Component Of Pathology Research Articles

Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability.

The biological mechanisms driving disability worsening in multiple sclerosis (MS) are only partly understood. Monitoring changes in lesion load on MRI has a limited predictive value on the progression of clinical disability, and there is an essential need for novel imaging markers specific for the main candidate mechanisms underlying neurodegeneration which include failing myelin repair, innate immune cell activation and gray matter neuronal damage. Positron Emission Tomography (PET) is an imaging technology based on the injection of radiotracers directed against specific molecular targets, which has recently allowed the selective quantification in-vivo of the key biological mechanisms relevant to MS pathophysiology. Pilot PET studies performed in patients with all forms of MS allowed to revisit the contribution of MS lesions to disability worsening and showed that the evolution of lesions toward chronic activation, together with their remyelination profile were relevant predictors of disability worsening. PET offers the opportunity to bridge a critical gap between neuropathology and in-vivo imaging. This technique provides an original approach to disentangle some of the most relevant pathological components driving MS progression, to follow-up their temporal evolution, to investigate their clinical relevance and to evaluate novel therapeutics aimed to prevent disease progression.

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last Decade.

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.

Borderline personality disorder is equally trait-like and state-like over ten years in adult psychiatric patients.

Borderline personality disorder (PD) has historically been cast as an unabating condition. Longitudinal data, however, support a more variable time course marked by remission and relapse. In the present study, we tested the possibility that borderline PD has both stable (i.e., consistently present across time and situation, as modern diagnostic systems stipulate) and dynamic (i.e., episodic and situational) elements. Participants were 668 patients from the Collaborative Longitudinal Personality Disorders Study who were administered semistructured diagnostic interviews 5 times over a decade. Trait-state-occasion modeling dissected borderline pathology into time-invariant (i.e., trait) and time-varying (i.e., state) components. Contradicting traditional views of PD intransigence, less than half of borderline PD variability (approximately 45%) was time-invariant (i.e., perfectly stable) over the study timeframe. Furthermore, we found that the time-invariant component of borderline pathology, which we termed borderline proneness, was very closely related (r = .81) to a previously validated Five Factor Model trait composite of borderline features. Moreover, the trait versus state components showed a clear pattern of discriminant validity in relation to several putative causal agents for borderline PD (i.e., environmental pathogens, temperament dimensions). We conclude that borderline pathology contains a stable core and sizable situational components, and that both elements relate systematically to normative personality dimensions and known risk factors. These findings have key implications for etiological research, prognosis, and treatment for borderline PD. (PsycINFO Database Record

Symbolic analysis of electric networks with higher order summative cofactors and parameter decision diagrams

SummaryThe paper introduces the concept of higher order summative cofactors (HOSCs) to the circuit analysis. Although the concept is not new, it is not well known. In the paper, some mathematical background of HOSCs is presented. The further development of the concept of HOSC will yield computer implementation arithmetic of HOSC. A cancellation‐free symbolic analysis technique, which is based on HOSC arithmetic, is presented. This technique allows results to be created directly from a netlist in the form of a binary decision diagram, which is called a parameter decision diagram. Additionally, HOSC arithmetic allows the calculation to be started in many places (sometimes distant) simultaneously. The techniques of rolling up the already analyzed parts of a circuit, which is built into HOSC arithmetic, result in a novel multilevel hierarchical analysis method that is called hierarchical parameter decision diagram (HPDD). Unlike in most hierarchical methods, the results that are obtained based on the subcircuit representation in HPDD always maintain a cancellation‐free form. The HPDD always represents the sum of the product form, which is heavily compressed due to the self‐similarities of the actual circuit. The time that is required for any recalculation of the transfer functions is greatly reduced. Analysis of models that are based on pathological components is also a natural consequence of using HOSC arithmetic.

Alterations of functional circuitry in aging brain and the impact of mutated APP expression.

