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

PubMed

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

2013-10-21

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

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

PubMed

Ghezzi, A; Comi, G; Federico, A

2011-02-01

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

Updating the mild encephalitis hypothesis of schizophrenia.

PubMed

Bechter, K

2013-04-05

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

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

PubMed

Gupta, Vinod Kumar

2005-01-01

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

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

NASA Technical Reports Server (NTRS)

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

1974-01-01

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

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

NASA Astrophysics Data System (ADS)

Koultchavenia, Ekaterina V.

2001-05-01

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

[Pathogenetic relationship between pterygium and dry eye syndrome (clinical and cytological study)].

PubMed

Petraevskiĭ, A V; Trishkin, K S

2014-01-01

To study the prevalence of dry eye syndrome in patients with initial primary pterygium for determination of a possible pathogenetic role of dry eye syndrome in the development of pterygium. 30 patients with initial primary pterygium; besides conventional ophthalmic assessment, cytological examination of bulbar conjunctiva was performed in all cases. Signs of dry eye syndrome, of similar severity in both eyes, were found in 100% of patients. Dry eye can be one of the precipitating factors of primary pterygium.

Homeopathic pathogenetic trials produce specific symptoms different from placebo.

PubMed

Möllinger, Heribert; Schneider, Rainer; Walach, Harald

2009-04-01

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

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

PubMed Central

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

2012-01-01

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

CMML AND aCML: NOVEL PATHOGENETIC LESIONS

PubMed Central

Muramatsu, Hideki; Makishima, Hideki; Maciejewski, Jaroslaw P.

2012-01-01

Summary Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping or next generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, UTX, EZH2) have been found. Various combinations of mutations suggest a multistep pathogenesis and may account for clinical heterogeneity. The prognostic and diagnostic significance of these molecular lesions, in particular their value as biomarkers of response or resistance to specific therapies, while uncertain now is likely to be clarified as large systematic studies come to completion. PMID:22289493

Altered consciousness states and endogenous psychoses: a common molecular pathway?

PubMed

Ciprian-Ollivier, J; Cetkovich-Bakmas, M G

1997-12-19

Interest in the role of indolamines in the pathogenesis of psychoses has been renewed in recent years by the development of atypical antipsychotic drugs such as clozapine, olanzapine, and risperidone, which act on serotonin receptors. Discovery of the hallucinogenic compounds called methylated indolealkyalamines (MIAs) (e.g. N,N-dimethylserotonin, or bufotenin, and N,N-dimethyltryptamine, or DMT) led proponents of the transmethylation hypothesis of schizophrenia to theorize that through some inborn error of metabolism, serotonin or tryptamine might undergo the addition of extra methyl radicals, thereby forming MIAs with hallucinogenic properties. Various studies have attempted to detect the excretion of MIAs, especially DMT, in the body fluids of psychotic patients and normal controls. Some of these studies have demonstrated elevated MIA concentrations in psychotic patients, including those with schizophrenia, compared with normal persons, and others have not. A number of variables may account for these contradictory findings. The mechanism whereby the beverage ayahuasca, which is used in certain cure and divination rituals in the Amazon Basin, exerts its hallucinogenic effects may serve as a model to explain the mechanism underlying hallucinogenic symptoms in schizophrenia and may lend support to the transmethylation hypothesis. Certain studies suggest that specific perceptual disturbances manifested by schizophrenic patients could contribute to progressive deterioration and negative symptomatology. All these findings point to the need for further study of the neurophysiology of MIAs and their pathogenetic role in endogenous psychoses.

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

PubMed

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

2007-01-01

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

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

PubMed

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

2018-01-01

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

In vitro streptozotocin model for modeling Alzheimer-like changes: effect on amyloid precursor protein secretases and glycogen synthase kinase-3.

PubMed

Plaschke, Konstanze; Kopitz, Jürgen

2015-04-01

There is accumulating evidence for a pathogenetic link between sporadic Alzheimer's disease (AD) and diabetes mellitus (DM). At subdiabetogenic doses, the cerebral administration of the diabetogenic substance streptozotocin (STZ) induces an insulin-resistant brain state (IRBS). The aim of the present pilot study was to investigate the effect of STZ on Alzheimer-like characteristics such as amyloid precursor protein (APP) cleavage secretases, betaA4 fragment, and glycogen synthase kinase (GSK) in vitro. Different STZ concentrations (0-5 mM) and incubation intervals (0-48 h) were tested to find appropriate cell culture conditions for further biochemical analyses in human neuroblastoma cells (SK-N-MC). Lactate dehydrogenase (LDH) was measured spectrophotometrically. Intracellular ATP was determined using bioluminescent luciferase assay. Secretase activity (alpha, beta, and gamma) was measured by employing commercial fluorometric secretase activity assay kits, betaA4 fragment by immunoprecipitation. Glycogen synthase kinase-3alpha/beta (total and phospho-GSK) content was assayed by ELISA technique. In vitro STZ administration (1 mM) induced a significant reduction in intracellular ATP concentration without pronounced cell death after 24 and 48 h as measured by LDH. Under these experimental conditions, a significant increase in beta-secretase and a significant drop in alpha-secretase were obtained, whereas gamma-secretase was not changed significantly. Simultaneously, the betaA4 concentration was increased by about threefold. Furthermore, STZ significantly increased total GSK and markedly decreased phospho-GSK. A direct link between STZ, intracellular ATP deficit, and Alzheimer-related enzymes was shown in this in vitro pilot study. Thus, these results support the hypothesis that sporadic AD is being recognized as an IRBS, which can be modulated by in vitro STZ model. Continuing investigations relating pathogenetic mechanisms and AD-like hallmarks are necessary to modulate different cascades of the IRBS using in vitro models.

The Scientific Method, Diagnostic Bayes, and How to Detect Epistemic Errors

NASA Astrophysics Data System (ADS)

Vrugt, J. A.

2015-12-01

In the past decades, Bayesian methods have found widespread application and use in environmental systems modeling. Bayes theorem states that the posterior probability, P(H|D) of a hypothesis, H is proportional to the product of the prior probability, P(H) of this hypothesis and the likelihood, L(H|hat{D}) of the same hypothesis given the new/incoming observations, \\hat {D}. In science and engineering, H often constitutes some numerical simulation model, D = F(x,.) which summarizes using algebraic, empirical, and differential equations, state variables and fluxes, all our theoretical and/or practical knowledge of the system of interest, and x are the d unknown parameters which are subject to inference using some data, \\hat {D} of the observed system response. The Bayesian approach is intimately related to the scientific method and uses an iterative cycle of hypothesis formulation (model), experimentation and data collection, and theory/hypothesis refinement to elucidate the rules that govern the natural world. Unfortunately, model refinement has proven to be very difficult in large part because of the poor diagnostic power of residual based likelihood functions tep{gupta2008}. This has inspired te{vrugt2013} to advocate the use of 'likelihood-free' inference using approximate Bayesian computation (ABC). This approach uses one or more summary statistics, S(\\hat {D}) of the original data, \\hat {D} designed ideally to be sensitive only to one particular process in the model. Any mismatch between the observed and simulated summary metrics is then easily linked to a specific model component. A recurrent issue with the application of ABC is self-sufficiency of the summary statistics. In theory, S(.) should contain as much information as the original data itself, yet complex systems rarely admit sufficient statistics. In this article, we propose to combine the ideas of ABC and regular Bayesian inference to guarantee that no information is lost in diagnostic model evaluation. This hybrid approach, coined diagnostic Bayes, uses the summary metrics as prior distribution and original data in the likelihood function, or P(x|\\hat {D}) ∝ P(x|S(\\hat {D})) L(x|\\hat {D}). A case study illustrates the ability of the proposed methodology to diagnose epistemic errors and provide guidance on model refinement.

