonomic regulatory function with vagal nerve stimulation resulting in anti-inflammatory effects and modulation of centrally-mediated mechanisms could be of clinical relevance. Evidence from experimental studies suggests that a therapeutic splenic ultrasound approach may prevent AKI via activation of the cholinergic anti-inflammatory pathway. This review briefly summarizes renal nerve anatomy, basic insights into neural control of renal function in the physiological state and the involvement of the autonomic nervous system in the pathophysiology of AKI chiefly due to sepsis, cardiopulmonary bypass and ischaemia/reperfusion experimental model. Finally, potentially preventive experimental pre-clinical approaches for the treatment of AKI aimed at sympathetic inhibition and/or parasympathetic stimulation are presented. © 2016 John Wiley & Sons Australia, Ltd.

Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates.

PubMed Central

Brouillet, E; Hantraye, P; Ferrante, R J; Dolan, R; Leroy-Willig, A; Kowall, N W; Beal, M F

1995-01-01

Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of 3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7624378

Modeling Autistic Features in Animals

PubMed Central

Patterson, Paul H.

2011-01-01

A variety of features of autism can be simulated in rodents, including the core behavioral hallmarks of stereotyped and repetitive behaviors, and deficits in social interaction and communication. Other behaviors frequently found in autism spectrum disorders (ASD) such as neophobia, enhanced anxiety, abnormal pain sensitivity and eye blink conditioning, disturbed sleep patterns, seizures, and deficits in sensorimotor gating are also present in some of the animal models. Neuropathology and some characteristic neurochemical changes that are frequently seen in autism, as well as alterations in the immune status in the brain and periphery are also found in some of the models. Several known environmental risk factors for autism have been successfully established in rodents, including maternal infection and maternal valproate administration. Also under investigation are a number of mouse models based on genetic variants associated with autism or on syndromic disorders with autistic features. This review briefly summarizes recent developments in this field, highlighting models with face and/or construct validity, and noting the potential for investigation of pathogenesis and early progress towards clinical testing of potential therapeutics. Wherever possible, reference is made to reviews rather than primary articles. PMID:21289542

Knowledge boosting: a graph-based integration approach with multi-omics data and genomic knowledge for cancer clinical outcome prediction

PubMed Central

Kim, Dokyoon; Joung, Je-Gun; Sohn, Kyung-Ah; Shin, Hyunjung; Park, Yu Rang; Ritchie, Marylyn D; Kim, Ju Han

2015-01-01

Objective Cancer can involve gene dysregulation via multiple mechanisms, so no single level of genomic data fully elucidates tumor behavior due to the presence of numerous genomic variations within or between levels in a biological system. We have previously proposed a graph-based integration approach that combines multi-omics data including copy number alteration, methylation, miRNA, and gene expression data for predicting clinical outcome in cancer. However, genomic features likely interact with other genomic features in complex signaling or regulatory networks, since cancer is caused by alterations in pathways or complete processes. Methods Here we propose a new graph-based framework for integrating multi-omics data and genomic knowledge to improve power in predicting clinical outcomes and elucidate interplay between different levels. To highlight the validity of our proposed framework, we used an ovarian cancer dataset from The Cancer Genome Atlas for predicting stage, grade, and survival outcomes. Results Integrating multi-omics data with genomic knowledge to construct pre-defined features resulted in higher performance in clinical outcome prediction and higher stability. For the grade outcome, the model with gene expression data produced an area under the receiver operating characteristic curve (AUC) of 0.7866. However, models of the integration with pathway, Gene Ontology, chromosomal gene set, and motif gene set consistently outperformed the model with genomic data only, attaining AUCs of 0.7873, 0.8433, 0.8254, and 0.8179, respectively. Conclusions Integrating multi-omics data and genomic knowledge to improve understanding of molecular pathogenesis and underlying biology in cancer should improve diagnostic and prognostic indicators and the effectiveness of therapies. PMID:25002459

Knowledge boosting: a graph-based integration approach with multi-omics data and genomic knowledge for cancer clinical outcome prediction.

PubMed

Kim, Dokyoon; Joung, Je-Gun; Sohn, Kyung-Ah; Shin, Hyunjung; Park, Yu Rang; Ritchie, Marylyn D; Kim, Ju Han

2015-01-01

Cancer can involve gene dysregulation via multiple mechanisms, so no single level of genomic data fully elucidates tumor behavior due to the presence of numerous genomic variations within or between levels in a biological system. We have previously proposed a graph-based integration approach that combines multi-omics data including copy number alteration, methylation, miRNA, and gene expression data for predicting clinical outcome in cancer. However, genomic features likely interact with other genomic features in complex signaling or regulatory networks, since cancer is caused by alterations in pathways or complete processes. Here we propose a new graph-based framework for integrating multi-omics data and genomic knowledge to improve power in predicting clinical outcomes and elucidate interplay between different levels. To highlight the validity of our proposed framework, we used an ovarian cancer dataset from The Cancer Genome Atlas for predicting stage, grade, and survival outcomes. Integrating multi-omics data with genomic knowledge to construct pre-defined features resulted in higher performance in clinical outcome prediction and higher stability. For the grade outcome, the model with gene expression data produced an area under the receiver operating characteristic curve (AUC) of 0.7866. However, models of the integration with pathway, Gene Ontology, chromosomal gene set, and motif gene set consistently outperformed the model with genomic data only, attaining AUCs of 0.7873, 0.8433, 0.8254, and 0.8179, respectively. Integrating multi-omics data and genomic knowledge to improve understanding of molecular pathogenesis and underlying biology in cancer should improve diagnostic and prognostic indicators and the effectiveness of therapies. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Autoimmune acute liver failure: proposed clinical and histological criteria.

PubMed

Stravitz, R Todd; Lefkowitch, Jay H; Fontana, Robert J; Gershwin, M Eric; Leung, Patrick S C; Sterling, Richard K; Manns, Michael P; Norman, Gary L; Lee, William M

2011-02-01

Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone. Copyright © 2010 American Association for the Study of Liver Diseases.

Right heart on multidetector CT

PubMed Central

Gopalan, D

2011-01-01

Right ventricular function plays an integral role in the pathogenesis and outcome of many cardiovascular diseases. Imaging the right ventricle has long been a challenge because of its complex geometry. In recent years there has been a tremendous expansion in multidetector row CT (MDCT) and its cardiac applications. By judicious modification of contrast medium protocol, it is possible to achieve good opacification of the right-sided cardiac chambers, thereby paving the way for exploring the overshadowed right heart. This article will describe the key features of right heart anatomy, review MDCT acquisition techniques, elaborate the various morphological and functional information that can be obtained, and illustrate some important clinical conditions associated with an abnormal right heart. PMID:22723537

[Chronic active Epstein-Barr virus infection].

PubMed

Kimura, Hiroshi

2011-12-01

The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.

3-Hydroxyanthranilate oxygenase activity is increased in the brains of Huntington disease victims

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

Schwarcz, R.; Okuno, E.; White, R.J.

1988-06-01

An excess of the tryptophan metabolite quinolinic acid in the brain has been hypothetically related to the pathogenesis of Huntington disease. Quinolinate's immediate biosynthetic enzyme, 3-hydroxyanthranilate oxygenase, has now been detected in human brain tissue. The activity of 3-hydroxyanthranilate oxygenase is increased in Huntington disease brains as compared to control brains. The increment is particularly pronounced in the striatum, which is known to exhibit the most prominent nerve-cell loss in Huntington disease. Thus, the Huntington disease brain has a disproportionately high capability to produce the endogenous excitotoxin quinolinic acid. This finding may be of relevance for clinical, neuropathologic, and biochemicalmore » features associated with Huntington disease.« less

Neonatal cholestasis and focal medullary dysplasia of the kidneys in a case of microcephalic osteodysplastic primordial dwarfism.

PubMed Central

Berger, A; Haschke, N; Kohlhauser, C; Amman, G; Unterberger, U; Weninger, M

1998-01-01

We report on a male infant who presented with intrauterine growth retardation, severe postnatal failure to thrive, microcephaly, facial dysmorphism, and skeletal dysplasia. The clinical and radiological findings are consistent with former descriptions of microcephalic osteodysplastic primordial dwarfism (MOPD) type I/III. In addition to previously published features, multiple fractures of the long bones, severe neonatal cholestasis, and histological dysplasia of the kidneys were found. The boy died at the age of 8 months. The new finding of focal renal medullary dysplasia further supports the hypothesis of a basic defect in tissue differentiation in the pathogenesis of this rare condition. Images PMID:9475098

Imaging normal pressure hydrocephalus: theories, techniques, and challenges.

PubMed

Keong, Nicole C H; Pena, Alonso; Price, Stephen J; Czosnyka, Marek; Czosnyka, Zofia; Pickard, John D

2016-09-01

The pathophysiology of NPH continues to provoke debate. Although guidelines and best-practice recommendations are well established, there remains a lack of consensus about the role of individual imaging modalities in characterizing specific features of the condition and predicting the success of CSF shunting. Variability of clinical presentation and imperfect responsiveness to shunting are obstacles to the application of novel imaging techniques. Few studies have sought to interpret imaging findings in the context of theories of NPH pathogenesis. In this paper, the authors discuss the major streams of thought for the evolution of NPH and the relevance of key imaging studies contributing to the understanding of the pathophysiology of this complex condition.

[Autism in children. Speech, behavior and motor activity point to diagnosis].

PubMed

Neumärker, K J

2001-02-01

Austistic disorders characteristically involve specific impairments of social skills, of the language and of stereotyped body movements. L Kanner and H. Asperger were the first to describe these psychopathologic features, which still form the core of the diagnostic criteria of contemporary psychiatric classification systems, ICD-10 and DSM-IV, in the category pervasive developmental disorders. Useful diagnostic tools have been developed to establish the clinical diagnosis. The results of research point to a predominantly genetic pathogenesis involving a complex interaction of multiple genes. While no causal treatments are available for these heterogenic disorders, there are many therapeutic concepts. Although some treatments may achieve significant improvements, autistic disorders usually mean a lifelong individual impairment.

The Roles of Cigarette Smoking and the Lung in the Transitions between Phases of Preclinical Rheumatoid Arthritis

PubMed Central

Sparks, Jeffrey A.; Karlson, Elizabeth W.

2016-01-01

While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis. PMID:26951253

CXCR4 pos circulating progenitor cells coexpressing monocytic and endothelial markers correlating with fibrotic clinical features are present in the peripheral blood of patients affected by systemic sclerosis.

PubMed

Campioni, Diana; Lo Monaco, Andrea; Lanza, Francesco; Moretti, Sabrina; Ferrari, Luisa; Fotinidi, Maria; La Corte, Renato; Cuneo, Antonio; Trotta, Francesco

2008-08-01

There is still controversy regarding the role of circulating endothelial and progenitor cells (CECs/CEPs) in the pathogenesis of systemic sclerosis (SSc). Using a sequential Boolean gating strategy based on a 4-color flow cytometric protocol, an increased number of CD31(pos)/CD184(pos)(CXCR4)/CD34(pos)/CD45(pos) and CD31(pos)/CD117(pos) (c-kit-R) /CD34(pos)/ CD45(pos) hematopoietic circulating progenitor cells (HCPCs) was detected in SSc patients compared with healthy subjects. In SSc, no circulating mature and progenitor endothelial cells were observed, while an enhanced generation of erythroid progenitor cells was found to be correlated with the presence of CD117+ HCPCs. The presence of freshly detected CXCR4posHCPC was correlated either to the in vitro cultured spindle-shaped endothelial like cells (SELC) with an endo/myelomonocytic profile or to SDF-1 and VEGF serum level. These data are related to more fibrotic clinical features of the disease, thus supporting a possible role of these cells in fibrosis.

ALCOHOLIC HEPATITIS: TRANSLATIONAL APPROACHES TO DEVELOP TARGETED THERAPIES

PubMed Central

Mandrekar, Pranoti; Bataller, Ramon; Tsukamoto, Hidekazu; Gao, Bin

2016-01-01

Alcoholic liver disease (ALD) is a leading cause of liver related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with ALD. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with AH is very high (20–50% at 3 months). Available therapies are not effective in many patients and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. This review article summarizes the unmet needs for translational studies on the pathogenesis of AH, pre-clinical translational tools, and emerging drug targets to benefit the AH patient. PMID:26940353

Infectious mononucleosis in university students in the United kingdom: evaluation of the clinical features and consequences of the disease.

PubMed

Macsween, Karen F; Higgins, Craig D; McAulay, Karen A; Williams, Hilary; Harrison, Nadine; Swerdlow, Anthony J; Crawford, Dorothy H

2010-03-01

Infectious mononucleosis (IM) is common among university students. We undertook to analyze the clinical features and sequelae of the disease in a cohort of students at Edinburgh University. Consecutive IM case patients were recruited from 2000 through 2002 at the University Health Service after diagnosis of IM. IM resulted in marked reductions in student study time, physical exercise, and non-exercise-related social activities, and sustained increases in reported number of hours of sleep. The disease profile differed between the sexes, with significantly more females reporting fatigue, which was more likely to be prolonged (P = .003) and to lead to loss of study time (P = .013). Female case patients were more likely to discontinue their studies following IM (16% vs 0%; P = .056). Within the typically elevated lymphocyte counts in IM, we identified an elevated gammadelta T cell component that may contribute to the disease pathogenesis. IM results in substantial morbidity among university students, reported as more profound in females, and affecting academic studies, physical exercise, and social activities. Immunization to prevent IM and strategies to reduce post-IM disability would be beneficial in this population.

[Diagnosis and treatment of heparin-induced thrombocytopenia (HIT) based on its atypical immunological features].

PubMed

Miyata, Shigeki; Maeda, Takuma

2016-03-01

Heparin-induced thrombocytopenia (HIT) is a prothrombotic side effect of heparin therapy caused by HIT antibodies, i.e., anti-platelet factor 4 (PF4)/heparin IgG with platelet-activating properties. For serological diagnosis, antigen immunoassays are commonly used worldwide. However, such assays do not indicate their platelet-activating properties, leading to low specificity for the HIT diagnosis. Therefore, over-diagnosis is currently the most serious problem associated with HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for appropriate HIT diagnosis. Recent advances in our understanding of the pathogenesis of HIT include it having several clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response on heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. These lines of evidence suggest that the mechanisms underlying HIT antibody formation may be compatible with a non-T cell-dependent immune reaction. These atypical clinical and serological features should be carefully considered while endeavoring to accurately diagnose HIT, which leads to appropriate therapies such as immediate administration of an alternative anticoagulant to prevent thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease

PubMed Central

Paulsson, Kajsa; Cazier, Jean-Baptiste; MacDougall, Finlay; Stevens, Jane; Stasevich, Irina; Vrcelj, Nikoletta; Chaplin, Tracy; Lillington, Debra M.; Lister, T. Andrew; Young, Bryan D.

2008-01-01

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. PMID:18458336

Calciphylaxis: diagnosis and clinical features.

PubMed

Hayashi, Matsuhiko

2013-08-01

Calciphylaxis is a relatively rare disease, observed mainly in patients on dialysis, associated with high mortality rates, and characterized by painful skin ulceration. The pathogenesis of calciphylaxis is virtually unknown, although several risk factors, including warfarin therapy, hypoalbuminemia, and disturbances in calcium-phosphate metabolism, have been reported. The prevalence of calciphylaxis in Japan is likely to be less than 1:10,000 dialysis patients per year based on our nationwide survey in 2009. However, the results of the survey also showed that about 60 % of nephrologists in Japan are not familiar with the disease itself and it is highly likely that calciphylaxis is being overlooked. To facilitate recognition of calciphylaxis, we have proposed diagnostic criteria. At present, there is no specific therapy for calciphylaxis and general supportive measures, especially antibiotics for the accompanying infection and wound care, are important. Recently, sodium thiosulfate has been increasingly used to treat calciphylaxis and its efficacy should be evaluated by large clinical trials.

Pathology and differential diagnosis of chronic, noninfectious gastritis.

PubMed

Polydorides, Alexandros D

2014-03-01

The histologic finding of chronic inflammation in an endoscopic mucosal biopsy of the stomach (chronic gastritis) is very common and usually reflects the presence of Helicobacter pylori infection. However, infectious organisms are not always present in biopsy material, and some cases of chronic gastritis do not result from H. pylori infection. Thus, the differential diagnosis of this finding is an important one for pathologists to keep in mind. This review presents the three most common and clinically significant causes of chronic, noninfectious gastritis, namely, autoimmune atrophic gastritis, lymphocytic gastritis, and gastric involvement in the setting of inflammatory bowel disease, especially Crohn disease. For each entity, a brief discussion of its etiology and pathogenesis, a review of the clinical and endoscopic features, and a description of the microscopic findings are presented in the context of the differential diagnosis of chronic gastritis with emphasis on helpful histopathologic hints and long-term sequelae. Copyright © 2014 Elsevier Inc. All rights reserved.

Epidemiological Distribution and Subtype Analysis of Premenstrual Dysphoric Disorder Syndromes and Symptoms Based on TCM Theories

PubMed Central

Wang, Haijun; Zhan, Xianghong; Liu, Hongqi; Wang, Xiaoyun; Li, Xia; Wang, Xiaoru; Wu, Jibiao

2017-01-01

We performed an epidemiological investigation of subjects with premenstrual dysphoric disorder (PMDD) to identify the clinical distribution of the major syndromes and symptoms. The pathogenesis of PMDD mainly involves the dysfunction of liver conveyance and dispersion. Excessive liver conveyance and dispersion are associated with liver-qi invasion syndrome, while insufficient liver conveyance and dispersion are expressed as liver-qi depression syndrome. Additionally, a nonconditional logistic regression was performed to analyze the symptomatic features of liver-qi invasion and liver-qi depression. As a result of this analysis, two subtypes of PMDD are proposed, namely, excessive liver conveyance and dispersion (liver-qi invasion syndrome) and insufficient liver conveyance and dispersion (liver-qi depression syndrome). Our findings provide an epidemiological foundation for the clinical diagnosis and treatment of PMDD based on the identification of different types. PMID:28698873

Color me bad: microbial pigments as virulence factors

PubMed Central

Liu, George Y.; Nizet, Victor

2009-01-01

A hallmark feature of several pathogenic microbes is the distinctive color of their colonies when propagated in the clinical laboratory. Such pigmentation comes in a variety of hues, and has often proven useful in presumptive clinical diagnosis. Recent advances in microbial pigment biochemistry and the genetic basis of pigment production has sometimes revealed a more sinister aspect to these curious materials that change the color of reflected light by selective light absorbance. In many cases, the microbial pigment contributes to disease pathogenesis by interfering with host immune clearance mechanisms or by exhibiting pro-inflammatory or cytotoxic properties. Here, we review several examples of pigments that promote microbial virulence, including the golden staphyloxanthin of Staphylococcus aureus, the blue-green pyocyanin of Pseudomonas spp., and the dark brown or black melanin pigments of Cryptococcus neoformans and Aspergillus spp. Targeted pigment neutralization may represent a viable concept to enhance treatment of certain difficult infectious disease conditions. PMID:19726196

Periodontal disease.

PubMed

Niemiec, Brook A

2008-05-01

Periodontal disease is the most commonly diagnosed problem in small animal veterinary medicine. In the vast majority of cases, however, there are little to no outward clinical signs of the disease process, and, therefore, therapy often comes very late in the disease course. Consequently, periodontal disease is also the most undertreated animal health problem. In addition, unchecked periodontal disease has numerous dire consequences both locally and systemically. These consequences are detailed in the article and should be utilized to educate clients and encourage compliance of therapeutic recommendations. The local consequences include oronasal fistulas, class II perio-endo lesions, pathologic fractures, ocular problems, osteomyelitis, and an increased incidence of oral cancer. Systemic diseases linked to periodontal disease include: renal, hepatic, pulmonary, and cardiac diseases; osteoporosis, adverse pregnancy effects, and diabetes mellitus. Before the discussion of consequences, this article covers the pathogenesis of periodontal disease, followed by clinical features and diagnostic tests.

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.

PubMed

Román, Gustavo C; Kalaria, Raj N

2006-12-01

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.

Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon?

PubMed Central

Das, Arup; McGuire, Paul G; Monickaraj, Finny

2016-01-01

The blood–retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti-VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti-VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials. PMID:26953018

Chromosome abnormalities and the genetics of congenital corneal opacification

PubMed Central

Mataftsi, A.; Islam, L.; Kelberman, D.; Sowden, J.C.

2011-01-01

Congenital corneal opacification (CCO) encompasses a broad spectrum of disorders that have different etiologies, including genetic and environmental. Terminology used in clinical phenotyping is commonly not specific enough to describe separate entities, for example both the terms Peters anomaly and sclerocornea have been ascribed to a clinical picture of total CCO, without investigating the presence or absence of iridocorneal adhesions. This is not only confusing but also unhelpful in determining valid genotype-phenotype correlations, and thereby revealing clues for pathogenesis. We undertook a systematic review of the literature focusing on CCO as part of anterior segment developmental anomalies (ASDA), and analyzed its association specifically with chromosomal abnormalities. Genes previously identified as being associated with CCO are also summarized. All reports were critically appraised to classify phenotypes according to described features, rather than the given diagnosis. Some interesting associations were found, and are discussed. PMID:21738392

Chromosome abnormalities and the genetics of congenital corneal opacification.

PubMed

Mataftsi, A; Islam, L; Kelberman, D; Sowden, J C; Nischal, K K

2011-01-01

Congenital corneal opacification (CCO) encompasses a broad spectrum of disorders that have different etiologies, including genetic and environmental. Terminology used in clinical phenotyping is commonly not specific enough to describe separate entities, for example both the terms Peters anomaly and sclerocornea have been ascribed to a clinical picture of total CCO, without investigating the presence or absence of iridocorneal adhesions. This is not only confusing but also unhelpful in determining valid genotype-phenotype correlations, and thereby revealing clues for pathogenesis. We undertook a systematic review of the literature focusing on CCO as part of anterior segment developmental anomalies (ASDA), and analyzed its association specifically with chromosomal abnormalities. Genes previously identified as being associated with CCO are also summarized. All reports were critically appraised to classify phenotypes according to described features, rather than the given diagnosis. Some interesting associations were found, and are discussed.

Are herpes virus associated to aggressive periodontitis? A review of literature

PubMed Central

Rodrigues, Patrícia Maria de Sousa; Teixeira, Ana Luísa; Kustner, Eduardo Chimenos; Medeiros, Rui

2015-01-01

Periodontal Disease includes a wide variety of infectious entities with various clinical manifestations in the oral cavity and responses to treatment. The determinants of clinical manifestations of periodontal disease include the type of infectious agent, the host immune response and environmental factors. Aggressive periodontitis (AP) is defined as a type of inflammation with specific clinical and laboratory features, which distinguish it from other types of periodontitis, with high incidence rates in a sub-group of individuals. Bacteria have been frequently mentioned as the agent inciting gingival inflammation and tissue destruction that underlies the pathogenesis of periodontitis. However, recent studies, with some controversial results, have suggested that the herpes family of viruses, including CMV and EBV-1 as well as papillomaviruses, HIV, Human T-lymphotropic virus type 1, Torquetenovirus and hepatitis B and C occur with high frequency in active periodontal lesions. There is a lack of information about this disease and the role of herpesviruses in its pathophysiology. This review provides a critical analysis of the scientific evidence linking bacteria and viruses with AP and their potential impact on clinical characteristics, prognosis and therapy. PMID:26980964

Milk and Soy Allergy

PubMed Central

Kattan, Jacob D.; Cocco, Renata R.; Järvinen, Kirsi M.

2011-01-01

SYNOPSIS Cow’s milk allergy (CMA) affects 2% to 3% of young children and presents with a wide range of immunoglobulin E (IgE-) and non-IgE-mediated clinical syndromes, which have a significant economic and lifestyle impact. Definitive diagnosis is based on a supervised oral food challenge (OFC), but convincing clinical history, skin prick testing, and measurement of cow’s milk (CM)-specific IgE can aid in the diagnosis of IgE-mediated CMA and occasionally eliminate the need for OFCs. It is logical that a review of CMA would be linked to a review of soy allergy, as soy formula is often an alternative source of nutrition for infants who do not tolerate cow’s milk. The close resemblance between the proteins from soy and other related plants like peanut, and the resulting cross-reactivity and lack of predictive values for clinical reactivity, often make the diagnosis of soy allergy far more challenging. This review examines the epidemiology, pathogenesis, clinical features, natural history and diagnosis of cow’s milk and soy allergy. Cross-reactivity and management of milk allergy are also discussed. PMID:21453810

Prostate cancer prevention agent development: Criteria and pipeline for candidate chemoprevention agents.

PubMed

Nelson, W G; Wilding, G

2001-04-01

Epidemiologic data suggest that prostate cancer morbidity and mortality ought to be preventable. New insights into the molecular pathogenesis of prostate cancer offer new opportunities for the discovery of prostate cancer chemoprevention drugs and new challenges for their development. Established pathways that lead to US Food and Drug Administration (FDA) approval of drugs for advanced prostate cancer may not be appropriate for the development of drugs for prostate cancer chemoprevention. For example, large randomized clinical trials designed to test the efficacy of new chemoprevention drugs on prostate cancer survival in the general population are likely to be conducted at great expense and take many years, threatening to increase commercial development risks while decreasing exclusive marketing revenues. As a consequence, to accelerate progress in research, new validated surrogate and strategic clinical trial endpoints, and new clinical trial designs featuring more precisely defined high-risk clinical trial cohorts, are needed. In this review, 10 criteria for prostate cancer chemoprevention agent development are offered and the pipeline of new prostate cancer chemoprevention drug candidates is considered.

Delayed-onset and recurrent limb weakness associated with West Nile virus infection.

PubMed

Sejvar, James J; Davis, Larry E; Szabados, Erica; Jackson, Alan C

2010-02-01

Human neurologic illness following infection with West Nile virus (WNV) may include meningitis, encephalitis, and acute flaccid paralysis (AFP). Most WNV-associated AFP is due to involvement of the spinal motor neurons producing an anterior (polio)myelitis. WNV poliomyelitis is typically characterized by acute and rapidly progressing limb weakness occurring early in the course of illness, which is followed by death or clinical plateauing with subsequent improvement to varying degrees. We describe four cases of WNV poliomyelitis in which the limb weakness was characterized by an atypical temporal pattern, including one case with onset several weeks after illness onset, and three cases developing relapsing or recurrent limb weakness following a period of clinical plateauing or improvement. Delayed onset or recurrent features may be due to persistence of viral infection or delayed neuroinvasion with delayed injury by excitotoxic or other mechanisms, by immune-mediated mechanisms, or a combination thereof. Further clinical and pathogenesis studies are needed to better understand the mechanisms for these phenomena. Clinicians should be aware of these clinical patterns in patients with WNV poliomyelitis.

[Clinicopathologic study of invasive fungal rhinosinusitis caused by Aspergillus and Mucorales].

PubMed

He, Chun-yan; Piao, Ying-shi; Tian, Cheng; Li, Li-li; Liu, Hong-gang

2012-10-01

To compare the differences in clinicopathologic features of invasive fungal rhinosinusitis caused by Aspergillus and Mucorales, and to discuss the pathogenesis of tissue injury induced by these two kinds of fungi. The clinical and pathologic features of 19 patients with invasive fungal rhinosinusitis due to Aspergillus (group A) and 16 patients with invasive fungal rhinosinusitis due to Mucorales (group M) were retrospectively reviewed. HE, PAS and GMS stains were performed on all the paraffin-embedded tissues. The diagnosis was confirmed by histologic examination and microbiological culture results. Amongst the group A patients, the clinical course was acute in 4 cases and chronic in 15 cases. Thirteen cases had underlying predisposing conditions, including diabetes (number = 4), malignant tumor (number = 5), history of trauma (number = 1) and radical maxillary sinus surgery (number = 3). Follow-up information was available in 13 patients. Seven of them died, 4 due to fungal encephalopathy and 3 due to underlying diseases. Amongst the group M patients, the clinical course was acute in 14 cases and chronic in 2 cases. Fourteen cases had underlying predisposing conditions, including diabetes (number = 8), malignant tumor (number = 5) and history of wisdom tooth extraction (number = 1). Follow-up information was available in 14 patients. Four of them died of fungal encephalopathy. There was significant difference in clinical onset between the two groups (P = 0.01). There was however no difference in terms of underlying predisposing conditions and disease mortality. Histologically, the microorganisms in group A patients formed fungal masses and attached to the mucosal surface, resulting in necrotic bands (11/19). Epithelioid granulomas were conspicuous but multinucleated giant cells were relatively rare. Deep-seated necrosis, granulomatous inflammation against fungal organisms (3/19) and vasculitis with thrombosis (4/19) were not common. On the other hand, large areas of geographic necrosis involving deep-seated tissue could be seen in group M patients (13/16). Isolated multinucleated giant cells were commonly seen. Granulomatous inflammation against fungal organisms were identified (16/16). Vasculitis and thrombosis were also observed (10/16). The invasiveness of Mucorales is remarkable; and when it causes invasive fungal rhinosinusitis, the clinical course is often acute and large areas of tissue necrosis can be seen. The invasiveness of Aspergillus in tissue is relatively mild. Granulomas are more common and the disease often runs a chronic clinical course. There is however no significant difference in long-term mortality. The pathogenesis may be related to the different components of the fungi.

Genital and reproductive organ complications of Crohn disease: technical considerations as it relates to perianal disease, imaging features, and implications on management.

PubMed

Kammann, Steven; Menias, Christine; Hara, Amy; Moshiri, Mariam; Siegel, Cary; Safar, Bashar; Brandes, Steven; Shaaban, Akram; Sandrasegaran, Kumar

2017-06-01

A relatively large proportion of patients with Crohn disease (CD) develop complications including abscess formation, stricture, and penetrating disease. A subset of patients will have genital and reproductive organ involvement of CD, resulting in significant morbidity. These special circumstances create unique management challenges that must be tailored to the activity, location, and extent of disease. Familiarity with the epidemiology, pathogenesis, imaging features, and treatment strategies for patients with genital CD can aid imaging diagnoses and guide appropriate patient management. The purpose of this study is to illustrate the spectrum of CD in the genital tract and reproductive organs and discuss the complex management strategies in these patients as it relates to imaging. Given the impact on patient outcome and treatment planning, familiarity with the epidemiology, pathogenesis, imaging features, and treatment of patients with genital Crohn disease can aid radiologic diagnoses and guide appropriate patient management.

Review article: pathogenesis and clinical manifestations of gastrointestinal involvement In systemic sclerosis

PubMed Central

Kumar, Sumit; Singh, Jagmohan; Rattan, Satish; DiMarino, Anthony J; Cohen, Sidney; Jimenez, Sergio A.

2017-01-01

SUMMARY Background Gastrointestinal tract involvement is a common cause of debilitating symptoms in patients with systemic sclerosis. There are no disease modifying therapies for this condition and the treatment remains symptomatic, largely owing to the lack of a clear understanding of its pathogenesis. Aim To investigate novel aspects of the pathogenesis of gastrointestinal involvement in systemic sclerosis To summarize existing knowledge regarding the cardinal clinical gastrointestinal manifestations of systemic sclerosis and its pathogenesis, emphasizing recent investigations that may be valuable in identifying potentially novel therapeutic targets. Methods Electronic (Pubmed/Medline) and manual Google search Results The gastrointestinal tract is the most common internal organ involved in systemic sclerosis. Any part of the gastrointestinal tract from the mouth to the anus can be affected. There is substantial variability in clinical manifestations and disease course and symptoms are non-specific and overlapping for a particular anatomical site. Gastrointestinal involvement can occur in the in the absence of cutaneous disease. Up to 8% of systemic sclerosis patients develop severe gastrointestinal tract symptoms. This subset of patients display increased mortality with only 15% survival at 9 years. Dysmotiity of the gastrointestinal tract causes the majority of symptoms. Recent investigations have identified a novel mechanism in the pathogenesis of gastrointestinal tract dysmotility mediated by functional anti-muscarinic receptor autoantibodies. Conclusion Despite extensive investigation the pathogenesis of gastrointestinal involvement in systemic sclerosis remains elusive. Although treatment currently remains symptomatic, an improved understanding of novel pathogenic mechanisms may allow the development of potentially highly effective approaches including intravenous immunoglobulin and microRNA based therapeutic interventions. PMID:28185291

Gene clusters of Hafnia alvei strain FB1 important in survival and pathogenesis: a draft genome perspective.