Alzheimer's disease (AD) is a disease of aging that results in cognitive impairment, dementia, and death. Pathognomonic features of AD are amyloid plaques composed of proteolytic fragments of the amyloid precursor protein (APP) and neurofibrillary tangles composed of hyperphosphorylated tau protein. One type of familial AD occurs when mutant forms of APP are inherited. Both APP and tau are components of the microtubule-based axonal transport system, which prompts the hypothesis that axonal transport is disrupted in AD, and that such disruption impacts cognitive function. Transgenic mice expressing mutated forms of APP provide preclinical experimental systems to study AD. Here, we perform manganese-enhanced magnetic resonance imaging to study transport from hippocampus to forebrain in four cohorts of living mice: young and old wild-type and transgenic mice expressing a mutant APP with both Swedish and Indiana mutations (APPSwInd). We find that transport is decreased in normal aging and further altered in aged APPSwInd plaque-bearing mice. These findings support the hypothesis that transport deficits are a component of AD pathology and thus may contribute to cognitive deficits.

Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

Inhibitory failure represents a core dysfunction in patients with schizophrenia (SP), which has predominantly been tested in the literature using reactive (ie, altering behavior after a stimulus) rather than proactive (ie, purposefully changing behavior before a stimulus) response inhibition tasks. The current study replicates/extends our previous findings of SP exhibiting sensorimotor cortex (SMC) hyperactivity and connectivity abnormalities in independent samples of patients and controls. Specifically, 49 clinically well-characterized SP and 54 matched healthy controls (HC) performed a proactive response inhibition task while undergoing functional magnetic resonance imaging and resting-state data collection. Results indicated that the majority of SP (84%) and HC (88%) successfully inhibited all overt motor responses following a cue, eliminating behavioral confounds frequently present in this population. Observations of left SMC hyperactivity during proactive response inhibition, reduced cortical connectivity with left SMC, and increased connectivity between left SMC and ventrolateral thalamus were replicated for SP relative to HC in the current study. Similarly, negative symptoms (eg, motor retardation) were again associated with SMC functional and connectivity abnormalities. In contrast, findings of a negative blood oxygenation level-dependent response in the SMC of HC did not replicate. Collectively, current and previous findings suggest that SMC connectivity abnormalities may be more robust relative to evoked hemodynamic signals during proactive response inhibition. In addition, there is strong support that these SMC abnormalities are a key component of SP pathology, along with dysfunction within other sensory cortices, and may be associated with certain clinical deficits such as negative symptoms.

Depletion of Ubiquilin induces an augmentation in soluble ubiquitinated Drosophila TDP-43 to drive neurotoxicity in the fly

The proteostasis machinery has critical functions in metabolically active cells such as neurons. Ubiquilins (UBQLNs) may decide the fate of proteins, with its ability to bind and deliver ubiquitinated misfolded or no longer functionally required proteins to the ubiquitin-proteasome system (UPS) and/or autophagy. Missense mutations in UBQLN2 have been linked to X-linked dominant amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD). Although aggregation-prone TAR DNA-binding protein 43 (TDP-43) has been recognized as a major component of the ubiquitin pathology, the mechanisms by which UBQLN involves in TDP-43 proteinopathy have not yet been elucidated in detail. We previously characterized a new Drosophila Ubiquilin (dUbqn) knockdown model that produces learning/memory and locomotive deficits during the proteostasis impairment. In the present study, we demonstrated that the depletion of dUbqn markedly affected the expression and sub-cellular localization of Drosophila TDP-43 (TBPH), resulting in a cytoplasmic ubiquitin-positive (Ub+) TBPH pathology. Although we found that the knockdown of dUbqn widely altered and affected the turnover of a large number of proteins, we herein showed that an augmented soluble cytoplasmic Ub+-TBPH is as a crucial source of neurotoxicity following the depletion of dUbqn. We demonstrated that dUbqn knockdown-related neurotoxicity may be rescued by either restoring the proteostasis machinery or reducing the expression of TBPH. These novel results extend our knowledge on the UBQLN loss-of-function pathomechanism and may contribute to the identification of new therapeutics for ALS-FTD and aging-related diseases.