Diuretics as pathogenetic treatment for heart failure

PubMed Central

Guglin, Maya

2011-01-01

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

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

PubMed

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

2010-04-01

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

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

PubMed

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

2017-06-01

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

Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes

PubMed Central

Numasawa-Kuroiwa, Yuko; Okada, Yohei; Shibata, Shinsuke; Kishi, Noriyuki; Akamatsu, Wado; Shoji, Masanobu; Nakanishi, Atsushi; Oyama, Manabu; Osaka, Hitoshi; Inoue, Ken; Takahashi, Kazutoshi; Yamanaka, Shinya; Kosaki, Kenjiro; Takahashi, Takao; Okano, Hideyuki

2014-01-01

Summary Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation. PMID:24936452

Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

PubMed Central

Polonikov, Alexey V.; Ivanov, Vladimir P.; Bogomazov, Alexey D.; Freidin, Maxim B.; Illig, Thomas; Solodilova, Maria A.

2014-01-01

Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma. PMID:24895604

The effects of heart rate control in chronic heart failure with reduced ejection fraction.

PubMed

Grande, Dario; Iacoviello, Massimo; Aspromonte, Nadia

2018-07-01

Elevated heart rate has been associated with worse prognosis both in the general population and in patients with heart failure. Heart rate is finely modulated by neurohormonal signals and it reflects the balance between the sympathetic and the parasympathetic limbs of the autonomic nervous system. For this reason, elevated heart rate in heart failure has been considered an epiphenomenon of the sympathetic hyperactivation during heart failure. However, experimental and clinical evidence suggests that high heart rate could have a direct pathogenetic role. Consequently, heart rate might act as a pathophysiological mediator of heart failure as well as a marker of adverse outcome. This hypothesis has been supported by the observation that the positive effect of beta-blockade could be linked to the degree of heart rate reduction. In addition, the selective heart rate control with ivabradine has recently been demonstrated to be beneficial in patients with heart failure and left ventricular systolic dysfunction. The objective of this review is to examine the pathophysiological implications of elevated heart rate in chronic heart failure and explore the mechanisms underlying the effects of pharmacological heart rate control.

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

PubMed

Andorn, Anne C.; Kalaria, Rajesh N.

2000-06-01

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

Minireaps! Mini-Research Papers That Make Kids Think!

ERIC Educational Resources Information Center

Polette, Nancy

1987-01-01

Describes the concept of the Minireap, a one-page research paper requiring little writing and a lot of thought. Three types of questions used for Minireaps--data interpretation, summary, and hypothesis--are illustrated. (MES)

Primary biliary cirrhosis: From bench to bedside

PubMed Central

Kouroumalis, Elias; Notas, George

2015-01-01

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

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

PubMed Central

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

2016-01-01

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

Hemagglutinin-specific neutralization of subacute sclerosing panencephalitis viruses

PubMed Central

Muller, Claude P.; Russell, Stephen J.

2018-01-01

Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal complication of measles caused by particular mutants of measles virus (MeV) that persist in the brain despite high levels of neutralizing antibodies. We addressed the hypothesis that antigenic drift is involved in the pathogenetic mechanism of SSPE by analyzing antigenic alterations in the MeV envelope hemagglutinin protein (MeV-H) found in patients with SSPE in relation to major circulating MeV genotypes. To this aim, we obtained cDNA for the MeV-H gene from tissue taken at brain autopsy from 3 deceased persons with SSPE who had short (3–4 months, SMa79), average (3.5 years, SMa84), and long (18 years, SMa94) disease courses. Recombinant MeVs with a substituted MeV-H gene were generated by a reverse genetic system. Virus neutralization assays with a panel of anti-MeV-H murine monoclonal antibodies (mAbs) or vaccine-immunized mouse anti-MeV-H polyclonal sera were performed to determine the antigenic relatedness. Functional and receptor-binding analysis of the SSPE MeV-H showed activity in a SLAM/nectin-4–dependent manner. Similar to our panel of wild-type viruses, our SSPE viruses showed an altered antigenic profile. Genotypes A, G3, and F (SSPE case SMa79) were the exception, with an intact antigenic structure. Genotypes D7 and F (SSPE SMa79) showed enhanced neutralization by mAbs targeting antigenic site IIa. Genotypes H1 and the recently reported D4.2 were the most antigenically altered genotypes. Epitope mapping of neutralizing mAbs BH015 and BH130 reveal a new antigenic site on MeV-H, which we designated Φ for its intermediate position between previously defined antigenic sites Ia and Ib. We conclude that SSPE-causing viruses show similar antigenic properties to currently circulating MeV genotypes. The absence of a direct correlation between antigenic changes and predisposition of a certain genotype to cause SSPE does not lend support to the proposed antigenic drift as a pathogenetic mechanism in SSPE. PMID:29466428

Hemagglutinin-specific neutralization of subacute sclerosing panencephalitis viruses.

PubMed

Muñoz-Alía, Miguel Ángel; Muller, Claude P; Russell, Stephen J

2018-01-01

Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal complication of measles caused by particular mutants of measles virus (MeV) that persist in the brain despite high levels of neutralizing antibodies. We addressed the hypothesis that antigenic drift is involved in the pathogenetic mechanism of SSPE by analyzing antigenic alterations in the MeV envelope hemagglutinin protein (MeV-H) found in patients with SSPE in relation to major circulating MeV genotypes. To this aim, we obtained cDNA for the MeV-H gene from tissue taken at brain autopsy from 3 deceased persons with SSPE who had short (3-4 months, SMa79), average (3.5 years, SMa84), and long (18 years, SMa94) disease courses. Recombinant MeVs with a substituted MeV-H gene were generated by a reverse genetic system. Virus neutralization assays with a panel of anti-MeV-H murine monoclonal antibodies (mAbs) or vaccine-immunized mouse anti-MeV-H polyclonal sera were performed to determine the antigenic relatedness. Functional and receptor-binding analysis of the SSPE MeV-H showed activity in a SLAM/nectin-4-dependent manner. Similar to our panel of wild-type viruses, our SSPE viruses showed an altered antigenic profile. Genotypes A, G3, and F (SSPE case SMa79) were the exception, with an intact antigenic structure. Genotypes D7 and F (SSPE SMa79) showed enhanced neutralization by mAbs targeting antigenic site IIa. Genotypes H1 and the recently reported D4.2 were the most antigenically altered genotypes. Epitope mapping of neutralizing mAbs BH015 and BH130 reveal a new antigenic site on MeV-H, which we designated Φ for its intermediate position between previously defined antigenic sites Ia and Ib. We conclude that SSPE-causing viruses show similar antigenic properties to currently circulating MeV genotypes. The absence of a direct correlation between antigenic changes and predisposition of a certain genotype to cause SSPE does not lend support to the proposed antigenic drift as a pathogenetic mechanism in SSPE.