PubMed

Tan, Jia-Yi; Yin, Wai-Fong; Chan, Kok-Gan

2014-01-01

Hafnia alvei is an opportunistic pathogen involved in various types of nosocomical infections. The species has been found to inhabit food and mammalian guts. However, its status as an enteropathogen, and whether the food-inhabiting strains could be a source of gastrointestinal infection remains obscure. In this report we present a draft genome of H. alvei strain FB1 isolated from fish paste meatball, a food popular among Malaysian and Chinese populations. The data was generated on the Illumina MiSeq platform. A comparative study was carried out on FB1 against two other previously sequenced H. alvei genomes. Several gene clusters putatively involved in survival and pathogenesis of H. alvei FB1 in food and gut environment were characterised in this study. These include the widespread colonisation island (WCI), the tad locus that is known to play an essential role in biofilm formation, a eut operon that might contribute to advantage in nutrient acquisition in gut environment, and genes responsible for siderophore production This features enable the bacteria to successful colonise in the host gut environment. With the whole genome data of H. alvei FB1 presented in this study, we hope to provide an insight into future studies on this candidate of enteropathogen by looking into the possible mechanisms employed to survive stresses and gain advantage in competitions, which eventually leads to successful colonisation and pathogenesis. This is to serve as the basis for more effective clinical diagnosis and treatment.

One year in review 2016: systemic lupus erythematosus.

PubMed

Adinolfi, Antonella; Valentini, Eleonora; Calabresi, Emanuele; Tesei, Giulia; Signorini, Viola; Barsotti, Simone; Tani, Chiara

2016-01-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a highly variable course and prognosis. The management of the disease is still a clinical challenge for the treating physicians as many aspects regarding the disease pathogenesis, clinical picture and outcomes remain to be elucidated. New and interesting data are emerging; here the recent literature on SLE pathogenesis, clinical and laboratory aspects, as well as treatments and comorbidities, are reviewed and the main findings summarised in order to provide a bird's eye on the relevant papers on these topics.

A case of coexistence of TSH/GH-secreting pituitary tumor and papillary thyroid carcinoma: Challenges in pathogenesis and management.

PubMed

Kiatpanabhikul, Phatharaporn; Shuangshoti, Shanop; Chantra, Kraisri; Navicharern, Patpong; Kingpetch, Kanaungnit; Houngngam, Natnicha; Snabboon, Thiti

2017-07-01

Co-existence of thyrotropin/growth hormone-secreting pituitary adenoma with differentiated thyroid carcinoma is exceedingly rare, with less than 15 cases having been reported. Its clinical presentation and treatment strategy are challenging. We report a case of pituitary macroadenoma, with clinical syndromes of acromegaly and hyperthyroidism, and a thyroid nodule, with cytologically confirmed to be a papillary thyroid carcinoma. Clinical implications, focusing on the strategy for proper management, and possible pathogenesis were discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tendinopathy: Investigating the Intersection of Clinical and Animal Research to Identify Progress and Hurdles in the Field

PubMed Central

Titan, Ashley; Andarawis-Puri, Nelly

2017-01-01

Biological treatments, surgical interventions, and rehabilitation exercises have been successfully used to treat tendinopathy, but the development of effective treatments has been hindered by the lack of mechanistic data regarding the pathogenesis of the disease.While insightful, clinical studies are limited in their capacity to provide data regarding the pathogenesis of tendinopathies, emphasizing the value of animal models and cell culture studies to fill this essential gap in knowledge.Clinical pathological findings from imaging studies or histological analysis are not universal across patients with tendinopathy and have not been clearly associated with the onset of symptoms.There are several unresolved controversies, including the cellular changes that accompany the tendinopathic disease state and the role of inflammation.Additional research is needed to correlate the manifestations of the disease with its pathogenesis, with the goal of reaching a field-wide consensus on the pathology of the disease state. Such a consensus will allow standardized clinical practices to more effectively diagnose and treat tendinopathy. PMID:27792676

Relationship between the iceA gene of Helicobacter pylori and clinical outcomes.

PubMed

Huang, Xiaojun; Deng, Zhaomin; Zhang, Qiang; Li, Wanyi; Wang, Baoning; Li, Mingyuan

2016-01-01

The complex pathogenesis of Helicobacter pylori (H. pylori) and the features of the host influence the diverse clinical outcomes. A mass of studies about virulence genes have accelerated the exploration of pathogenesis of H. pylori infection. Induced by contact with epithelium gene A (iceA) is one of the biggest concerned virulence genes. In this study, we explored the relationship between iceA and the magnitude of the risk for clinical outcomes and the prevalence of iceA-positive H. pylori in People's Republic of China and other countries. We searched the electronic databases of PubMed, Embase, CNKI, VIP, and Wanfang by literature search strategy. The studies conforming to the inclusion criteria were assessed. With these data, we systematically analyzed the relationship between the iceA gene of H. pylori and clinical outcomes. Nineteen articles with 22 studies, a total of 2,657 cases, were involved in the study. The iceA1 gene was significantly associated with peptic ulcer disease (odds ratio =1.28, 95% confidence interval =1.03-1.60; P=0.03), especially in People's Republic of China (odds ratio =1.40, 95% confidence interval =1.07-1.83; P=0.01). Moreover, the prevalence of iceA1 was significantly higher than iceA2 in People's Republic of China (P<0.0001). The prevalence of both iceA1 and iceA2 was significantly different (P<0.0001) in People's Republic of China and in other countries. The system analysis showed that infection with the iceA1-positive H. pylori significantly increased the overall risk for peptic ulcer disease, especially in People's Republic of China. The iceA2 gene status and clinical outcome of H. pylori infection have no significant correlation. H. pylori iceA1 genotype is the major epidemic strain in People's Republic of China.

Sweat glucose and GLUT2 expression in atopic dermatitis: Implication for clinical manifestation and treatment

PubMed Central

Ono, Emi; Mori, Yuki; Yoshioka, Yoshichika; Nomura, Yuko; Munetsugu, Takichi; Yokozeki, Hiroo; Katayama, Ichiro

2018-01-01

Sweat includes active components and metabolites, which are needed to maintain skin homeostasis. Component changes in sweat derived from atopic dermatitis (AD) have been reported. To investigate the influence of sweat components on the pathogenesis of AD, we performed a multifaceted assessment, including nuclear magnetic resonance spectroscopy-based metabolomic analysis, and linked these features to clinical features of AD. Distinctive properties of AD sweat are the quite-variation in protein, anti-microbial peptides and glucose concentrations. pH, sodium, and other salt levels in sweat of AD were comparable to that of healthy subjects. Sweat from AD patients with acute inflammation had a more prominent increase in glucose concentration than sweat from healthy individuals or those with AD with chronic inflammation. Topical glucose application delayed recovery of transepidermal water loss in barrier-disrupted mice. Furthermore, the glucose transporter GLUT2 was highly expressed in the lumen of sweat glands from AD patients. AD patients with chronic inflammation had significantly increased GLUT2 mRNA expression and near normal sweat glucose levels. Despite the small sample size in our study, we speculate that the increased glucose levels might be affected by AD severity and phenotype. We hope that this report will bring novel insight into the impact of sweat components on the clinical manifestation of AD. PMID:29677207

REGγ regulates ERα degradation via ubiquitin–proteasome pathway in breast cancer

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

Chai, Fan; Liang, Yan; Bi, Jiong

2015-01-02

Highlights: • High expression of REGγ is correlated with ERα status and poor clinical features. • Cell growth, mobility and invasion are significantly impaired by REGγ knockdown. • REGγ indirectly regulates ERα protein expression. - Abstract: REGγ is a proteasome coactivator which regulates proteolytic activity in eukaryotic cells. Abundant lines of evidence have showed that REGγ is over expressed in a number of human carcinomas. However, its precise role in the pathogenesis of cancer is still unclear. In this study, by examining 200 human breast cancer specimens, we demonstrated that REGγ was highly expressed in breast cancers, and the expressionmore » of REGγ was positively correlated with breast cancer patient estrogen receptor alpha (ERα) status. Moreover, the expression of REGγ was found positively associated with poor clinical features and low survival rates in ERα positive breast cancer patients. Further cell culture studies using MCF7 and BT474 breast cancer cell lines showed that cell proliferation, motility, and invasion capacities were decreased significantly by REGγ knockdown. Lastly, we demonstrated that REGγ indirectly regulates the degradation of ERα protein via ubiquitin–proteasome pathway. In conclusion, our findings provide the evidence that REGγ expression was positively correlated with ERα status and poor clinical prognosis in ERα positive breast cancer patients. As well, we disclose a new connection between the two molecules that are both highly expressed in most breast cancer cases.« less

Autoantibodies against complement components in systemic lupus erythematosus - role in the pathogenesis and clinical manifestations.

PubMed

Hristova, M H; Stoyanova, V S

2017-12-01

Many complement structures and a number of additional factors, i.e. autoantibodies, receptors, hormones and cytokines, are implicated in the complex pathogenesis of systemic lupus erythematosus. Genetic defects in the complement as well as functional deficiency due to antibodies against its components lead to different pathological conditions, usually clinically presented. Among them hypocomplementemic urticarial vasculitis, different types of glomerulonephritis as dense deposit disease, IgA nephropathy, atypical haemolytic uremic syndrome and lupus nephritis are very common. These antibodies cause conformational changes leading to pathological activation or inhibition of complement with organ damage and/or limited capacity of the immune system to clear immune complexes and apoptotic debris. Finally, we summarize the role of complement antibodies in the pathogenesis of systemic lupus erythematosus and discuss the mechanism of some related clinical conditions such as infections, thyroiditis, thrombosis, acquired von Willebrand disease, etc.

Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

PubMed Central

Zielinski, Daniel C.; Filipp, Fabian V.; Bordbar, Aarash; Jensen, Kasper; Smith, Jeffrey W.; Herrgard, Markus J.; Mo, Monica L.; Palsson, Bernhard O.

2015-01-01

Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways dysregulated by drugs are linked to the development of side effects. We show such dysregulated metabolic pathways contain genes with sequence variants affecting side effect incidence, play established roles in pathophysiology, have significantly altered activity in corresponding diseases, are susceptible to metabolic inhibitors and are effective targets for therapeutic nutrient supplementation. Our results indicate that metabolic dysregulation represents a common mechanism underlying side effect pathogenesis that is distinct from the role of metabolism in drug clearance. We suggest that elucidating the relationships between the cellular response to drugs, genetic variation of patients and cell metabolism may help managing side effects by personalizing drug prescriptions and nutritional intervention strategies. PMID:26055627

Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data.

PubMed

Martyanov, Viktor; Whitfield, Michael L

2016-01-01

The goal of this review is to summarize recent advances into the pathogenesis and treatment of systemic sclerosis (SSc) from genomic and proteomic studies. Intrinsic gene expression-driven molecular subtypes of SSc are reproducible across three independent datasets. These subsets are a consistent feature of SSc and are found in multiple end-target tissues, such as skin and esophagus. Intrinsic subsets as well as baseline levels of molecular target pathways are potentially predictive of clinical response to specific therapeutics, based on three recent clinical trials. A gene expression-based biomarker of modified Rodnan skin score, a measure of SSc skin severity, can be used as a surrogate outcome metric and has been validated in a recent trial. Proteome analyses have identified novel biomarkers of SSc that correlate with SSc clinical phenotypes. Integrating intrinsic gene expression subset data, baseline molecular pathway information, and serum biomarkers along with surrogate measures of modified Rodnan skin score provides molecular context in SSc clinical trials. With validation, these approaches could be used to match patients with the therapies from which they are most likely to benefit and thus increase the likelihood of clinical improvement.

Reversible splenial lesion syndrome associated with lobar pneumonia

PubMed Central

Li, Chunrong; Wu, Xiujuan; Qi, Hehe; Cheng, Yanwei; Zhang, Bing; Zhou, Hongwei; Lv, Xiaohong; Liu, Kangding; Zhang, Hong-Liang

2016-01-01

Abstract Background: Reversible splenial lesion syndrome (RESLES) is a rare clinico-radiological disorder with unclear pathophysiology. Clinically, RESLES is defined as reversible isolated splenial lesions in the corpus callosum, which can be readily identified by magnetic resonance imaging (MRI) and usually resolve completely over a period of time. RESLES could be typically triggered by infection, antiepileptic drugs (AEDs), poisoning, etc. More factors are increasingly recognized. Methods and results: We reported herein an 18-year-old female patient with lobar pneumonia who developed mental abnormalities during hospitalization. An isolated splenial lesion in the corpus callosum was found by head MRI and the lesion disappeared 15 days later. Based on her clinical manifestations and radiological findings, she was diagnosed with lobar pneumonia associated RESLES. We further summarize the up-to-date knowledge about the etiology, possible pathogenesis, clinical manifestations, radiological features, treatment, and prognosis of RESLES. Conclusion: This report contributes to the clinical understanding of RESLES which may present with mental abnormalities after infection. The characteristic imaging of reversible isolated splenial lesions in the corpus callosum was confirmed in this report. The clinical manifestations and lesions on MRI could disappear naturally after 1 month without special treatment. PMID:27684805

IFNγ-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis.

PubMed

Kumar, Pawan

2017-12-01

IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb-coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB-IRIS and in Mtb-infected PD-1 -/- mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.

New Metrics for Evaluating Viral Respiratory Pathogenesis

PubMed Central

Menachery, Vineet D.; Gralinski, Lisa E.; Baric, Ralph S.; Ferris, Martin T.

2015-01-01

Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease. Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections. This methodology closely tracked with traditional pathogenesis metrics, distinguished both virus- and dose-specific responses, and identified long-term respiratory changes following both SARS-CoV and Influenza A Virus infection. Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis. PMID:26115403

Primary xanthoma of the mandible

PubMed Central

de Moraes Ramos-Perez, FM; de Pádua, JM; Silva-Sousa, YTC; de Almeida, OP; da Cruz Perez, DE

2011-01-01

Bone xanthomas are rare and are usually are associated with endocrine or metabolic diseases, mainly lipid disorders. In the absence of systemic diseases, the lesion is called a primary xanthoma. Primary mandibular xanthomas are extremely rare. The aim of this report is to describe the clinical and radiographic findings of a primary mandibular xanthoma, discussing the epidemiological features, pathogenesis and differential diagnosis. A 25-year-old man was referred for evaluation of a left mandibular lesion detected in a routine radiographic exam. Radiographically, there was a diffuse, unilocular and radiolucent lesion, with irregular margins located adjacent to the surface from the distal root of the left mandibular third molar. The lesion was excised under local anaesthesia. Microscopically, there were several cells with a foamy and granular cytoplasm and central small, round nuclei, similar to xanthomatous macrophages. No lipid disorders were diagnosed. According to these features, the diagnosis of primary mandibular xanthoma was established. In conclusion, xanthomas of the jaws are rare and all seem to be primary and occur exclusively in the mandible. PMID:21831981

Posterior ankle impingement in athletes: Pathogenesis, imaging features and differential diagnoses.

PubMed

Hayashi, Daichi; Roemer, Frank W; D'Hooghe, Pieter; Guermazi, Ali

2015-11-01

Posterior ankle impingement is a clinical diagnosis which can be seen following a traumatic hyper-plantar flexion event and may lead to painful symptoms in athletes such as female dancers ('en pointe'), football players, javelin throwers and gymnasts. Symptoms of posterior ankle impingement are due to failure to accommodate the reduced interval between the posterosuperior aspect of the talus and tibial plafond during plantar flexion, and can be due to osseous or soft tissue lesions. There are multiple causes of posterior ankle impingement. Most commonly, the structural correlates of impingement relate to post-traumatic synovitis and intra-articular fibrous bands-scar tissue, capsular scarring, or bony prominences. The aims of this pictorial review article is to describe different types of posterior ankle impingement due to traumatic and non-traumatic osseous and soft tissue pathology in athletes, to describe diagnostic imaging strategies of these pathologies, and illustrate their imaging features, including relevant differential diagnoses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Secondary psychoses: an update

PubMed Central

Keshavan, Matcheri S; Kaneko, Yoshio

2013-01-01

Psychotic disorders due to a known medical illness or substance use are collectively termed secondary psychoses. In this paper, we first review the historic evolution of the concept of secondary versus primary psychosis and how this distinction supplanted the earlier misleading classification of psychoses into organic and functional. We then outline the clinical features and approach to the diagnosis of secondary psychotic disorders. Features such as atypical presentation, temporal relation to detectable medical cause, evidence of direct physiological causal relationship to the etiological agent, and the absence of evidence of a primary psychotic illness that may better explain the presentation suggest consideration of a secondary psychosis. Finally, we discuss how careful studies of secondary psychotic disorders can help elucidate the pathophysiology of primary, or idiopathic, psychotic disorders such as schizophrenia. We illustrate this issue through a discussion of three secondary psychotic disorders — psychoses associated with temporal lobe epilepsy, velocardiofacial syndrome, and N-methyl D-aspartate (NMDA) receptor encephalitis — that can, respectively, provide neuroanatomical, genetic, and neurochemical models of schizophrenia pathogenesis. PMID:23471787

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development.

PubMed

Blakely, Pennelope K; Delekta, Phillip C; Miller, David J; Irani, David N

2015-02-01

While alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. One such pathogen, western equine encephalitis virus (WEEV), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. Although WEEV also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and to evaluate candidate antiviral therapies. We have optimized conditions to infect mice with a low passage isolate of WEEV, thereby allowing detailed investigation of virus tropism, replication, neuroinvasion, and neurovirulence. We find that host factors strongly influence disease outcome, and in particular, that age, gender, and genetic background all have significant effects on disease susceptibility independent of virus tropism or replication within the central nervous system. Our data show that experimental variables can be adjusted in mice to recapitulate disease features known to occur in both non-human primates and humans, thus aiding further study of WEEV pathogenesis and providing a realistic therapeutic window for antiviral drug delivery.

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development

PubMed Central

Blakely, Pennelope K.; Delekta, Phillip C.; Miller, David J.; Irani, David N.

2014-01-01

While alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. One such pathogen, western equine encephalitis virus (WEEV), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. Although WEEV also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and to evaluate candidate antiviral therapies. We have optimized conditions to infect mice with a low passage isolate of WEEV, thereby allowing detailed investigation of virus tropism, replication, neuroinvasion, and neurovirulence. We find that host factors strongly influence disease outcome, and in particular that age, gender and genetic background all have significant effects on disease susceptibility independent of virus tropism or replication within the central nervous system. Our data show that experimental variables can be adjusted in mice to recapitulate disease features known to occur in both non-human primates and humans, thus aiding further study of WEEV pathogenesis and providing a realistic therapeutic window for antiviral drug delivery. PMID:25361697

Subcutaneous phaeohyphomycosis caused by Cladophialophora bantiana.

PubMed

Hussey, Sean M; Gander, Rita; Southern, Paul; Hoang, Mai P

2005-06-01

Primary subcutaneous phaeohyphomycosis can rarely be caused by Cladophialophora bantiana, and we present the histologic and culture findings of such a case. A 32-year-old African American woman with systemic lupus erythematosus presented with a 2-year history of multiple, recurrent, tender, and ulcerated skin nodules with purulent drainage on her upper back. Histologic sections of the excision demonstrated features of phaeohyphomycosis. Culture findings were characteristic of C bantiana. Of interest, at age 10 she had sustained traumatic implantation of wood splinters into this area during a tornado, yet clinical symptoms of a subcutaneous infection did not manifest until she developed lupus erythematosus at age 27. Our case highlights the role of trauma and immunosuppression in the pathogenesis of subcutaneous phaeohyphomycosis.

[Advance of the study on LRRK2 gene in Parkinson's disease].

PubMed

Zhang, Yu; Chen, Shengdi

2008-12-01

The leucine-rich repeat kinase2 (LRRK2) has been identified to be the gene causing autosomal dominant inherited Parkinson's disease(PD)8. The clinical features of this type of PD are similar to those of idiopathic PD, but the pathological changes are diverse. The mutation types and frequencies of the LRRK2 distribute unevenly in different populations. LRRK2 is a large complex protein with multiple functions and expresses widely in human body. Sequence alignment shows that LRRK2 might be a multiple function kinase for substrate phosphorylation and might also act as a scaffolding protein. Further study on the physiological function and pathogenic mechanism of LRRK2 will help to find out the possible pathogenesis and new treatment for PD.

Intestinal Effector T Cells in Health and Disease

PubMed Central

Maynard, Craig L.; Weaver, Casey T.

2011-01-01

Summary Crohn’s disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance. PMID:19766082

Normal CAG and CCG repeats in the Huntington`s disease genes of Parkinson`s disease patients

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

Rubinsztein, D.C.; Leggo, J.; Barton, D.E.

1995-04-24

The clinical features of Parkinson`s disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington`s disease. Therefore, the CAG and CCG repeats in the Huntington`s disease gene were investigated in 45 Parkinson`s disease patients and compared to 40 control individuals. All of the Parkinson`s disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson`s disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington`s disease gene are not likely to contribute to the pathogenesis of Parkinson`s disease.more » 12 refs., 2 figs.« less

Neurological disorders and inflammatory bowel diseases

PubMed Central

Casella, Giovanni; Tontini, Gian Eugenio; Bassotti, Gabrio; Pastorelli, Luca; Villanacci, Vincenzo; Spina, Luisa; Baldini, Vittorio; Vecchi, Maurizio

2014-01-01

Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease (IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms. PMID:25083051

Inflammation in renal atherosclerotic disease.

PubMed

Udani, Suneel M; Dieter, Robert S

2008-07-01

The study of renal atherosclerotic disease has conventionally focused on the diagnosis and management of renal artery stenosis. With the increased understanding of atherosclerosis as a systemic inflammatory process, there has been increased interest in vascular biology at the microvasculature level. While different organ beds share some features, the inflammation and injury in the microvasculature of the kidney has unique elements as well. Understanding of the pathogenesis yields a better understanding of the clinical manifestations of renal atherosclerotic disease, which can be very subtle. Furthermore, identifying the molecular mechanisms responsible for the progression of kidney damage can also direct clinicians and scientists toward targeted therapies. Existing therapies used to treat atherosclerotic disease in other vascular beds may also play a role in the treatment of renal atherosclerotic disease.

Traumatic Arteriovenous Fistula of the Scalp in the Left Temporoparietal Region with Intra- and Extracranial Blood Supply

PubMed Central

Zheng, Feng; Augustus Pitts, Herbert; Goldbrunner, Roland; Krischek, Boris

2016-01-01

Traumatic AVF of the scalp is a rare abnormal vascular disease. It is defined as a communication between the high flow arterial system and the low flow venous network, which directly connects the arterial feeding vessels of the scalp and the draining veins without an intervening capillary bed. The superficial temporal artery (STA) was involved in 90% of the cases, and 71% of the patients only had one dominant feeding STA. Here, we report the case of a rare large traumatic arteriovenous fistula (AVF) of the scalp that is fed by intra- and extracranial blood supply. The clinical and radiological features are presented, and the possible pathogenesis and surgical technique are discussed. PMID:26885435

Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: A possible link between cerebral and retinal microvascular abnormalities.

PubMed

Umemura, Toshitaka; Kawamura, Takahiko; Hotta, Nigishi

2017-03-01

Diabetes patients have more than double the risk of ischemic stroke compared with non-diabetic individuals, and its neuroimaging characteristics have important clinical implications. To understand the pathophysiology of ischemic stroke in diabetes, it is important to focus not only on the stroke subtype, but also on the size and location of the occlusive vessels. Specifically, ischemic stroke in diabetes patients might be attributed to both large and small vessels, and intracranial internal carotid artery disease and small infarcts of the posterior circulation often occur. An additional feature is that asymptomatic lacunar infarctions are often seen in the basal ganglia and brain stem on brain magnetic resonance imaging. In particular, cerebral small vessel disease (SVD), including lacunar infarctions, white matter lesions and cerebral microbleeds, has been shown to be associated not only with stroke incidence, but also with the development and progression of dementia and diabetic microangiopathy. However, the pathogenesis of cerebral SVD is not fully understood. In addition, data on the association between neuroimaging findings of the cerebral SVD and diabetes are limited. Recently, the clinical importance of the link between cerebral SVD and retinal microvascular abnormalities has been a topic of considerable interest. Several clinical studies have shown that retinal microvascular abnormalities are closely related to cerebral SVD, suggesting that retinal microvascular abnormalities might be pathophysiologically linked to ischemic cerebral SVD. We review the literature relating to the pathophysiology and neuroimaging of cerebrovascular disease in diabetes, and discuss the problems based on the concept of cerebral large and small vessel disease. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis.

PubMed

Wei, P; Hu, G-H; Kang, H-Y; Yao, H-B; Kou, W; Liu, H; Hong, S-L

2014-02-01

A predominant Th17 population is a marker of allergic rhinitis (AR). As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting the development of specific Th cells. However, its role in AR remains undefined. To analyze the potential role of AhR in the pathogenesis of AR. In total, 30 AR patients and 13 healthy controls were recruited for this study and AR patients had clinical features, as demonstrated by rhinoconjunctivitis quality of life questionnaires, total symptom scores and visual analog scale scores. The expression of AhR, IL-17 and IL-22 and the presence of Th17 cells in peripheral blood mononuclear cells were measured before and after treatment with the nontoxic AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Pretreatment ITE studies revealed that all AR patients had a significant increase in AhR expression compared with controls and AhR expression positively correlated with clinical parameters. After ITE intervention, a severe reduction in the differentiation of Th17 cells and the production of IL-17 and IL-22 was noted in both AR patients and normal subjects. Simultaneously, a dramatic enhancement of AhR expression was also observed in all healthy controls, but not in AR patients. The results suggested that the AhR may be one of the mechanisms underlying the Th17 response during the pathogenesis of AR and AhR levels were closely related to clinical severity in all AR patients. Additionally, ITE may represent a new drug candidate in the treatment of AR.

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity.

PubMed

Kent, D

2015-11-01

This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complement-mediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR.

Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection.

PubMed

Tincati, Camilla; Douek, Daniel C; Marchetti, Giulia

2016-01-01

Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota.

The pathogenesis of Foot-and-Mouth Disease in pigs

USDA-ARS?s Scientific Manuscript database

The greatest segment of foot-and-mouth disease (FMD) clinical research has been dedicated to elucidating pathogenesis and enhancing vaccine protection in cattle with less efforts invested in studies that are specific to pigs. However, accumulated evidence from FMD outbreaks and experimental invest...

Lipidomic profiling reveals distinct differences in plasma lipid composition in healthy, prediabetic, and type 2 diabetic individuals

PubMed Central

Zhong, Huanzi; Fang, Chao; Fan, Yanqun; Lu, Yan; Wen, Bo; Ren, Huahui; Hou, Guixue; Yang, Fangming; Xie, Hailiang; Jie, Zhuye; Peng, Ye; Ye, Zhiqiang; Wu, Jiegen; Zi, Jin; Zhao, Guoqing; Chen, Jiayu; Bao, Xiao; Hu, Yihe; Gao, Yan; Zhang, Jun; Yang, Huanming; Wang, Jian; Madsen, Lise; Kristiansen, Karsten

2017-01-01

Abstract The relationship between dyslipidemia and type 2 diabetes mellitus (T2D) has been extensively reported, but the global lipid profiles, especially in the East Asia population, associated with the development of T2D remain to be characterized. Liquid chromatography coupled to tandem mass spectrometry was applied to detect the global lipidome in the fasting plasma of 293 Chinese individuals, including 114 T2D patients, 81 prediabetic subjects, and 98 individuals with normal glucose tolerance (NGT). Both qualitative and quantitative analyses revealed a gradual change in plasma lipid features with T2D patients exhibiting characteristics close to those of prediabetic individuals, whereas they differed significantly from individuals with NGT. We constructed and validated a random forest classifier with 28 lipidomic features that effectively discriminated T2D from NGT or prediabetes. Most of the selected features significantly correlated with diabetic clinical indices. Hydroxybutyrylcarnitine was positively correlated with fasting plasma glucose, 2-hour postprandial glucose, glycated hemoglobin, and insulin resistance index (HOMA-IR). Lysophosphatidylcholines such as lysophosphatidylcholine (18:0), lysophosphatidylcholine (18:1), and lysophosphatidylcholine (18:2) were all negatively correlated with HOMA-IR. The altered plasma lipidome in Chinese T2D and prediabetic subjects suggests that lipid features may play a role in the pathogenesis of T2D and that such features may provide a basis for evaluating risk and monitoring disease development. PMID:28505362

Comparative pathogenesis of rabies in bats and carnivores, and implications for spillover to humans.

PubMed

Begeman, Lineke; GeurtsvanKessel, Corine; Finke, Stefan; Freuling, Conrad M; Koopmans, Marion; Müller, Thomas; Ruigrok, Tom J H; Kuiken, Thijs

2018-04-01

Bat-acquired rabies is becoming increasingly common, and its diagnosis could be missed partly because its clinical presentation differs from that of dog-acquired rabies. We reviewed the scientific literature to compare the pathogenesis of rabies in bats and carnivores-including dogs-and related this pathogenesis to differences in the clinical presentation of bat-acquired and dog-acquired rabies in human beings. For bat-acquired rabies, we found that the histological site of exposure is usually limited to the skin, the anatomical site of exposure is more commonly the face, and the virus might be more adapted for entry via the skin than for dog-acquired rabies. These factors could help to explain several differences in clinical presentation between individuals with bat-acquired and those with dog-acquired rabies. A better understanding of these differences should improve the recording of a patient's history, enable drawing up of a more sophisticated list of clinical characteristics, and therefore obtain an earlier diagnosis of rabies after contact with a bat or carnivore that has rabies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hashimoto thyroiditis: clinical and diagnostic criteria.

PubMed

Caturegli, P; De Remigis, A; Rose, N R

2014-01-01

Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Hypertrophic Osteoarthropathy: Clinical and Imaging Features.

PubMed

Yap, Felix Y; Skalski, Matthew R; Patel, Dakshesh B; Schein, Aaron J; White, Eric A; Tomasian, Anderanik; Masih, Sulabha; Matcuk, George R

2017-01-01

Hypertrophic osteoarthropathy (HOA) is a medical condition characterized by abnormal proliferation of skin and periosteal tissues involving the extremities and characterized by three clinical features: digital clubbing (also termed Hippocratic fingers), periostosis of tubular bones, and synovial effusions. HOA can be a primary entity, known as pachydermoperiostosis, or can be secondary to extraskeletal conditions, with different prognoses and management implications for each. There is a high association between secondary HOA and malignancy, especially non-small cell lung cancer. In such cases, it can be considered a form of paraneoplastic syndrome. The most prevalent secondary causes of HOA are pulmonary in origin, which is why this condition was formerly referred to as hypertrophic pulmonary osteoarthropathy. HOA can also be associated with pleural, mediastinal, and cardiovascular causes, as well as extrathoracic conditions such as gastrointestinal tumors and infections, cirrhosis, and inflammatory bowel disease. Although the skeletal manifestations of HOA are most commonly detected with radiography, abnormalities can also be identified with other modalities such as computed tomography, magnetic resonance imaging, and bone scintigraphy. The authors summarize the pathogenesis, classification, causes, and symptoms and signs of HOA, including the genetics underlying the primary form (pachydermoperiostosis); describe key findings of HOA found at various imaging modalities, with examples of underlying causative conditions; and discuss features differentiating HOA from other causes of multifocal periostitis, such as thyroid acropachy, hypervitaminosis A, chronic venous insufficiency, voriconazole-induced periostitis, progressive diaphyseal dysplasia, and neoplastic causes such as lymphoma. © RSNA, 2016.