2313 Characterization of the host pericyte role in glioblastoma angiogenesis

OBJECTIVES/SPECIFIC AIMS: Glioblastoma (GBM) carries a prognosis of 14.6 months mean survival despite maximal surgical, chemotherapeutic, and radiation therapy. The pericyte is a recently characterized cell shown to be a critical component of cerebral vessel physiology and pathology. Importantly, alterations in pericyte densities have shown resulting changes in breast and lung tumor growth. We leverage transgenic pericyte-deficient mouse models to evaluate resulting behavior of implanted patient-derived GBM. METHODS/STUDY POPULATION: Patient-derived, green fluorescent protein labeled, GBM will be implanted in right frontal bregma of both 6-month old pericyte-deficient (PDGFR+/−) mice and age-matched wild-type littermate controls (IACUC 20755, IRB 16-00929), which are immunosuppressed via daily intraperitoneal cyclosporine injection. In total, 30 mice of both genders are included in tumor and control cohorts. Fixed cortical sections following 3-week period will be stained for pericytes (NG2), endothelium (CD31), hypoxia (piminidazole), and tumor size. One-way ANOVA with will used to compare groups using SAS software (Cary, NC). RESULTS/ANTICIPATED RESULTS: Feasibility studies show robust in vitro growth of patient-derived GBM cells, showing continued growth over 10 cellular division passages. Lentivirally transduced GFP reveals reliable tumor tracking both in vitro and in vivo. Transgenic mice at 6 months display reproducibly decreased pericyte and microvascular density in triplicate. Wild-type mice tolerate tumor injection up to three weeks with visible tumor growth, peritumoral hypervascularity, and no evidence of mouse neural dysfunction. With current cohorts recently implanted with tumor, we anticipate a significant decrease in tumor size with Cohen’s d effect size of 0.5 in GBM implanted in pericyte-deficient mice when compared to control. Effect sizes are based moderate to large (effect size 0.5–0.8) reductions of in vitro GBM growth in vascular gene (TGF-β knockdown studies). In addition, tagged tumor-derived pericytes should comprise a greater proportion of new vasculature in pericyte-knockdown mice to overcome host pericyte depletion. Finally, tumors in transgenic mice should show increased hypoxia from limitations in angiogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: Feasibility studies show successful tracking of fluorescently tagged-patient derived GBM samples in transgenic mice with decreased vasculature. GBM grafts show no evidence of immunogenic response with cyclosporine protocol. Successful limitation of tumor size with reduced pericyte density will provide support to increasing study of blood-brain barrier, stem cell activity and inflammatory activity of pericyte microenvironments altering GBM behavior. Furthermore, implementation of known pericyte targeted therapies, such as imantinib, can be evaluated for GBM patient treatment efficacy. Studies with assembled clinical translational research scholar mentorship team will allow the principal investigator to develop an independent career with laboratory focused on contributing to improved patient outcomes, translating successful pericyte-targeted results to patient trials.

2267 Radiofrequency renal denervation attenuates kidney fibrosis in spontaneously hypertensive rats

OBJECTIVES/SPECIFIC AIMS: The goal of this study was to investigate whether RF-RDN attenuates renal fibrosis and inflammation in SHR with established hypertension. METHODS/STUDY POPULATION: Twenty-two-week-old SHR received bilateral RF-RDN or Sham-RDN (Biosense Webster Stockert 70 generator and RF-probe). Four weeks later, SHR were sacrificed and paraffin sections of kidneys were stained for fibrosis by Masson’s trichrome staining. Kidney tissue were homogenized for measurement of cytokines levels by ELISA. RESULTS/ANTICIPATED RESULTS: The results showed that Sham-RDN treated SHR had extensive fibrosis as demonstrated by moderate thickening of Bowman’s capsule, collagen deposition in glomerulus, extensive tubulointerstitial fibrosis, and segmental glomerulosclerosis. In contrast, RF-RDN significantly reduced each of these pathological components of fibrosis in kidney cortex and medulla as compared with Sham-RDN treated kidneys. In other studies, RF-RDN decreased B cells, CD4+ T cells, and CD8+ T cells in the kidney of SHR as measured by flow cytometry. Meanwhile, kidney tissue levels of IL-17, INF-γ, MIP-3a, TNF-α, and TGF-β were decreased as compared with respective levels in Sham-RDN. DISCUSSION/SIGNIFICANCE OF IMPACT: Together, these findings demonstrate that removal of the influence of heightened renal sympathetic activity by RF-RDN decreases kidney inflammatory markers and attenuates renal fibrosis in hypertensive SHR.