[Asthma and metabolic syndrome: Clinical and pathogenetic relationships].

PubMed

Budnevsky, A V; Malysh, E Yu; Ovsyannikov, E S; Drobysheva, E S

2015-01-01

Asthma and metabolic syndrome (MS) are common and social diseases. External and internal factors influencing the development and manifestations of asthma are identified; among which there is obesity that is a major risk factor for MS. Accordingly, the concurrence of asthma and MS and to study their clinical and pathogenetic relationships are a topical problem. There is a tendency to identify a particular asthma phenotype that is characterized by later-onset disease in the presence of obesity; the low prevalence of atopy, low serum level of IgE, and a poorly-controlled course with a trend of standard therapy resistance. It is necessary to understand the essence of asthma cause-effect relationships in the presence of obesity for defining management tactics for this group of patients.

[Pathogenetic therapy of mastopathies in the prevention of breast cancer].

PubMed

Iaritsyn, S S; Sidorenko, L N

1979-01-01

The breast cancer morbidity among the population of the city of Leningrad has been analysed. It was shown that there is a tendency to the increased number of breast cancer patients. In this respect attention is given to the prophylactic measures, accomplished in Leningrad City oncological dyspensary. As proved statistically, the pathogenetic therapy of mastopathy is a factor contributing to less risk of malignant transformation. For the statistical analysis the authors used the data of 132 breast cancer patients; previously operated upon for local fibroadenomatosis, and the data of 259 control patients. It was found that among the patients with fibroadenomatosis who subsequently developed cancer of the mammary gland, the proportion of untreated patients was 2.8 times as much as in the control group.

[Development of immunologic deficiency conditions and sensitization in industrial workers and methodologic approach to their detection and evaluation].

PubMed

Dueva, L A; Ivanova, L A; Pavlova, T A

1989-01-01

The principal mechanisms forming the basis of detoxication abnormalities have been analysed using the data of research into the status of the hepatic monooxygenase enzyme system, which is responsible for the liver detoxication potential, and the literature reports. Irrespective of the pathology, a similar depression of the monooxygenase enzyme system of hepatocytes was revealed in acute stercoraceous peritonitis, acute ileus, burn disease, acute renal failure, and pyo-inflammatory conditions in the maxillofacial region. A pathogenetic model is proposed, which explains the mechanism of hepatic detoxication dysfunction in endogenous intoxications of different etiology. New approaches to the therapy of detoxication abnormalities in the conditions attended with endotoxemic syndrome are discussed proceeding from the pathogenetic mechanisms.

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

PubMed

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

1990-01-01

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

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

PubMed

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

2012-09-20

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

A Pathogenetic Classification of Diabetic Macular Edema.

PubMed

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

2018-04-11

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

Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

PubMed Central

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

2014-01-01

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

Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria

PubMed Central

Jauregui, Alexandra; Mintz, Daniel H; Mundel, Peter; Fornoni, Alessia

2010-01-01

Purpose of review In diabetic nephropathy (DN), insulin resistance and hyperinsulinemia correlate with the development of albuminuria. The possibility that altered insulin signaling in glomerular cells and particularly podocytes contributes to the development of DN will be discussed. Recent findings While normal podocytes uptake glucose in response to insulin, diabetic podocytes become insulin resistant in experimental DN prior to the development of significant albuminuria. Both clinical and experimental data suggest that insulin sensitizers may be renoprotective independently of their systemic effects on the metabolic control of diabetes. Summary We will review the clinical and experimental evidence that altered insulin signaling correlates with the development of DN in both type 1 and type 2 diabetes, and that insulin sensitizers may be superior to other hypoglycemic agents in the prevention of DN. We will then review potential mechanisms by which altered podocyte insulin signaling may contribute to the development of DN. Understanding the role of podocyte in glucose metabolism is important because it may lead to the discovery of novel pathogenetic mechanisms of DN, it may affect current strategies for prevention and treatment of DN, and it may allow for the identification of novel therapeutic targets. PMID:19724224

[Correction of indigestion in chronic biliary pancreatitis].

PubMed

Trukhan, D I; Tarasova, L V

2013-01-01

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

PROTEOMICS OF THE AMNIOTIC FLUID IN ASSESSMENT OF THE PLACENTA – RELEVANCE FOR PRETERM BIRTH

PubMed Central

Buhimschi, Irina A.; Buhimschi, Catalin S.

2008-01-01

Proteomics is the study of expressed proteins and has emerged as a complement to genomic research. The major advantage of proteomics over DNA-RNA based technologies is that it more closely relates to phenotype and not the source code. Proteomics thus holds the promise of providing direct insight into the true mechanisms of human disease. Historically, examination of the placenta was the first modality to subclassify pathogenetical entities responsible for preterm birth. Because placenta is a key pathophysiological participant in several major obstetrical syndromes (preterm birth, preeclampsia, intrauterine growth restriction) identification of relevant biomarkers of placental function can profoundly impact on the prediction of fetal outcome and treatment efficacy. Proteomics is a young science and studies that associate proteomic patterns with long-term outcome require follow-up of children up to school age. In the interim, placental pathological footprints of cellular injury can be useful as intermediate outcomes. Furthermore, knowledge of the identity of the dys-regulated proteins may provide the necessary insight into novel pathophysiological pathways and unravel possible targets for therapeutic intervention that could not have been envisioned through hypothesis-driven approaches. PMID:18191197

Central Sensitization-Based Classification for Temporomandibular Disorders: A Pathogenetic Hypothesis

PubMed Central

Cattaneo, Ruggero; Marci, Maria Chiara; Pietropaoli, Davide; Ortu, Eleonora

2017-01-01

Dysregulation of Autonomic Nervous System (ANS) and central pain pathways in temporomandibular disorders (TMD) is a growing evidence. Authors include some forms of TMD among central sensitization syndromes (CSS), a group of pathologies characterized by central morphofunctional alterations. Central Sensitization Inventory (CSI) is useful for clinical diagnosis. Clinical examination and CSI cannot identify the central site(s) affected in these diseases. Ultralow frequency transcutaneous electrical nerve stimulation (ULFTENS) is extensively used in TMD and in dental clinical practice, because of its effects on descending pain modulation pathways. The Diagnostic Criteria for TMD (DC/TMD) are the most accurate tool for diagnosis and classification of TMD. However, it includes CSI to investigate central aspects of TMD. Preliminary data on sensory ULFTENS show it is a reliable tool for the study of central and autonomic pathways in TMD. An alternative classification based on the presence of Central Sensitization and on individual response to sensory ULFTENS is proposed. TMD may be classified into 4 groups: (a) TMD with Central Sensitization ULFTENS Responders; (b) TMD with Central Sensitization ULFTENS Nonresponders; (c) TMD without Central Sensitization ULFTENS Responders; (d) TMD without Central Sensitization ULFTENS Nonresponders. This pathogenic classification of TMD may help to differentiate therapy and aetiology. PMID:28932132

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

PubMed

Taurisano, Roberta; Maiorana, Arianna; De Benedetti, Fabrizio; Dionisi-Vici, Carlo; Boldrini, Renata; Deodato, Federica

2014-10-01

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher's disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

The fecal microbiome of ALS patients.