The Immunoregulatory Effects of Traditional Chinese Medicine on Psoriasis via its Action on Interleukin: Advances and Considerations.

PubMed

Wu, Minfeng; Deng, Yu; Li, Su; Chen, Yu; Guo, Dongjie; Jin, Xingxiu; Xu, Qi; Li, Bin; Li, Fulun

2018-05-08

Psoriasis is a chronic inflammatory cutaneous disease characterized by clinical manifestations of erythema and white scales. The pathogenesis of psoriasis is not yet clear. Despite a combination of hormonal therapy and physiotherapy used in Western medicine, the condition often relapses after withdrawal of drugs. Traditional Chinese medicine (TCM) has therapeutic features and may be a clinically effective formula by regulating unbalanced immune systems, such as by targeting interleukins. In this paper, we review recent research about how Chinese medicine immunoregulates psoriasis via interleukins, and systematically summarizes the related mechanisms. There are three common pathways leading to psoriasis: (1) Th17 cells secrete IL-17, which is stimulated by IL-23; (2) Th1 cells secrete IL-21, TNF-[Formula: see text] and IFN-[Formula: see text], with the help of Th17 cells; (3) Th22 cells secrete IL-22 under the stimulation of Th17 cells. Clinical and experiment data indicate that TCM could modify psoriasis by antagonizing or regulating interleukin and IL-23/IL-17 axis to inhibit the main pathways.

Chronic Rhinosinusitis with Nasal Polyps

PubMed Central

Stevens, Whitney W.; Schleimer, Robert P.; Kern, Robert C.

2016-01-01

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an important clinical entity diagnosed by the presence of both subjective and objective evidence of chronic sinonasal inflammation. Symptoms include anterior or posterior rhinorrhea, nasal congestion, hyposmia and/or facial pressure or pain that last for greater than 12 weeks duration. Nasal polyps are inflammatory lesions that project into the nasal airway, are typically bilateral, and originate from the ethmoid sinus. Males are more likely to be affected than females but no specific genetic or environmental factors have been strongly linked to the development of this disorder to date. CRSwNP is frequently associated with asthma and allergic rhinitis but the cellular and molecular mechanisms that contribute to the clinical symptoms are not fully understood. Defects in the sinonasal epithelial cell barrier, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis. Additional studies are needed to further explore the clinical and pathophysiological features of CRSwNP so that biomarkers can be identified and novel advances can be made to improve the treatment and management of this disease. PMID:27393770

Osteogenesis Imperfecta: A Review with Clinical Examples

PubMed Central

van Dijk, F.S.; Cobben, J.M.; Kariminejad, A.; Maugeri, A.; Nikkels, P.G.J.; van Rijn, R.R.; Pals, G.

2011-01-01

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the ‘Sillence classification’), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI. PMID:22570641

Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance.

PubMed

Barber, Thomas M; Dimitriadis, George K; Andreou, Avgi; Franks, Stephen

2016-06-01

Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue. © 2016 Royal College of Physicians.

Cytokine profiles in localized scleroderma and relationship to clinical features.

PubMed

Kurzinski, Katherine; Torok, Kathryn S

2011-08-01

Localized scleroderma (LS) is a disfiguring autoimmune disease of the skin and underlying tissue that mainly affects the pediatric population. Inflammation of the tissue leads to fibrosis and atrophy, causing physical and psychological disability that can continue throughout childhood into adulthood. Available therapies for LS have had variable effects and are associated with morbidity themselves. A better understanding of the pathophysiology of LS, especially during the active inflammatory phase, would lead to more directed and efficacious therapies. As in systemic sclerosis (SSc), the other form of scleroderma, T-helper (Th) cells and their associated cytokines have been suggested to contribute significantly to the pathophysiology of LS supported by the presence of cytokines from these lineages in the sera and tissue of LS patients. It is postulated that the imbalance between Th1/Th2/Th17 cell subsets drives inflammation in the early stages of disease (Th1 and Th17 predominant) and fibrosis in the later stages of scleroderma (Th2 predominant). We review the available experimental data regarding cytokines in LS and compare them to available clinical disease severity and activity features. This provides the platform to launch further investigations into the role of select cytokines in the pathogenesis of LS and to provide directed therapeutic options in the future. Published by Elsevier Ltd.

Dominant inheritance of cerebral gigantism.

PubMed

Zonana, J; Sotos, J F; Romshe, C A; Fisher, D A; Elders, M J; Rimoin, D L

1977-08-01

Cerebral gigantism is a syndrome consisting of characteristic dysmorphic features, accelerated growth in early childhood, and variable degrees of mental retardation. Its etiology and pathogenesis have not been defined. Three families are presented with multiple affected members. The vertical transmission of the trait and equal expression in both sexes in these families indicates a genetic etiology with a dominant pattern of inheritance, probably autosomal. As in previously reported cases, extensive endocrine evaluation failed to define the pathogenesis of the accelerated growth present in this disorder.

Molecular insights into Burkholderia pseudomallei and Burkholderia mallei pathogenesis.

PubMed

Galyov, Edouard E; Brett, Paul J; DeShazer, David

2010-01-01

Burkholderia pseudomallei and Burkholderia mallei are closely related gram-negative bacteria that can cause serious diseases in humans and animals. This review summarizes the current and rapidly expanding knowledge on the specific virulence factors employed by these pathogens and their roles in the pathogenesis of melioidosis and glanders. In particular, the contributions of recently identified virulence factors are described in the context of the intracellular lifestyle of these pathogens. Throughout this review, unique and shared virulence features of B. pseudomallei and B. mallei are discussed.

The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD.

PubMed

Leung, Janice M; Tiew, Pei Yee; Mac Aogáin, Micheál; Budden, Kurtis F; Yong, Valerie Fei Lee; Thomas, Sangeeta S; Pethe, Kevin; Hansbro, Philip M; Chotirmall, Sanjay H

2017-05-01

COPD is a major global concern, increasingly so in the context of ageing populations. The role of infections in disease pathogenesis and progression is known to be important, yet the mechanisms involved remain to be fully elucidated. While COPD pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are strongly associated with acute exacerbations of COPD (AECOPD), the clinical relevance of these pathogens in stable COPD patients remains unclear. Immune responses in stable and colonized COPD patients are comparable to those detected in AECOPD, supporting a role for chronic colonization in COPD pathogenesis through perpetuation of deleterious immune responses. Advances in molecular diagnostics and metagenomics now allow the assessment of microbe-COPD interactions with unprecedented personalization and precision, revealing changes in microbiota associated with the COPD disease state. As microbial changes associated with AECOPD, disease severity and therapeutic intervention become apparent, a renewed focus has been placed on the microbiology of COPD and the characterization of the lung microbiome in both its acute and chronic states. Characterization of bacterial, viral and fungal microbiota as part of the lung microbiome has the potential to reveal previously unrecognized prognostic markers of COPD that predict disease outcome or infection susceptibility. Addressing such knowledge gaps will ultimately lead to a more complete understanding of the microbe-host interplay in COPD. This will permit clearer distinctions between acute and chronic infections and more granular patient stratification that will enable better management of these features and of COPD. © 2017 Asian Pacific Society of Respirology.

Gene clusters of Hafnia alvei strain FB1 important in survival and pathogenesis: a draft genome perspective

PubMed Central

2014-01-01

Background Hafnia alvei is an opportunistic pathogen involved in various types of nosocomical infections. The species has been found to inhabit food and mammalian guts. However, its status as an enteropathogen, and whether the food-inhabiting strains could be a source of gastrointestinal infection remains obscure. In this report we present a draft genome of H. alvei strain FB1 isolated from fish paste meatball, a food popular among Malaysian and Chinese populations. The data was generated on the Illumina MiSeq platform. Results A comparative study was carried out on FB1 against two other previously sequenced H. alvei genomes. Several gene clusters putatively involved in survival and pathogenesis of H. alvei FB1 in food and gut environment were characterised in this study. These include the widespread colonisation island (WCI), the tad locus that is known to play an essential role in biofilm formation, a eut operon that might contribute to advantage in nutrient acquisition in gut environment, and genes responsible for siderophore production This features enable the bacteria to successful colonise in the host gut environment. Conclusion With the whole genome data of H. alvei FB1 presented in this study, we hope to provide an insight into future studies on this candidate of enteropathogen by looking into the possible mechanisms employed to survive stresses and gain advantage in competitions, which eventually leads to successful colonisation and pathogenesis. This is to serve as the basis for more effective clinical diagnosis and treatment. PMID:25075225

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

PubMed Central

Craggs, Lucinda JL; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

2014-01-01

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID:25323665

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

PubMed Central

da Fontoura Budaszewski, Renata; von Messling, Veronika

2016-01-01

Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the Canine distemper virus (CDV) causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the Measles virus (MeV) and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development. PMID:27727184

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

PubMed Central

2010-01-01

Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed. PMID:20092634

Potential role of the Virchow Robin space in the pathogenesis of bacterial meningitis.

PubMed

Chan, Patrick; Meerdink, Denis J; Uchizono, James A

2017-11-01

Meningitis is an infectious disease commonly arising from a bacterial etiology. The rapid progression of morbidity and mortality due to bacterial meningitis requires critical and imminent time-dependent clinical intervention. Although it is unambiguously clear that bacteria must infiltrate the cerebrospinal fluid, the sequence of events in the pathogenesis of bacterial meningitis has not been fully elucidated. Most reviews of the pathogenesis of bacterial meningitis do not specify the anatomical location of bacteria following BBB traversal. We propose an additional hypothesis focusing on the Virchow-Robin space (VRS). The VRS consists of a small, but identifiable perivascular space formed by a sheath of cells derived from the pia mater. The VRS has been described as an immunological space and possibly having a role in several neuropathological diseases. Solute exchange between cerebrospinal fluid and extracellular fluid occurs at the VRS, with subsequent drainage into the subarachnoid space. Because the VRS is continuous with the subpial space, a more direct route to the meninges is facilitated. The involvement of the VRS may have profound implications on the pathogenesis and therapeutic strategies: (1) nasopharyngeal colonization; (2) penetration into the blood stream after crossing the mucosal and epithelial membranes; (3) proliferation in the bloodstream; (4) extravasations through the endothelium of the post-capillary venules to the perivascular VRS; (5) migration from VRS to subpial space; (6) traversal through pia mater, entering the CSF in the subarachnoid space; (7) invasion of the meninges. The implication of the VRS in the pathogenesis of bacterial meningitis would be twofold. First, the VRS could provide an additional route of entry of bacteria into the brain. Second, the VRS could provide an area for bacterial proliferation, and thereby serve as a bacterial reservoir in relatively close proximity to the meninges. The clinical consequences of this hypothesis are: 1) clinical interpretation of laboratory findings, and 2) effective antibiotic delivery into the VRS. If the role of the VRS is established as part of bacterial meningitis pathogenesis, antibiotic pharmacokinetics and pharmacodynamics in the VRS need to be determined. This may result in developing novel antibiotic delivery and clinical strategies to improve morbidity and mortality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

PubMed Central

2011-01-01

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. PMID:21303513

HIV Vaccine for Prevention and Cure, A Mission Possible.

PubMed

Lu, Da-Yong; Wu, Hong-Ying; Ding, Jian; Sastry, Nagendra; Lu, Ting-Ren

2016-01-01

HIV/AIDS was once a highly deadly infective disease that killed the global people of a million annually two decades ago. While we are enjoying the HIV therapeutic advances (mostly important from HAART invention), one obvious drawback is still unresolved-unable to clearance all HIV from infected human bodies. As a result, a series of different therapeutic attempts have been proposed based on present knowledge of different features of HIV-induced pathogenesis and human mortalities. Facing this shortcoming, innovative designs and update of HIV vaccines and other types of HIV therapeutic inventions can be a final solution for completely HIV clearance and infection managements in human beings. Owing to these scientific and medical significances, several experimental and clinical attempts have to be made. Among these attempts, part of them (updating HIV vaccine developments and clinical routines) are quite promising and noteworthy. In this article, we offer the general information of this attempt and discuss it separately, especially on the respects of HIV vaccine strategic innovations.

Phyllodes tumours of the breast: a consensus review

PubMed Central

Tan, Benjamin Y; Acs, Geza; Apple, Sophia K; Badve, Sunil; Bleiweiss, Ira J; Brogi, Edi; Calvo, José P; Dabbs, David J; Ellis, Ian O; Eusebi, Vincenzo; Farshid, Gelareh; Fox, Stephen B; Ichihara, Shu; Lakhani, Sunil R; Rakha, Emad A; Reis-Filho, Jorge S; Richardson, Andrea L; Sahin, Aysegul; Schmitt, Fernando C; Schnitt, Stuart J; Siziopikou, Kalliopi P; Soares, Fernando A; Tse, Gary M; Vincent-Salomon, Anne; Tan, Puay Hoon

2016-01-01

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours. PMID:26768026

Clinico-pathological features of kidney disease in diabetic cases.

PubMed

Furuichi, Kengo; Shimizu, Miho; Okada, Hirokazu; Narita, Ichiei; Wada, Takashi

2018-03-21

Diabetic kidney disease is the major cause of end-stage kidney disease in developed countries. However, the onset of kidney disorder and the progression pattern of kidney dysfunction and proteinuria greatly vary cases by cases. Therefore, risk classification with clinical data and pathological findings is important. Recent clinico-pathological study with kidney biopsy samples from diabetic patients revealed that pathological changes of diabetic nephropathy are characteristic and have special impacts on prognosis in each clinical stage. Moreover, comparison of the clinico-pathological findings of diabetic nephropathy with hypertensive nephrosclerosis revealed that there are few differences in their pathological findings in cases with low albuminuria and preserved estimated glomerular filtration rate (eGFR). Because it is so difficult to clearly distinguish pure kidney lesions caused by diabetes and kidney lesions due to effects other than diabetes, it is vital that these overlapped pathological findings be confirmed on kidney biopsy in cases of early stage diabetes. Further research is warranted regarding the pathogenesis of diabetic nephropathy and indication of kidney biopsy in diabetic cases.

Inherited dystonias: clinical features and molecular pathways.

PubMed

Weisheit, Corinne E; Pappas, Samuel S; Dauer, William T

2018-01-01

Recent decades have witnessed dramatic increases in understanding of the genetics of dystonia - a movement disorder characterized by involuntary twisting and abnormal posture. Hampered by a lack of overt neuropathology, researchers are investigating isolated monogenic causes to pinpoint common molecular mechanisms in this heterogeneous disease. Evidence from imaging, cellular, and murine work implicates deficiencies in dopamine neurotransmission, transcriptional dysregulation, and selective vulnerability of distinct neuronal populations to disease mutations. Studies of genetic forms of dystonia are also illuminating the developmental dependence of disease symptoms that is typical of many forms of the disease. As understanding of monogenic forms of dystonia grows, a clearer picture will develop of the abnormal motor circuitry behind this relatively common phenomenology. This chapter focuses on the current data covering the etiology and epidemiology, clinical presentation, and pathogenesis of four monogenic forms of isolated dystonia: DYT-TOR1A, DYT-THAP1, DYT-GCH1, and DYT-GNAL. Copyright © 2018 Elsevier B.V. All rights reserved.

Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers

PubMed Central

DeKosky, Steven T.; Blennow, Kaj; Ikonomovic, Milos D.; Gandy, Sam

2014-01-01

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)—which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression—has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. PMID:23558985

Mitochondria in lung disease

PubMed Central

Cloonan, Suzanne M.; Choi, Augustine M.K.

2016-01-01

Mitochondria are a distinguishing feature of eukaryotic cells. Best known for their critical function in energy production via oxidative phosphorylation (OXPHOS), mitochondria are essential for nutrient and oxygen sensing and for the regulation of critical cellular processes, including cell death and inflammation. Such diverse functional roles for organelles that were once thought to be simple may be attributed to their distinct heteroplasmic genome, exclusive maternal lineage of inheritance, and ability to generate signals to communicate with other cellular organelles. Mitochondria are now thought of as one of the cell’s most sophisticated and dynamic responsive sensing systems. Specific signatures of mitochondrial dysfunction that are associated with disease pathogenesis and/or progression are becoming increasingly important. In particular, the centrality of mitochondria in the pathological processes and clinical phenotypes associated with a range of lung diseases is emerging. Understanding the molecular mechanisms regulating the mitochondrial processes of lung cells will help to better define phenotypes and clinical manifestations associated with respiratory disease and to identify potential diagnostic and therapeutic targets. PMID:26928034

Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers.

PubMed

DeKosky, Steven T; Blennow, Kaj; Ikonomovic, Milos D; Gandy, Sam

2013-04-01

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)--which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression--has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE.

Clinical features and the degree of cerebrovascular stenosis in different types and subtypes of cerebral watershed infarction.

PubMed

Li, Yue; Li, Man; Zhang, Xiaoyu; Yang, Shuna; Fan, Huimin; Qin, Wei; Yang, Lei; Yuan, Junliang; Hu, Wenli

2017-08-29

Whether there are differences in pathogenesis among different types and subtypes of cerebral watershed infarction (WSI) is controversial since they have been combined into a single group in most previous studies. We prospectively identified 340 supratentorial WSI patients at Beijing Chao-Yang Hospital, Capital Medical University, China and classified them based on diffusion-weighted imaging(DWI) templates. Baseline characteristics, clinical courses and neuroradiological features were compared among patients with different types and subtypes of WSI. We identified 92 patients with cortical watershed infarction (CWI), 112 with internal watershed infarction (IWI) and 136 with mixed-type infarction. Compared with CWI patients, more IWI patients had critical stenosis of internal carotid artery (ICA) (P < 0.001). For the CWI group, patients with anterior watershed infarction (AWI) were more prone to critical ICA stenosis than those with posterior watershed infarction (PWI) (P = 0.011). For the IWI group, critical ICA stenosis was more prevalent in patients with partial IWI (P-IWI) than in those with confluent IWI (C-IWI) (P = 0.026). IWI patients were more frequently found to have clinical deterioration during the first 7 days of hospitalization and a poor prognosis at the 90th day than in CWI patients (P = 0.003 and P = 0.014, respectively). IWI, especially the P-IWI subtype, is associated with hemodynamic impairment (HDI), whereas CWI has a weaker correlation with ICA steno-occlusion. Furthermore, IWI patients are more prone to poor prognosis.

Different frequencies and effects of ABCB1 T3435C polymorphism on clinical and laboratory features of B cell chronic lymphocytic leukemia in Kurdish patients.

PubMed

Maroofi, Farzad; Amini, Sabrieh; Roshani, Daem; Ghaderi, Bayazid; Abdi, Mohammad

2015-04-01

Finding the effects of gene polymorphism on cancer pathogenesis is very desirable. The ATP-binding cassette is involved in drug metabolism, and the polymorphism of this gene may be an important risk factor in B cell chronic lymphocytic leukemia (B-CLL) or progression and/or response to chemotherapy agents. For the first time, the present study was aimed to evaluate the probable effects of ABCB1 T3435C polymorphism on clinical and laboratory features of Kurdish patients with B-CLL. This descriptive analytical case-control study was performed on 50 B-CLL patients and 100 healthy subjects. Serum levels of beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH) and blood WBC, RBC, Plt and ESR were measured. The T3435C polymorphism of the ABCB1 gene was determined by PCR-RFLP. Concentration of serum and blood markers was significantly higher in the malignant group than in the benign subjects. The CC genotype had the highest frequency (66%) in the patient groups. There are no significant differences between the genotypes and type of treatment. Our results demonstrate the high frequency of C allele of ABCB1 T3435C in B-CLL patients with Kurdish ethnicity. We also show that this polymorphism has a significant risk factor in B-CLL. However, the effect of this polymorphism on clinical and laboratory characteristics of B-CLL patients was not significant.

Clinical variability of Waardenburg-Shah syndrome in patients with proximal 13q deletion syndrome including the endothelin-B receptor locus.

PubMed

Tüysüz, Beyhan; Collin, Anna; Arapoğlu, Müjde; Suyugül, Nezir

2009-10-01

Waardenburg-Shah syndrome (Waardenburg syndrome type IV-WS4) is an auditory-pigmentary disorder that combines clinical features of pigmentary abnormalities of the skin, hair and irides, sensorineural hearing loss, and Hirschsprung disease (HSCR). Mutations in the endothelin-B receptor (EDNRB) gene on 13q22 have been found to cause this syndrome. Mutations in both alleles cause the full phenotype, while heterozygous mutations cause isolated HSCR or HSCR with minor pigmentary anomalies and/or sensorineural deafness. We investigated the status of the EDNRB gene, by FISH analysis, in three patients with de novo proximal 13q deletions detected at cytogenetic analysis and examined the clinical variability of WS4 among these patients. Chromosome 13q was screened with locus specific FISH probes and breakpoints were determined at 13q22.1q31.3 in Patients 1 and 3, and at 13q21.1q31.3 in Patient 2. An EDNRB specific FISH probe was deleted in all three patients. All patients had common facial features seen in proximal 13q deletion syndrome and mild mental retardation. However, findings related to WS4 were variable; Patient 1 had hypopigmentation of the irides and HSCR, Patient 2 had prominent bicolored irides and mild bilateral hearing loss, and Patient 3 had only mild unilateral hearing loss. These data contribute new insights into the pathogenesis of WS4.

Scombroid fish poisoning syndrome.

PubMed

Dickinson, G

1982-09-01

Two patients presented to the emergency department with features of a histamine-like reaction and were subsequently determined to have scombroid fish poisoning. It is important to recognize the syndrome as an intoxication rather than an allergic reaction in order that the source of the toxin can be identified and further cases prevented. A review of the features and pathogenesis of the syndrome is presented.

The role of clusterin in Alzheimer's disease: pathways, pathogenesis, and therapy.

PubMed

Yu, Jin-Tai; Tan, Lan

2012-04-01

Genetic variation in clusterin gene, also known as apolipoprotein J, has been associated with Alzheimer's disease (AD) through replicated genome-wide studies, and plasma clusterin levels are associated with brain atrophy, baseline prevalence and severity, and rapid clinical progression in patients with AD, highlighting the importance of clusterin in AD pathogenesis. Emerging data suggest that clusterin contributes to AD through various pathways, including amyloid-β aggregation and clearance, lipid metabolism, neuroinflammation, and neuronal cell cycle control and apoptosis. Moreover, epigenetic regulation of the clusterin expression also seems to play an important role in the pathogenesis of AD. Emerging knowledge of the contribution of clusterin to the pathogenesis of AD presents new opportunities for AD therapy.

Mumps virus pathogenesis: Insights and knowledge gaps.

PubMed

Gouma, Sigrid; Koopmans, Marion P G; van Binnendijk, Rob S

2016-12-01

The recent mumps outbreaks among MMR vaccinated persons have raised questions about the biological mechanisms related to mumps symptoms and complications in the background of waning immunity. Contrary to other paramyxoviruses, the understanding of mumps virus pathogenesis is limited, and further in-depth clinical studies are required to provide answers to important research questions.

Pathogenesis of infectious disease of mice caused by H5N1 avian influenza virus.

PubMed

Evseenko, V A; Sharshov, K A; Bukin, E K; Zaykovskaya, A V; Ternovoy, V A; Ignatyev, G M; Shestopalov, A M; Netesov, S V; Shkurupiy, V A; Drozdov, I G

2008-12-01

The pathogenesis of a disease caused by Qinghai-like H5N1 influenza virus in BALB/c mice was studied. Clinical, morphological, and immunological characteristics of the experimental infection caused by highly pathogenic A/duck/Tuva/01/06/ (H5N1) virus are described.

[TORCH syndrome: Rational approach of pre and post natal diagnosis and treatment. Recommendations of the Advisory Committee on Neonatal Infections Sociedad Chilena de Infectología, 2016].

PubMed

Cofre, Fernanda; Delpiano, Luis; Labraña, Yenis; Reyes, Alejandra; Sandoval, Alejandra; Izquierdo, Giannina

2016-04-01

There is a lot of bacterial, viral or parasite infections who are able to be transmitted vertically from the mother to the fetus or newborn which implicates an enormous risk for it. The TORCH acronym is used universally to refer to a fetus or newborn which presents clinical features compatible with a vertically acquired infection and allows a rational diagnostic and therapeutic approach. The traditional "TORCH test" is nowadays considered not appropriate and it has been replaced for specific test for specific pathogens under well defined circumstances. The present document reviews the general characteristics, epidemiology, pathogenesis, diagnostic and therapeutic options for the most frequently involved pathogens in the fetus or newborn with TORCH suspicion.

PubMed Central

Gallo, A.; Fusconi, M.; Pagliuca, G.; Greco, A.; De Virgilio, A.; De Vincentiis, M.

2017-01-01

SUMMARY Autoimmune diseases of major salivary glands include Sjögren's syndrome and a complex of disorders classified as immunoglobulin G4-related diseases. These pathologies are characterised by an autoimmune reaction mediated by T-helper lymphocytes that targets the ducts of exocrine glands in Sjögren's syndrome and glandular parenchyma in immunoglobulin G4-related diseases. Immunoglobulin G4-related diseases represent recently introduced multi-organ diseases that also involve the salivary glands. However, the morbid conditions once known as Mikulicz's disease and Kuttner's tumour were recently considered as two variants of immunoglobulin G4-related diseases affecting the major salivary glands ( immunoglobulin G4-related sialadenitis). This review briefly summarises the pathogenesis and clinical features of autoimmune diseases of the major salivary glands, focusing on the diagnostic and therapeutic role of sialendoscopy. PMID:28516978

The nexus between periodontics and oral pathology.

PubMed

Rich, Alison M; Seo, Benedict; Parachuru, Venkata; Hussaini, Haizal M

2017-06-01

A wide variety of lesions may arise from the oral mucosa, fibrous connective tissue, bone and cementum of the periodontium. The commonest pathology occurs as a result of bacterial infection and is very well known to dentists and periodontists, but rarer conditions present as gingival pathology. The pathogenesis of these conditions ranges from genetic to traumatic to immunological to neoplastic, and includes benign, malignant and metastatic lesions. This paper outlines some of these conditions and describes how the periodontist and oral pathologist can work together using a framework, and how with careful consideration of the clinical features and the use of appropriate special tests, including obtaining an adequate tissue specimen, a timely and accurate diagnosis can be obtained. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Urinary Tract Infection: Pathogenesis and Outlook

PubMed Central

McLellan, Lisa K.; Hunstad, David A.

2016-01-01

The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities. PMID:27692880

Transformation of Follicular Lymphoma

PubMed Central

Lossos, Izidore S.; Gascoyne, Randy D.

2011-01-01

Histological transformation of follicular lymphoma (FL) to a more aggressive non-Hodgkin's lymphomas is a pivotal event in the natural history of FL and is associated with poor outcome. While commonly observed in clinical practice and despite multiple studies designed to address its pathogenesis, the biology of this process represents an enigma. In this chapter we present a state of the art review summarizing the definition of histologic transformation, its incidence, pathogenesis, clinical manifestations, treatment and outcome. Furthermore, we specifically emphasize gaps in our knowledge that should be addressed in future studies. PMID:21658615

Proximal tubulopathies associated with monoclonal light chains: the spectrum of clinicopathologic manifestations and molecular pathogenesis.

PubMed

Herrera, Guillermo A

2014-10-01

Lesions associated with monoclonal light and heavy chains display a variety of glomerular, tubular interstitial, and vascular manifestations. While some of the entities are well recognized, including light and heavy chain deposition diseases, AL (light chain) and AH (heavy chain) amyloidosis, and light chain ("myeloma") cast nephropathy, other lesions centered on proximal tubules are much less accurately identified, properly diagnosed, and adequately understood in terms of pathogenesis and molecular mechanisms involved. These proximal tubule-centered lesions are typically associated with monoclonal light chains and have not been reported in patients with circulating monoclonal heavy chains. To determine the incidence of proximal tubulopathies in a series of patients with monoclonal light chain-related renal lesions and characterize them with an emphasis on clinical correlations and elucidation of molecular mechanisms involved in their pathogenesis. A study of 5410 renal biopsies with careful evaluation of light microscopic, immunofluorescence, and electron microscopic findings was conducted to identify these monoclonal light/heavy chain-related lesions. In selected cases, ultrastructural immunolabeling was performed to better illustrate and understand molecular mechanisms involved or to resolve specific diagnostic difficulties. In all, 2.5% of the biopsies were diagnosed as demonstrating renal pathology associated with monoclonal light or heavy chains. Of these, approximately 46% were classified as proximal tubule-centered lesions, also referred to as monoclonal light chain-associated proximal tubulopathies. These proximal tubulopathies were divided into 4 groups defined by characteristic immunomorphologic manifestations associated with specific clinical settings. These are important lesions whose recognition in the different clinical settings is extremely important for patients' clinical management, therapeutic purposes, and prognosis. These entities have been segregated into 4 distinct variants, conceptualized morphologically and clinically. Specific mechanisms involved in their pathogenesis are proposed.

Recent progress in melasma pathogenesis.

PubMed

Lee, Ai-Young

2015-11-01

Melasma is a common skin pigmentation condition. Given therapeutic difficulty as one of the biggest concerns, understanding of the etiology and pathogenesis of melasma becomes essential. UV irradiation, female sex hormones, and inflammatory processes are addressed as triggering factors with genetic predisposition. The mechanism of UV-induced melanogenesis has been extensively investigated as a model system to study melasma pathogenesis. Hitherto, treatment modalities for melasma are similar to other hyperpigmentation disorders. However, individual triggering factors induce a separate pigmentation disease, whose pathogenic mechanisms and clinical phenotypes are different from the ones encountered in melasma. Fortunately, there have been ongoing updates on melasma pathogenesis with regard to major triggering factors. Presence of certain factors working independently of UV exposure and role of dermal factors and microRNAs are being identified as novel discoveries about melasma pathogenesis. In this review, the melasma pathogenesis is reviewed in association with updated and new findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of VEGF, Nitric Oxide, and Sympathetic Neurotransmitters in the Pathogenesis of Tendinopathy: A Review of the Current Evidences

PubMed Central

Vasta, Sebastiano; Di Martino, Alberto; Zampogna, Biagio; Torre, Guglielmo; Papalia, Rocco; Denaro, Vincenzo

2016-01-01

Chronic tendinopathy is a painful common condition affecting athletes as well as the general population undergoing to tendon overuse. Although its huge prevalence, little is known about tendinopathy pathogenesis, and even cloudier is its treatment. Traditionally, tendinopathy has been defined as a lack of tendon ability to overcome stressing stimuli with appropriate adaptive changes. Histologic studies have demonstrated the absence of inflammatory infiltrates, as a consequence conventional antinflammatory drugs have shown little or no effectiveness in treating tendinopathies. New strategies should be therefore identified to address chronic tendon disorders. Angiofibroblastic changes have been highlighted as the main feature of tendinopathy, and vascular endothelial growth factor (VEGF) has been demonstrated as one of the key molecules involved in vascular hyperplasia. More recently, attention has been focused on new peptides such as Substance P, nitric oxide, and calcitonin gene-related peptide (CGRP). Those new findings support the idea of a nerve-mediated disregulation of tendon metabolism. Each of those molecules could be a target for new treatment options. This study aimed to systematically review the current available clinical and basic science in order to summarize the latest evidences on the pathophysiology and its effect on treatment of chronic tendinopathy, and to spread suggestions for future research on its treatment. PMID:27555817

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma.

PubMed

Feller, Liviu; Khammissa, Razia A G; Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma

PubMed Central

Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown. PMID:28638859

Citral is renoprotective for focal segmental glomerulosclerosis by inhibiting oxidative stress and apoptosis and activating Nrf2 pathway in mice.

PubMed

Yang, Shun-Min; Hua, Kuo-Feng; Lin, Yu-Chuan; Chen, Ann; Chang, Jia-Ming; Kuoping Chao, Louis; Ho, Chen-Lung; Ka, Shuk-Man

2013-01-01

The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litseacubeba, a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model.

Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

PubMed Central

Yang, Shun-Min; Hua, Kuo-Feng; Lin, Yu-Chuan; Chen, Ann; Chang, Jia-Ming; Kuoping Chao, Louis; Ho, Chen-Lung; Ka, Shuk-Man

2013-01-01

The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litsea cubeba , a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model. PMID:24069362

Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus)

PubMed Central

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Laws, Thomas R; Taylor, Christopher; Smith, Simon A; Salguero, Francisco J; Lever, Mark S

2013-01-01

Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals’ lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. PMID:23441639

So close and yet so far – Molecular Microbiology of Campylobacter fetus subspecies

PubMed Central

Sprenger, H.; Zechner, E. L.; Gorkiewicz, G.

2012-01-01

Campylobacter fetus comprises two subspecies, C. fetus subsp. fetus and C. fetus subsp. venerealis, which are considered emerging pathogens in humans and animals. Comparisons at the genome level have revealed modest subspecies-specific variation; nevertheless, these two subspecies show distinct host and niche preferences. C. fetus subsp. fetus is a commensal and pathogen of domesticated animals that can be transmitted to humans via contaminated food. The clinical features of human infection can be severe, especially in impaired hosts. In contrast, C. fetus subsp. venerealis is a sexually transmitted pathogen essentially restricted to cattle. Infections leading to bovine venereal campylobacteriosis cause substantial economic losses due to abortion and infertility. Recent genome sequencing of the two subspecies has advanced our understanding of C. fetus adaptations through comparative genomics and the identification of subspecies-specific gene regions predicted to be involved in pathogenesis. The most striking difference between the subspecies is the highly subspecies-specific association of a pathogenicity island in the C. fetus subsp. venerealis chromosome. The inserted region encodes a Type 4 secretion system, which contributes to virulence properties of this organism in vitro. This review describes the main differences in epidemiological, phenotypic, and molecular characteristics of the two subspecies and summarizes recent advances towards understanding the molecular mechanisms of C. fetus pathogenesis. PMID:24611123

The Role of Antigenic Drive and Tumor-Infiltrating Accessory Cells in the Pathogenesis of Helicobacter-Induced Mucosa-Associated Lymphoid Tissue Lymphoma

PubMed Central

Mueller, Anne; O’Rourke, Jani; Chu, Pauline; Chu, Amanda; Dixon, Michael F.; Bouley, Donna M.; Lee, Adrian; Falkow, Stanley

2005-01-01

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue type is closely linked to chronic Helicobacter pylori infection. Most clinical and histopathological features of the tumor can be reproduced by prolonged Helicobacter infection of BALB/c mice. In this study, we have addressed the role of antigenic stimulation in the pathogenesis of the lymphoma by experimental infection with Helicobacter felis, followed by antibiotic eradication therapy and subsequent re-infection. Antimicrobial therapy was successful in 75% of mice and led to complete histological but not “molecular” tumor remission. Although lympho-epithelial lesions disappeared and most gastric lymphoid aggregates resolved, transcriptional profiling revealed the long-term mucosal persistence of residual B cells. Experimental re-introduction of Helicobacter led to very rapid recurrence of the lymphomas, which differed from the original lesions by higher proliferative indices and more aggressive behavior. Immunophenotyping of tumor cells revealed massive infiltration of lesions by CD4+ T cells, which express CD28, CD69, and interleukin-4 but not interferon-γ, suggesting that tumor B-cell proliferation was driven by Th 2-polarized, immunocompetent, and activated T cells. Tumors were also densely colonized by follicular dendritic cells, whose numbers were closely associated with and predictive of treatment outcome. PMID:16127158

Persistent hyperplastic primary vitreous: congenital malformation of the eye.

PubMed

Shastry, Barkur S

2009-12-01

Persistent hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature, is a rare congenital developmental malformation of the eye, caused by the failure of regression of the primary vitreous. It is divided into anterior and posterior types and is characterized by the presence of a vascular membrane located behind the lens. The condition can be of an isolated type or can occur with other ocular disorders. Most cases of PHPV are sporadic, but it can be inherited as an autosomal dominant or recessive trait. Inherited PHPV also occurs in several breeds of dogs and cats. In a limited number of cases, Norrie disease and FZD4 genes are found to be mutated in unilateral and bilateral PHPV. These genes when mutated also cause Norrie disease pseudoglioma and familial exudative vitreoretinopathy that share some of the clinical features with PHPV. Mice lacking arf and p53 tumour suppressor genes as well as Norrie disease pseudoglioma and LRP5 genes suggest that these genes are needed for hyaloid vascular regression. These experiments also indicate that abnormalities in normal apoptosis and defects in Wnt signalling pathway may be responsible for the pathogenesis of PHPV. Identification of other candidate genes in the future may provide a better understanding of the pathogenesis of the condition that may lead to a better therapeutic approach and better management.

Eosinophilic esophagitis in an octogenarian

PubMed Central

Trifan, Anca; Stoica, Oana; Chihaia, Catalin-Alexandru; Danciu, Mihai; Stanciu, Carol; Singeap, Ana-Maria

2016-01-01

Abstract Introduction: Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by a marked eosinophilic infiltrate in the esophageal mucosa. What was once considered a rare disease has nowadays become one of the most frequent esophageal diseases in the Western countries, occupying a place just next to the gastroesophageal reflux disease. EoE etiology and pathogenesis remain largely unknown, although most studies consider that allergic and genetic factors play the most important role. Methods: We report the case of EoE in an elderly male (octogenarian), giving a brief review of the current data related to epidemiology, pathogenesis, diagnosis, and treatment of the disease. Results: Dysphagia to solid foods was the leading symptom, and endoscopic findings included white exudates, longitudinal furrows, and concentric mucosal rings, all suggestive for EoE. Diagnosis relied on histological findings in esophageal mucosal biopsies (>30 eosinophils per high power field). He was treated with topical steroids for 8 weeks, symptoms improved gradually and the patient remained in remission at the 8-month follow-up. Conclusion: This case emphasizes that EoE may occur in very old patients and gastroenterologists should have a high index of suspicion of this disorder in any elderly with dysphagia and endoscopic relevant features. PMID:27741150

Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma.

PubMed

Komabayashi, Yuki; Kishibe, Kan; Nagato, Toshihiro; Ueda, Seigo; Takahara, Miki; Harabuchi, Yasuaki

2014-01-01

Nasal NK/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-associated malignancy and has distinct clinical and histological features. However, its genetic features are hitherto unclear. MicroRNAs (miRNAs) play a crucial role in the pathogenesis of several malignancies via regulating gene expression. In this study, we investigated whether the specific microRNAs were related to the tumor behaviors in NNKTL. MiRNA array and Quantitative RT-PCR analyses revealed that miR-15a was expressed at a much lower level in NNKTL cells (SNK-1, SNK-6, and SNT-8) than in normal peripheral NK cells and EBV-negative NK cell line KHYG-1. Quantitative PCR and western blot analyses showed that the expression of MYB and cyclin D1, which are validated targets of miR-15a, was higher in NNKTL cells. Transfection of NNKTL cells (SNK-6 and SNT-8) with a miR-15a precursor decreased MYB and cyclin D1 levels, thereby blocking G1/S transition and cell proliferation. Knockdown of EBV-encoded latent membrane protein 1 (LMP1) significantly increased miR-15a expression in SNK-6 cells. In NNKTL tissues, we found that reduced miR-15a expression, which correlated with MYB and cyclin D1 expression, was associated with poor prognosis of NNKTL patients. These data suggest that downregulation of miR-15a, possibly due to LMP1, implicates in the pathogenesis of NNKTL by inducing cell proliferation via MYB and cyclin D1. Thus, miR-15a could be a potential target for antitumor therapy and a prognostic predictor for NNKTL. Copyright © 2013 Wiley Periodicals, Inc.

Pathogenesis of coxsackievirus B2 in mice: characterization of clinical isolates of the coxsackievirus B2 from patients with myocarditis and aseptic meningitis in Korea.

PubMed

Hong, Jiyoung; Kang, Bunghak; Yeo, Sanggu; Jee, Youngmee; Park, Jae-Hak

2017-12-31

Group B coxsackieviruses (CVBs) are a group of common human pathogens producing various clinical symptoms. Although the virology of CVB is well known, there is limited information on viral pathogenesis and the relationship between clinical symptoms and viral phenotype, particularly for CVB type 2 (CVB2). In 2004 in Korea, two CVB2 strains were isolated: CB2/04/279 from stool of an acute myocarditis patient with heart failure and CB2/04/243 from an aseptic meningitis patient. In this study, a high degree of homology was observed between the CB2/04/279 and CB2/04/243 full genome sequences. The two Korean CVB2 isolates had 93.1% homology compared to 82.1%-82.5% nucleotide sequence identity with the cardiovirulence-associated reference CVB strain Ohio-1 (CVB/O). CVB2-induced pathogenesis was analyzed, focusing on virus-induced pathology of various tissues in 4-week-old BALB/c inbred male mice. Myocarditis developed and extensive pancreatic inflammation was observed in all mice infected with CB2/04/279 or CVB/O, but not in animals infected with CB2/04/243. This is the first report of the full-genomic sequence and pathogenesis of the CVB2 strain isolated from an acute myocarditis patient in Korea.

Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I

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

Metheny, L.J.; Amedeo, M.S.; Cappione, J.

Neurofibromatosis type I (NF1) is a common genetic disease which leads to a variety of clinical features affecting cells of neural crest origin. In the period since the NF1 gene was isolated 1991, our understanding of the genetics of NF1 has increased remarkably. One of the most striking aspects of NF1 genetics is its complexity, both in terms of gene organization and expression. The gene is large and, when mutated, gives rise to diverse manifestations. A growing body of data suggests that mutations in the NF1 gene alone may not be responsible for all of the features of this disease.more » Epigenetic mechanisms, those which affect the NF1 transcript, play a role in the normal expression of the NF1 gene. Therefore, aberrations in those epigenetic processes are most likely pathogenic. Herein we summarize salient aspects of the vast body of NF1 literature and provide some insights into the myriad of regulatory mechanisms that may go awry in the genesis of this common but complex disease. 58 refs., 3 figs.« less

Down Syndrome - Genetics and Cardiogenetics.

PubMed

Plaiasu, Vasilica

2017-09-01

During the last years, Down syndrome has been the focus of special attention. Down syndrome is a genetic disorder characterized by distinct physical features and some degree of cognitive disability. Patients with Down syndrome also present many other congenital anomalies. The mapping for phenotypes to specific regions of chromosome 21 permits to identify which genes (or small regions) contribute to the phenotypic features of Down syndrome and thus, to understand its pathogenesis. Mainly there are three cytogenetic forms of Down syndrome: free trisomy 21, mosaic trisomy 21 and robertsonian translocation trisomy 21. Prenatal and postnatal testing has become commonly used to diagnose different cases presenting the same pathology. Early clinical diagnosis is extremely important for patient prognosis. Lately, advances in Down syndrome research have been registered, but little is known about cardiovascular phenotype in Down syndrome. About half of patients with Down syndrome have congenital heart disease, and atrioventricular septal defects are the most common defects found. Basic research on Down syndrome is now rapidly accelerating, using new genomic technologies. There were many studies performed to identify a correlation between genotype and phenotype in Down syndrome.

Collagenous gastritis: an unusual association with profound weight loss.

PubMed

Wang, Hanlin L; Shah, Amit G; Yerian, Lisa M; Cohen, Russell D; Hart, John

2004-02-01

Collagenous gastritis is a distinctive disorder characterized by thickening of the subepithelial collagen layer in the gastric mucosa. Although this entity was recognized in 1989, its etiology, pathogenesis, and clinicopathologic features remain poorly understood because of its rarity. An unusual case of collagenous gastritis was observed in a 37-year-old man who presented with profound weight loss, a feature that has not previously been emphasized.

Clinical implications of chromosomal abnormalities in gastric adenocarcinomas

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

Wu, Chew-Wun; Chen, Gen-Der; Fann, Cathy S.-J.

2003-06-23

Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53more » percent), 20q13-qter (48 percent), 1p32-p36 (42 percent), 22q12-qter (27 percent), 17p13-pter (24 percent), 16p13-pter (21 percent), 6p21-pter (19 percent), 20p12-pter (19 percent), 7p21-pter (18 percent), 3q28-qter (8 percent), and 13q13-q14 (8 percent), and losses at 18q12-qter (11 percent), 3p12 (8 percent), 3p25-pter (8 percent), 5q14-q23 (8 percent), and 9p21-p23 (5 percent), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.« less

Molecular insights into primary hyperoxaluria type 1 pathogenesis.

PubMed

Cellini, Barbara; Oppici, Elisa; Paiardini, Alessandro; Montioli, Riccardo

2012-01-01

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of glyoxylate metabolism caused by the deficiency of liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme. The PH1 pathogenesis is mostly due to single point mutations (more than 150 so far identified) on the AGXT gene, and is characterized by a marked heterogeneity in terms of genotype, enzymatic and clinical phenotypes. This article presents an up to date review of selected aspects of the biochemical properties of the two allelic forms of AGT and of some PH1-causing variants. These recent discoveries highlight the effects at the protein level of the pathogenic mutations, and, together with previous cell biology and clinical data, (i) improve the understanding of the molecular basis of PH1 pathogenesis, and (ii) help to delineate perspectives for predicting the response to pyridoxine treatment or for suggesting new strategies for PH1 patients bearing the analyzed mutations.

Helicobacter pylori virulence and cancer pathogenesis

PubMed Central

Yamaoka, Yoshio; Graham, David Y

2014-01-01

Helicobacter pylori is human gastric pathogen that causes chronic and progressive gastric mucosal inflammation and is responsible for the gastric inflammation-associated diseases, gastric cancer and peptic ulcer disease. specific outcomes reflect the interplay between host-, environmental- and bacterial-specific factors. Progress in understanding putative virulence factors in disease pathogenesis has been limited and many false leads have consumed scarce resources. Few in vitro–in vivo correlations or translational applications have proved clinically relevant. Reported virulence factor-related outcomes reflect differences in relative risk of disease rather than specificity for any specific outcome. Studies of individual virulence factor associations have provided conflicting results. Since virulence factors are linked, studies of groups of putative virulence factors are needed to provide clinically useful information. Here, the authors discuss the progress made in understanding the role of H. pylori virulence factors CagA, vacuolating cytotoxin, OipA and DupA in disease pathogenesis and provide suggestions for future studies. PMID:25052757

Helicobacter pylori virulence and cancer pathogenesis.

PubMed

Yamaoka, Yoshio; Graham, David Y

2014-06-01

Helicobacter pylori is human gastric pathogen that causes chronic and progressive gastric mucosal inflammation and is responsible for the gastric inflammation-associated diseases, gastric cancer and peptic ulcer disease. Specific outcomes reflect the interplay between host-, environmental- and bacterial-specific factors. Progress in understanding putative virulence factors in disease pathogenesis has been limited and many false leads have consumed scarce resources. Few in vitro-in vivo correlations or translational applications have proved clinically relevant. Reported virulence factor-related outcomes reflect differences in relative risk of disease rather than specificity for any specific outcome. Studies of individual virulence factor associations have provided conflicting results. Since virulence factors are linked, studies of groups of putative virulence factors are needed to provide clinically useful information. Here, the authors discuss the progress made in understanding the role of H. pylori virulence factors CagA, vacuolating cytotoxin, OipA and DupA in disease pathogenesis and provide suggestions for future studies.

Pi (Spleen)-deficiency syndrome in tumor microenvironment is the pivotal pathogenesis of colorectal cancer immune escape.

PubMed

Sun, Xue-Gang; Lin, Xiao-Chang; Diao, Jian-Xin; Yu, Zhi-Ling; Li, Kun

2016-10-01

Cancer immunoediting consists of three sequential phases: elimination, equilibrium, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibrium phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi (Spleen)-deficiency. Classic quotations, immune evidence and clinical observations suggest that Spleen (but not other organs) deficiency is the key pathogenesis of colorectal cancer (CRC) microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-derived immunosuppressive factors and surrendered immune cells-regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages (TAMs) constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of tumor environment and immunoediting.

Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis.

PubMed

Iwata, Naoko; Iwama, Shintaro; Sugimura, Yoshihisa; Yasuda, Yoshinori; Nakashima, Kohtaro; Takeuchi, Seiji; Hagiwara, Daisuke; Ito, Yoshihiro; Suga, Hidetaka; Goto, Motomitsu; Banno, Ryoichi; Caturegli, Patrizio; Koike, Teruhiko; Oshida, Yoshiharu; Arima, Hiroshi

2017-06-01

IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear. In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects. We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence. APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases. Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release

PubMed Central

Greene, Neil G.; Narciso, Ana R.; Filipe, Sergio R.; Camilli, Andrew

2015-01-01

Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx and is a significant pathogen worldwide. Pneumolysin (Ply) is a multi-functional, extracellular virulence factor produced by this organism that is critical for pathogenesis. Despite the absence of any apparent secretion or cell surface attachment motifs, Ply localizes to the cell envelope of actively growing cells. We sought to characterize the consequences of this surface localization. Through functional assays with whole cells and subcellular fractions, we determined that Ply activity and its release into the extracellular environment are inhibited by peptidoglycan (PG) structure. The ability of PG to inhibit Ply release was dependent on the stem peptide composition of this macromolecule, which was manipulated by mutation of the murMN operon that encodes proteins responsible for branched stem peptide synthesis. Additionally, removal of choline-binding proteins from the cell surface significantly reduced Ply release to levels observed in a mutant with a high proportion of branched stem peptides suggesting a link between this structural feature and surface-associated choline-binding proteins involved in PG metabolism. Of clinical relevance, we also demonstrate that a hyperactive, mosaic murMN allele associated with penicillin resistance causes decreased Ply release with concomitant increases in the amount of branched stem peptides. Finally, using a murMN deletion mutant, we observed that increased Ply release is detrimental to virulence during a murine model of pneumonia. Taken together, our results reveal a novel role for branched stem peptides in pneumococcal pathogenesis and demonstrate the importance of controlled Ply release during infection. These results highlight the importance of PG composition in pathogenesis and may have broad implications for the diverse PG structures observed in other bacterial pathogens. PMID:26114646

Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release.

PubMed

Greene, Neil G; Narciso, Ana R; Filipe, Sergio R; Camilli, Andrew

2015-06-01

Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx and is a significant pathogen worldwide. Pneumolysin (Ply) is a multi-functional, extracellular virulence factor produced by this organism that is critical for pathogenesis. Despite the absence of any apparent secretion or cell surface attachment motifs, Ply localizes to the cell envelope of actively growing cells. We sought to characterize the consequences of this surface localization. Through functional assays with whole cells and subcellular fractions, we determined that Ply activity and its release into the extracellular environment are inhibited by peptidoglycan (PG) structure. The ability of PG to inhibit Ply release was dependent on the stem peptide composition of this macromolecule, which was manipulated by mutation of the murMN operon that encodes proteins responsible for branched stem peptide synthesis. Additionally, removal of choline-binding proteins from the cell surface significantly reduced Ply release to levels observed in a mutant with a high proportion of branched stem peptides suggesting a link between this structural feature and surface-associated choline-binding proteins involved in PG metabolism. Of clinical relevance, we also demonstrate that a hyperactive, mosaic murMN allele associated with penicillin resistance causes decreased Ply release with concomitant increases in the amount of branched stem peptides. Finally, using a murMN deletion mutant, we observed that increased Ply release is detrimental to virulence during a murine model of pneumonia. Taken together, our results reveal a novel role for branched stem peptides in pneumococcal pathogenesis and demonstrate the importance of controlled Ply release during infection. These results highlight the importance of PG composition in pathogenesis and may have broad implications for the diverse PG structures observed in other bacterial pathogens.

Cerebral malaria in children: using the retina to study the brain

PubMed Central

Beare, Nicholas A. V.; Taylor, Terrie E.; Barrera, Valentina; White, Valerie A.; Hiscott, Paul; Molyneux, Malcolm E.; Dhillon, Baljean; Harding, Simon P.

2014-01-01

Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes. PMID:24578549

Identification of syncytial mutations in a clinical isolate of herpes simplex virus 2

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

Muggeridge, Martin I.; Grantham, Michael L.; Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130

2004-10-25

Small polykaryocytes resulting from cell fusion are found in herpes simplex virus (HSV) lesions in patients, but their significance for viral spread and pathogenesis is unclear. Although syncytial variants causing extensive fusion in tissue culture can be readily isolated from laboratory strains, they are rarely found in clinical isolates, suggesting that extensive cell fusion may be deleterious in vivo. Syncytial mutations have previously been identified for several laboratory strains, but not for clinical isolates of HSV type 2. To address this deficiency, we studied a recent syncytial clinical isolate, finding it to be a mixture of two syncytial and onemore » nonsyncytial strain. The two syncytial strains have novel mutations in glycoprotein B, and in vitro cell fusion assays confirmed that they are responsible for syncytium formation. This panel of clinical strains may be ideal for examining the effect of increased cell fusion on pathogenesis.« less

Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression.

PubMed

Marsden, W N

2011-10-01

Typically the monoamine system has been the central focus of neurobiological research into depression and represents the major target of modern antidepressant medications; although the extent to which monoamines such as serotonin play a role in the pathogenesis of depression is still not clear. Recent research advancements have expanded the neurotransmitter-level focus of mood disorders to incorporate intracellular pathways and regional brain circuitry. As such the importance of other systems has emerged including those related to neuroplastic signal transduction and gene transcription cascades within cortico-limbic circuits. Indeed mounting evidence suggests interaction with these pathways is required for the chronic therapeutic effect of current clinical antidepressants. Dysfunction of the glutamatergic system has also emerged as a major pathological feature in depression, and glutamatergic agents have demonstrated rapid and robust antidepressant activity in humans. In particular, the glutamate receptors (AMPAR, NMDAR & mGluR) are intrinsically connected to neuronal efficiency and inefficiency cascades, so their dysfunction may account for alterations to multiple signal transduction pathways in depression. This article presents concepts supporting a NMDA hypothesis of depression, whereby the pathogenesis of depression may arise from stressors inducing excessive NMDAR activity which acts heterogeneously at both cellular and regional levels to disrupt normal neurobiological function and induce the depressive phenotype. In this hypothesis multiple psychological and environmental stressors are united in their capacity to potentiate excessive tonic and phasic NMDAR activation on neurons and glia. Such NMDAR dysfunction may lead to: disruption of glia processes and tripartite signalling; potentiation of extrasynaptic inefficiency/LTD pathways in some regions (e.g. prefrontal cortex & hippocampus); potentiation of synaptic efficiency/LTP pathways in other regions (e.g. amygdala); and regional disruption of cortico-limbic circuits and dopaminergic reward pathways (e.g. nucleus accumbens). This model unites depression with a variety of stressors including glucocorticoids, inflammation, oxidative stress, magnesium deficiency, hyperhomocysteinemia, and bio-energetic dysfunction; and also helps explain comorbidity with other neurological and affective disorders. In particular, a neurometabolic contribution to the aetiology of depressive as well as other neurological and affective disorders is explored. Copyright © 2011 Elsevier Ltd. All rights reserved.

The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity.

PubMed

Liu, Wendy; Fackler, William; Rice, Thomas W; Richter, Joel E; Achkar, Edgar; Goldblum, John R

2002-06-01

Pseudoachalasia is an esophageal motor disorder usually associated with malignancy that has clinical, radiographic, and manometric findings that are often indistinguishable from primary achalasia. There are few reports examining the histologic features of the associated neoplasms and their relationship with the esophageal myenteric plexus. We studied the clinical and pathologic features of 13 cases of pseudoachalasia seen at our institution between 1979 and 1999. Detailed clinical and radiographic data were obtained from medical records. In all cases available histologic material was reviewed to confirm the presence and type of associated neoplasm. When possible, the relationship of the neoplasm to the esophageal myenteric plexus was examined. In selected cases immunohistochemical stains were performed to further evaluate this relationship. All patients had clinical, radiographic, and manometric features similar to primary achalasia. The cohort included seven men and six women, age range 24-79 years (median 61 years). Associated neoplasms included esophageal adenocarcinoma arising in Barrett's esophagus (n = 1), adenocarcinoma of the esophagogastric junction (n = 7), metastatic renal cell carcinoma to the esophagogastric junction (n = 1), breast adenocarcinoma (n = 1), pulmonary small cell carcinoma (n = 1), pleural malignant mesothelioma (n = 1), and mediastinal fibrosis (n = 1). The mechanism of pseudoachalasia was consistent with neoplastic infiltration of the esophageal myenteric plexus in 11 cases. Neoplastic cells surrounded myenteric ganglion cells, which appeared normal in number and morphology. In the patient with pulmonary small cell carcinoma, there was no evidence of neoplastic infiltration of the esophagogastric junction, and anti-ANNA-1 antibody was detected, suggesting a paraneoplastic syndrome. Tissue obtained at the time of esophagomyotomy revealed lymphocytic myenteric inflammation and marked depletion of ganglion cells identical to that seen in primary achalasia. The mechanism pseudoachalasia in the patient with breast adenocarcinoma is uncertain, as there was no evidence of direct involvement of the esophagogastric junction. In summary, we describe 13 cases of pseudoachalasia resulting in a clinical syndrome indistinguishable from primary achalasia. The most common mechanism is direct involvement of the esophageal myenteric plexus by neoplastic cells. Rarely, a distant neoplasm may cause this syndrome as a paraneoplastic process.

Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.

PubMed

Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; Ballina-García, Francisco Javier; Suárez, Ana

2016-01-01

Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis. Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro. Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade. An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

Association of Clinical Features with Human Leukocyte Antigen in Japanese Patients with Ulcerative Colitis.

PubMed

Iwamoto, Taku; Yashima, Kazuo; Morio, Keiko; Ueda, Naoki; Ikebuchi, Yuichiro; Kawaguchi, Koichiro; Harada, Kenichi; Isomoto, Hajime

2018-03-01

The human leukocyte antigen (HLA) region has been found to be involved in the pathogenesis of inflammatory bowel disease (IBD), which is classified into ulcerative colitis (UC) and Crohn's disease (CD), by genome-wide association studies. The aim of this study was to confirm whether HLA-alleles confer susceptibility to UC and to determine whether HLA-allel1es are associated with the clinical phenotypes in Japanese patients with UC. In this study, HLA typing was performed by PCR-sequence-specific oligonucleotides (PCR-SSO) to confirm the correlation between UC and HLA alleles (for HLA-A, B, DRB1) in 45 Japanese UC patients. In addition, whether the HLA alleles are related to patient and clinical background characteristics was examined. Overall, 62.2%, and 66.7% of the 45 UC patients had HLA-B*52 and HLA-DRB1*15, respectively. These allele frequencies were significantly higher than in previously reported Japanese control persons ( P < 0.0001). The frequencies of extraintestinal manifestations [odds ratio (OR) = 0.12, P = 0.039] and a history of colectomy (OR = 0.18, P = 0.046) were lower in HLA-B*52-positive UC patients than in HLA-B*52 negative UC patients. The white blood cell (WBC) count was significantly higher in HLA-DRB1*15-positive patients (9430 ± 4592/μL) than in HLA-DRB1*15-negative patients (6729 ± 2160/μL). Thus, HLA-B*52 and DRB1*15 appear to be associated with disease features and severity in Japanese UC patients. These results indicate that HLA-B*52 and DRB1*15 are not only associated with overall UC susceptibility, but also with the clinical phenotypes in Japanese patients.

Report of a new case with pentasomy X and novel clinical findings

PubMed Central

Demirhan, O; Tanriverdi, N; Yilmaz, MB; Kocaturk-Sel, S; Inandiklioglu, N; Luleyap, U; Akbal, E; Comertpay, G; Tufan, T; Dur, O

2015-01-01

Pentasomy X is an extremely rare sex chromosome abnormality, a condition that only affects females, in which three more X chromosomes are added to the normally present two chromosomes in females. We investigated the novel clinical findings in a 1-year-old female baby with pentasomy X, and determined the parental origins of the X chromosomes. Our case had thenar atrophy, postnatal growth deficiency, developmental delay, mongoloid slant, microcephaly, ear anomalies, micrognathia and congenital heart disease. A conventional cytogenetic technique was applied for the diagnosis of the polysomy X, and quantitative fluorescent polymerase chain reaction (QF-PCR) using 11 inherited short tandem repeat (STR) alleles specific to the chromosome X for the determination of parental origin of X chromosomes. A cytogenetic evaluation revealed that the karyotype of the infant was 49,XXXXX. Comparison of the infant’s features with previously reported cases indicated a clinically recognizable specific pattern of malformations referred to as the pentasomy X syndrome. However, to the best of our know-ledge, this is the first report of thenar atrophy in a patient with 49,XXXXX. The molecular analysis suggested that four X chromosomes of the infant originated from the mother as a result of the non disjunction events in meiosis I and meiosis II. We here state that the clinical manifestations seen in our case were consistent with those described previously in patients with pentasomy X. The degree of early hypotonia constitutes an important early prognostic feature in this syndrome. The pathogenesis of pentasomy X is not clear at present, but it is thought to be caused by successive maternal non disjunctions. PMID:26929910

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in Nagano, Japan: clinical, radiological, and cytokine studies of 13 patients.

PubMed

Oide, T; Ohara, S; Oguchi, K; Maruyama, M; Yazawa, M; Inoue, K; Sekijima, Y; Tokuda, T; Ikeda, S

2004-01-01

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) has so far been reported almost exclusively from the USA and Europe. We carried out this study to define the clinical characteristics of this syndrome in Japanese patients. Prospectively, we identified 13 Japanese patients with RS3PE (5 men and 8 women, age 72.7 +/- 11.8 years (mean +/- SD)) without underlying neoplasm. Their clinical features were summarized, pertinent laboratory data including serum/synovial interleukin-6 (IL-6) concentrations were obtained, and extensive radiologic studies using magnetic resonance imaging and 67gallium-citrate (67Ga) whole body scintigram were performed. All patients suffered from proximal arthralgia/myalgia in addition to typical distal symptoms of RS3PE, and all experienced systemic symptoms such as fever, malaise, and weight loss. In laboratory examinations, anemia and elevated inflammatory markers were often remarkable. Magnetic resonance imaging showed severe tenosynovitis of the hands. 67Ga-scintigram revealed radioisotope accumulation in both proximal and distal joints of the extremities. IL-6 activity was markedly elevated both in the serum (mean 82.4 +/- 62.1 (SD) pg/ml, normal range 0.157-2.94) and in the synovial fluid (mean 3350 +/- 633 (SD) pg/ml). Compared with cases reported previously from the USA/Europe, Japanese patients with RS3PE are characterized by more prominent systemic symptoms/signs associated with marked inflammatory responses including elevated IL-6 activity. All patients had proximal as well as distal synovitis which could be demonstrated by 67Ga-scintigram. These clinical features were very similar to those of polymyalgia rheumatica, suggesting that RS3PE and polymyalgia rheumatica are closely related disorders which may have a common pathogenesis.

Dengue fever in travellers and risk of local spreading: case reports from Southern Italy and literature update.

PubMed

Fabrizio, Claudia; Lepore, Luciana; Chironna, Maria; Angarano, Gioacchino; Saracino, Annalisa

2017-01-01

Dengue fever (DF), an arbovirosis caused by Dengue viruses (DV, serotypes 1-4), is responsible for an increasing number of travel-related acute febrile illnesses due to population growth, climate changes, spreading by viremic travellers, and improved laboratory diagnosis. The presence of efficient vectors (mosquito Aedes albopictus) has also been described in temperate regions including Italy which is considered the most heavily infected European country. Normally characterized by non-specific signs and symptoms, DF incidence is probably underestimated, especially in non-endemic countries, but the risk of severe forms is substantial. Between August and November 2013, five DF patients (4 males, age 23-38) were observed in the Infectious Disease Clinic (University of Bari, Southern Italy). All had just returned from DF endemic areas (2 French Polynesia, 3 Dominican Republic); 4/5 were hospitalized. Common clinical features included acute febrile syndrome, headache (2 with retro-orbital pain), rash (all patients), two with bleeding manifestations and one with gum bleeding. Laboratory tests demonstrated leukopenia (4 patients), elevated liver enzymes (3 patients), and thrombocytopenia (1 patient). Serum samples for DV antibodies and RNA detection were analyzed by the Regional Arbovirosis Reference Laboratory. Viral RNA was identified in 2/5 patients (DV-4) and seroconversion in the remaining cases. All patients made a complete recovery. Recent literature was reviewed, focusing on epidemiology and vector distribution (especially European and Italian territories), pathogenesis, clinical features, diagnosis, and treatment including vaccine strategies. The occurrence of 5 DF cases during the period of highest vector activity (June-November) in Italy emphasizes the risk of local outbreaks in temperate regions. This paper highlights the importance of clinical alert for dengue also in non-endemic countries.

Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.

PubMed

Speck, Olga; Tang, Weihua; Morgan, Douglas R; Kuan, Pei Fen; Meyers, Michael O; Dominguez, Ricardo L; Martinez, Enrique; Gulley, Margaret L

2015-10-01

Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

Urinary Tract Infection: Pathogenesis and Outlook.

PubMed

McLellan, Lisa K; Hunstad, David A

2016-11-01

The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cracking the Crack Dance: A Case Report on Cocaine-induced Choreoathetosis.

PubMed

Narula, Naureen; Siddiqui, Faraz; Katyal, Nakul; Krishnan, Nithya; Chalhoub, Michel

2017-12-22

Movement disorders represent one of the less common presentations of cocaine toxicity observed in clinical practice. Given the magnitude of crack cocaine use, it is vital to understand the underlying pathogenesis. We present a case of a patient who clinically exhibited cocaine-induced choreoathetosis. The diagnosis was confirmed after ruling out all other organic causes of de novo choreoathetoid movement. This case highlights the association of cocaine with choreoathetoid movements. We propose a preliminary understanding of the underlying pathogenesis, which may help intensivists better recognize this uncommon phenomenon.

On bioartificial liver assist system: theoretical exploration and strategies for further development.

PubMed

Shi, Q

2000-11-01

The major difficulty in establishing a clinical effective bioartificial liver assist device for treatment of fulminate hepatic failure is limitation of our knowledge and technologies about fresh cell behaviors in culture and a lack of knowledge about the etiology and pathogenesis of hepatic coma. Increasing data from clinical and laboratory investigation have accrued indicating that toxins from necrotic liver tissue, mainly as oxygen reactive substances, have a role in the pathogenesis of hepatic encephalopathy and even multiple system organs failure. This paper presents the data available and suggests a new pathway for artificial and bioartificial liver assist system.

Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance.

PubMed

Barber, Thomas M; Dimitriadis, George K; Andreou, Avgi; Franks, Stephen

2015-12-01

Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue. © Royal College of Physicians 2015. All rights reserved.

Etiological and Clinical Features of Childhood Psychotic Symptoms

PubMed Central

Polanczyk, Guilherme; Moffitt, Terrie E.; Arseneault, Louise; Cannon, Mary; Ambler, Antony; Keefe, Richard S. E.; Houts, Renate; Odgers, Candice L.; Caspi, Avshalom

2013-01-01

Context It has been reported that childhood psychotic symptoms are common in the general population and may signal neurodevelopmental processes that lead to schizophrenia. However, it is not clear whether these symptoms are associated with the same extensive risk factors established for adult schizophrenia. Objective To examine the construct validity of children’s self-reported psychotic symptoms by testing whether these symptoms share the risk factors and clinical features of adult schizophrenia. Design Prospective, longitudinal cohort study of a nationally representative birth cohort in Great Britain. Participants A total of 2232 twelve-year-old children followed up since age 5 years (retention, 96%). Main Outcome Measure Children’s self-reported hallucinations and delusions. Results Children’s psychotic symptoms are familial and heritable and are associated with social risk factors (eg, urbanicity); cognitive impairments at age 5; home-rearing risk factors (eg, maternal expressed emotion); behavioral, emotional, and educational problems at age 5; and comorbid conditions, including self-harm. Conclusions The results provide a comprehensive picture of the construct validity of children’s self-reported psychotic symptoms. For researchers, the findings indicate that children who have psychotic symptoms can be recruited for neuroscience research to determine the pathogenesis of schizophrenia. For clinicians, the findings indicate that psychotic symptoms in childhood are often a marker of an impaired developmental process and should be actively assessed. PMID:20368509

Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

PubMed Central

Yadak, Rana; Sillevis Smitt, Peter; van Gisbergen, Marike W.; van Til, Niek P.; de Coo, Irenaeus F. M.

2017-01-01

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease. PMID:28261062

Personality traits and emotional patterns in irritable bowel syndrome.

PubMed

Muscatello, Maria Rosaria A; Bruno, Antonio; Mento, Carmela; Pandolfo, Gianluca; Zoccali, Rocco A

2016-07-28

The review focuses on those personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), constructs (alexithymia and distressed - Type D personality) and emotional patterns (negative and positive) that are of particular concern in health psychology, with the aim to highlight their potential role on the pathogenesis, onset, symptom clusters, clinical course, and outcome of irritable bowel syndrome (IBS). Personality traits and emotional patterns play key roles in affecting autonomic, immune, inflammatory, and endocrine functions, thus contributing not only to IBS clinical expression and symptomatic burden, but also to disease physiopathology. In this sense, psychological treatments should address those personality traits and emotional features that are constitutive of, and integral to IBS. The biopsychosocial model of illness applied to IBS acknowledges the interaction between biological, psychological, environmental, and social factors in relation to pain and functional disability. A holistic approach to IBS should take into account the heterogeneous nature of the disorder, and differentiate treatments for different types of IBS, also considering the marked individual differences in prevalent personality traits and emotional patterns. Beyond medications, and lifestyle/dietary interventions, psychological and educational treatments may provide the optimal chance of addressing clinical symptoms, comorbid conditions, and quality of life in IBS patients.

Tuberculous Lymphadenitis and Parotitis.

PubMed

Cataño, Juan Carlos; Robledo, Jaime

2016-12-01

Tuberculous lymphadenitis is the most common extrapulmonary manifestation of disseminated tuberculosis (TB). It is considered to be the local manifestation of the systemic disease that has disseminated to local lymph nodes, but a high index of suspicion is needed for the diagnosis, because there are several infectious and noninfectious diseases that can mimic the same clinical picture. In recent years, different diagnostic methods have been introduced, including fine-needle aspiration cytology, which has emerged as a simple outpatient diagnostic procedure that replaced the complete excisional node biopsy, and a number of molecular methods which have greatly improved diagnostic accuracy. This chapter covers the most actual knowledge in terms of epidemiology, clinical manifestations, pathogenesis, and treatment and emphasizes current trends in diagnosis of tuberculous lymphadenitis. TB parotid gland involvement is extremely rare, even in countries in which TB is endemic. Because of the clinical similarity, parotid malignancy and other forms of parotid inflammatory disease always take priority over the rarely encountered TB parotitis when it comes to differential diagnosis. As a result, clinicians often fail to make a timely diagnosis of TB parotitis when facing a patient with a slowly growing parotid lump. This chapter highlights the most important features of this uncommon disease.

Current approaches to challenging scenarios in myeloproliferative neoplasms.

PubMed

Zimran, Eran; Hoffman, Ronald; Kremyanskaya, Marina

2018-06-01

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia and primary myelofibrosis are clonal hematological malignancies that originate at the level of the hematopoietic stem cell, and are characterized by excessive proliferation of cells belonging to one or more of the myeloid lineages. Central to the pathogenesis of the MPNs is constitutive activation of the JAK/STAT signaling pathway due to a family of driver mutations affecting JAK2, CALR or MPL. These disorders share common clinical and laboratory features, a significant burden of systemic symptoms, increased risk of developing arterial and venous thrombotic events, and the potential to progress to myelofibrosis and acute leukemia. Areas covered: We identified four clinical situations which represent challenging management dilemmas for patients with MPNs. Our conclusions and recommendations are based on a literature search using MEDLINE and recent meeting abstracts using the keywords, focusing on publications directly addressing these scenarios and on recent contributions to the field. Expert commentary: Multi-center efforts to study large cohorts of MPN patients have led to more uniform and evidence-based approaches to key aspects in MPN management. However, treatment strategies to deal with specific clinical scenarios are lacking.

Emerging importance of ALK in neuroblastoma

PubMed Central

Azarova, Anna M.; Gautam, Gargi; George, Rani E.

2011-01-01

Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed, F1174L has shown more potent transforming activity in vivo than the second most common activating mutation, R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition. PMID:21945349

Personality traits and emotional patterns in irritable bowel syndrome

PubMed Central

Muscatello, Maria Rosaria A; Bruno, Antonio; Mento, Carmela; Pandolfo, Gianluca; Zoccali, Rocco A

2016-01-01

The review focuses on those personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), constructs (alexithymia and distressed - Type D personality) and emotional patterns (negative and positive) that are of particular concern in health psychology, with the aim to highlight their potential role on the pathogenesis, onset, symptom clusters, clinical course, and outcome of irritable bowel syndrome (IBS). Personality traits and emotional patterns play key roles in affecting autonomic, immune, inflammatory, and endocrine functions, thus contributing not only to IBS clinical expression and symptomatic burden, but also to disease physiopathology. In this sense, psychological treatments should address those personality traits and emotional features that are constitutive of, and integral to IBS. The biopsychosocial model of illness applied to IBS acknowledges the interaction between biological, psychological, environmental, and social factors in relation to pain and functional disability. A holistic approach to IBS should take into account the heterogeneous nature of the disorder, and differentiate treatments for different types of IBS, also considering the marked individual differences in prevalent personality traits and emotional patterns. Beyond medications, and lifestyle/dietary interventions, psychological and educational treatments may provide the optimal chance of addressing clinical symptoms, comorbid conditions, and quality of life in IBS patients. PMID:27605876

Advances in the molecular genetics of gliomas - implications for classification and therapy.

PubMed

Reifenberger, Guido; Wirsching, Hans-Georg; Knobbe-Thomsen, Christiane B; Weller, Michael

2017-07-01

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives.

PubMed

Peterson, Lisa K; Willis, Rohan; Harris, E Nigel; Branch, Ware D; Tebo, Anne E

2016-01-01

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-β2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts. © 2016 Elsevier Inc. All rights reserved.

[Functional (psychogenic) vertigo].

PubMed

Diukova, G M; Zamergrad, M V; Golubev, V L; Adilova, S M; Makarov, S A

Psychogenic (functional) vertigo is in second place by frequency after benign positional paroxysmal vertigo. It is often difficult to make the diagnosis, diagnostic program is expensive and traditional treatment often is not effective. This literature review covers current concepts on the terminology, clinical signs, pathogenesis and treatment approaches with regard to functional vertigo. Special attention is given to cerebral mechanisms of the pathogenesis including cognitive aspects.

Role of natural killer cells in lung cancer.

PubMed

Aktaş, Ozge Nur; Öztürk, Ayşe Bilge; Erman, Baran; Erus, Suat; Tanju, Serhan; Dilege, Şükrü

2018-06-01

One of the key immune cells involved in the pathogenesis of lung cancer is natural killer (NK) cells and these cells are novel targets for therapeutic applications in lung cancer. The purpose of this review is to summarize the current literature on lung cancer pathogenesis with a focus on the interaction between NK cells and smoking, how these factors are related to the pathogenesis of lung cancer and how NK cell-based immunotherapy effect lung cancer survival. The relevant literature from PubMed and Medline databases is reviewed in this article. The cytolytic potential of NK cells are reduced in lung cancer and increasing evidence suggests that improving NK cell functioning may induce tumor regression. Recent clinical trials on NK cell-based novel therapies such as cytokines including interleukin (IL)-15, IL-12 and IL-2, NK-92 cell lines and allogenic NK cell immunotherapy showed promising results with less adverse effects on the lung cancer survival. The NK cell targeting strategy has not yet been approved for lung cancer treatment. More clinical studies focusing on the role of NK cells in lung cancer pathogenesis are warranted to develop novel NK cell-based therapeutic approaches for the treatment of lung cancer.

Biological and Clinical Implications of Comorbidities in Parkinson’s Disease

PubMed Central

Santiago, Jose A.; Bottero, Virginie; Potashkin, Judith A.

2017-01-01

A wide spectrum of comorbidities has been associated with Parkinson’s disease (PD), a progressive neurodegenerative disease that affects more than seven million people worldwide. Emerging evidence indicates that chronic diseases including diabetes, depression, anemia and cancer may be implicated in the pathogenesis and progression of PD. Recent epidemiological studies suggest that some of these comorbidities may increase the risk of PD and precede the onset of motor symptoms. Further, drugs to treat diabetes and cancer have elicited neuroprotective effects in PD models. Nonetheless, the mechanisms underlying the occurrence of these comorbidities remain elusive. Herein, we discuss the biological and clinical implications of comorbidities in the pathogenesis, progression, and clinical management, with an emphasis on personalized medicine applications for PD. PMID:29255414

Insulin Resistance and Alzheimer's Disease: Bioenergetic Linkages.

PubMed

Neth, Bryan J; Craft, Suzanne

2017-01-01

Metabolic dysfunction is a well-established feature of Alzheimer's disease (AD), evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets.

[Clinical analysis of 6 cases of Bartter syndrome].

PubMed

Yin, Fang-mei; Zheng, Fang-qiu; Zhang, Xin; Wu, Mei-jun; Wei, Hong-yan; Ma, Zhong-shu; Lu, Biao; Qiu, Ming-cai

2011-03-01

To summarize the clinical characteristics of Bartter syndrome and investigate its pathogenesis. The clinical data of 6 cases of Bartter syndrome at our hospital from November 2006 to May 2010 were analyzed retrospectively. The onset age of Bartter syndrome was 13-35 years old. The main symptoms included weakness (6/6), paralysis (1/6), numbness (5/6) and tetany (4/6). All patients had normal blood pressure. The biochemical tests showed persistent hypokalemia, metabolic alkalosis (6/6) and hyperreninemia. The pathological examination of deltoid muscle biopsy showed the swelling, degeneration and necrosis of myocytes and the deposition of immunocomplex in myolemma. And the pathological examination of renal biopsy showed the hyperplasia of juxtaglomerular apparatus (5/6) and the deposition of immunocomplex. All symptoms were relieved after a therapy of potassium supplementation or a combination of indomethacin, spironolactone and immunosuppressant. When such clinical features as weakness, paralysis, tetany, hypokalemic alkalosis and normotension are encountered, Bartter syndrome should be suspected. Serum electrolytes, blood gas analysis and activation of the renin-angiotensin-aldosterone system should be examined for a definite diagnosis. The treatment of choice includes potassium and magnesium supplementation or in combination with prostaglandin synthetase inhibitor, aldosterone antagonist and immunosuppressant. Immunologic mechanism may participate in the course of Bartter syndrome.

Gender differences in clinicoepidemiological features of vitiligo: a cross-sectional analysis.

PubMed

Patil, Sharmila; Gautam, Manjyot; Nadkarni, Nitin; Saboo, Neha; Godse, Kiran; Setia, Maninder Singh

2014-01-01

Background. Vitiligo has important clinical and social consequences particularly in the pigmented skin. The present study was conducted to assess the differences in clinicoepidemiological presentation of vitiligo in males and females and to understand the factors associated with spread of vitiligo in them. Methods. This is a cross-sectional analysis of secondary clinical data of 168 vitiligo patients at a tertiary medical centre at Navi Mumbai. We used logistic regression models to estimate the association between gender and clinical characteristics of vitiligo and to evaluate the factors associated with spread of vitiligo. Results. There were no significant differences between the mean ages of males and females; however, males reported a longer duration of disease (6.9 (10.4) years) compared with females (4.9 (7.4) years). Males were significantly more likely to report a family history of vitiligo compared with females (adjusted OR (aOR): 16.87, 95% CI: 2.16 to 131.69). Even though females were more likely to report spread of lesions, the association was not statistically significant (OR: 1.21, 95% CI: 0.62 to 2.36). Discussion. The differences in the clinical presentations between genders highlight the need to understand the different factors (possibly genetic) that may play a part in the pathogenesis of this multifactorial disease in males and females.

Predicting fibromyalgia, a narrative review: are we better than fools and children?

PubMed

Ablin, J N; Buskila, D

2014-09-01

Fibromyalgia syndrome (FMS) is a common and intriguing condition, manifest by chronic pain and fatigue. Although the pathogenesis of FMS is not yet completely understood, predicting the future development of FMS and chronic pain is a major challenge with great potential advantages, both from an individual as well as an epidemiological standpoint. Current knowledge indicates a genetic underpinning for FMS, and as increasing data are accumulated regarding the genetics involved, the prospect of utilizing these data for prediction becomes ever more attractive. The co-existence of FMS with multiple other functional disorders indicates that the clinical identification of such symptom constellations in a patient can alert the physician to the future development of FMS. Hypermobility syndrome is another clinical (as well as genetic) phenotype that has emerged as a risk factor for the development of FMS. Stressful events, including early life trauma, are also harbingers of the future development of FMS. Functional neuroimaging may help to elucidate the neural processes involved in central sensitization, and may ultimately also evolve into markers of predictive value. Last but not least, obesity and disturbed sleep are clinical (inter-related) features relevant for this spectrum. Future efforts will aim at integrating genetic, clinical and physiological data in the prediction of FMS and chronic pain. © 2014 European Pain Federation - EFIC®

[A Case of Clinically Mild Encephalitis/encephalopathy with a Reversible Splenial Lesion due to Dengue Fever].

PubMed

Saito, Nobuo; Kitashouji, Emi; Kojiro, Maiko; Furumoto, Akitugu; Morimoto, Konosuke; Morita, Kouichi; Ariyoshi, Koya

2015-07-01

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) has been recently proposed as a clinical-radiological syndrome. Several causes of MERS have been reported including infectious diseases. We present herein on a case of MERS induced by dengue fever in a Japanese traveler. A 48-year-old male returning from Thailand and Cambodia was admitted for an unknown fever. Following admission, the dengue virus was diagnosed with a positive RT-PCR result. On day 5 of the illness, regardless of reduced fever, weakness suddenly developed in both upper limbs. A cerebral MRI showed hyperintensities in the splenium of the corpus callosum on T2-weighted and diffusion-weighted images. The symptoms resolved completely within two days of onset. The patient was diagnosed as having MERS due to the MRI features and the mild clinical course. Although only a few cases of MERS caused by dengue fever have been reported, the condition is possibly underdiagnosed. It is hypothesized that dengue fever can induce MERS as dengue fever can cause increased endothelium permeability and hypo-sodium which have been proposed in the pathogenesis of MERS. However, there is currently limited evidence for this. Further research is recommended to demonstrate a causal association between dengue fever and MERS.

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.

PubMed

Sperling, Adam S; Gibson, Christopher J; Ebert, Benjamin L

2017-01-01

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

A Review of the Pathophysiology and Treatment of Psychosis in Parkinson’s Disease

PubMed Central

Zahodne, Laura B.; Fernandez, Hubert H.

2011-01-01

Psychotic symptoms in Parkinson’s disease (PD) are relatively common, and in addition to being a disturbance to patients’ daily lives, they have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past fifteen years, from an initial interpretation of symptoms as dopaminergic drug side effects to the current view of a complex interplay of extrinsic and disease-related factors. The present article reviews the unique clinical features of psychosis as expressed in PD, associated risk factors, and current theories behind its pathogenesis, including medications, visual processing deficits, sleep disturbances, genetics, and neurochemical and structural abnormalities. Finally, we review both traditional and emergent management strategies for PD psychosis, including antipsychotic agents, cholinesterase inhibitors, electroconvulsive therapy (ECT), and other pharmacological and psychological interventions. PMID:18665659

Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma.

PubMed

Ram Kumar, Ram Mohan; Schor, Nina Felice

2018-04-24

Neuroblastoma (NB), a developmental cancer, is often fatal, emphasizing the need to understand its pathogenesis and identify new therapeutic targets. The heterogeneous pathological and clinical phenotype of NB underscores the cryptic biological and genetic features of this tumor that result in outcomes ranging from rapid progression to spontaneous regression. Despite recent genome-wide mutation analyses, most primary NBs do not harbor driver mutations, implicating epigenetically-mediated gene regulatory mechanisms in the initiation and maintenance of NB. Aberrant epigenomic mechanisms, as demonstrated by global changes in DNA methylation signatures, acetylation, re-distribution of histone marks, and change in the chromatin architecture, are hypothesized to play a role in NB oncogenesis. This paper reviews the evidence for, putative mechanisms underlying, and prospects for therapeutic targeting of NB oncogenesis related to DNA methylation.

Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome

PubMed Central

Zentner, Gabriel E.; Layman, Wanda S.; Martin, Donna M.; Scacheri, Peter C.

2010-01-01

CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities (including deafness) is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. De novo mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. Here, we review the clinical features of 379 CHARGE patients who tested positive or negative for mutations in CHD7. We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals. We also highlight recent genetic and genomic studies that have provided functional insights into CHD7 and the pathogenesis of CHARGE syndrome. PMID:20186815

[Conservative management of endometrioma in women undergoing in vitro fertilization].

PubMed

Santulli, P; Somigliana, E; Bourdon, M; Maignien, C; Marcellin, L; Gayet, V; Chapron, C

2017-03-01

Endometriosis is a chronic disease. The pathogenesis is actually still unclear. Endometriosis is responsible for infertility and/or pelvic pain. One of the most important features of the disease is the heterogeneity (clinical and anatomical). Among the different phenotypes of endometriosis, the ovarian endometrioma seems to most important lesion in the management of endometriosis-related infertility. Surgical treatment is associated to a decrease of the ovarian reserve and a potential detrimental effect on in vitro fecondation (IVF) outcomes. Thus, the choice between conservative or surgical management of endometrioma before IVF is actually debated. The advantages and drawback of surgical and conservative management should be discussed before to plan the treatment. In the present review, we aimed at assessing the risks of a conservative management of endometrioma as compared to surgery before IVF. Copyright © 2017. Published by Elsevier Masson SAS.

Animal models of medullary thyroid cancer: state of the art and view to the future.

PubMed

Vitale, Giovanni; Gaudenzi, Germano; Circelli, Luisa; Manzoni, Marco F; Bassi, Andrea; Fioritti, Niccolò; Faggiano, Antongiulio; Colao, Annamaria

2017-01-01

Medullary thyroid carcinoma is a neuroendocrine tumour originating from parafollicular C cells accounting for 5-10% of thyroid cancers. Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid carcinoma. These drugs increase progression-free survival; however, they are often poorly tolerated and most treatment responses are transient. Animal models are indispensable tools for investigating the pathogenesis, mechanisms for tumour invasion and metastasis and new therapeutic approaches for cancer. Unfortunately, only few models are available for medullary thyroid carcinoma. This review provides an overview of the state of the art of animal models in medullary thyroid carcinoma and highlights future developments in this field, with the aim of addressing salient features and clinical relevance. © 2017 Society for Endocrinology.

Phenytoin-induced severe gingival overgrowth in a child

PubMed Central

Kumar, Rakesh; Singh, Rajeev Kumar; Verma, Nidhi; Verma, Umesh Pratap

2014-01-01

Gingival enlargement or overgrowth (GO) is a common complication of the anticonvulsant drug phenytoin (PHT). GO is evident in almost half of the patients receiving PHT therapy. PHT-induced gingival overgrowth (PGO) is more common in children than in adults and affects both males and females equally. PGO may vary from mild to severe and does not seem to be dose dependant. It is supposed that PHT and its metabolites cause a direct effect on the periodontal tissues; however, poor oral hygiene may contribute to the severity of gingival inflammation in patients with PGO. Management of PGO includes meticulous oral hygiene practice to reduce inflammation and surgical excision of the overgrown tissue, known as gingivectomy. We present a case of PHT-induced severe GO in a 10-year-old boy and discuss the clinical features, aetiology, pathogenesis and management of PGO. PMID:25053668

[Rapidly progressive pulmonary malignant perivascular epithelioid cell tumor: a case report and literature review].

PubMed

Shi, X Y; Long, F; Liang, B; Su, L L; Li, H C; Jiang, S J

2016-10-12

Objective: To analyze the pathogenesis, clinical features, diagnosis and differential diagnosis of primary perivascular epithelioid cell tumor(PEComa). Methods: The clinical features, auxiliary examinations and diagnosis of a case with rapidly progressive pulmonary malignant PEComa were reported and the related literatures were reviewed.The literature review was carried out respectively in Wanfang Data, CNKI and PubMed from Jan. 1975 to Jul. 2015 with "pulmonary malignant perivascular epithelioid cell tumor" and "PEComa" being the search terms. Results: A 50 year-old female patient was admitted to the hospital on September 4, 2014 because of cough and dyspnea for 60 days, hemoptysis for 40 days and fever for 7 days.Chest CT scan showed diffuse small nodules with infiltrative border and multiple pure and mixed ground-glass opacity. Transbronchial lung biopsy (TBLB) was performed and the pathological study confirmed the diagnosis of primary pulmonary malignant PEComa. The patient declined further specific therapy, but followed by rapidly progressive respiratory failure, and died two weeks after the diagnosis. A total of 8 literatures were retrieved from Wanfang Data, CNKI and PubMed and all of them were case reports.There were 3 male and 5 female patients, aging from 50 to 79 years.Radiographically, the previously reported cases presented as round and well-circumscribed masses with or without multiple nodules in both lungs. The symptoms had no specificity. Conclusions: Pulmonary malignant PEComa is a rare disease.It is easily misdiagnosed because of non-specific clinical and imaging manifestations.The final diagnosis depends on pathological biopsy.TBLB is an effective diagnostic method.

Nonalcoholic fatty liver disease: Evolving paradigms

PubMed Central

Lonardo, Amedeo; Nascimbeni, Fabio; Maurantonio, Mauro; Marrazzo, Alessandra; Rinaldi, Luca; Adinolfi, Luigi Elio

2017-01-01

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including ”lean NAFLD” has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible. PMID:29085206

Clinical, histopathological and immunological characteristics of exfoliative cutaneous lupus erythematosus in 25 German short-haired pointers.

PubMed

Bryden, Sharon L; White, Stephen D; Dunston, Stanley M; Burrows, Amanda K; Olivry, Thierry

2005-08-01

Clinical, histopathological and immunological features of exfoliative cutaneous lupus erythematosus, an uncommon generalized exfoliative dermatitis occurring exclusively in German short-haired pointers, were characterized in 25 dogs. The disease affects young adult dogs and its familial incidence strongly suggests a hereditary origin. Lesions were characterized by scaling and alopecia affecting 100 (25/25) and 76% (19/25) of dogs, respectively. Follicular casts were present in 28% (7/25) of dogs. The muzzle, pinnae and dorsum were typically affected. Generalized skin lesions were described in 52% (13/25) of dogs. Systemic signs of pain and lameness affected several dogs. Anaemia and thrombocytopenia were detected in several dogs with a more severe clinical phenotype. The most common histopathological features were hyperkeratosis and a lymphocytic interface dermatitis. Direct immunostaining revealed IgG deposition in the epidermal and follicular basement membrane of 100 (19/19) and 41% (7/17) of dogs, respectively. Circulating antifollicular and antisebaceous gland IgG antibodies were demonstrated by indirect immunostaining in 57% (4/7) of dogs. This disease usually responds poorly to immunosuppressive therapy and it has a guarded prognosis. Where outcome was recorded, 85% (10/12) of dogs were euthanased due to either a failure to respond to, or complications associated with, immunomodulatory therapy. Two affected dogs are in remission and maintained on immunomodulatory dosages of prednisolone. This study demonstrates the existence of a cellular and humoral immune response directed against the epidermal basement membrane of dogs with exfoliative cutaneous lupus erythematosus. Additional studies are required to further characterize the immunological pathogenesis of this disease.

Hyperammonemia and Systemic Inflammatory Response Syndrome Predicts Presence of Hepatic Encephalopathy in Dogs with Congenital Portosystemic Shunts

PubMed Central

Tivers, Mickey S.; Handel, Ian; Gow, Adam G.; Lipscomb, Vicky J.; Jalan, Rajiv; Mellanby, Richard J.

2014-01-01

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with liver disease. The pathogenesis of he is incompletely understood although ammonia and inflammatory cytokines have been implicated as key mediators. To facilitate further mechanistic understanding of the pathogenesis of HE, a large number of animal models have been developed which often involve the surgical creation of an anastomosis between the hepatic portal vein and the caudal vena cava. One of the most common congenital abnormalities in dogs is a congenital portosystemic shunt (cpss), which closely mimics these surgical experimental models of HE. Dogs with a cPSS often have clinical signs which mimic clinical signs observed in humans with HE. Our hypothesis is that the pathogenesis of HE in dogs with a cPSS is similar to humans with HE. The aim of the study was to measure a range of clinical, haematological and biochemical parameters, which have been linked to the development of HE in humans, in dogs with a cPSS and a known HE grade. One hundred and twenty dogs with a cPSS were included in the study and multiple regression analysis of clinical, haematological and biochemical variables revealed that plasma ammonia concentrations and systemic inflammatory response syndrome scores predicted the presence of HE. Our findings further support the notion that the pathogenesis of canine and human HE share many similarities and indicate that dogs with cPSS may be an informative spontaneous model of human HE. Further investigations on dogs with cPSS may allow studies on HE to be undertaken without creating surgical models of HE thereby allowing the number of large animals used in animal experimentation to be reduced. PMID:24392080

Hyperammonemia and systemic inflammatory response syndrome predicts presence of hepatic encephalopathy in dogs with congenital portosystemic shunts.

PubMed

Tivers, Mickey S; Handel, Ian; Gow, Adam G; Lipscomb, Vicky J; Jalan, Rajiv; Mellanby, Richard J

2014-01-01

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with liver disease. The pathogenesis of he is incompletely understood although ammonia and inflammatory cytokines have been implicated as key mediators. To facilitate further mechanistic understanding of the pathogenesis of HE, a large number of animal models have been developed which often involve the surgical creation of an anastomosis between the hepatic portal vein and the caudal vena cava. One of the most common congenital abnormalities in dogs is a congenital portosystemic shunt (cpss), which closely mimics these surgical experimental models of HE. Dogs with a cPSS often have clinical signs which mimic clinical signs observed in humans with HE. Our hypothesis is that the pathogenesis of HE in dogs with a cPSS is similar to humans with HE. The aim of the study was to measure a range of clinical, haematological and biochemical parameters, which have been linked to the development of HE in humans, in dogs with a cPSS and a known HE grade. One hundred and twenty dogs with a cPSS were included in the study and multiple regression analysis of clinical, haematological and biochemical variables revealed that plasma ammonia concentrations and systemic inflammatory response syndrome scores predicted the presence of HE. Our findings further support the notion that the pathogenesis of canine and human HE share many similarities and indicate that dogs with cPSS may be an informative spontaneous model of human HE. Further investigations on dogs with cPSS may allow studies on HE to be undertaken without creating surgical models of HE thereby allowing the number of large animals used in animal experimentation to be reduced.

Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus.

PubMed

Weckerle, Corinna E; Mangale, Dorothy; Franek, Beverly S; Kelly, Jennifer A; Kumabe, Marissa; James, Judith A; Moser, Kathy L; Harley, John B; Niewold, Timothy B

2012-09-01

Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multiancestral SLE cohort. We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme-linked immunosorbent assay, and IFNα was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. Serum TNFα levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease. Copyright © 2012 by the American College of Rheumatology.

Positivity rates of antithyroid antibody, antinuclear antibody and thyroid peroxidase antibody in different types of vitiligo.