Tricuspid Regurgitation - Medical Management and Evolving Interventional Concepts.

Severe tricuspid regurgitation (TR) is a complex condition of the right ventricle (RV) and tricuspid valve apparatus and is frequently associated with symptomatic heart failure and a significant morbidity and mortality. In these patients, left heart pathologies lead to chronic pressure overload of the RV, eventually causing progressive RV dilatation and functional TR. Therefore, TR cannot be considered as isolated heart valve disease pathology but has to be understood and treated as one component of a complex structural RV pathology and is frequently also a marker of an advanced stage of cardiac disease. In these patients, medical therapy restricted to diuretics and heart failure medication is frequently ineffective. Also, severe TR in the setting of advanced heart failure constitutes a high risk for cardiac surgery. Neither one of these treatment options has demonstrated a beneficial effect on long-term prognosis. The recent innovations in transcatheter technology led to efforts to develop interventional approaches to severe TR. Multiple innovative treatment concepts are currently under preclinical and clinical investigation to replace or repair TV function. However, up to date none of these approaches is established and there is still a lack of clinical data to support the efficacy of transcatheter TR treatment.

The Exosomal/Total α-Synuclein Ratio in Plasma Is Associated With Glucocerebrosidase Activity and Correlates With Measures of Disease Severity in PD Patients.

Intensive research efforts in the field of Parkinson’s disease (PD) are focusing on identifying reliable biomarkers which possibly help physicians in predicting disease onset, diagnosis, and progression as well as evaluating the response to disease-modifying treatments. Given that abnormal alpha-synuclein (α-syn) accumulation is a primary component of PD pathology, this protein has attracted considerable interest as a potential biomarker for PD. Alpha-synuclein can be detected in several body fluids, including plasma, where it can be found as free form or in association with exosomes, small membranous vesicles secreted by virtually all cell types. Together with α-syn accumulation, lysosomal dysfunctions seem to play a central role in the pathogenesis of PD, given the crucial role of lysosomes in the α-syn degradation. In particular, heterozygous mutations in the GBA1 gene encoding lysosomal enzyme glucocerebrosidase (GCase) are currently considered as the most important risk factor for PD. Different studies have found that GCase deficiency leads to accumulation of α-syn; whereas at the same time, increased α-syn may inhibit GCase function, thus inducing a bidirectional pathogenic loop. In this study, we investigated whether changes in plasma total and exosome-associated α-syn could correlate with disease status and clinical parameters in PD and their relationship with GCase activity. We studied 39 PD patients (mean age: 65.2 ± 8.9; men: 25), without GBA1 mutations, and 33 age-matched controls (mean age: 61.9 ± 6.2; men: 15). Our results showed that exosomes from PD patients contain a greater amount of α-syn compared to healthy subjects (25.2 vs. 12.3 pg/mL, p < 0.001) whereas no differences were found in plasma total α-syn levels (15.7 vs. 14.8 ng/mL, p = 0.53). Moreover, we highlighted a significant increase of plasma exosomal α-syn/total α-syn ratio in PD patients (1.69 vs. 0.89, p < 0.001), which negatively correlates with disease severity (p = 0.014). Intriguingly, a significant inverse correlation between GCase activity and this ratio in PD subjects was found (p = 0.006). Additional and large-scale studies comparing GCase activity and pathological protein levels will be clearly needed to corroborate these data and determine whether the association between key players in the lysosomal system and α-syn can be used as diagnostic or prognostic biomarkers for PD.