PubMed

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

2018-01-01

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

Cerebrospinal Fluid Amyloid-β 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease.

PubMed

Santangelo, Roberto; Cecchetti, Giordano; Bernasconi, Maria Paola; Cardamone, Rosalinda; Barbieri, Alessandra; Pinto, Patrizia; Passerini, Gabriella; Scomazzoni, Francesco; Comi, Giancarlo; Magnani, Giuseppe

2017-01-01

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

An exploratory study of the relationship between neurological soft signs and theory of mind deficits in schizophrenia.

PubMed

Romeo, Stefano; Chiandetti, Alessio; Siracusano, Alberto; Troisi, Alfonso

2014-08-15

Indirect evidence suggests partially common pathogenetic mechanisms for Neurological Soft Signs (NSS), neurocognition, and social cognition in schizophrenia. However, the possible association between NSS and mentalizing impairments has not yet been examined. In the present study, we assessed the ability to attribute mental states to others in patients with schizophrenia and predicted that the presence of theory of mind deficits would be significantly related to NSS. Participants were 90 clinically stable patients with a DSM-IV diagnosis of schizophrenia. NSS were assessed using the Neurological Evaluation Scale (NES). Theory of mind deficits were assessed using short verbal stories designed to measure false belief understanding. The findings of the study confirmed our hypothesis. Impaired sequencing of complex motor acts was the only neurological abnormality correlated with theory of mind deficits. By contrast, sensory integration, motor coordination and the NES Others subscale had no association with patients׳ ability to pass first- or second-order false belief tasks. If confirmed by future studies, the current findings provide the first preliminary evidence for the claim that specific NSS and theory of mind deficits may reflect overlapping neural substrates. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Turnaround Arts Initiative: Summary of Key Findings

ERIC Educational Resources Information Center

Stoelinga, Sara Ray; Silk, Yael; Reddy, Prateek; Rahman, Nadiv

2015-01-01

Turnaround Arts is a public-private partnership that aims to test the hypothesis that strategically implementing high-quality and integrated arts education programming in high-poverty, chronically underperforming schools adds significant value to school-wide reform. In 2014, the Turnaround Arts initiative completed an evaluation report covering…

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

PubMed

Altomonte, M; Pucillo, C; Maio, M

1999-06-01

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

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

PubMed

Sato, Kohji

2013-04-01

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

[Chronic Rhinosinusitis - EPOS 2012 Part I].

PubMed

Riechelmann, H

2013-03-01

An expert group of the European Academy of Allergy and Clinical Immunology (EAACI) and the European Rhinologic Society (ERS) has recently published the revised position paper for acute and chronic rhinosinusitis (EPOS 2012). In the following article, the most important aspects of the EPOS 2012 paper concerning chronic rhinosinusitis (CRS) are referenced. Every 10th European is suffering from a chronic inflammation of the nose and paranasal sinuses.2 EPOS key messages according CRS are: 1. CRS is an inflammatory disease, not an infection. 2. CRS comes in 2 different subtypes, namely CRS without polyps (CRSsNP) and CRS with polyps (CRSwNP). CRSwNP is diagnosed, when nasal polyps are visible at an appropriate nasal endoscopic examination. Otherwise CRSsNP is classified. In the EPOS 2012 paper the current pathogenetic knowledge of these 2 different CRS subtypes are discussed. Current research focuses on epithelial/immune cell interactions, the biofilm hypothesis and the superantigen hypothesis. Both CRS subtypes may be associated with different frequencies with other diseases, especially allergies, asthma and aspirin exacerbated respiratory disease (AERD). These comorbidities should be recorded and treated. The standard diagnostic procedures include medical history, nasal endoscopy, CT-scans of the paranasal sinus, and allergy test of common inhalant allergens. The classification of disease severity in mild, moderate and severe was complemented with a concept of symptom control in controlled, partly controlled and uncontrolled. Also, a 'difficult-to-treat-CRS' was defined. The choice of therapy depends upon symptom intensity. In patients with moderate and severe symptoms, usually several weeks of conservative treatment including topical steroids are administered. In non-responders, surgical treatment (functional endonasal sinus surgery) is indicated. The EPOS Group offers evidence-based treatment algorithms for general practitioners and ENT-specialists. © Georg Thieme Verlag KG Stuttgart · New York.

Pseudotumor Cerebri and Glymphatic Dysfunction.

PubMed

Bezerra, Marcio Luciano de Souza; Ferreira, Ana Carolina Andorinho de Freitas; de Oliveira-Souza, Ricardo

2017-01-01

In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of β-amyloid in Alzheimer's disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses.

Pseudotumor Cerebri and Glymphatic Dysfunction

PubMed Central

Bezerra, Marcio Luciano de Souza; Ferreira, Ana Carolina Andorinho de Freitas; de Oliveira-Souza, Ricardo

2018-01-01

In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of β-amyloid in Alzheimer’s disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses. PMID:29387036

The Pak-U.S. Alliance in the Fight Against Terrorism: A Cost-Benefit Analysis

DTIC Science & Technology

2011-12-01

Micro-Alliance, Entrepreneurship , Game Theoretical Approach, Perceptions and Realities, Military-Centric Assistance, Population-Centric Approach...40 4. Entrepreneurship and Micro-Alliances ...........................................41 E. SUMMARY...through educational reforms, trade and employment ( entrepreneurship ). 6 6. Hypothesis-3: Promoting converging interests/common goals and removing

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

PubMed

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

1996-07-01

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

Unscaled Bayes factors for multiple hypothesis testing in microarray experiments.

PubMed

Bertolino, Francesco; Cabras, Stefano; Castellanos, Maria Eugenia; Racugno, Walter

2015-12-01

Multiple hypothesis testing collects a series of techniques usually based on p-values as a summary of the available evidence from many statistical tests. In hypothesis testing, under a Bayesian perspective, the evidence for a specified hypothesis against an alternative, conditionally on data, is given by the Bayes factor. In this study, we approach multiple hypothesis testing based on both Bayes factors and p-values, regarding multiple hypothesis testing as a multiple model selection problem. To obtain the Bayes factors we assume default priors that are typically improper. In this case, the Bayes factor is usually undetermined due to the ratio of prior pseudo-constants. We show that ignoring prior pseudo-constants leads to unscaled Bayes factor which do not invalidate the inferential procedure in multiple hypothesis testing, because they are used within a comparative scheme. In fact, using partial information from the p-values, we are able to approximate the sampling null distribution of the unscaled Bayes factor and use it within Efron's multiple testing procedure. The simulation study suggests that under normal sampling model and even with small sample sizes, our approach provides false positive and false negative proportions that are less than other common multiple hypothesis testing approaches based only on p-values. The proposed procedure is illustrated in two simulation studies, and the advantages of its use are showed in the analysis of two microarray experiments. © The Author(s) 2011.