PubMed

Lim, H K; Bae, M I; Jeong, K H; Shin, M K; Lee, M-H

2016-04-01

Vitiligo is associated with various autoimmune disorders, and organ-specific autoantibodies are frequently found in patients with this disorder. Vitiligo is classically divided into segmental vitiligo (SV) and nonsegmental vitiligo (NSV), and it is believed that the pathogenesis differs between these two types. As the NSV type is related to an autoimmune mechanism, autoantibody detection rates are likely to be higher in the NSV type than in the segmental type; however, no comparative studies have been performed. To analyse the rates of autoantibody positivity according to the clinical features in patients with vitiligo. Rates of antithyroid antibody (Tg Ab), antinuclear antibody (ANA) and thyroid peroxidase antibody (TPO Ab) positivity were analysed and compared according to the sex, clinical type and age of onset of 807 patients with vitiligo. There were 106 patients with SV (13.1%) and 701 patients with NSV (86.9%). Tg Ab and ANA positivity did not differ between the SV and NSV types. A positive TPO Ab result was obtained in 16 patients with SV (15.1%) and 173 patients with NSV (24.7%). The TPO Ab positivity rate was significantly higher in NSV (χ² = 4.14, P < 0.05). The positivity rates of the three autoantibodies differed significantly according to age of onset (P = 0.001, P = 0.02 and P < 0.001 for Tg Ab, ANA and TPO Ab positivity, respectively). The TPO Ab positivity rate also showed a sex difference (P < 0.001). The positivity rates for the three autoantibodies showed differences according to age of onset and sex. The rates of Tg Ab and ANA positivity showed no significant differences according to clinical type, but the TPO Ab positivity rate was significantly different between SV and NSV. It appears likely that an autoimmune mechanism contributes to the pathogenesis of SV. © 2015 British Association of Dermatologists.

Genomic signatures characterize leukocyte infiltration in myositis muscles.

PubMed

Zhu, Wei; Streicher, Katie; Shen, Nan; Higgs, Brandon W; Morehouse, Chris; Greenlees, Lydia; Amato, Anthony A; Ranade, Koustubh; Richman, Laura; Fiorentino, David; Jallal, Bahija; Greenberg, Steven A; Yao, Yihong

2012-11-21

Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development. In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls. Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes. Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials.

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.

Circulating anti-retinal antibodies as immune markers in age-related macular degeneration

PubMed Central

Patel, Nishal; Ohbayashi, Masahara; Nugent, Alex K; Ramchand, Kanchan; Toda, Masako; Chau, Kai-Yin; Bunce, Catey; Webster, Andrew; Bird, Alan C; Ono, Santa Jeremy; Chong, Victor

2005-01-01

Age-related macular maculopathy (ARM) and age-related macular degeneration (AMD) are the leading causes of blindness in the Western world. Despite the magnitude of this clinical problem, very little is known about the pathogenesis of the disease. In this study, we analysed the sera (using indirect immunohistochemistry and Western blot analysis) from a very large cohort of such patients and normal age-matched controls to detect circulating anti-retinal antibodies. Patients with bilateral drusen (n = 64) and with chorioretinal neovascularization (CNV) (n = 51) were recruited in addition to age-matched control subjects (n = 39). The sera were analysed for anti-retinal immunoglobulins on retinal sections. The data were then correlated with the clinical features graded according to the International Classification and Grading System of ARM and AMD. The sera of patients with drusen (93·75%) and CNV (82·27%) were found to have a significantly (P = 0·02) higher titre of autoantibodies to the retina in comparison with controls (8·69%), indicating significant evidence of involvement of the immune process in early stages of AMD. Subsequent statistical analysis of the drusen group showed significant progressive staining (P = 0·0009) in the nuclei layers from early to late stages of ARM. Western blotting confirmed the presence of anti-retinal immunoglobulins to retinal antigens. As anti-retinal immunoglobulins are present in patients with bilateral drusen and exudative AMD, these antibodies could play a significant role in the pathogenesis of AMD. Whilst we do not have evidence that these antibodies precede disease onset, the possibility that their presence might contribute to disease progression needs to be investigated. Finally, the eventual identification of the target antigens detected by these antibodies may permit the future development of new diagnostic methods for ARM and AMD. PMID:15946260

Deep Brain Stimulation to Alleviate Freezing of Gait and Cognitive Dysfunction in Parkinson's Disease: Update on Current Research and Future Perspectives.

PubMed

Huang, Chuyi; Chu, Heling; Zhang, Yan; Wang, Xiaoping

2018-01-01

Freezing of gait (FOG) is a gait disorder featured by recurrent episodes of temporary gait halting and mainly found in advanced Parkinson's disease (PD). FOG has a severe impact on the quality of life of patients with PD. The pathogenesis of FOG is unclear and considered to be related to several brain areas and neural circuits. Its close connection with cognitive disorder has been proposed and some researchers explain the pathogenesis using the cognitive model theory. FOG occurs concurrently with cognitive disorder in some PD patients, who are poorly responsive to medication therapy. Deep brain stimulation (DBS) proves effective for FOG in PD patients. Cognitive impairment plays a role in the formation of FOG. Therefore, if DBS works by improving the cognitive function, both two challenging conditions can be ameliorated by DBS. We reviewed the clinical studies related to DBS for FOG in PD patients over the past decade. In spite of the varying stimulation parameters used in different studies, DBS of either subthalamic nucleus (STN) or pedunculopontine nucleus (PPN) alone or in combination can improve the symptoms of FOG. Moreover, the treatment efficacy can last for 1-2 years and DBS is generally safe. Although few studies have been conducted concerning the use of DBS for cognitive disorder in FOG patients, the existing studies seem to indicate that PPN is a potential therapeutic target to both FOG and cognitive disorder. However, most of the studies have a small sample size and involve sporadic cases, so it remains uncertain which nucleus is the optimal target of stimulation. Prospective clinical trials with a larger sample size are needed to systematically assess the efficacy of DBS for FOG and cognitive disorder.

[Spinocerebellar ataxias in infancy: pathogenesis of potassium and calcium channels' diseases, clinical features and therapeutical approach].

PubMed

Bozzola, E; Savasta, S; Peruzzi, C; Bozzola, M; Bona, G

2007-04-01

In infancy, the autosomal dominant inherited ataxias are severe neurological diseases, due to inherited mutations of ion channels. The main forms are: episodic ataxia type 1 (EA1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6). EA1 is due to a mutation in KCNA1, the gene encoding human Kv1.1 on chromosome 12p13, which contributes as a subunit to the formation of potassium channels in motor nerve terminals and in many central nervous system neurones. To date, there are fifteen different mutations, which affect potassium channel's properties and lead to phenotypic variability and to different responses to therapy. EA2 can result from mutations in the CACNA1A gene, encoding calcium channels on chromosome 19p13.1 and widely distributed throughout the central nervous system. To date, associated with EA2, in the CACNA1A gene thirty different mutations have been described, resulting in altered or truncated protein products and, as a consequence, in nonfunctional calcium channels. There is phenotypic variability, also inside the same family, without correlation genotype-phenotype. SCA6 is a progressive neurodegenerative disease due to mutations of the CACNA1A gene. CACNA1A is responsible for both EA2 and SCA6. Nevertheless, the pathogenesis of the two diseases is different: SCA6 is associated with small expansion of a CAGn repeat, while EA2 is due to point mutations. Clinically, SCA6 is characterized by a slowly progressive development and by an inverse correlation between the number of repeats and the severity of the disease.

Potential oxidative stress biomarkers of mild cognitive impairment due to Alzheimer disease.

PubMed

García-Blanco, Ana; Baquero, Miguel; Vento, Máximo; Gil, Esperanza; Bataller, Luis; Cháfer-Pericás, Consuelo

2017-02-15

The high and increasing incidence of Alzheimer Disease (AD) worldwide is a major global concern. Classical diagnosis is carried out in the dementia phase, often in the moderate stages when treatment efficacy is limited. Nowadays, early diagnosis, even in pre-dementia stages, is possible in selected cases within an appropriate clinical setting, employing cerebral spinal fluid (CSF) sample analysis and neuroimaging procedures. In spite of the accurate diagnosis achieved by novel CSF biomarkers or positron emission tomography beta-amyloid tracers, these tests are invasive and expensive. Therefore, important work is being carried out to discover reliable biomarkers in peripheral biofluids (blood, plasma, urine) to be incorporated in clinical routine for early AD diagnosis. Although the nature of AD pathogenesis is complex, it is known that oxidative stress plays a key role, for which biomarkers are easily determined in peripheral biofluids. This review summarizes recent research on oxidative stress biomarkers in mild cognitive impairment due to AD. Among them, a promising research line is the study of the relationship between lipid peroxidation biomarkers and early AD clinical features. Results show a pronounced imbalance between scientific production and clinical reality due to the lack of clinical validation. We conclude that an important field in oxidative stress biomarkers could be developed with the aim to help clinicians in early disease diagnosis, effective treatment initiation and reliable disease monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

The Evolving Classification of Pulmonary Hypertension.

PubMed

Foshat, Michelle; Boroumand, Nahal

2017-05-01

- An explosion of information on pulmonary hypertension has occurred during the past few decades. The perception of this disease has shifted from purely clinical to incorporate new knowledge of the underlying pathology. This transfer has occurred in light of advancements in pathophysiology, histology, and molecular medical diagnostics. - To update readers about the evolving understanding of the etiology and pathogenesis of pulmonary hypertension and to demonstrate how pathology has shaped the current classification. - Information presented at the 5 World Symposia on pulmonary hypertension held since 1973, with the last meeting occurring in 2013, was used in this review. - Pulmonary hypertension represents a heterogeneous group of disorders that are differentiated based on differences in clinical, hemodynamic, and histopathologic features. Early concepts of pulmonary hypertension were largely influenced by pharmacotherapy, hemodynamic function, and clinical presentation of the disease. The initial nomenclature for pulmonary hypertension segregated the clinical classifications from pathologic subtypes. Major restructuring of this disease classification occurred between the first and second symposia, which was the first to unite clinical and pathologic information in the categorization scheme. Additional changes were introduced in subsequent meetings, particularly between the third and fourth World Symposia meetings, when additional pathophysiologic information was gained. Discoveries in molecular diagnostics significantly progressed the understanding of idiopathic pulmonary arterial hypertension. Continued advancements in imaging modalities, mechanistic pathogenicity, and molecular biomarkers will enable physicians to define pulmonary hypertension phenotypes based on the pathobiology and allow for treatment customization.

Pathogenesis of Salmonellosis: Salmonella Exotoxins

DTIC Science & Technology

1982-03-08

of Salmonella enteritidis , which included 9630 serotype newport, 9136 serotype newport, 10016 serotype javiana, and 8832, serotype javiana were also...supplied by Dr. T. Huber. Additionally, four clinical isolates of Salmonella enteritidis , which included 986 serotype typhimurium, 2000 serotype...77Z7I AD _ REPORT NUMBER 3 0 Pathogenesis of Salmonellosis: Salmonella Exotoxins Annual Progress Report (9/1/79-8/31/80) M Johnny W. Peterson, Ph.D

Pharmacotherapy of Systemic Sclerosis

PubMed Central

Postlethwaite, Arnold E.; Harris, L. Jeff; Raza, Syed H.; Kodura, Swapna; Akhigbe, Titilola

2010-01-01

Importance of the field Systemic-sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. Presently, there is no cure for SSc. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc. Areas covered in this review All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed.gov database were searched, relevant articles were then reviewed and used as sources of information for this review. What the reader will gain This review attempts for the reader to highlight some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease plus provide a review of results of completed clinical trials and current on-going clinical trials that address organ specific or global therapies for this disease which can aid physicians who provide medical care for patients with SSc. Take home message SSc is a complex autoimmune disease, the pathogenesis of which although not completely understood is under active study, and new insights into pathogenesis are continuously being discovered. Although there is no effective disease modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation. PMID:20210685

Gorlin-Goltz syndrome: incidental finding on routine ct scan following car accident.

PubMed

Kalogeropoulou, Christina; Zampakis, Petros; Kazantzi, Santra; Kraniotis, Pantelis; Mastronikolis, Nicholas S

2009-11-25

Gorlin-Goltz syndrome is a rare hereditary disease. Pathogenesis of the syndrome is attributed to abnormalities in the long arm of chromosome 9 (q22.3-q31) and loss or mutations of human patched gene (PTCH1 gene). Multiple basal cell carcinomas (BCCs), odontogenic keratocysts, skeletal abnormalities, hyperkeratosis of palms and soles, intracranial ectopic calcifications of the falx cerebri and facial dysmorphism are considered the main clinical features. Diagnosis is based upon established major and minor clinical and radiological criteria and ideally confirmed by DNA analysis. Because of the different systems affected, a multidisciplinary approach team of various experts is required for a successful management. We report the case of a 19 year-old female who was involved in a car accident and found to present imaging findings of Gorlin-Goltz syndrome during a routine whole body computed tomography (CT) scan in order to exclude traumatic injuries. Radiologic findings of the syndrome are easily identifiable on CT scans and may prompt to early verification of the disease, which is very important for regular follow-up and better survival rates from the co-existent diseases.

[Modern Views on Children's Interstitial Lung Disease].

PubMed

Boĭtsova, E V; Beliashova, M A; Ovsiannikov, D Iu

2015-01-01

Interstitial lung diseases (ILD, diffuse lung diseases) are a heterogeneous group of diseases in which a pathological process primarily involved alveoli and perialveolar interstitium, resulting in impaired gas exchange, restrictive changes of lung ventilation function and diffuse interstitial changes detectable by X-ray. Children's interstitial lung diseases is an topical problem ofpediatricpulmonoogy. The article presents current information about classification, epidemiology, clinical presentation, diagnostics, treatment and prognosis of these rare diseases. The article describes the differences in the structure, pathogenesis, detection of various histological changes in children's ILD compared with adult patients with ILD. Authors cite an instance of registers pediatric patients with ILD. The clinical semiotics of ILD, the possible results of objective research, the frequency of symptoms, the features of medical history, the changes detected on chest X-rays, CT semiotics described in detail. Particular attention was paid to interstitial lung diseases, occurring mainly in newborns and children during the first two years of life, such as congenital deficiencies of surfactant proteins, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis. The diagnostic program for children's ILD, therapy options are presented in this article.

Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management

PubMed Central

Pandey, Sanjay; Srivanitchapoom, Prachaya

2017-01-01

Levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after long duration of treatment, but occasionally, this may be seen even after few days or months of treatment. LID is broadly classified as peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia. Pathogenesis of LID is complex, and different neurotransmitters such as dopamine, glutamine, adenosine, and gamma-aminobutyric acid play important role altering the normal physiology of direct and indirect pathway of cortico-basal ganglia-thalamic loop responsible for fine motor control. Treatment of LID requires careful history taking and clinical examination to find the type of dyskinesia as different approach is required for different types. Changes in dopaminergic medication including continuous dopaminergic stimulation are very helpful in the management of peak-dose dyskinesia. Different types of surgical approaches including unilateral pallidotomy and deep brain stimulation have given very good result in patients, who cannot be managed by medications alone. The surgical management of LID is dealt with in detail in another review in this series. PMID:28904447

New insights into the pathophysiology of post-stroke spasticity.

PubMed

Li, Sheng; Francisco, Gerard E

2015-01-01

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

New insights into the pathophysiology of post-stroke spasticity

PubMed Central

Li, Sheng; Francisco, Gerard E.

2015-01-01

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

Diagnostic and therapeutic advancements for aerobic vaginitis.

PubMed

Han, Cha; Wu, Wenjuan; Fan, Aiping; Wang, Yingmei; Zhang, Huiying; Chu, Zanjun; Wang, Chen; Xue, Fengxia

2015-02-01

Aerobic vaginitis (AV) is a newly defined clinical entity that is distinct from candidiasis, trichomoniasis and bacterial vaginosis (BV). Because of the poor recognition of AV, this condition can lead to treatment failures and is associated with severe complications, such as pelvic inflammatory disease, infertility, preterm birth and foetal infections. This review describes the diagnosis and treatment of AV and the relationship between AV and pregnancy. The characteristics of AV include severely depressed levels of lactobacilli, increased levels of aerobic bacteria and an inflamed vagina. The diagnosis is made by microscopy on wet mounts of fresh vaginal fluid, and some distinct clinical features are recognized. Vaginal suppositories that contain kanamycin or clindamycin have shown curative effects in nonpregnant women. Additionally, the application of topical probiotics can restore the vaginal flora and reduce the recurrence of AV. Clindamycin vaginal suppositories and probiotics may be a better choice for gravida with AV than metronidazole. AV requires prompt attention, and the early diagnosis and treatment of AV during pregnancy significantly improves perinatal outcomes. Further research is needed to define the pathogenesis, diagnostic criteria and standard treatment guidelines for AV.

Typhoid fever as cellular microbiological model.

PubMed

de Andrade, Dahir Ramos; de Andrade Júnior, Dahir Ramos

2003-01-01

The knowledge about typhoid fever pathogenesis is growing in the last years, mainly about the cellular and molecular phenomena that are responsible by clinical manifestations of this disease. In this article are discussed several recent discoveries, as follows: a) Bacterial type III protein secretion system; b) The five virulence genes of Salmonella spp. that encoding Sips (Salmonella invasion protein) A, B, C, D and E, which are capable of induce apoptosis in macrophages; c) The function of Toll R2 and Toll R4 receptors present in the macrophage surface (discovered in the Drosophila). The Toll family receptors are critical in the signalizing mediated by LPS in macrophages in association with LBP and CD14; d) The lines of immune defense between intestinal lumen and internal organs; e) The fundamental role of the endothelial cells in the inflammatory deviation from bloodstream into infected tissues by bacteria. In addition to above subjects, the authors comment the correlation between the clinical features of typhoid fever and the cellular and molecular phenomena of this disease, as well as the therapeutic consequences of this knowledge.

Mutation in PLK4, encoding a master regulator of centriole formation, defines a novel locus for primordial dwarfism.

PubMed

Shaheen, Ranad; Al Tala, Saeed; Almoisheer, Agaadir; Alkuraya, Fowzan S

2014-12-01

Primordial dwarfism (PD) is a heterogeneous clinical entity characterised by severe prenatal and postnatal growth deficiency. Despite the recent wave of disease gene discovery, the causal mutations in many PD patients remain unknown. To describe a PD family that maps to a novel locus. Clinical, imaging and laboratory phenotyping of a new family with PD followed by autozygosity mapping, linkage analysis and candidate gene sequencing. We describe a multiplex consanguineous Saudi family in which two full siblings and one half-sibling presented with classical features of Seckel syndrome in addition to optic nerve hypoplasia. We were able to map the phenotype to a single novel locus on 4q25-q28.2, in which we identified a five base-pair deletion in PLK4, which encodes a master regulator of centriole duplication. Our discovery further confirms the role of genes involved in centriole biology in the pathogenesis of PD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Unicameral Bone Cysts of the Pelvis

PubMed Central

Hammoud, Sommer; Weber, Kristy; McCarthy, Edward F

2005-01-01

Unicameral bone cysts of the pelvis are extremely rare. This study summarizes the clinical, radiologic and pathologic features of 16 cases. Patients ranged in age from nine to 69. Most lesions were in the anterior portion of the iliac wing; many appeared to be related to an open iliac crest apophysis. This suggests that the pathogenesis of unicameral bone cysts in this portion of the ilium is similar to that seen in the proximal humerus and the proximal femur. The correct diagnosis was made preoperatively in only five cases. This indicates that, although they are well documented, unicameral bone cysts of the pelvis remain a diagnostic problem. Patients received a spectrum of treatments from curettage to observation. There appeared to be no difference in the outcome after any form of treatment. Therefore, unicameral bone cysts of the pelvis can be managed conservatively. The choice to manage patients conservatively depends on making the correct diagnosis based on clinical history and imaging. The most effective imaging is a combination of plain radiographs, computed tomography (CT) and magnetic resonance imaging (MRI). PMID:16089077

Unicameral bone cysts of the pelvis: a study of 16 cases.

PubMed

Hammoud, Sommer; Weber, Kristy; McCarthy, Edward F

2005-01-01

Unicameral bone cysts of the pelvis are extremely rare. This study summarizes the clinical, radiologic and pathologic features of 16 cases. Patients ranged in age from nine to 69. Most lesions were in the anterior portion of the iliac wing; many appeared to be related to an open iliac crest apophysis. This suggests that the pathogenesis of unicameral bone cysts in this portion of the ilium is similar to that seen in the proximal humerus and the proximal femur. The correct diagnosis was made preoperatively in only five cases. This indicates that, although they are well documented, unicameral bone cysts of the pelvis remain a diagnostic problem. Patients received a spectrum of treatments from curettage to observation. There appeared to be no difference in the outcome after any form of treatment. Therefore, unicameral bone cysts of the pelvis can be managed conservatively. The choice to manage patients conservatively depends on making the correct diagnosis based on clinical history and imaging. The most effective imaging is a combination of plain radiographs, computed tomography (CT) and magnetic resonance imaging (MRI).

Experimental infection of human volunteers with Haemophilus ducreyi: fifteen years of clinical data and experience.

PubMed

Janowicz, Diane M; Ofner, Susan; Katz, Barry P; Spinola, Stanley M

2009-06-01

Haemophilus ducreyi causes chancroid, which facilitates transmission of human immunodeficiency virus type 1. To better understand the biology of H. ducreyi, we developed a human inoculation model. In the present article, we describe clinical outcomes for 267 volunteers who were infected with H. ducreyi. There was a relationship between papule formation and estimated delivered dose. The outcome (either pustule formation or resolution) of infected sites for a given subject was not independent; the most important determinants of pustule formation were sex and host effects. When 41 subjects were infected a second time, their outcomes segregated toward their initial outcome, confirming the host effect. Subjects with pustules developed local symptoms that required withdrawal from the study after a mean of 8.6 days. There were 191 volunteers who had tissue biopsy performed, 173 of whom were available for follow-up analysis; 28 (16.2%) of these developed hypertrophic scars, but the model was otherwise safe. Mutant-parent trials confirmed key features in H. ducreyi pathogenesis, and the model has provided an opportunity to study differential human susceptibility to a bacterial infection.

Update on pigment dispersion syndrome and pigmentary glaucoma.

PubMed

Okafor, Kingsley; Vinod, Kateki; Gedde, Steven J

2017-03-01

The present article reviews the clinical features and pathogenesis of pigment dispersion syndrome and pigmentary glaucoma and provides an update regarding their diagnosis and management. Newer imaging modalities including ultrasound biomicroscopy and anterior segment optical coherence tomography facilitate visualization of the iris concavity characteristic of eyes with pigment dispersion syndrome and pigmentary glaucoma. Patients with pigmentary glaucoma may be distinguished from those with other glaucoma types by the presence of typical symptoms, personality type, and patterns of diurnal intraocular pressure fluctuation. Although laser iridotomy has been shown to alter iris anatomy in pigmentary glaucoma, it is not proven to slow visual field progression. Multiple trials have validated the safety and efficacy of filtering surgery in treating pigmentary glaucoma, with fewer studies published on the role of micro-invasive glaucoma surgery. Literature from the review period has further defined the unique clinical characteristics of pigment dispersion syndrome and pigmentary glaucoma. Laser surgery has a limited role in the management of these entities, whereas trabeculectomy remains an acceptable first-line surgical treatment. Further studies are needed to define the potential application of the newer micro-invasive glaucoma procedures in pigmentary glaucoma.

The MiRNA Journey from Theory to Practice as a CNS Biomarker.

PubMed

Stoicea, Nicoleta; Du, Amy; Lakis, D Christie; Tipton, Courtney; Arias-Morales, Carlos E; Bergese, Sergio D

2016-01-01

MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders.

The MiRNA Journey from Theory to Practice as a CNS Biomarker

PubMed Central

Stoicea, Nicoleta; Du, Amy; Lakis, D. Christie; Tipton, Courtney; Arias-Morales, Carlos E.; Bergese, Sergio D.

2016-01-01

MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders. PMID:26904099

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

PubMed Central

Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

2016-01-01

Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

Meta-Analysis of the Changes of Peripheral Blood T Cell Subsets in Patients with Brucellosis

PubMed Central

Zheng, Rongjiong; Xie, Songsong; Niyazi, Shaniya; Lu, Xiaobo; Zhou, Yan

2018-01-01

Brucellosis is one of the most prevalent zoonotic diseases in the world, but its pathogenesis is not very clear. At present, it is thought that it may be related to the immunity of T cells. The conclusions of related studies are inconsistent, and its clinical significance is not explicit. We searched published articles in electronic databases up to December 2017 identified as relating to the clinical features of human brucellosis in China. Only eight studies had sufficient quality for data extraction. Meta-analysis showed a significantly decreased proportion of CD4+ T cells in human brucellosis patients compared to healthy subject individuals. The frequency of CD8+ T cells was significantly higher in human brucellosis patients than that in the healthy control group. The pooled analysis presented a significant decrease of the CD4+/CD8+ ratio in human brucellosis patients compared to healthy subjects. There is immunologic dysfunction of T lymphocyte in patients with human brucellosis, the CD4+ and CD8+ T cells might be the important factors affecting the progress of brucellosis. PMID:29888294

Immunopathogenesis of Dengue Virus-Induced Redundant Cell Death: Apoptosis and Pyroptosis.

PubMed

Suwanmanee, San; Luplertlop, Natthanej

Dengue virus infection is a self-limited condition, which is of particular importance in tropical and subtropical regions and for which no specific treatment or effective vaccine is available. There are several hypotheses explaining dengue pathogenesis. These usually refer to host immune responses, including antibody-dependent enhancement, cytokine expression, and dengue virus particles including NS1 protein, which lead to cell death by both apoptosis and pyroptosis. A clear understanding of the pathogenesis should facilitate the development of vaccines and therapies. This review focuses on the immunopathogenesis in relation to clinical manifestations and patterns of cell death, focusing on the pathogenesis of severe dengue.

The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis

PubMed Central

Asano, Yoshihide; Bujor, Andreea M.; Trojanowska, Maria

2013-01-01

Systemic sclerosis (SSc) is an autoimmune inflammatory disease with unknown etiology characterized by microvascular injury and fibrosis of the skin and internal organs. A growing body of evidence suggests that deficiency of the transcription factor Fli1 (Friend leukemia integration-1) has a pivotal role in the pathogenesis of SSc. Fli1 is expressed in fibroblasts, endothelial cells, and immune cells, and has important roles in the activation, differentiation, development, and survival of these cells. Previous studies demonstrated that Fli1 is downregulated in SSc fibroblasts by an epigenetic mechanism and a series of experiments with Fli1-deficient animal models revealed that Fli1 deficiency in fibroblasts and endothelial cells reproduces the histopathologic features of fibrosis and vasculopathy in SSc, respectively. In this article, we review the impact of Fli1 deficiency on the pathogenesis of SSc and discuss a new therapeutic strategy for SSc by targeting the transcription factor Fli1. PMID:20663647

Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes

PubMed Central

Lorenzi, Hernan; Khan, Asis; Behnke, Michael S.; Namasivayam, Sivaranjani; Swapna, Lakshmipuram S.; Hadjithomas, Michalis; Karamycheva, Svetlana; Pinney, Deborah; Brunk, Brian P.; Ajioka, James W.; Ajzenberg, Daniel; Boothroyd, John C.; Boyle, Jon P.; Dardé, Marie L.; Diaz-Miranda, Maria A.; Dubey, Jitender P.; Fritz, Heather M.; Gennari, Solange M.; Gregory, Brian D.; Kim, Kami; Saeij, Jeroen P. J.; Su, Chunlei; White, Michael W.; Zhu, Xing-Quan; Howe, Daniel K.; Rosenthal, Benjamin M.; Grigg, Michael E.; Parkinson, John; Liu, Liang; Kissinger, Jessica C.; Roos, David S.; David Sibley, L

2016-01-01

Toxoplasma gondii is among the most prevalent parasites worldwide, infecting many wild and domestic animals and causing zoonotic infections in humans. T. gondii differs substantially in its broad distribution from closely related parasites that typically have narrow, specialized host ranges. To elucidate the genetic basis for these differences, we compared the genomes of 62 globally distributed T. gondii isolates to several closely related coccidian parasites. Our findings reveal that tandem amplification and diversification of secretory pathogenesis determinants is the primary feature that distinguishes the closely related genomes of these biologically diverse parasites. We further show that the unusual population structure of T. gondii is characterized by clade-specific inheritance of large conserved haploblocks that are significantly enriched in tandemly clustered secretory pathogenesis determinants. The shared inheritance of these conserved haploblocks, which show a different ancestry than the genome as a whole, may thus influence transmission, host range and pathogenicity. PMID:26738725

Invasive mold infections: virulence and pathogenesis of mucorales.

PubMed

Morace, Giulia; Borghi, Elisa

2012-01-01

Mucorales have been increasingly reported as cause of invasive fungal infections in immunocompromised subjects, particularly in patients with haematological malignancies or uncontrolled diabetes mellitus and in those under deferoxamine treatment or undergoing dialysis. The disease often leads to a fatal outcome, but the pathogenesis of the infection is still poorly understood as well as the role of specific virulence determinants and the interaction with the host immune system. Members of the order Mucorales are responsible of almost all cases of invasive mucormycoses, the majority of the etiological agents belonging to the Mucoraceae family. Mucorales are able to produce various proteins and metabolic products toxic to animals and humans, but the pathogenic role of these potential virulence factors is unknown. The availability of free iron in plasma and tissues is believed to be crucial for the pathogenesis of these mycoses. Vascular invasion and neurotropism are considered common pathogenic features of invasive mucormycoses.

Is there a common pathogenesis in aggressive periodontitis & ankylosing spondylitis in HLA-B27 patient?

PubMed

Agrawal, Neeraj; Agarwal, Kavita; Varshney, Atul; Agrawal, Navneet; Dubey, Ashutosh

2016-05-01

HLA-B27 is having strong association to ankylosing spondylitis (AS) and other inflammatory diseases collectively known as seronegative spondyloarthropathy. In literature, although the evidence for association between AS and periodontitis as well as AS and HLA-B27 are there but the association of aggressive periodontitis in HLA-B27 positive patient with AS are not there. We hypothesize that there may be a common pathogenesis in aggressive periodontitis and ankylosing spondylitis in HLA-B27 patient. A 27-years-old female presented with the features of generalized aggressive periodontitis and difficulty in walking. On complete medical examination, ankylosing spondylitis was diagnosed with further positive HLA-B27 phenotype and negative rheumatic factor. This report may open up a new link to explore in the pathogenesis of aggressive periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders?

PubMed

Rego, Eduardo M; Pandolfi, Pier Paolo

2002-08-01

Chromosomal translocations are frequently involved in the pathogenesis of leukemias, lymphomas and sarcomas. They can lead to aberrant expression of oncogenes or the generation of chimeric proteins. Classically, one of the products is thought to be oncogenic. For example, in acute promyelocytic leukaemia (APL), reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene lead to the formation of two fusion genes: X-RARalpha and RARalpha-X (where X is the alternative RARalpha fusion partner: PML, PLZF, NPM, NuMA and STAT 5b). The X-RARalpha fusion protein is indeed oncogenic. However, recent data indicate that the RARalpha-X product is also critical in determining the biological features of this leukemia. Here, we review the current knowledge on the role of reciprocal products in cancer pathogenesis, and highlight how their expression might impact on the biology of their respective tumour types.