Expanded acceptance of acute exacerbation of nonspecific interstitial pneumonia, including 7 additional cases with detailed clinical pathologic correlation.

Acute exacerbation is uncommonly diagnosed in patients with nonspecific interstitial pneumonia (NSIP) and its pathologic features have received relatively little attention compared to idiopathic pulmonary fibrosis. We retrospectively studied 14 consecutive cases of histopathologically proven NSIP by surgical lung biopsy. The diagnosis of acute exacerbation was confirmed clinically. We analyzed whether four reported pathologic features, including organizing pneumonia lesion, alveolar hemorrhage, many fibroblastic foci, and focal hyaline membranes were present and suggestive of acute exacerbation of NSIP or not. Acute exacerbation in patients with NSIP was diagnosed in 8 cases, while the remaining 6 cases were diagnosed as clinically stable. Seven cases of organizing pneumonia lesion, 7 of alveolar hemorrhage, 6 of many fibroblastic foci, and 3 of focal hyaline membranes were identified as the main pathologic components in patients with acute exacerbation. Organizing pneumonia lesion and many fibroblastic foci were identified in 2 and 3 stable cases, respectively. Having more than two components was significantly associated with acute exacerbation. Evaluation of lung biopsies with NSIP for organizing pneumonia lesions, alveolar hemorrhage, many fibroblastic foci, and focal hyaline membranes may be useful to predict the possibility of acute exacerbation.

Eosinophils on Transbronchial Biopsies Are Predictive of Reduced Survival After Lung Transplantation

While eosinophils are recognized as components of acute rejection pathology, the relationship between their presence on transbronchial biopsies (TBBx) and long-term outcomes has not been assessed. The aim of this study is to determine whether eosinophils in lung transplant recipient TBBx is associated with survival and CLAD outcomes.

Radiofrequency Renal Denervation Decreases Fibrosis in Kidney Cortex and Medulla in Spontaneously Hypertensive Rats (SHR)

There are over 8.3 million people in the US that have chronic kidney disease (CKD), which ultimately can progress to end stage renal fibrosis. Despite an increasing prevalence of CKD, there are no new therapies targeting fibrosis. Our previous studies showed that removal of the renal nerves by radiofrequency renal denervation (RF‐RDN) decreases blood pressure, sympathetic activity, and renal inflammation in hypertensive SHR. Renal fibrosis is a common consequence of chronic kidney inflammation. Therefore, these studies investigated whether RF‐RDN will attenuate renal fibrosis in hypertensive SHR. 22‐week old SHR (n=7/group) received bilateral RF‐RDN or Sham‐RDN (Biosense Webster Stockert 70 generator and RF‐probe). Four weeks later, rat kidneys from all animals were harvested and paraffin sections were stained for fibrosis by Masson's trichrome staining. A pathologist, who was blinded to treatment groups, evaluated each kidney section for fibrosis. The results showed that Sham‐RDN treated SHR had extensive fibrosis demonstrated by moderate thickening of Bowman's capsule, collagen deposition in glomerulus, extensive tubulointerstitial fibrosis, and segmental glomerulosclerosis. In contrast, RF‐RDN significantly reduced each of these pathological components of fibrosis in kidney cortex and medulla. Chemokines play a critical role in mediating the infiltration of immune cells and subsequent fibrosis formation. Therefore, in other studies we measured (ELISA) expression levels of Chemokine ligand 5 (CCL5), CCL2 and CXCL16 in kidney homogenates from RF‐RDN or Sham‐RDN SHR. RF‐RDN decreased CCL5 expression in kidney of SHR compared to Sham‐RDN (78.9±1.7 vs 87.9±2.7 pg/mg protein). RF‐RDN did not alter CCL5 expression in normotensive WKY (68.0±2.2 vs 68.4±3.3 pg/mg protein). These findings suggest that RF‐RDN may offer a novel therapy for renal fibrosis and CCL5 may serve as a potential therapeutic target to treat CKD.Support or Funding InformationNIGMS of NIH U54 GM104940 LA CaTS Roadmap Scholar to JG. NIH P30GM106392 to DRK &amp; Pilot project to JG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CD58; leucocyte function adhesion-3 (LFA-3) could be used as a differentiating marker between immune and non-immune thyroid disorders