Anencephaly with incomplete twinning (diprosopus).

PubMed

Riccardi, V M; Bergmann, C A

1977-10-01

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

Severe Mental Retardation in Children in a Northern Swedish County

ERIC Educational Resources Information Center

And Others; Gustavson, K. H.

1977-01-01

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

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

PubMed

Fasano, Mauro; Monti, Chiara; Alberio, Tiziana

2016-09-01

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

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

PubMed

Chakravarty, Ambar

2011-10-01

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

De novo development of artistic creativity in Alzheimer's disease

PubMed Central

Chakravarty, Ambar

2011-01-01

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

Pectus excavatum: history, hypotheses and treatment options

PubMed Central

Brochhausen, Christoph; Turial, Salmai; Müller, Felix K.P.; Schmitt, Volker H.; Coerdt, Wiltrud; Wihlm, Jean-Marie; Schier, Felix; Kirkpatrick, C. James

2012-01-01

Pectus excavatum and pectus carinatum represent the most frequent chest wall deformations. However, the pathogenesis is still poorly understood and research results remain inconsistent. To focus on the recent state of knowledge, we summarize and critically discuss the pathological concepts based on the history of these entities, beginning with the first description in the sixteenth century. Based on the early clinical descriptions, we review and discuss the different pathogenetic hypotheses. To open new perspectives for the potential pathomechanisms, the embryonic and foetal development of the ribs and the sternum is highlighted following the understanding that the origin of these deformities is given by the disruption in the maturation of the parasternal region. In the second, different therapeutical techniques are highlighted and based on the pathogenetic hypotheses and the embryological knowledge potential new biomaterial-based perspectives with interesting insights for tissue engineering-based treatment options are presented. PMID:22394989

Investigating the Cosmic Web with Topological Data Analysis

NASA Astrophysics Data System (ADS)

Cisewski-Kehe, Jessi; Wu, Mike; Fasy, Brittany; Hellwing, Wojciech; Lovell, Mark; Rinaldo, Alessandro; Wasserman, Larry

2018-01-01

Data exhibiting complicated spatial structures are common in many areas of science (e.g. cosmology, biology), but can be difficult to analyze. Persistent homology is a popular approach within the area of Topological Data Analysis that offers a new way to represent, visualize, and interpret complex data by extracting topological features, which can be used to infer properties of the underlying structures. In particular, TDA may be useful for analyzing the large-scale structure (LSS) of the Universe, which is an intricate and spatially complex web of matter. In order to understand the physics of the Universe, theoretical and computational cosmologists develop large-scale simulations that allow for visualizing and analyzing the LSS under varying physical assumptions. Each point in the 3D data set represents a galaxy or a cluster of galaxies, and topological summaries ("persistent diagrams") can be obtained summarizing the different ordered holes in the data (e.g. connected components, loops, voids).The topological summaries are interesting and informative descriptors of the Universe on their own, but hypothesis tests using the topological summaries would provide a way to make more rigorous comparisons of LSS under different theoretical models. For example, the received cosmological model has cold dark matter (CDM); however, while the case is strong for CDM, there are some observational inconsistencies with this theory. Another possibility is warm dark matter (WDM). It is of interest to see if a CDM Universe and WDM Universe produce LSS that is topologically distinct.We present several possible test statistics for two-sample hypothesis tests using the topological summaries, carryout a simulation study to investigate the suitableness of the proposed test statistics using simulated data from a variation of the Voronoi foam model, and finally we apply the proposed inference framework to WDM vs. CDM cosmological simulation data.

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

PubMed

Sass, Louis A; Borda, Juan P

2015-12-01

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

Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms.

PubMed

Askanas, Valerie; Engel, W King

2002-10-01

Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion body myopathies are progressive muscle diseases that lead to severe disability. We discuss recent advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. Our basic hypothesis is that over-expression of amyloid-beta precursor protein within aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis: (a) increased transcription and accumulation of amyloid-beta precursor protein, and accumulation of its proteolytic fragment Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol accumulation possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss unfolded and/or misfolded proteins as a possible mechanism in formation of the inclusion bodies and their consequences. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease brain are discussed. Unfolding knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion body myopathies may lead to new therapeutic avenues.

The Rorschach test and Gilles de la Tourette's syndrome: a pilot case-control study.

PubMed

Balottin, Umberto; Rossi, Maura; Rossi, Giorgio; Viganò, Lucia; Nanti, Marta; Salini, Silvia; Lanzi, Giovanni; Termine, Cristiano

2009-10-01

To date only three studies, all lacking a control group, have investigated the personality style underlying tic disorders or Tourette's syndrome (TS), using the projective Rorschach test. Despite the recent controversy about its proper use in clinical practice and research, the Rorschach test may be useful to explore personality organization in TS. The research hypothesis under investigation in this exploratory study was that young TS patients exhibit a peculiar personality organization, with significantly increased indicators of poor emotional control, aggression, anxiety and depression, on the Rorschach test, compared to healthy controls. We analyed the Rorschach protocols of 17 newly diagnosed paediatric TS patients and 17 age- and sex-matched healthy controls. Compared with the controls young TS patients recorded significantly lower mean percentages of F and F+ responses and a significantly higher number of FM and FC responses, thus showing reduced control of emotions and difficulty in integrating aggressivity. Furthermore, associations emerged between comorbidity with ADHD and increased emotional instability and between severity of tics and of OCD and a pattern of emotional hyper-control and application of rigid defensive mechanisms. These results seem to confirm the existence of a peculiar personality style in young TS patients and may have important implications, both pathogenetic and therapeutic.

Creative Futures: Act, Sing, Play. Evaluation Report and Executive Summary

ERIC Educational Resources Information Center

Haywood, Sarah; Griggs, Julia; Lloyd, Cheryl; Morris, Stephen; Kiss, Zsolt; Skipp, Amy

2015-01-01

Act, Sing, Play (ASP) offered music and drama tuition to Year 2 pupils. The aim of the programme was to evaluate whether music workshops had a bigger impact than drama workshops in terms of pupils' maths and literacy attainment. The evaluation was based on the hypothesis that participation in high-quality music instruction promotes educational…

A Study on CPH and Debate Summary in FLL

ERIC Educational Resources Information Center

Liu, Zhiliang

2009-01-01

The optimal age in FLL (foreign language learning) for children has been discussed over 50 years but there is no satisfactory conclusion for us. However, the notion "the younger, the better" in FLL has a big market in the world. As a result, the distorted hypothesis is being spread widely as a true and complete theory. Specifically…

[Biliary ileus. Case report and therapeutic considerations].

PubMed

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

1995-01-01

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-29

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

Ameloblastic fibrosarcoma. Report of a case in a Nigerian.

PubMed

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

1978-08-01

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

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

PubMed

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

2000-08-01

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

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

PubMed

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

1998-02-01

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

[Pneumonia in wounded].