Immunoglobulin G4-related acquired hemophilia: A case report

PubMed Central

Li, Xiaoyan; Duan, Wei; Zhu, Xiang; Xu, Jianying

2016-01-01

Acquired hemophilia A (AHA) is a relatively rare and life-threatening bleeding disorder whose pathogenesis is not completely understood. The present study reports a rare case of immunogubulin (IgG)4-related AHA with multisystemic involvement. A 55-year old male patient presented with symptoms of bronchial asthma and multiple subdermal hematomas. Chest computed tomography showed multiple diffuse nodular lesions with thickening of bronchovascular bundles, and scattered high-density spots in both lung lobes. Laboratory investigations showed increased activated partial prothrombin time (120.0 sec), a markedly decreased factor VIII (FVIII) activity (0.5%), a high-titer of FVIII inhibitor (27.2 Bethesda units/ml) and a marked increase in serum IgG4 (>4.03 g/l) level. Left inguinal lymph node biopsy revealed capsular thickening with marked lymphoplasmacytic infiltration, occlusive phlebitis and irregular fibrosis. Immunostaining revealed numerous IgG4-positive plasma cells (>100 cells/human plasma fibronectin) in the nodular lesions, with an IgG4/IgG ratio of >40%. The symptoms were markedly alleviated following corticosteroid therapy. The current study presents the first reported case of a rare IgG4-related AHA that presented with unusual clinical features and multisystemic involvement. The patient responded well to corticosteroid therapy. Documentation of such rare cases will help in characterizing the pathogenesis, and prompt recognition and timely treatment of this rare disorder. PMID:28105131

Disentangling Human Tolerance and Resistance Against HIV

PubMed Central

Regoes, Roland R.; McLaren, Paul J.; Battegay, Manuel; Bernasconi, Enos; Calmy, Alexandra; Günthard, Huldrych F.; Hoffmann, Matthias; Rauch, Andri; Telenti, Amalio; Fellay, Jacques

2014-01-01

In ecology, “disease tolerance” is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis. PMID:25226169

Strain-dependent induction of epithelial cell oncosis by Campylobacter jejuni is correlated with invasion ability and is independent of cytolethal distending toxin.

PubMed

Kalischuk, Lisa D; Inglis, G Douglas; Buret, Andre G

2007-09-01

Induction of host cell death is thought to play an important role in bacterial pathogenesis. Campylobacter jejuni is a prevalent cause of bacterial enteritis; however, its effects on enterocytes remain unclear. The present study indicates for the first time that C. jejuni induces oncotic, rather than apoptotic death of T84 enterocytes. C. jejuni-treated enterocytes exhibited extensive cytoplasmic vacuolation, rapid (3-6 h) loss of plasma membrane integrity ('cytotoxicity'), loss of mitochondrial transmembrane potential, and ATP depletion. Enterocytes also exhibited increased oligonucleosomal DNA fragmentation, a feature characteristic of apoptosis. However, consistent with a non-apoptotic process, DNA fragmentation and cytotoxicity were not caspase dependent. During apoptosis, caspases mediate cleavage of poly(ADP-ribose) polymerase; however, cleavage was not observed in C. jejuni-treated monolayers. Cytotoxicity, ATP depletion and DNA fragmentation were not prevented by the deletion of the cytolethal distending toxin (CDT) gene, indicating that C. jejuni causes enterocyte oncosis via a mechanism that is CDT independent. The ability to cause oncosis was significantly decreased in a FlaAFlaB mutant (CDT(+)) that was defective in the ability to adhere and invade enterocytes. Analysis of clinical isolates revealed that oncosis was strain dependent and correlated with increased invasive ability. These observations offer new insights into the pathogenesis of C. jejuni infection.

Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus).

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Laws, Thomas R; Taylor, Christopher; Smith, Simon A; Salguero, Francisco J; Lever, Mark S

2013-04-01

Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50 , were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals' lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. © 2013 Crown copyright. International Journal of Experimental Pathology © 2013 International Journal of Experimental Pathology.

Molecular markers in pediatric neuro-oncology.

PubMed

Ichimura, Koichi; Nishikawa, Ryo; Matsutani, Masao

2012-09-01

Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment.

Role of Mast Cells in Oral Lichen Planus and Oral Lichenoid Reactions.

PubMed

Ramalingam, Suganya; Malathi, Narasimhan; Thamizhchelvan, Harikrishnan; Sangeetha, Narasimhan; Rajan, Sharada T

2018-01-01

Oral lichen planus (OLP) is a chronic T cell mediated disease of oral mucosa, skin, and its appendages with a prevalence of 0.5 to 2.6% worldwide. Oral lichenoid reactions (OLR) are a group of lesions with diverse aetiologies but have clinical and histological features similar to OLP, thereby posing a great challenge in differentiating both lesions. Mast cells are multifunctional immune cells that play a major role in the pathogenesis of lichen planus by release of certain chemical mediators. Increased mast cell densities with significant percentage of degranulation have been observed as a consistent finding in pathogenesis of oral lichen planus. The current study was aimed at quantifying the mast cells in histopathological sections of OLP and OLR thereby aiding a means of distinguishing these lesions. The study group involved 21 cases of oral lichen planus, 21 cases of oral lichenoid reactions, and 10 control specimens of normal buccal mucosa. All the cases were stained with Toluidine Blue and routine haematoxylin and eosin and the mast cells were quantified. The results were analyzed using the Kruskal-Wallis test and an intergroup analysis was performed using Mann-Whitney U test. The number of mast cells showed an increased value in oral lichen planus when compared to oral lichenoid reaction and thus an estimation of mast cells count could aid in distinguishing OLP from OLR histopathologically.

Differences in subependymal vein anatomy may predispose preterm infants to GMH-IVH.

PubMed

Tortora, Domenico; Severino, Mariasavina; Malova, Mariya; Parodi, Alessandro; Morana, Giovanni; Sedlacik, Jan; Govaert, Paul; Volpe, Joseph J; Rossi, Andrea; Ramenghi, Luca Antonio

2018-01-01

The anatomy of the deep venous system plays an important role in the pathogenesis of brain lesions in the preterm brain as shown by different histological studies. The aims of this study were to compare the subependymal vein anatomy of preterm neonates with germinal matrix haemorrhage-intraventricular haemorrhage (GMH-IVH), as evaluated by susceptibility-weighted imaging (SWI) venography, with a group of age-matched controls with normal brain MRI, and to explore the relationship between the anatomical features of subependymal veins and clinical risk factors for GMH-IVH. SWI venographies of 48 neonates with GMH-IVH and 130 neonates with normal brain MRI were retrospectively evaluated. Subependymal vein anatomy was classified into six different patterns: type 1 represented the classic pattern and types 2-6 were considered anatomic variants. A quantitative analysis of the venous curvature index was performed. Variables were analysed by using Mann-Whitney U and χ 2 tests, and a multiple logistic regression analysis was performed to evaluate the association between anatomical features, clinical factors and GMH-IVH. A significant difference was noticed among the six anatomical patterns according to the presence of GMH-IVH (χ 2 =14.242, p=0.014). Anatomic variants were observed with higher frequency in neonates with GMH-IVH than in controls (62.2% and 49.6%, respectively). Neonates with GMH-IVH presented a narrower curvature of the terminal portion of subependymal veins (p<0.05). These anatomical features were significantly associated with GMH-IVH (p<0.05). Preterm neonates with GMH-IVH show higher variability of subependymal veins anatomy confirming a potential role as predisposing factor for GMH-IVH. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

PubMed

Wilson, Gabrielle R; Sim, Joe C H; McLean, Catriona; Giannandrea, Maila; Galea, Charles A; Riseley, Jessica R; Stephenson, Sarah E M; Fitzpatrick, Elizabeth; Haas, Stefan A; Pope, Kate; Hogan, Kirk J; Gregg, Ronald G; Bromhead, Catherine J; Wargowski, David S; Lawrence, Christopher H; James, Paul A; Churchyard, Andrew; Gao, Yujing; Phelan, Dean G; Gillies, Greta; Salce, Nicholas; Stanford, Lynn; Marsh, Ashley P L; Mignogna, Maria L; Hayflick, Susan J; Leventer, Richard J; Delatycki, Martin B; Mellick, George D; Kalscheuer, Vera M; D'Adamo, Patrizia; Bahlo, Melanie; Amor, David J; Lockhart, Paul J

2014-12-04

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of α-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of α-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Host genetic determinants of HIV pathogenesis: an immunologic perspective.

PubMed

Hunt, Peter W; Carrington, Mary

2008-05-01

The purpose of this review is to highlight recent advances in our understanding of host genetic determinants of HIV pathogenesis and to provide a theoretical framework for interpreting these studies in the context of our evolving understanding of HIV immunopathogenesis. The first genome-wide association analysis of host determinants of HIV pathogenesis and other recent studies evaluating the interaction between killer cell immunoglobulin-like receptors and human leukocyte antigen alleles have implicated both adaptive and innate immune responses in the control of HIV replication. Furthermore, genetic variation associated with the expression of CCR5 and its ligand have been strongly associated with both decreased susceptibility to HIV infection and delayed clinical progression, independent of their effects on viral replication, suggesting a potential role for CCR5 inhibitors as immune-based therapies in HIV disease. Host factors associated with the control of HIV replication may help identify important targets for vaccine design, while those associated with delayed clinical progression provide targets for future immune-based therapies against HIV infection.

Immunological Mechanisms Implicated in the Pathogenesis of Chronic Urticaria and Hashimoto Thyroiditis.

PubMed

Berghi, Nicolae Ovidiu

2017-08-01

Autoimmunity represents the attack of the immune system of an organism against its own cells and tissues. Autoimmune diseases may affect one organ (Hashimoto thyroiditis) or can be systemic (chronic urticaria). Many factors are implicated in the pathogenesis of autoimmunity (white cells, cytokines, chemokines). Hashimoto thyroiditis has been associated with chronic urticaria in the last 3 decades in a number of clinical studies. Anti-thyroid antibodies have been documented in a proportion ranging from 10% to 30% in chronic urticaria patients in different countries from 3 continents. Two of the factors involved in the mechanism of autoimmunity are present both in the pathophysiology of Hashimoto thyroiditis and chronic urticaria. According to recent studies, IL6 is implicated in the pathogenesis of both diseases. TregsCD4+CD25+Foxp3+ cells have also been implicated in the pathological mechanisms of these 2 entities. This review offers an explanation of the clinical and statistical association between these two diseases from the pathophysiological point of view.

Molecular biology, pathogenesis and pathology of mumps virus

PubMed Central

Rubin, Steven; Eckhaus, Michael; Rennick, Linda J; Bamford, Connor GG; Duprex, W Paul

2014-01-01

Mumps is caused by the mumps virus (MuV), a member of the Paramyxoviridae family of enveloped, non-segmented, negative-sense RNA viruses. Mumps is characterized by painful inflammatory symptoms, such as parotitis and orchitis. The virus is highly neurotropic, with laboratory evidence of central nervous system (CNS) infection in approximately half of cases. Symptomatic CNS infection occurs less frequently; nonetheless, prior to the introduction of routine vaccination, MuV was a leading cause of aseptic meningitis and viral encephalitis in many developed countries. Despite being one of the oldest recognized diseases, with a worldwide distribution, surprisingly little attention has been given to its study. Cases of aseptic meningitis associated with some vaccine strains and a global resurgence of cases, including in highly vaccinated populations, has renewed interest in the virus, particularly in its pathogenesis and the need for development of clinically relevant models of disease. In this review we summarize the current state of knowledge on the virus, its pathogenesis and its clinical and pathological outcomes. PMID:25229387

Updates of the role of oxidative stress in the pathogenesis of ovarian cancer.

PubMed

Saed, Ghassan M; Diamond, Michael P; Fletcher, Nicole M

2017-06-01

Clinical and epidemiological investigations have provided evidence supporting the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS), collectively known as oxidative stress, in the etiology of cancer. Exogenous factors such as chronic inflammation, infection and hypoxia are major sources of cellular oxidative stress. Specifically, oxidative stress plays an important role in the pathogenesis, neoangiogenesis, and dissemination of local or distant ovarian cancer, as it is known to induce phenotypic modifications of tumor cells by cross talk between tumor cells and the surrounding stroma. Subsequently, the biological significance of the relationship between oxidative stress markers and various stages of epithelial ovarian cancer highlights potential therapeutic interventions as well as provides urgently needed early detection biomarkers. In the light of our scientific research and the most recent experimental and clinical observations, this review provides the reader with up to date most relevant findings on the role of oxidative stress in the pathogenesis of ovarian cancer and the possible therapeutic implications. Copyright © 2017 Elsevier Inc. All rights reserved.

[Research progress of needles with knife-edge for carotid cardiac syndrome].

PubMed

Tan, Lingqiong; Zhao, Yanling

2015-04-01

According to topographic anatomy, pathogenesis and by retrieving, summarizing and analyzing literature regarding needle-knife and needles with knife-edge for carotid cardiac syndrome, it is found out that clinical misdiagnosis rate of carotid cardiac syndrome is considerably high. Needle-knife and needles with knife-edge could significantly improve the clinical symptoms of carotid cardiac syndrome, showing characteristic and advantage in treatment, but it is deficient in technique standard and efficacy criteria that should be united and authoritative. Researches regarding pathogenesis of carotid cardiac syndrome are not systematic. Clinical observation regarding long-term efficacy and relapse of needle-knife and needles with knife-edge treatment is rare. It is believed that the awareness on carotid cardiac syndrome should be increased to reduce misdiagnosis; scientific and standardized technique standard and efficacy criteria should be established; systematic and comprehensive researches regarding mechanism of needle-knife and needles with knife-edge for carotid cardiac syndrome should be launched; besides, clinical discussion regarding its long-term efficacy should start to provide a better clinical guideline.

Integrative Data Analysis of Multi-Platform Cancer Data with a Multimodal Deep Learning Approach.

PubMed

Liang, Muxuan; Li, Zhizhong; Chen, Ting; Zeng, Jianyang

2015-01-01

Identification of cancer subtypes plays an important role in revealing useful insights into disease pathogenesis and advancing personalized therapy. The recent development of high-throughput sequencing technologies has enabled the rapid collection of multi-platform genomic data (e.g., gene expression, miRNA expression, and DNA methylation) for the same set of tumor samples. Although numerous integrative clustering approaches have been developed to analyze cancer data, few of them are particularly designed to exploit both deep intrinsic statistical properties of each input modality and complex cross-modality correlations among multi-platform input data. In this paper, we propose a new machine learning model, called multimodal deep belief network (DBN), to cluster cancer patients from multi-platform observation data. In our integrative clustering framework, relationships among inherent features of each single modality are first encoded into multiple layers of hidden variables, and then a joint latent model is employed to fuse common features derived from multiple input modalities. A practical learning algorithm, called contrastive divergence (CD), is applied to infer the parameters of our multimodal DBN model in an unsupervised manner. Tests on two available cancer datasets show that our integrative data analysis approach can effectively extract a unified representation of latent features to capture both intra- and cross-modality correlations, and identify meaningful disease subtypes from multi-platform cancer data. In addition, our approach can identify key genes and miRNAs that may play distinct roles in the pathogenesis of different cancer subtypes. Among those key miRNAs, we found that the expression level of miR-29a is highly correlated with survival time in ovarian cancer patients. These results indicate that our multimodal DBN based data analysis approach may have practical applications in cancer pathogenesis studies and provide useful guidelines for personalized cancer therapy.

Rationale for Developing a Specimen Bank to Study the Pathogenesis of High-Grade Serous Carcinoma: A Review of the Evidence.

PubMed

Sherman, Mark E; Drapkin, Ronny I; Horowitz, Neil S; Crum, Christopher P; Friedman, Sue; Kwon, Janice S; Levine, Douglas A; Shih, Ie-Ming; Shoupe, Donna; Swisher, Elizabeth M; Walker, Joan; Trabert, Britton; Greene, Mark H; Samimi, Goli; Temkin, Sarah M; Minasian, Lori M

2016-09-01

Women with clinically detected high-grade serous carcinomas (HGSC) generally present with advanced-stage disease, which portends a poor prognosis, despite extensive surgery and intensive chemotherapy. Historically, HGSCs were presumed to arise from the ovarian surface epithelium (OSE), but the inability to identify early-stage HGSCs and their putative precursors in the ovary dimmed prospects for advancing our knowledge of the pathogenesis of these tumors and translating these findings into effective prevention strategies. Over the last decade, increased BRCA1/2 mutation testing coupled with performance of risk-reducing surgeries has enabled studies that have provided strong evidence that many, but probably not all, HGSCs among BRCA1/2 mutation carriers appear to arise from the fallopian tubes, rather than from the ovaries. This shift in our understanding of the pathogenesis of HGSCs provides an important opportunity to achieve practice changing advances; however, the scarcity of clinically annotated tissues containing early lesions, particularly among women at average risk, poses challenges to progress. Accordingly, we review studies that have kindled our evolving understanding of the pathogenesis of HGSC and present the rationale for developing an epidemiologically annotated national specimen resource to support this research. Cancer Prev Res; 9(9); 713-20. ©2016 AACR. ©2016 American Association for Cancer Research.

Ocular Adverse Events Associated with Antibody–Drug Conjugates in Human Clinical Trials

PubMed Central

Miller, Paul E.; Mannis, Mark J.

2015-01-01

Abstract This article reviews ocular adverse events (AEs) reported in association with administration of antibody–drug conjugates (ADCs) in human clinical trials. References reporting ocular toxicity or AEs associated with ADCs were collected using online publication searches. Articles, abstracts, or citations were included if they cited ocular toxicities or vision-impairing AEs with a confirmed or suspected association with ADC administration. Twenty-two references were found citing ocular or vision-impairing AEs in association with ADC administration. All references reported use of ADCs in human clinical trials for treatment of various malignancies. The molecular target and cytotoxic agent varied depending on the ADC used. Ocular AEs affected a diversity of ocular tissues. The most commonly reported AEs involved the ocular surface and included blurred vision, dry eye, and corneal abnormalities (including microcystic corneal disease). Most ocular AEs were not severe (≤ grade 2) or dose limiting. Clinical outcomes were not consistently reported, but when specified, most AEs improved or resolved with cessation of treatment or with ameliorative therapy. A diverse range of ocular AEs are reported in association with administration of ADCs for the treatment of cancer. The toxicologic mechanism(s) and pathogenesis of such events are not well understood, but most are mild in severity and reversible. Drug development and medical professionals should be aware of the clinical features of these events to facilitate early recognition and intervention in the assessment of preclinical development programs and in human clinical trials. PMID:26539624

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis.

PubMed

Lupia, Enrico; Pigozzi, Luca; Goffi, Alberto; Hirsch, Emilio; Montrucchio, Giuseppe

2014-11-07

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis

PubMed Central

Lupia, Enrico; Pigozzi, Luca; Goffi, Alberto; Hirsch, Emilio; Montrucchio, Giuseppe

2014-01-01

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis. PMID:25386068

Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages

PubMed Central

Neth, Bryan J.; Craft, Suzanne

2017-01-01

Metabolic dysfunction is a well-established feature of Alzheimer’s disease (AD), evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets. PMID:29163128

Inflammation and Epstein-Barr Virus Infection Are Common Features of Myasthenia Gravis Thymus: Possible Roles in Pathogenesis

PubMed Central

Cavalcante, Paola; Maggi, Lorenzo; Colleoni, Lara; Caldara, Rosa; Motta, Teresio; Giardina, Carmelo; Antozzi, Carlo; Berrih-Aknin, Sonia; Bernasconi, Pia; Mantegazza, Renato

2011-01-01

The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus. PMID:21961056

General introduction to the psychotherapy of Pierre Janet.

PubMed

Bühler, K E; Heim, G

2001-01-01

This article deals with Pierre Janet's concept of "Psychological Analysis" (analyse psychologique). It brings out Janet's criticism of Sigmund Freud's ideas, and delineates the difference between psychological analysis (Janet) and psychoanalysis (Freud). Further it points out that Janet's theories on the pathogenesis of neurotic disorders rely on the concept of psychic trauma and associated fixed ideas. Mental force and mental tension, described in greater detail, are essential for the pathogenesis of mental disorders. According to Janet, a significant characteristic of the neurotically disturbed person is a feature that Von Gebsattel calls "Werdenshemmung" ("inhibition of becoming"), a state which impairs the life development of the ill person.

Gorlin-Goltz syndrome.

PubMed

Joshi, Priya Shirish; Deshmukh, Vijay; Golgire, Someshwar

2012-01-01

Gorlin-Goltz syndrome is an uncommon autosomal dominant inherited disorder, which is characterized by multiple odontogenic Keratocysts and basal cell carcinomas, skeletal, dental, ophthalmic, and neurological abnormalities, intracranial ectopic calcifications of the falx cerebri, and facial dysmorphism. Pathogenesis of the syndrome is attributed to abnormalities in the long arm of chromosome 9 (q22.3-q31) and loss or mutations of human patched gene (PTCH1 gene). Diagnosis is based upon established major and minor clinical and radiological criteria and ideally confirmed by deoxyribo nucleic acid analysis. We report a case of a 9-year-old girl presenting with three major and one minor feature of Gorlin-Goltz syndrome. Radiologic findings of the syndrome are easily identifiable on Orthopantomogram, chest X-ray, and Computed tomography scans. These investigations prompt an early verification of the disease, which is very important to prevent recurrence and better survival rates from the coexistent diseases.

Gorlin-Goltz syndrome

PubMed Central

Joshi, Priya Shirish; Deshmukh, Vijay; Golgire, Someshwar

2012-01-01

Gorlin-Goltz syndrome is an uncommon autosomal dominant inherited disorder, which is characterized by multiple odontogenic Keratocysts and basal cell carcinomas, skeletal, dental, ophthalmic, and neurological abnormalities, intracranial ectopic calcifications of the falx cerebri, and facial dysmorphism. Pathogenesis of the syndrome is attributed to abnormalities in the long arm of chromosome 9 (q22.3-q31) and loss or mutations of human patched gene (PTCH1 gene). Diagnosis is based upon established major and minor clinical and radiological criteria and ideally confirmed by deoxyribo nucleic acid analysis. We report a case of a 9-year-old girl presenting with three major and one minor feature of Gorlin-Goltz syndrome. Radiologic findings of the syndrome are easily identifiable on Orthopantomogram, chest X-ray, and Computed tomography scans. These investigations prompt an early verification of the disease, which is very important to prevent recurrence and better survival rates from the coexistent diseases. PMID:22363371

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever

PubMed Central

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J.; Scott, Dana P.; Feldmann, Heinz; Ebihara, Hideki

2016-01-01

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. PMID:27976688

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever.

PubMed

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki

2016-12-15

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF.

Resolution of radiation-induced acneform eruption following treatment with tretinoin and minocycline: a case report.

PubMed

Parr, Karina; Mahmoudizad, Rod; Grimwood, Ronald

2013-07-01

Postradiation comedogenesis is an uncommon side effect of radiation therapy, with few cases reported in the medical literature. The proposed etiology of this reaction is alteration of pilosebaceous unit secretions and retention of proliferating ductal keratinocytes due to stricture and scarring. We report a case of a 48-year-old woman who had been treated for infiltrating ductal carcinoma of the right breast with lumpectomy and radiation therapy. She subsequently developed open and closed comedones as well as tender inflammatory papules and papulopustules in the irradiated area. Our patient was treated with tretinoin cream and oral minocycline, with rapid improvement in symptoms and complete resolution of lesions after 2 months of therapy. We review the literature on the pathogenesis, clinical features, and treatment of postradiation acne, and discuss rapid resolution of a radiation-induced acneform eruption after combination treatment with tretinoin and minocycline.

Advances in mechanisms of asthma, allergy, and immunology in 2010.

PubMed

Broide, David H; Finkelman, Fred; Bochner, Bruce S; Rothenberg, Marc E

2011-03-01

2010 was marked by rapid progress in our understanding of the cellular and molecular mechanisms involved in the pathogenesis of allergic inflammation and asthma. Studies published in the Journal of Allergy and Clinical Immunology described advances in our knowledge of cells associated with allergic inflammation (mast cells, eosinophils, dendritic cells, and T cells), as well as IgE, cytokines, receptors, signaling molecules, and pathways. Studies used animal models, as well as human cells and tissues, to advance our understanding of mechanisms of asthma, eosinophilic esophagitis, food allergy, anaphylaxis and immediate hypersensitivity, mast cells and their disorders, atopic dermatitis, nasal polyposis, and hypereosinophilic syndromes. Additional studies provided novel information about the induction and regulation of allergic inflammation and the genetic contribution to allergic inflammation. Critical features of these studies and their potential effects on human atopic disorders are summarized here. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

[MCTD--mixed connective tissue disease].

PubMed

Haustein, Uwe-Frithjof

2005-02-01

Mixed connective tissue disease is a disease entity characterized by overlapping symptoms of lupus erythematosus (LE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA). Diagnostic criteria include high titers of antibodies against U1RNP as well as the presence of at least 3 of 5 of the following clinical features: edema of hands, synovitis, myositis, Raynaud phenomenon and acroscierosis. In terms of the pathogenesis, genetic as well as infectious (viral) factors appear to play a role. The acceptance of MCTD as a distinct disease entity is controversial. Terms such as "undifferentiated connective tissue disease" or "overlapping syndromes" are not helpful. One-quarter of MCTD patients transform into LE, while one-third progress to SSc. Therapeutic recommendations are glucocorticoids in combination with immunosuppressive agents and endothelin receptor antagonists. Double blind studies are not available. The prognosis is relatively good. Causes of death include pulmonary hypertension, infections and both pulmonary and cardiac failure.

[Lobular idiopathic granulomatos mastitis. About 10 cases].

PubMed

Hmissa, Sihem; Sahraoui, Wassila; Missaoui, Nabiha; Stita, Wided; Mokni, Moncef; Yacoubi, Mohamed T; Khairi, Hedi; Korbi, Sadok

2006-06-01

Our retrospective study was performed on 10 cases of granulomatous mastitis registered in Obstetric Gynaecology Department and Pathology Department of CHU F. Hached, Sousse, during 8 years period. The mean age was 36.4 years (range 32-59). Among these 10 cases. 8 were observed in reproductive-age women and 2 were noted in menopausal women. Clinical findings showed unilateral breast nodule associated with inflammatory signs in 4 cases, mammelonary retraction in 2 cases and serous or sero-purulent mamelonnary flow in 4 cases. Mamnmographic examination suggested a malignant tumor in 5 patients. In all cases, the diagnosis is made by histopathology. Surgical treatment consisted in wide excision with drainage or radical mastectomy, eventually with combination with antibiotic therapy and non steroid anti-inflammatory drugs. Prognostic features showed a good cicatrization in 4 cases, local recurrence and cutaneous fistulization in one patient. Granulomatous mastitis aetiology is still unclear, auto-immune aetio-pathogenesis appears more interesting and should be clarified.

Evidence from animal models on the pathogenesis of PCOS.

PubMed

Walters, K A; Bertoldo, M J; Handelsman, D J

2018-06-01

Polycystic ovarian syndrome (PCOS) is the most common endocrine condition in women, and is characterized by reproductive, endocrine and metabolic features. However, there is no simple unequivocal diagnostic test for PCOS, its etiology remains unknown and there is no cure. Hence, the management of PCOS is suboptimal as it relies on the ad hoc empirical management of its symptoms only. Decisive studies are required to unravel the origins of PCOS, but due to ethical and logistical reasons these are not possible in humans. Experimental animal models for PCOS have been established which have enhanced our understanding of the mechanisms underlying PCOS and propose novel mechanism-based therapies to treat the condition. This review examines the findings from various animal models to reveal the current knowledge of the mechanisms underpinning the development of PCOS, and also provides insights into the implications from these studies for improved clinical management of this disorder. Copyright © 2018 Elsevier Ltd. All rights reserved.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association.

PubMed

Feingold, Brian; Mahle, William T; Auerbach, Scott; Clemens, Paula; Domenighetti, Andrea A; Jefferies, John L; Judge, Daniel P; Lal, Ashwin K; Markham, Larry W; Parks, W James; Tsuda, Takeshi; Wang, Paul J; Yoo, Shi-Joon

2017-09-26

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. © 2017 American Heart Association, Inc.

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome).

PubMed

Bresler, Scott C; Padwa, Bonnie L; Granter, Scott R

2016-06-01

Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy.

Aspirin-exacerbated respiratory disease: Prevalence, diagnosis, treatment, and considerations for the future.

PubMed

Kennedy, Joshua L; Stoner, Ashley N; Borish, Larry

2016-11-01

Aspirin-exacerbated respiratory disease (AERD) is a late onset condition characterized by the Samter triad (aspirin sensitivity [as well as sensitivity to any nonselective cyclooxygenase inhibitor], nasal polyps, asthma) and additional features, including eosinophilic chronic rhinosinusitis, hypereosinophilia, anosmia, frequent absence of atopy, and, intolerance to ingestion of red wine and other alcoholic beverages. The diagnosis is rare, and, because of this, it is also often missed by physicians. However, it is highly overexpressed in patients with severe asthma (and severe chronic rhinosinusitis with nasal polyps), which makes its recognition essential. For this review, we considered mechanisms involved in the pathogenesis of this disease and discussed the clinical symptoms of AERD. We also discussed the role of aspirin desensitization in the treatment of AERD. Also, we considered medications (e.g, leukotriene modifiers) and surgical interventions that have a role in the treatment of AERD.

Merkel cell carcinoma: Do you know your guidelines?

PubMed

Miles, Brett A; Goldenberg, David

2016-05-01

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy that exhibits clinically aggressive features and is associated with a poor prognosis. The incidence of MCC seems to be increasing for reasons unknown, and is estimated to be 0.32/100,000 in the United States. This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of MCC. Resection of MCC with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. High-risk patients should undergo adjuvant radiotherapy, which improves oncologic outcomes. The role of chemotherapy is less clear and is currently reserved for advanced-stage MCC and palliative therapy. The pathogenesis of MCC has recently been impacted with the discovery of the Merkel cell polyomavirus (MCPyV). Research to establish targeted and immunologic therapeutic options are ongoing. © 2015 Wiley Periodicals, Inc.

Metaphyseal chondrodysplasia.

PubMed Central

Spranger, J. W.

1977-01-01

Any review of the metaphyseal chondrodysplasias is complicated by their variety and mainly unknown pathogenesis. The more familiar types display considerable clinical and radiological diversity: even more so the rarer disorders which still require complete definition, but differences in their mode of inheritance make diagnostic precision mandatory. These dysplasias present in infancy or in childhood, when the patient, usually dwarfed, may be proportionate, so that some forms may be confused with rickets or other lesions. Mental retardation is unusual, but the skin, hair, nails and facies provide valuable diagnostic features. Radiological abnormalities mainly affect the metaphyses of the shortened limb bones, less often the skull, vertebrae, pelvis, ribs and extremities, and sometimes their distribution may indicate the specific type of dysplasia. In a further complex group multiple systems are involved, notably the pancreas, intestine and lympho-reticular, causing malabsorption and haematological or immunological disorders. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:335375

Thyroid disease and the nervous system.

PubMed

Wood-Allum, Clare A; Shaw, Pamela J

2014-01-01

Thyroid disorders are common in the general population and in hospitalized patients. Thyroid disease may present first with neurological complications or else may occur concurrently in patients suffering other neurological disorders, particularly those with an autoimmune etiology. For this reason neurologists will commonly encounter patients with thyroid disease. This chapter provides an overview of the neurological complications and associations of disorders of the thyroid gland. Particular emphasis is placed on conditions such as thyrotoxic periodic paralysis and myxedema coma in which the underlying thyroid disorder may be occult leading to a first, often emergency, presentation to a neurologist. Information about clinical features, diagnosis, pathogenesis, therapy, and prognosis is provided. Emphasis is placed on those aspects most likely to be relevant to the practicing neurologist and the interested reader is directed to references to good, recent review articles for further information. © 2014 Elsevier B.V. All rights reserved.

A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis.

PubMed

van Hal, T W; van Bon, L; Radstake, T R D J

2011-01-01

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations and immunological disturbances and fibrosis, the order of which remains to be fully determined. Clinically, patients show clear signs of hypoxia in skin and internal organs. The low oxygen tension is potentially caused by a yet to be indentified circuitry involving the three features that typify SSc. In addition, once present, the hypoxia creates a vicious circle of ongoing pathology. In this paper, we provide an overview of the evidence that points towards the mechanisms causing hypoxia in SSc. In addition, data that suggest how hypoxia itself may orchestrate worsening of symptoms is presented. Altogether, it is clear that hypoxia is an important hallmark in SSc patients. By providing an overview of the mechanisms at play and the possible therapeutic avenues that have emerged, we hope to stimulate researchers to provide novel clues into the conundrum in SSc patients.

Analysis of the treatment of 576 patients with congenital craniovertebral junction malformations.