The link between Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) has been debated for decades due to the shared pathological and immunological components. Immune intolerance and inappropriate immune reaction against self-thyroid cells are distinctive features of both diseases, but definitive data for the clinical presentation of autoimmune thyroid disease remains unclear. To analyse the expression of T-regulatory cells, CD58, the CD4/CD8 ratio and the neutrophil/lymphocyte ratio and to determine if these parameters could be used as differentiating markers between auto- and non-immune thyroid diseases, 75 patients were enrolled in this study—40 with autoimmune thyroid disease (HT and GD ), 15 with non-immune thyroid disease, and 20 healthy controls. Multicolour flow cytometry was used to analyse CD58, T-regulatory cells (Treg) expressing CD4, CD25, HLA-DR and CD8 using different stained fluorescent labelled monoclonal antibodies. The neutrophils and lymphocyte ratio was also measured. Lower expression of Treg with higher expression of CD58 (LFA-3) was found in the autoimmune diseases when compared with the non-immune and control groups. ROC analysis showed that CD58 with sensitivity 88% and specificity 100% with cut-off value more than or equal to 29.9 indicates Hashimoto’s disease, while lower value indicates colloid goitre, and higher or equal to 29.84 indicates Graves’ disease and lower indicates colloid goitre with 100% sensitivity and specificity. CD58 could be used as differentiating marker between immune and non-immune thyroid disorders.

LncRNAs, DNA Methylation, and the Pathobiology of Exfoliation Glaucoma.

Exfoliation glaucoma (XFG) is a clinically aggressive and genetically distinct form of glaucoma that results in neuronal death and irreversible blindness. Gene variants associate with many neurodegenerative diseases including XFG, Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, variants found within the same gene can either confer risk for or provide protection against all 3 of these diseases, complicating the genetic component of pathology. Unfortunately, studies that examine proteins encoded by genes having relevant variants have failed to produce therapeutic interventions that slow or stop the progression of XFG, PD, or AD in patients. This roadblock has researchers focusing on alternative pathways that may be dysregulated and potentially lead to the development of disease. Two emerging areas of research in PD and AD are the pathobiology of long noncoding RNAs and DNA methylation. This review briefly introduces the roles of long noncoding RNAs and DNA methylation in disease pathogenesis, and highlights some of the cutting edge work that has been carried out in PD and AD, along with the limited but important studies in XFG. Finally, we propose a new direction for XFG research that may explain apparently conflicting genetic data and lead to the discovery of novel dysregulated pathways that will allow for targeted therapeutic development.

ICD-11: Neurocognitive Disorders

The section 06 (Mental, Behavioural or Neurodevelopmental Disorders) of the current version Beta Draft (Mortality and Morbidity Statistics, 16.12.2017) of the ICD 11 (International Statistical Classification of Diseases and Related Health Problems) replaces the F0-section of the ICD-10. Several changes, particularly with regard to the classification of neurodegenerative disorders have been introduced. It can be considered a progress that the concept of "organic" syndromes has been dropped and that the section focusses on acquired conditions with cognition as the main area of symptoms. Regarding dementia, the 06 section still uses a syndromal approach of for example dementia due to Alzheimer disease (AD). The development of biomarkers and the molecular concept of AD is not incorporated, yet. In section 08 (Diseases of the Nervous System) Alzheimer disease without reference to symptoms can be classified, however, this section also misses reference to biomarkers, which leaves uncertainty of how the diagnosis should be made.In section 06 the condition of minor neurocognitive disorder was originally only defined as a syndrome without reference to a disease. This has been modified and it is now possible to classify the condition in association with a disease (e. g. AD), however, also without reference to biomarkers.The syndromal approach of section 06 is of value, since in many parts of the world, there is no access to AD biomarkers and all current therapies are tested and in some cases approved for Alzheimer dementia rather than AD as a molecular condition. The lack of any reference to AD biomarkers within ICD-11 so far, however, is a highly relevant limitation with the development of treatments, which target specific components of pathology (e. g. anti-amyloid treatment).