PubMed

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

2015-02-01

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

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

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

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

1993-10-01

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

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

PubMed Central

Pasipoularides, Ares

2016-01-01

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

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

PubMed

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

1990-01-01

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

Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

PubMed Central

Campa, Claudio; Costagliola, Ciro; Incorvaia, Carlo; Sheridan, Carl; Semeraro, Francesco; De Nadai, Katia; Sebastiani, Adolfo; Parmeggiani, Francesco

2010-01-01

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed. PMID:20871825

Increasing Treatment Seeking Among At-Risk Service Members Returning from Warzones

DTIC Science & Technology

2017-03-01

treatment among at-risk service members. Hypothesis 1a: Participants receiving the cognitive -behavioral (CB) intervention will have significant...Participants assigned to the treatment condition are presented an individualized cognitive -behavioral (CB) intervention. The CB intervention takes 45-60... cognitive -behavioral intervention 6 3. OVERALL PROJECT SUMMARY Recruitment for this trial began on March 2, 2013. We aimed to recruit

Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

PubMed Central

Martin, Olwenn V.; Shialis, Tassos; Lester, John N.; Scrimshaw, Mark D.; Boobis, Alan R.; Voulvoulis, Nikolaos

2008-01-01

Background Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. Objectives We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored. Results We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Conclusions The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population. PMID:18288311

Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis.

PubMed

Martin, Olwenn V; Shialis, Tassos; Lester, John N; Scrimshaw, Mark D; Boobis, Alan R; Voulvoulis, Nikolaos

2008-02-01

Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-alpha-mediated mode of action was specifically explored. We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.

'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 3: Anti-Yo/CDR2, anti-Nb/AP3B2, PCA-2, anti-Tr/DNER, other antibodies, diagnostic pitfalls, summary and outlook.

PubMed

Jarius, S; Wildemann, B

2015-09-17

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa head antibodies' due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

Too clean, or not too clean: the Hygiene Hypothesis and home hygiene

PubMed Central

Bloomfield, SF; Stanwell-Smith, R; Crevel, RWR; Pickup, J

2006-01-01

Summary The ‘hygiene hypothesis’ as originally formulated by Strachan, proposes that a cause of the recent rapid rise in atopic disorders could be a lower incidence of infection in early childhood, transmitted by unhygienic contact with older siblings. Use of the term ‘hygiene hypothesis’ has led to several interpretations, some of which are not supported by a broader survey of the evidence. The increase in allergic disorders does not correlate with the decrease in infection with pathogenic organisms, nor can it be explained by changes in domestic hygiene. A consensus is beginning to develop round the view that more fundamental changes in lifestyle have led to decreased exposure to certain microbial or other species, such as helminths, that are important for the development of immunoregulatory mechanisms. Although this review concludes that the relationship of the hypothesis to hygiene practice is not proven, it lends strong support to initiatives seeking to improve hygiene practice. It would however be helpful if the hypothesis were renamed, e.g. as the ‘microbial exposure’ hypothesis, or ‘microbial deprivation’ hypothesis, as proposed for instance by Bjorksten. Avoiding the term ‘hygiene’ would help focus attention on determining the true impact of microbes on atopic diseases, while minimizing risks of discouraging good hygiene practice. PMID:16630145

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

PubMed

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

2017-10-01

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

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

PubMed

Riabova, M A

2011-01-01

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

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

ERIC Educational Resources Information Center

Hulbert, T. P.

1994-01-01

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

Familial autoimmune myasthenia gravis with different pathogenetic antibodies.

PubMed Central

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

1988-01-01

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

Testicular cancer in twins: a meta-analysis.

PubMed

Neale, R E; Carrière, P; Murphy, M F G; Baade, P D

2008-01-15

In a meta-analysis of testicular cancer in twins, twins had a 30% increased risk (estimate 1.31, 95% CI 1.1-1.6), providing indirect support for the hypothesis that in utero hormone variations influence risk of testicular cancer. The summary-estimate for dizygotic twins was 1.3 (1.0-1.7) and for monozygotic or same sex twins 1.4 (1.2-1.8).

Microarray-Based Gene Expression Analysis for Veterinary Pathologists: A Review.

PubMed

Raddatz, Barbara B; Spitzbarth, Ingo; Matheis, Katja A; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Ulrich, Reiner

2017-09-01

High-throughput, genome-wide transcriptome analysis is now commonly used in all fields of life science research and is on the cusp of medical and veterinary diagnostic application. Transcriptomic methods such as microarrays and next-generation sequencing generate enormous amounts of data. The pathogenetic expertise acquired from understanding of general pathology provides veterinary pathologists with a profound background, which is essential in translating transcriptomic data into meaningful biological knowledge, thereby leading to a better understanding of underlying disease mechanisms. The scientific literature concerning high-throughput data-mining techniques usually addresses mathematicians or computer scientists as the target audience. In contrast, the present review provides the reader with a clear and systematic basis from a veterinary pathologist's perspective. Therefore, the aims are (1) to introduce the reader to the necessary methodological background; (2) to introduce the sequential steps commonly performed in a microarray analysis including quality control, annotation, normalization, selection of differentially expressed genes, clustering, gene ontology and pathway analysis, analysis of manually selected genes, and biomarker discovery; and (3) to provide references to publically available and user-friendly software suites. In summary, the data analysis methods presented within this review will enable veterinary pathologists to analyze high-throughput transcriptome data obtained from their own experiments, supplemental data that accompany scientific publications, or public repositories in order to obtain a more in-depth insight into underlying disease mechanisms.

[HLA-B27 Positive Acute Anterior Uveitis - A Translational Perspective].

PubMed

Heiligenhaus, Arnd; Kasper, Maren; Grajewski, Rafael

2017-05-01

Background HLA-B27 positive acute anterior uveitis is the most common type of uveitis, and it is an autoimmune disease that can be triggered by infections. The precise mechanism of the interaction between involved microbes (mostly gram negative bacteria) and the host immune system is not clear. The disease probably results from an imbalance between pro- and anti-inflammatory components. Project description This article gives a compact overview about the current knowledge of the clinic and the etiopathogenesis of acute anterior uveitis as a basis for future research approaches. The goal of the current research is to classify the cellular and molecular pathogenetic factors in acute anterior uveitis. In this regard, a project on uveitis within the clinical research unit FOR 2240 "(Lymph)Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye", examines the hypothesis that dysregulation of regulatory cell populations and anti-inflammatory cytokines, such as interleukin-10 (IL-10), might contribute to the development of ocular autoimmunity following infections. The goal is to establish new markers for individual susceptibility in the risk group of the HLA-B27 positive population, because only about 1% of the HLA-B27 positive population will eventually develop acute anterior uveitis. Conclusions Translational research approaches to identify predisposed risk groups from the HLA-B27 population could improve patient care both on a prophylactic and a therapeutic level. Georg Thieme Verlag KG Stuttgart · New York.

Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. off.

PubMed Central

Goligorsky, M S; DiBona, G F

1993-01-01

Reorientation of the alpha 3 subunit of integrins from predominantly basal to the apical cell surface of cultured renal tubular epithelial cells subjected to oxidant stress has previously been demonstrated. The present study was designed to assess functional competence of ectopically expressed apical integrins. Cell-cell adhesion assay revealed enhanced cytoatractant properties of stressed cells. Stressed epithelial cells exhibited specific recognition and binding of laminin-coated latex beads. These processes were inhibited with the peptide Gly-Arg-Gly-Asp-Asn-Pro (GRGDNP) suggesting a role of RGD-recognizing integrins in augmented adhesion to stressed cells. Given that such enhanced adhesion in in vivo acute renal failure may govern tubular obstruction by desquamated epithelium, a physiological marker of patency of tubular lumen, proximal tubular pressure, was monitored in rats subjected to 60 min of renal ischemia followed by reperfusion. Proximal tubular pressure increased 2-fold after 2 hr of reperfusion in animals that had undergone 60 min of ischemia. Infusion of GRGDNP into the renal artery during reperfusion period virtually abolished an increase in proximal tubular pressure observed in ischemic acute renal failure. These in vitro and in vivo findings are consistent with the hypothesis that RGD-recognizing integrins play an important role in the pathogenesis of tubular obstruction in ischemic acute renal failure. Images Fig. 2 Fig. 3 PMID:8516318

Effect of desipramine and fluoxetine on energy metabolism of cerebral mitochondria.

PubMed

Villa, Roberto Federico; Ferrari, Federica; Gorini, Antonella; Brunello, Nicoletta; Tascedda, Fabio

2016-08-25

Brain bioenergetic abnormalities in mood disorders were detected by neuroimaging in vivo studies in humans. Because of the increasing importance of mitochondrial pathogenetic hypothesis of Depression, in this study the effects of sub-chronic treatment (21days) with desipramine (15mg/kg) and fluoxetine (10mg/kg) were evaluated on brain energy metabolism. On mitochondria in vivo located in neuronal soma (somatic) and on mitochondria of synapses (synaptic), the catalytic activities of regulatory enzymes of mitochondrial energy-yielding metabolic pathways were assayed. Antidepressants in vivo treatment modified the activities of selected enzymes of different mitochondria, leading to metabolic modifications in the energy metabolism of brain cortex: (a) the enhancement of cytochrome oxidase activity on somatic mitochondria; (b) the decrease of malate, succinate dehydrogenase and glutamate-pyruvate transaminase activities of synaptic mitochondria; (c) the selective effect of fluoxetine on enzymes related to glutamate metabolism. These results overcome the conflicting data so far obtained with antidepressants on brain energy metabolism, because the enzymatic analyses were made on mitochondria with diversified neuronal in vivo localization, i.e. on somatic and synaptic. This research is the first investigation on the pharmacodynamics of antidepressants studied at subcellular level, in the perspective of (i) assessing the role of energy metabolism of cerebral mitochondria in animal models of mood disorders, and (ii) highlighting new therapeutical strategies for antidepressants targeting brain bioenergetics. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Cortisol Awakening Response in Elite Military Men: Summary Parameters, Stability Measurement, and Effect of Compliance.

PubMed

Taylor, Marcus K; Hernández, Lisa M; Fuller, Shiloah A; Sargent, Paul; Padilla, Genieleah A; Harris, Erica

2016-11-01

The cortisol awakening response (CAR) holds promise as a clinically important marker of health status. However, CAR research is routinely challenged by its innate complexity, sensitivity to confounds, and methodological inconsistencies. In this unprecedented characterization of CAR in elite military men (N = 58), we established summary parameters, evaluated sampling stability across two consecutive days, and explored the effect of subject compliance. Average salivary cortisol concentrations increased nearly 60% within 30 minutes of waking, followed by a swift recovery to waking values at 60 minutes. Approximately one in six were classified as negative responders (i.e., <0% change from waking to 30-minute postawakening). Three summary parameters of magnitude, as well as three summary parameters of pattern, were computed. Consistent with our hypothesis, summary parameters of magnitude displayed superior stability compared with summary parameters of pattern in the total sample. As expected, compliance with target sampling times was relatively good; average deviations of self-reported morning sampling times in relation to actigraph-derived wake times across both days were within ±5 minutes, and nearly two-thirds of the sample was classified as CAR compliant across both days. Although compliance had equivocal effects on some measures of magnitude, it substantially improved the stability of summary parameters of pattern. The first of its kind, this study established the foundation for a program of CAR research in a profoundly resilient yet chronically stressed population. Building from this, our forthcoming research will evaluate demographic, biobehavioral, and clinical determinants of CAR in this unique population. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

Multiple Hypothesis Testing for Experimental Gingivitis Based on Wilcoxon Signed Rank Statistics

PubMed Central

Preisser, John S.; Sen, Pranab K.; Offenbacher, Steven

2011-01-01

Dental research often involves repeated multivariate outcomes on a small number of subjects for which there is interest in identifying outcomes that exhibit change in their levels over time as well as to characterize the nature of that change. In particular, periodontal research often involves the analysis of molecular mediators of inflammation for which multivariate parametric methods are highly sensitive to outliers and deviations from Gaussian assumptions. In such settings, nonparametric methods may be favored over parametric ones. Additionally, there is a need for statistical methods that control an overall error rate for multiple hypothesis testing. We review univariate and multivariate nonparametric hypothesis tests and apply them to longitudinal data to assess changes over time in 31 biomarkers measured from the gingival crevicular fluid in 22 subjects whereby gingivitis was induced by temporarily withholding tooth brushing. To identify biomarkers that can be induced to change, multivariate Wilcoxon signed rank tests for a set of four summary measures based upon area under the curve are applied for each biomarker and compared to their univariate counterparts. Multiple hypothesis testing methods with choice of control of the false discovery rate or strong control of the family-wise error rate are examined. PMID:21984957

Sleep Related Breathing Disorders in Adults with Down Syndrome.

ERIC Educational Resources Information Center

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

2003-01-01

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

Renal involvement in Gaucher's disease.

PubMed Central

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

1981-01-01

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

[Canine atopic dermatitis].

PubMed

Bensignor, Emmanuel

2010-10-01

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

Pathogenetic Basis of Aortopathy and Aortic Valve Disease

ClinicalTrials.gov

2018-02-19

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

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

PubMed

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

2013-02-01

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

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

PubMed

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

1993-03-01

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

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

ERIC Educational Resources Information Center

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

2007-01-01

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

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

PubMed

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

1993-02-01

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

Pathogenesis diagnosis and management of paraneoplastic glomerulonephritis

PubMed Central

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

2011-01-01

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

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

PubMed

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

1991-06-01

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

A comparison of predictions obtained from wind tunnel tests and the results from cruising flight: Airbus and Concorde. [conferences

NASA Technical Reports Server (NTRS)

Berger, J.

1979-01-01

Following a summary of the methods used to establish aerodynamic data and propulsion data, a comparison was made in the form of the drag (or thrust) difference between flight results and predictions made on the basis of these data. Certain hypothesis and improvements on aerodynamic data were presented in order to explain the slight deficit found on Airbus and Concorde.

Hetero-Interfaces For Extreme Electronic Environments

DTIC Science & Technology

2014-07-23

summary of such new hypothesis and supporting or conflicting results we have observed in the path to understand the electrical behavior of such oxide ...interface Ti4+ becomes Ti3.5+. Unlike semiconductors, at the oxide interface there can be multiple quantum wells; sub-bands of Ti 3d orbitals exist... oxidizing conditions, the conductivity decreases tremendously as also shown in our results (Figure 2); an unexpected result if the electronic

West Virginians in Their Own State and in Cleveland, Ohio. Summary and Conclusions of a Comparative Social Study. West Virginia University, Appalachian Center Information Report 3.

ERIC Educational Resources Information Center

Photiadis, John D.

Nonmigrants, returned migrants, migrants living in Cleveland ghettos, and migrants living in Cleveland suburbs were studied in order to: (1) examine social and sociopsychological characteristics of West Virginians living in their own state and in Cleveland and (2) test the hypothesis that in order to satisfy societal expectations in terms of…

Testicular cancer in twins: a meta-analysis

PubMed Central

Neale, R E; Carrière, P; Murphy, M F G; Baade, P D

2007-01-01

In a meta-analysis of testicular cancer in twins, twins had a 30% increased risk (estimate 1.31, 95% CI 1.1–1.6), providing indirect support for the hypothesis that in utero hormone variations influence risk of testicular cancer. The summary-estimate for dizygotic twins was 1.3 (1.0–1.7) and for monozygotic or same sex twins 1.4 (1.2–1.8). PMID:18071360

[Animal models of neurodegenerative diseases].

PubMed

Langui, Dominique; Lachapelle, François; Duyckaerts, Charles

2007-02-01

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

Fully Bayesian tests of neutrality using genealogical summary statistics.

PubMed

Drummond, Alexei J; Suchard, Marc A

2008-10-31

Many data summary statistics have been developed to detect departures from neutral expectations of evolutionary models. However questions about the neutrality of the evolution of genetic loci within natural populations remain difficult to assess. One critical cause of this difficulty is that most methods for testing neutrality make simplifying assumptions simultaneously about the mutational model and the population size model. Consequentially, rejecting the null hypothesis of neutrality under these methods could result from violations of either or both assumptions, making interpretation troublesome. Here we harness posterior predictive simulation to exploit summary statistics of both the data and model parameters to test the goodness-of-fit of standard models of evolution. We apply the method to test the selective neutrality of molecular evolution in non-recombining gene genealogies and we demonstrate the utility of our method on four real data sets, identifying significant departures of neutrality in human influenza A virus, even after controlling for variation in population size. Importantly, by employing a full model-based Bayesian analysis, our method separates the effects of demography from the effects of selection. The method also allows multiple summary statistics to be used in concert, thus potentially increasing sensitivity. Furthermore, our method remains useful in situations where analytical expectations and variances of summary statistics are not available. This aspect has great potential for the analysis of temporally spaced data, an expanding area previously ignored for limited availability of theory and methods.

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

PubMed

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

2012-01-01

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

[Malassezia related diseases].

PubMed

Sei, Yoshihiro

2012-01-01

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

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

ERIC Educational Resources Information Center

Back, Stephen A.

2006-01-01

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

Update on embryology of the upper limb.

PubMed

Al-Qattan, Mohammad M; Kozin, Scott H

2013-09-01

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

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

PubMed

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

2015-07-01

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

Trust in Leadership DEOCS 4.1 Construct Validity Summary

DTIC Science & Technology

2017-08-01

Item Corrected Item- Total Correlation Cronbach’s Alpha if Item Deleted Four-point Scale Items I can depend on my immediate supervisor to meet...1974) were used to assess the fit between the data and the factor. The BTS hypothesizes that the correlation matrix is an identity matrix. The...to reject the null hypothesis that the correlation matrix is an identity, and to conclude that the factor analysis is an appropriate method to

Neurotox-98 Neuroprotection by Progesterones Through Stimulation of Mitochondrial Gene Expression

DTIC Science & Technology

2006-06-01

excitotoxicity that leads to neuronal cell loss. However, surprisingly little is known of the mechanism for this effect . The working hypothesis for the...regulation that is independent of energy status of the cell . Although not included in the publication, we tested for effects of progesterone on... effects (Goodman et al., 1996); however, high levels of progesterone did nothing to protect the animals from seizures or neuronal cell death. In summary

Occupational exposure to polychlorinated biphenyls and risk of cutaneous melanoma: a meta-analysis.

PubMed

Boffetta, Paolo; Catalani, Simona; Tomasi, Cesare; Pira, Enrico; Apostoli, Pietro

2018-01-01

The aim of this study was to carry out a meta-analysis of studies on exposure to polychlorinated biphenyls (PCBs) and the risk of malignant melanoma (MM). We searched Scopus, PubMed, and reference lists; among 807 potentially relevant articles, we selected those based on 12 populations. Data were extracted according to a standardized form; the Newcastle-Ottawa Scale was used to assess study quality. Meta-analyses were carried out according to fixed-effect and random-effects models. The fixed-effect summary relative risk (RR) for MM was 0.91 [95% confidence interval (CI): 0.82-1.00]; the random-effects summary RR was 1.05 (95% CI: 0.78-1.32). The random-effects summary RR from eight occupational cohorts was 1.13 (95% CI: 0.91-1.35) and that from four community-based studies was 0.84 (95% CI: 0.36-1.31). The quality of the studies and the methods for PCB exposure assessment did not influence the RR. These results do not support the hypothesis of an association between PCB exposure and the risk of MM.

Potential Theory for Directed Networks

PubMed Central

Zhang, Qian-Ming; Lü, Linyuan; Wang, Wen-Qiang; Zhou, Tao

2013-01-01

Uncovering factors underlying the network formation is a long-standing challenge for data mining and network analysis. In particular, the microscopic organizing principles of directed networks are less understood than those of undirected networks. This article proposes a hypothesis named potential theory, which assumes that every directed link corresponds to a decrease of a unit potential and subgraphs with definable potential values for all nodes are preferred. Combining the potential theory with the clustering and homophily mechanisms, it is deduced that the Bi-fan structure consisting of 4 nodes and 4 directed links is the most favored local structure in directed networks. Our hypothesis receives strongly positive supports from extensive experiments on 15 directed networks drawn from disparate fields, as indicated by the most accurate and robust performance of Bi-fan predictor within the link prediction framework. In summary, our main contribution is twofold: (i) We propose a new mechanism for the local organization of directed networks; (ii) We design the corresponding link prediction algorithm, which can not only testify our hypothesis, but also find out direct applications in missing link prediction and friendship recommendation. PMID:23408979

Debates—Hypothesis testing in hydrology: Pursuing certainty versus pursuing uberty

NASA Astrophysics Data System (ADS)

Baker, Victor R.

2017-03-01

Modern hydrology places nearly all its emphasis on science-as-knowledge, the hypotheses of which are increasingly expressed as physical models, whose predictions are tested by correspondence to quantitative data sets. Though arguably appropriate for applications of theory to engineering and applied science, the associated emphases on truth and degrees of certainty are not optimal for the productive and creative processes that facilitate the fundamental advancement of science as a process of discovery. The latter requires an investigative approach, where the goal is uberty, a kind of fruitfulness of inquiry, in which the abductive mode of inference adds to the much more commonly acknowledged modes of deduction and induction. The resulting world-directed approach to hydrology provides a valuable complement to the prevailing hypothesis- (theory-) directed paradigm.