PubMed

Li, Lianfeng; Yu, Xinguang; Wang, Peng; Chen, Lifeng

2012-01-01

We aim to report our experience treating craniovertebral junction malformations (CVJM) and to investigate the management of this uncommon condition. Between 2000 and 2009, 629 patients with CVJM underwent surgery in our department. Fifty-three patients were lost to follow-up; therefore 576 patients completed follow-up, for an average period of 3 years and 2 months. All patients were diagnosed on the basis of clinical presentation and imaging features, and we found that anomalies of the occipitocervical junction manifested as four major types. Different microsurgical treatments were carried out in these patients according to disease type, and the effectiveness of individualised treatments was analysed. Categorizing patients with CVJM into these four types to simplify this somewhat unclear area could provide insight into the pathogenesis of the anomaly and a basis for rational surgical treatment. Copyright © 2011. Published by Elsevier Ltd.

Diagnosis and management of severe respiratory acidosis: a 65-year-old man with a double-lung transplant and shortness of breath.

PubMed

Adrogué, Horacio J

2010-11-01

Respiratory acidosis is characterized by a primary increase in whole-body carbon dioxide stores caused by a positive carbon dioxide balance. This acid-base disorder, if severe, may be life-threatening, therefore requiring prompt recognition and expert management. The case presented highlights the essential features of the diagnosis and management of respiratory acidosis. A brief description of the modifiers of carbon dioxide production, the pathogenesis of respiratory acidosis, and an algorithm for assessment and management of this disorder is included. Key teaching points include the clinical value of both arterial and venous blood gas analyses and the importance of proper recognition of a primary respiratory arrest in contrast to primary circulatory arrest when managing a patient who requires resuscitation from "cardiorespiratory arrest." Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

T cell-B cell interactions in primary immunodeficiencies.

PubMed

Tangye, Stuart G; Deenick, Elissa K; Palendira, Umaimainthan; Ma, Cindy S

2012-02-01

Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected individuals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes. © 2012 New York Academy of Sciences.

Aspirin-exacerbated respiratory disease: Prevalence, diagnosis, treatment, and considerations for the future

PubMed Central

Stoner, Ashley N.; Borish, Larry

2016-01-01

Aspirin-exacerbated respiratory disease (AERD) is a late onset condition characterized by the Samter triad (aspirin sensitivity [as well as sensitivity to any nonselective cyclooxygenase inhibitor], nasal polyps, asthma) and additional features, including eosinophilic chronic rhinosinusitis, hypereosinophilia, anosmia, frequent absence of atopy, and, intolerance to ingestion of red wine and other alcoholic beverages. The diagnosis is rare, and, because of this, it is also often missed by physicians. However, it is highly overexpressed in patients with severe asthma (and severe chronic rhinosinusitis with nasal polyps), which makes its recognition essential. For this review, we considered mechanisms involved in the pathogenesis of this disease and discussed the clinical symptoms of AERD. We also discussed the role of aspirin desensitization in the treatment of AERD. Also, we considered medications (e.g, leukotriene modifiers) and surgical interventions that have a role in the treatment of AERD. PMID:28124651

A hybrid computational approach for efficient Alzheimer's disease classification based on heterogeneous data.

PubMed

Ding, Xuemei; Bucholc, Magda; Wang, Haiying; Glass, David H; Wang, Hui; Clarke, Dave H; Bjourson, Anthony John; Dowey, Le Roy C; O'Kane, Maurice; Prasad, Girijesh; Maguire, Liam; Wong-Lin, KongFatt

2018-06-27

There is currently a lack of an efficient, objective and systemic approach towards the classification of Alzheimer's disease (AD), due to its complex etiology and pathogenesis. As AD is inherently dynamic, it is also not clear how the relationships among AD indicators vary over time. To address these issues, we propose a hybrid computational approach for AD classification and evaluate it on the heterogeneous longitudinal AIBL dataset. Specifically, using clinical dementia rating as an index of AD severity, the most important indicators (mini-mental state examination, logical memory recall, grey matter and cerebrospinal volumes from MRI and active voxels from PiB-PET brain scans, ApoE, and age) can be automatically identified from parallel data mining algorithms. In this work, Bayesian network modelling across different time points is used to identify and visualize time-varying relationships among the significant features, and importantly, in an efficient way using only coarse-grained data. Crucially, our approach suggests key data features and their appropriate combinations that are relevant for AD severity classification with high accuracy. Overall, our study provides insights into AD developments and demonstrates the potential of our approach in supporting efficient AD diagnosis.

Serrated Colon Polyps as Precursors to Colorectal Cancer

PubMed Central

Sweetser, Seth; Smyrk, Thomas C.; Sinicrope, Frank A.

2013-01-01

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights have included an increased recognition of the malignant potential of different types of serrated polyps, such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors, such as microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. There is evidence that the serrated pathway contributes to interval or missed cancers. These data have important implications for clinical practice and CRC prevention, since hyperplastic polyps were previously regarded as having no malignant potential. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins, and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps, which would facilitate their detection and removal, to ensure a high-quality colonoscopy examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in post-polypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. PMID:23267866

TFG-MET fusion in an infantile spindle cell sarcoma with neural features.

PubMed

Flucke, Uta; van Noesel, Max M; Wijnen, Marc; Zhang, Lei; Chen, Chun-Liang; Sung, Yun-Shao; Antonescu, Cristina R

2017-09-01

An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here, we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials. © 2017 Wiley Periodicals, Inc.

Inflammatory bowel disease and thromboembolism

PubMed Central

Zezos, Petros; Kouklakis, Georgios; Saibil, Fred

2014-01-01

Patients with inflammatory bowel disease (IBD) have an increased risk of vascular complications. Thromboembolic complications, both venous and arterial, are serious extraintestinal manifestations complicating the course of IBD and can lead to significant morbidity and mortality. Patients with IBD are more prone to thromboembolic complications and IBD per se is a risk factor for thromboembolic disease. Data suggest that thrombosis is a specific feature of IBD that can be involved in both the occurrence of thromboembolic events and the pathogenesis of the disease. The exact etiology for this special association between IBD and thromboembolism is as yet unknown, but it is thought that multiple acquired and inherited factors are interacting and producing the increased tendency for thrombosis in the local intestinal microvasculature, as well as in the systemic circulation. Clinicians’ awareness of the risks, and their ability to promptly diagnose and manage tromboembolic complications are of vital importance. In this review we discuss how thromboembolic disease is related to IBD, specifically focusing on: (1) the epidemiology and clinical features of thromboembolic complications in IBD; (2) the pathophysiology of thrombosis in IBD; and (3) strategies for the prevention and management of thromboembolic complications in IBD patients. PMID:25320522

Screening for genetic causes of growth hormone hypersecretion.

PubMed

Rostomyan, Liliya; Beckers, Albert

Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage. In addition to mutations or deletions, copy number variation at the GPR101 locus may also lead to mixed GH and prolactin secreting pituitary adenomas in the setting of X-linked acrogigantism (X-LAG syndrome). In X-LAG syndrome and in McCune Albright syndrome, mosaicism for GPR101 duplications and activating GNAS1 mutations, respectively, contribute to the genetic pathogenesis. As only 5% of pituitary adenomas have a known cause, efficient deployment of genetic testing requires detailed knowledge of clinical characteristics and potential associated syndromic features in the patient and their family. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

PubMed

Jellinger, Kurt A

2012-05-01

Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general. © 2011 The Author Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Membranoproliferative glomerulonephritis associated with autoimmune diseases.

PubMed

Zand, Ladan; Fervenza, Fernando C; Nasr, Samih H; Sethi, Sanjeev

2014-04-01

Membranoproliferative glomerulonephritis (MPGN) has been classified based on its pathogenesis into immune complex-mediated and complement-mediated MPGN. The immune complex-mediated type is secondary to chronic infections, autoimmune diseases or monoclonal gammopathy. There is a paucity of data on MPGN associated with autoimmune diseases. We reviewed the Mayo Clinic database over a 10-year period and identified 12 patients with MPGN associated with autoimmune diseases, after exclusion of systemic lupus erythematosus. The autoimmune diseases included rheumatoid arthritis, primary Sjögren's syndrome, undifferentiated connective tissue disease, primary sclerosing cholangitis and Graves' disease. Nine of the 12 patients were female, and the mean age was 57.9 years. C4 levels were decreased in nine of 12 patients tested. The serum creatinine at time of renal biopsy was 2.2 ± 1.0 mg/dl and the urinary protein was 2,850 ± 3,543 mg/24 h. Three patients required dialysis at the time of renal biopsy. Renal biopsy showed an MPGN in all cases, with features of cryoglobulins in six cases; immunoglobulin (Ig)M was the dominant Ig, and both subendothelial and mesangial electron dense deposits were noted. Median follow-up was 10.9 months. Serum creatinine and proteinuria improved to 1.6 ± 0.8 mg/dl and 428 ± 677 mg/24 h, respectively, except in 3 patients with end-stage renal disease. In summary, this study describes the clinical features, renal biopsy findings, laboratory evaluation, treatment and prognosis of MPGN associated with autoimmune diseases.

Follicular contact dermatitis revisited: A review emphasizing neomycin-associated follicular contact dermatitis

PubMed Central

Cohen, Philip R

2014-01-01

Follicular contact dermatitis clinically presents as individual papules that include a central hair follicle. Pathologic features involve the follicle and the surrounding dermis: spongiosis and vesicle formation of the follicular epithelium associated with perifollicular and perivascular lymphocytic inflammation. Using the PubMed database, an extensive literature search was performed on follicular contact dermatitis and neomycin. Relevant papers were reviewed and the clinical and pathologic features, the associated chemicals (including a more detailed description of neomycin), the hypothesized pathogenesis, and the management of follicular contact dermatitis were described. Several agents-either as allergens or irritants-have been reported to elicit follicular contact dermatitis. Several hypotheses have been suggested for the selective involvement of the follicles in follicular contact dermatitis: patient allergenicity, characteristics of the agent, vehicle containing the agent, application of the agent, and external factors. The differential diagnosis of follicular contact dermatitis includes not only recurrent infundibulofolliculitis, but also drug eruption, mite infestation, viral infection, and dermatoses that affect hair follicles. The primary therapeutic intervention for follicular contact dermatitis is withdrawal of the causative agent; treatment with a topical corticosteroid preparation may also promote resolution of the dermatitis. In conclusion, follicular contact dermatitis may be secondary to allergens or irritants; topical antibiotics, including neomycin, may cause this condition. Several factors may account for the selective involvement of the hair follicle in this condition. Treatment of the dermatitis requires withdrawal of the associated topical agent; in addition, topical corticosteroids may be helpful to promote resolution of lesions. PMID:25516854

Sepsis-induced acute kidney injury in patients with cirrhosis.

PubMed

Angeli, Paolo; Tonon, Marta; Pilutti, Chiara; Morando, Filippo; Piano, Salvatore

2016-01-01

Acute kidney injury (AKI) is a common and life-threatening complication in patients with cirrhosis. Recently, new criteria for the diagnosis of AKI have been proposed in patients with cirrhosis by the International Club of Ascites. Almost all types of bacterial infections can induce AKI in patients with cirrhosis representing its most common precipitating event. The bacterial infection-induced AKI usually meets the diagnostic criteria of hepatorenal syndrome (HRS). Well in keeping with the "splanchnic arterial vasodilation hypothesis", it has been stated that HRS develops as a consequence of a severe reduction of effective circulating volume related to splanchnic arterial vasodilation and to an inadequate cardiac output. Nevertheless, the role of bacterial infections in precipitating organ failures, including renal failure, is enhanced when their course is characterized by the development of a systemic inflammatory response syndrome (SIRS), thus, when sepsis occurs. Sepsis has been shown to be capable to induce "per se" AKI in animals as well as in patients conditioning also the features of renal damage. This observation suggests that when precipitated by sepsis, the pathogenesis and the clinical course of AKI also in patients with cirrhosis may differentiate to a certain extent from AKI with another or no precipitating factor. The purpose of this review is to describe the features of AKI precipitated by bacterial infections and to highlight whether infection and/or the development of SIRS may influence its clinical course, and, in particular, the response to treatment.

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects.

PubMed

Verdelli, C; Corbetta, S

2017-01-01

Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow-up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed. © 2017 European Society of Endocrinology.

Reticular telangiectatic erythema: case report and literature review.

PubMed

Beutler, Bryce D; Cohen, Philip R

2015-01-01

Reticular telangiectatic erythema is a benign cutaneous reaction that may occur in patients who have received a subcutaneous implantable cardioverter-defibrillator. Reticular telangiectatic erythema is characterized by asymptomatic telangiectasias, blanchable erythematous patches, or both overlying and/or adjacent to the subcutaneous implantable cardioverter-defibrillator. We describe a man who developed reticular telangiectatic erythema after receiving a subcutaneous implantable cardioverter-defibrillator and review the salient features of this condition. We also summarize the conditions that can mimic reticular telangiectatic erythema. The features of a man with reticular telangiectatic erythema are presented and the literature on reticular telangiectatic erythema is reviewed. Our patient developed reticular telangiectatic erythema within one month of subcutaneous implantable cardioverter-defibrillator insertion. The subcutaneous manifestations were asymptomatic. The patient concurred to have periodic clinical follow up and his condition will be monitored for any changes. Reticular telangiectatic erythema is a benign condition characterized by the development of erythema, telangiectasia, or both following insertion of a subcutaneous implantable cardioverter-defibrillator. Other subcutaneous implantable cardioverter-defibrillator-related side effects, such as pressure dermatitis and contact dermatitis, can mimic the condition. Reticular telangiectatic erythema can also be observed following insertion of other devices or, rarely, in the absence of inserted devices. Local microcirculatory changes and subcutaneous implantable cardioverter-defibrillator-related obstruction of blood flow have been suggested as possible mechanisms of pathogenesis. The diagnosis can usually be established by clinical presentation. Therefore, patch testing can usually be omitted. Reticular telangiectatic erythema is typically asymptomatic and thus removal of the device is not required.

Current perspectives on the epidemiology and pathogenesis of clinically significant Vibrio spp.

PubMed Central

Janda, J M; Powers, C; Bryant, R G; Abbott, S L

1988-01-01

Recent taxonomic advances have now implicated several different Vibrio species as human pathogens. While the most common clinical presentation of Vibrio infection continues to be gastroenteritis, an increasing number of extraintestinal infections are being reported, particularly in immunocompromised individuals. Detection of Vibrio infections requires a good clinical history and the use of appropriate isolation and identification procedures by the laboratory to confirm illnesses attributed to Vibrio species. Except for Vibrio cholerae O1 and Vibrio parahaemolyticus, there is little direct evidence linking the production of a myriad of cell-associated or extracellular factors produced by each species with human disease and pathogenesis. Many questions regarding pathogenic Vibrio species remain unanswered, including their frequency and distribution in environmental specimens (water, shellfish), infective doses, virulence potential of individual isolates, and markers associated with such strains. Images PMID:3058295

Humoral Epitope Spreading in Autoimmune Bullous Diseases

PubMed Central

Didona, Dario; Di Zenzo, Giovanni

2018-01-01

Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches. PMID:29719538

New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities.

PubMed

Abou Zahr, Abdallah; Bernabe Ramirez, Carolina; Wozney, Jocelyn; Prebet, Thomas; Zeidan, Amer M

2016-01-01

Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS. Further understanding of abnormal signal transduction and aberrant apoptosis pathways has led to development of new rational therapies that are in advanced phases of clinical translation. This review seeks to describe recent developments in our understanding of the pathogenesis of MDS and the potential therapeutic implications of these observations.

Pathogenesis of Rift Valley Fever in Rhesus Monkeys: Role of Interferon Response

DTIC Science & Technology

1990-01-01

hemorrhagic fever characterized by epistaxis, petechial to purpuric cutaneous lesions, anorexia, and vomiting prior to death. The 14 remaining monkeys survived...DMI, FILE Copy Arch Virol (1990) 110: 195-212 Amhivesirology ( by Springer-Verlag 1990 00 N Pathogenesis of Rift Valley fever in rhesus monkeys: (NI...inoculated intravenously with Rift Valley fever (RVF) virus presented clinical disease syndromes similar to human cases of RVF. All 17 infected monkeys

Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches

PubMed Central

Sahu, Praveen K.; Satpathi, Sanghamitra; Behera, Prativa K.; Mishra, Saroj K.; Mohanty, Sanjib; Wassmer, Samuel Crocodile

2015-01-01

Cerebral malaria is a severe neuropathological complication of Plasmodium falciparum infection. It results in high mortality and post-recovery neuro-cognitive disorders in children, even after appropriate treatment with effective anti-parasitic drugs. While the complete landscape of the pathogenesis of cerebral malaria still remains to be elucidated, numerous innovative approaches have been developed in recent years in order to improve the early detection of this neurological syndrome and, subsequently, the clinical care of affected patients. In this review, we briefly summarize the current understanding of cerebral malaria pathogenesis, compile the array of new biomarkers and tools available for diagnosis and research, and describe the emerging therapeutic approaches to tackle this pathology effectively. PMID:26579500

Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

PubMed Central

Garg, Abhimanyu; Subramanyam, Lalitha; Agarwal, Anil K.; Simha, Vinaya; Levine, Benjamin; D'Apice, Maria Rosaria; Novelli, Giuseppe; Crow, Yanick

2009-01-01

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A. PMID:19875478

Underestimated Amoebic Appendicitis among HIV-1-Infected Individuals in Japan.

PubMed

Kobayashi, Taiichiro; Watanabe, Koji; Yano, Hideaki; Murata, Yukinori; Igari, Toru; Nakada-Tsukui, Kumiko; Yagita, Kenji; Nozaki, Tomoyoshi; Kaku, Mitsuo; Tsukada, Kunihisa; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Oka, Shinichi

2017-01-01

Entamoeba histolytica is not a common causative agent of acute appendicitis. However, amoebic appendicitis can sometimes be severe and life threatening, mainly due to a lack of awareness. Also, its frequency, clinical features, and pathogenesis remain unclear. The study subjects were HIV-1-infected individuals who presented with acute appendicitis and later underwent appendectomy at our hospital between 1996 and 2014. Formalin-fixed paraffin-embedded preserved appendix specimens were reexamined by periodic acid-Schiff (PAS) staining and PCR to identify undiagnosed amoebic appendicitis. Appendectomies were performed in 57 patients with acute appendicitis. The seroprevalence of E. histolytica was 33% (14/43) from the available stored sera. Based on the medical records, only 3 cases were clinically diagnosed as amoebic appendicitis, including 2 diagnosed at the time of appendectomy and 1 case diagnosed by rereview of the appendix after the development of postoperative complications. Retrospective analyses using PAS staining and PCR identified 3 and 3 more cases, respectively. Thus, E. histolytica infection was confirmed in 9 cases (15.8%) in the present study. Apart from a significantly higher leukocyte count in E. histolytica-positive patients than in negative patients (median, 13,760 versus 10,385 cells/μl, respectively, P = 0.02), there were no other differences in the clinical features of the PCR-positive and -negative groups. In conclusion, E. histolytica infection was confirmed in 9 (15.8%) of the appendicitis cases. However, only 3, including one diagnosed after intestinal perforation, were diagnosed before the present analyses. These results strongly suggest there is frequently a failure to detect trophozoites in routine examination, resulting in an underestimation of the incidence of amoebic appendicitis. Copyright © 2016 Kobayashi et al.

Attenuated variants of Lesch-Nyhan disease

PubMed Central

Ceballos-Picot, Irene; Torres, Rosa J.; Visser, Jasper E.; Schretlen, David J.; Verdu, Alfonso; Laróvere, Laura E.; Chen, Chung-Jen; Cossu, Antonello; Wu, Chien-Hui; Sampat, Radhika; Chang, Shun-Jen; de Kremer, Raquel Dodelson; Nyhan, William; Harris, James C.; Reich, Stephen G.; Puig, Juan G.

2010-01-01

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency. PMID:20176575

[Analysis of risk factors for low bone mineral density in patients with inflammatory bowel disease].

PubMed

Park, Jae Jung; Jung, Sung Ae; Noh, Young Wook; Kang, Min Jung; Jung, Ji Min; Kim, Seong Eun; Jung, Hye Kyung; Shim, Ki Nam; Kim, Tae Hun; Yoo, Kwon; Moon, Il Hwan; Hong, Young Sun

2010-04-01

Several clinical risk factors for low bone mineral density (BMD) in the patients with inflammatory bowel disease (IBD) have been suggested. However, its prevalence and pathophysiology in Korean population have not been fully studied. The aim of this study was to investigate the prevalence and risk factors for low BMD in Korean IBD patient. BMD of the lumbar spine and femur was evaluated using dual-energy X-ray absorptiometry in 30 patients with IBD. Biochemical parameters of bone metabolism, such as serum calcium, phosphorus, osteocalcin, and deoxypyridinoline were measured. The associations between low BMD and clinical parameters such as disease duration, disease activity, drug history, body mass index (BMI), and others were evaluated retrospectively using medical records. Low BMD at the lumbar spine or femur was observed in 63.3% of the patients, and there was no significant difference between the patients with Crohns disease and ulcerative colitis. Clinical and biochemical parameters were irrelevant to BMD. In the patients without glucocorticoid treatment prior to BMD measurement, already 50.0% of patients had low BMD. Low BMD is a common feature in Korean IBD patients, even those who do not use glucocorticoid. The multiple factors may be involved in the pathogenesis of low BMD. Therefore, BMD should be examined in all IBD patients, irrespective of glucocorticoid treatment.

Genetic advances in sarcomeric cardiomyopathies: state of the art

PubMed Central

Ho, Carolyn Y.; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y.; Pinto, Yigal

2015-01-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. PMID:25634555

Combination therapy for treatment or prevention of atherosclerosis: Focus on the lipid-RAAS interaction☆

PubMed Central

Koh, Kwang Kon; Han, Seung Hwan; Oh, Pyung Chun; Shin, Eak Kyun; Quon, Michael J.

2010-01-01

Large clinical trials demonstrate that control of blood pressure or hyperlipidemia reduces risk for cardiovascular events by ~30%. Factors that may further reduce remaining risk are not definitively established. One potential target is atherosclerosis, a crucial feature in the pathogenesis of cardiovascular diseases whose development is determined by multiple mechanism including complex interactions between endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance as well as cross-talk between hyperlipidemia and the rennin–angiotensin–aldosterone system may contribute to development of atherosclerosis. Therefore, one appealing strategy for prevention or treatment of atherosclerosis may be to simultaneously address several risk factors with combination therapies that target multiple pathogenic mechanisms. Combination therapy with statins, peroxisome proliferators-activated receptor agonists, and rennin–angiotensin–aldosterone system blockers demonstrate additive beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapies in patients with cardiovascular risk factors. Additive beneficial effects of combined therapy are mediated by both distinct and interrelated mechanisms, consistent with both pre-clinical and clinical investigations. Thus, combination therapy may be an important concept in developing more effective strategies to treat and prevent atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and insulin resistance. PMID:19800624

Omics strategies for revealing Yersinia pestis virulence

PubMed Central

Yang, Ruifu; Du, Zongmin; Han, Yanping; Zhou, Lei; Song, Yajun; Zhou, Dongsheng; Cui, Yujun

2012-01-01

Omics has remarkably changed the way we investigate and understand life. Omics differs from traditional hypothesis-driven research because it is a discovery-driven approach. Mass datasets produced from omics-based studies require experts from different fields to reveal the salient features behind these data. In this review, we summarize omics-driven studies to reveal the virulence features of Yersinia pestis through genomics, trascriptomics, proteomics, interactomics, etc. These studies serve as foundations for further hypothesis-driven research and help us gain insight into Y. pestis pathogenesis. PMID:23248778

Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors.

PubMed

Kienle, Dirk; Katzenberger, Tiemo; Ott, German; Saupe, Doreen; Benner, Axel; Kohlhammer, Holger; Barth, Thomas F E; Höller, Sylvia; Kalla, Jörg; Rosenwald, Andreas; Müller-Hermelink, Hans Konrad; Möller, Peter; Lichter, Peter; Döhner, Hartmut; Stilgenbauer, Stephan

2007-07-01

There is evidence for a direct role of quantitative gene expression deregulation in mantle-cell lymphoma (MCL) pathogenesis. Our aim was to investigate gene expression associations with other pathogenic factors and the significance of gene expression in a multivariate survival analysis. Quantitative expression of 20 genes of potential relevance for MCL prognosis and pathogenesis were analyzed using real-time reverse transcriptase polymerase chain reaction and correlated with clinical and genetic factors, tumor morphology, and Ki-67 index in 65 MCL samples. Genomic losses at the loci of TP53, RB1, and P16 were associated with reduced transcript levels of the respective genes, indicating a gene-dosage effect as the pathomechanism. Analysis of gene expression correlations between the candidate genes revealed a separation into two clusters, one dominated by proliferation activators, another by proliferation inhibitors and regulators of apoptosis. Whereas only weak associations were identified between gene expression and clinical parameters or blastoid morphology, several genes were correlated closely with the Ki-67 index, including the short CCND1 variant (positive correlation) and RB1, ATM, P27, and BMI (negative correlation). In multivariate survival analysis, expression levels of MYC, MDM2, EZH2, and CCND1 were the strongest prognostic factors independently of tumor proliferation and clinical factors. These results indicate a pathogenic contribution of several gene transcript levels to the biology and clinical course of MCL. Genes can be differentiated into factors contributing to proliferation deregulation, either by enhancement or loss of inhibition, and proliferation-independent factors potentially contributing to MCL pathogenesis by apoptosis impairment.

Multifocal fibrosing thyroiditis: report of 55 cases of a poorly recognized entity.

PubMed

Fellegara, Giovanni; Rosai, Juan

2015-03-01

During the course of our consultation activity, we have recognized a peculiar form of thyroiditis in which multiple foci of fibrosis, most of which were associated with reactive atypia of the surrounding follicles, are present. We have referred to this condition, both in our consultation reports and in the third series of A.F.I.P. Fascicle on Tumors of the Thyroid Gland, as "multifocal fibrosing thyroiditis" or (less frequently) "multifocal sclerosing thyroiditis," which are descriptive terms that highlight the benign/inflammatory nature of the process, its multiplicity, and its unknown pathogenesis. The aim of this study is to better define the morphologic features of this process and correlate it with some clinical data. With this purpose, the consultation files of one of the authors (J.R.) were searched for cases coded as multifocal fibrosing thyroiditis or multifocal sclerosing thyroiditis in a 20-year period ranging from January 1989 to December 2009. A total of 55 cases were identified that displayed the above-listed features. There were 51 (93%) female and 4 (7%) male patients (F/M=12.75), with ages ranging between 15 and 71 years (mean age, 47.03 y; median age, 44.5 y). Microscopically, multiple foci of fibrosis were identified in all cases, their number ranging from 2 to 51 per case (mean number, 16), with a mean diameter of 3 mm (range: 0.36 to 15.1 mm). Although heterogenous in shape and size, the individual foci were rather similar to each other in composition, being characterized by a fibrotic poorly cellular center that merged with a cellular peripheral zone. Some of the follicular structures present at the periphery of the scar and-to a lesser extent-those entrapped inside it underwent complex reactive and regenerative (atypical) changes that simulated malignancy. We discuss the differential diagnosis with other benign and malignant thyroid conditions and speculate about its pathogenesis and possible relationship with papillary thyroid microcarcinoma.

Clinical characteristics of acute encephalopathy with acute brain swelling: A peculiar type of acute encephalopathy.

PubMed

Nukui, Megumi; Kawawaki, Hisashi; Inoue, Takeshi; Kuki, Ichiro; Okazaki, Shin; Amo, Kiyoko; Togawa, Masao; Ishikawa, Junichi; Rinka, Hiroshi; Shiomi, Masashi

2018-06-07

Acute encephalopathy has been observed with acute brain swelling (ABS) that is characterized by rapid progression to whole-brain swelling. The objective of this study was to describe the clinical characteristics of ABS. We encountered four patients with ABS and retrospectively investigated their clinical data with a medical chart review. Three patients had seizure clustering or status epilepticus in the clinical course. Signs of elevated intracranial pressure (ICP) appeared 3-9 h after the first convulsive attack in three patients. In all patients, signs of brainstem involvement appeared 1-8 h after signs of elevated ICP. Mild hyponatremia that progressed after signs of elevated ICP appeared was noted in three patients. Brain CT revealed mild brain swelling in the initial phase, which rapidly progressed to whole-brain swelling. No focal abnormalities were detected on brain MRI in one patient. Continuous electroencephalography was initially normal, but in two patients, high-amplitude slow waves appeared with rapid changes before signs of brainstem involvement. Although recovery was achieved without sequelae in two patients, outcome was fatal for the other two. The pathogenesis of ABS has yet to be clarified, but clinical features in our patients are not consistent with any established subtypes of acute encephalopathy. Therefore, we believe that ABS should be recognized as a new type of acute encephalopathy. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes.

PubMed

Kerr, J R; Burke, B; Petty, R; Gough, J; Fear, D; Mattey, D L; Axford, J S; Dalgleish, A G; Nutt, D J

2008-06-01

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. The authors have recently reported a study of gene expression that identified differential expression of 88 human genes in patients with CFS/ME. Clustering of quantitative PCR (qPCR) data from patients with CFS/ME revealed seven distinct subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes and severity. In this study, for each CFS/ME subtype, those genes whose expression differed significantly from that of normal blood donors were identified, and then gene interactions, disease associations and molecular and cellular functions of those gene sets were determined. Genomic analysis was then related to clinical data for each CFS/ME subtype. Genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was the mildest. Clinical features of each subtype were as follows: subtype 1 (cognitive, musculoskeletal, sleep, anxiety/depression); subtype 2 (musculoskeletal, pain, anxiety/depression); subtype 3 (mild); subtype 4 (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6 (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, anxiety/depression). It was particularly interesting that in the seven genomically derived subtypes there were distinct clinical syndromes, and that those which were most severe were also those with anxiety/depression, as would be expected in a disease with a biological basis.

Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis.

PubMed

Jenner, Peter; Morris, Huw R; Robbins, Trevor W; Goedert, Michel; Hardy, John; Ben-Shlomo, Yoav; Bolam, Paul; Burn, David; Hindle, John V; Brooks, David

2013-01-01

The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

[Melasma : An update on the clinical picture, treatment, and prevention].

PubMed

Becker, S; Schiekofer, C; Vogt, T; Reichrath, J

2017-02-01

Melasma, also known as chloasma or mask of pregnancy, presents clinically as hyperpigmented skin areas, which develop mostly in the face as a consequence of increased synthesis of melanin. The established treatment options, including topically applied agents and the use of various laser systems, mostly result in improvement but not in complete remission of the lesions. Because of its significant impact on quality of life and the limited effectivity of available treatment options, the management of melasma is challenging for the treating physician. Although many risk factors, including pregnancy and UV exposure, have been identified, the pathogenesis is not yet fully understood. Avoiding solar or artificial UV exposure is of high importance both for the prevention of melasma and for the clinical outcome of existing lesions. In order to avoid vitamin D deficiency, oral vitamin D supplementation should be recommended. In this review, we give an update on clinical aspects, epidemiology, pathogenesis and therapy of melasma and give an outlook on future developments.

Tetraphocomelia with the Waardenburg syndrome and multiple malformations.

PubMed

Wu, Hue-Tsi; Wainwright, Helen; Beighton, Peter

2009-04-01

A male infant delivered spontaneously at the 29th week of pregnancy had gross tetraphocomelia and features of the Waardenburg syndrome. There were no relevant factors in the pregnancy nor family history. It is possible that microdeletions or contiguous gene defects are involved in the pathogenesis of these malformations.

An update on acquired nystagmus.

PubMed

Rucker, Janet C

2008-01-01

Proper evaluation and treatment of acquired nystagmus requires accurate characterization of nystagmus type and visual effects. This review addresses important historical and examination features of nystagmus and current concepts of pathogenesis and treatment of gaze-evoked nystagmus, nystagmus due to vision loss, acquired pendular nystagmus, peripheral and central vestibular nystagmus, and periodic alternating nystagmus.