Features of obesity treatment in patients with gastroesophageal reflux disease

В последние несколько десятилетий во всём мире возрастает распространённость таких нозологических форм, как гастроэзофагеальная рефлюксная болезнь и ожирение. Сочетание данных видов патологии чаще отмечают у пациентов, имеющих проблемы в питании и образе жизни, а также генетическую предрасположенность по данным нозологиям. Отмечено, что у пациентов с ожирением повышена предрасположенность к возникновению диафрагмальных грыж и механическому повреждению гастроэзофагеального соединения, что возникает на фоне увеличенного интрагастрального давления и повышенного градиента давления между желудком и пищеводом, а также вследствие растяжения проксимального отдела желудка. Одним из основных патогенетических моментов гастроэзофагеальной рефлюксной болезни бывает спонтанная релаксация нижнего пищеводного сфинктера. Согласно последним исследованиям, при ожирении частота постпрандиальных спонтанных релаксаций нижнего пищеводного сфинктера увеличивается даже при отсутствии диафрагмальных грыж, неэрозивной гастроэзофагеальной рефлюксной болезни и рефлюкс-эзофагита. Многообразие метаболических нарушений, наблюдаемых у данных пациентов, предполагает комплексный подход к лечению, направленный как на эффективное снижение кислотно-пептического фактора, так и на коррекцию избытка массы тела. Среди основных направлений лечения обеих составляющих данной сочетанной патологии выделяют как немедикаментозные, так и медикаментозные методы лечения. Важную роль в терапии отводят мероприятиям, способствующим ведению здорового образа жизни: отказу от курения, снижению массы тела, диетическому питанию, оздоровительной физической культуре. Особое внимание среди лекарственной терапии у пациентов с гастроэзофагеальной рефлюксной болезнью и ожирением, позволяющей достичь оптимального кислотоснижающего эффекта, отводят группе ингибиторов протонной помпы (ингибиторов H+,K+-АТФазы), имеющих более низкую аффинность к печёночной цитохром Р450-ферментной системе, не оказывающей влияния на её активность и не дающей клинически значимых перекрёстных реакций с другими препаратами.

Report and Recommendations of the Association of Pathology Chairs’ Autopsy Working Group

Autopsy has been a foundation of pathology training for many years, but hospital autopsy rates are notoriously low. At the 2014 meeting of the Association of Pathology Chairs, some pathologists suggested removing autopsy from the training curriculum of pathology residents to provide additional months for training in newer disciplines, such as molecular genetics and informatics. At the same time, the American Board of Pathology received complaints that newly hired pathologists recently certified in anatomic pathology are unable to perform an autopsy when called upon to do so. In response to a call to abolish autopsy from pathology training on the one hand and for more rigorous autopsy training on the other, the Association of Pathology Chairs formed the Autopsy Working Group to examine the role of autopsy in pathology residency training. After 2 years of research and deliberation, the Autopsy Working Group recommends the following:Autopsy should remain a component of anatomic pathology training.A training program must have an autopsy service director with defined responsibilities, including accountability to the program director to record every autopsy performed by every resident.Specific entrustable activities should be defined that a resident must master in order to be deemed competent in autopsy practice, as well as criteria for gaining the trust to perform the tasks without direct supervision.Technical standardization of autopsy performance and reporting must be improved.The current minimum number of 50 autopsies should not be reduced until the changes recommended above have been implemented.

Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease.

Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal-Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (1-3), 1 with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free Aβ and metal-Aβ, as well as scavenge free radicals. Compound 2 with the moderate oxidation potential significantly alters the aggregation of Cu(II)-Aβ42. The hardly oxidizable compound, 3, relative to 1 and 2, indicates no noticeable interactions with all pathogenic factors, including metal-free Aβ, metal-Aβ, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties.