tbuckley/cabot-search huggingface dataset:
Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review
Authors: Xiao-dong Pan, Xiao-chun Chen
Journal: Translational Neurodegeneration (2013)

Frontotemporal lobar degeneration (FTLD) represents a group of clinically, neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype. FTLD is pathologically characterized by the frontal and temporal lobar atrophy. Frontotemporal dementia (FTD) clinically presents with abnormalities of behavior and personality and language impairments variants. The clinical spectrum of FTD encompasses distinct canonical syndromes: behavioural variant of FTD (bvFTD) and primary progressive aphasia. The later includes nonfluent/agrammatic variant PPA (nfvPPA or PNFA), semantic variant PPA (svPPA or SD) and logopenic variant PPA (lvPPA). In addition, there is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The FTLD spectrum disorders are based upon the predominant neuropathological proteins (containing inclusions of hyperphosphorylated tau or ubiquitin protein, e.g transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and fusedin-sarcoma protein in neurons and glial cells) into three main categories: (1) microtubule-associated protein tau (FTLD-Tau); (2) TAR DNA-binding protein-43 (FTLD-TDP); and (3) fused in sarcoma protein (FTLD-FUS). There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies, which are chromosome 9 open reading frame 72 (C9ORF72) gene, granulin (GRN) gene, microtubule associated protein tau gene (MAPT), the gene encoding valosin-containing protein (VCP) and the charged multivesicular body protein 2B (CHMP2B). In this review, recent advances on the different clinic variants, neuroimaging, genetics, pathological subtypes and clinicopathological associations of FTD will be discussed.
Cost effectiveness of the determination of autoantibodies against cyclic citrullinated peptide in the early diagnosis of rheumatoid arthritis
Authors: A Konnopka, K Conrad, C Baerwald, H-H Konig
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To estimate the incremental cost-effectiveness ratio (ICER) of antibodies against cyclic citrullinated peptides (aCCP) in the early diagnosis of rheumatoid arthritis (RA). <h3>Methods:</h3> A Markov model was used to model 10-year progression of RA in patients first diagnosed with undifferentiated arthritis (UA) and to estimate the incremental costs and quality-adjusted life years (QALYs) of using aCCP additionally to American College of Rheumatology (ACR) criteria. The impact of later diagnosis and treatment due to non-use of aCCP was modelled as increased Health Assessment Questionnaire (HAQ) progression. Utilities were assigned to HAQ states for calculating QALYs. Uncertainty was analysed using univariate and probabilistic sensitivity analyses (Monte Carlo simulation). <h3>Results:</h3> Baseline ICER was €930/QALY. Univariate sensitivity analyses identified the impact of later diagnosis on HAQ progression as a major source of uncertainty, resulting in an ICER range from "dominance" to €153 092/QALY, compared with a maximum ICER of €4870/QALY for other variables. Monte Carlo simulation resulted in a 95% uncertainty interval from –€3537/QALY (dominance) to €5429/QALY; when indirect costs were considered, Monte Carlo simulation resulted in a 95% uncertainty interval from –€78 115/QALY (dominance) to –€23 444/QALY (dominance). <h3>Conclusions:</h3> Using aCCP in the diagnosis of RA in patients with UA is likely to be cost effective compared with using ACR criteria alone. When indirect costs are incorporated, aCCP seems to save costs. Clearly, more research is needed relating the effects of diagnosis and treatment on the long-term course and the resulting functional impairment of RA as measured by the HAQ.
Specificity of human lymphocyte complement receptors.
Authors: G D Ross, M J Polley
Journal: The Journal of Experimental Medicine (1975)

Erythrocytes, bone marrow-derived lymphocytes, monocytes, and granulocytes were shown to have a receptor activity for C4. Theis C4 receptor activity was studied in relation to the previously identified C3b and C3d receptors. By assay for inhibition of rosette formation by fluid-phase complement (C), only two different lymphocyte C receptors were demonstrated. The immune adherence receptor, the only one of the two shared in common with erythrocytes, was specific for C4 or the C3c region of C3b, but was unreactive with C3d. The other lymphocyte receptor, the C3d receptor, was specific for C3d fragments, but would also react to a lesser extent with the C3d region of uncleaved C3b. ThC3d receptor did not react with either C3c or C4. This specificity of the C3d receptor allowed certain cells which contained only C3d receptors to form rosettes with EAC1-3b and EAC1-3d, but not with EAC14. However, because C3d receptors bound EAC1-3d or C3d fragments more firmly than they did EAC1-3b or C3b fragments, many other types of cells containing only C3d receptors, formed rosettes with EAC1-3d but not with EAC1-3b. Erythrocytes and those lymphocytes which contained only immune adherence receptors, formed rosettes with EAC14 and EAC1-3D but not with EAC1-3d. A double-label assay was devised for the simultaneous detection of both types of C receptors on individual lymphocytes. This assay involved fluorescence labeling of one of the two C receptors with soluble C fragments in combination with the usual rosette method for labeling the other type of C receptor. With this double-label assay, it was observed that the two different lymphocyte C receptors capped independently and thus were located on different molecules which could each move through the fluid membrane matrix independently of the other.
Methylenetetrahydrofolate reductase (MTHFR) 677C&amp;gt;T polymorphism and risk of pediatric non-Hodgkin lymphoma in a German study population
Authors: Martin Stanulla, Kathrin Seidemann, Eckart Schnakenberg, Marion Book, Andrea Mehles, Karl Welte, Martin Schrappe, Alfred Reiter
Journal: Blood (2005)
Coexpressed Nitric Oxide Synthase and Apical β1 Integrins Influence Tubule Cell Adhesion after Cytokine-Induced Injury
Authors: PAUL A. GLYNNE, JOANNA PICOT, THOMAS J. EVANS
Journal: Journal of the American Society of Nephrology (2001)

In sepsis-induced acute renal failure, actin cytoskeletal alterations result in shedding of proximal tubule epithelial cells (PTEC) and tubular obstruction. This study examined the hypothesis that inflammatory cytokines, released early in sepsis, cause PTEC cytoskeletal damage and alter integrin-dependent cell-matrix adhesion. The question of whether the intermediate nitric oxide (NO) modulates these cytokine effects was also examined. After exposure of human PTEC to tumor necrosis factor-alpha, interleukin-1 alpha, and interferon-gamma, the actin cytoskeleton was disrupted and cells became elongated, with extension of long filopodial processes. Cytokines induced shedding of viable, apoptotic, and necrotic PTEC, which was dependent on NO synthesized by inducible NO synthase (iNOS) produced as a result of cytokine actions on PTEC. Basolateral exposure of polarized PTEC monolayers to cytokines induced maximal NO-dependent cell shedding, mediated in part through NO effects on cGMP. Cell shedding was accompanied by dispersal of basolateral beta(1) integrins and E-cadherin, with corresponding upregulation of integrin expression in clusters of cells elevated above the epithelial monolayer. These cells demonstrated coexpression of iNOS and apically redistributed beta(1) integrins. Attachment studies demonstrated that the major ligand involved in cell anchorage was laminin, probably through interactions with the integrin alpha(3)beta(1). This interaction was downregulated by cytokines but was not dependent on NO. These studies provide a mechanism by which inflammatory cytokines induce PTEC damage in sepsis, in the absence of hypotension and ischemia. Future therapeutic strategies aimed at specific iNOS inhibition might inhibit PTEC shedding after cytokine-induced injury and delay the onset of acute renal failure in sepsis.
A Study of Women Who Stalk
Authors: Rosemary Purcell, Michele Pathé, Paul E. Mullen
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors examined whether female stalkers differ from their male counterparts in psychopathology, motivation, behavior, and propensity for violence. METHOD: Female (N=40) and male (N=150) stalkers referred to a forensic mental health clinic were compared. RESULTS: In this cohort, female stalkers were outnumbered by male stalkers by approximately four to one. The demographic characteristics of the groups did not differ, although more male stalkers reported a history of criminal offenses. Higher rates of substance abuse were also noted among the male stalkers, but the psychiatric status of the groups did not otherwise differ. The duration of stalking and the frequency of associated violence were equivalent between groups. The nature of the prior relationship with the victim differed, with female stalkers more likely to target professional contacts and less likely to harass strangers. Female stalkers were also more likely than male stalkers to pursue victims of the same gender. The majority of female stalkers were motivated by the desire to establish intimacy with their victim, whereas men showed a broader range of motivations. CONCLUSIONS: Female and male stalkers vary according to the motivation for their pursuit and their choice of victim. A female stalker typically seeks to attain a close intimacy with her victim, who usually is someone previously known and frequently is a person cast in the professional role of helper. While the contexts for stalking may differ by gender, the intrusiveness of the behaviors and potential for harm does not.
Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System
Authors: Yasuhiro Nakashima, Diana A. Yanez, Marlin Touma, Haruko Nakano, Artur Jaroszewicz, Maria C. Jordan, Matteo Pellegrini, Kenneth P. Roos, Atsushi Nakano
Journal: Circulation Research (2014)

Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation.In this study, we circumvented these limitations by atrial-restricted deletion of Nkx2-5.Atrial-specific Nkx2-5 mutants died shortly after birth with hyperplastic working myocytes and conduction system including two nodes and internodal tracts. Multicolor reporter analysis revealed that Nkx2-5-null cardiomyocytes displayed clonal proliferative activity throughout the atria, indicating the suppressive role of Nkx2-5 in cardiomyocyte proliferation after chamber ballooning stages. Transcriptome analysis revealed that aberrant activation of Notch signaling underlies hyperproliferation of mutant cardiomyocytes, and forced activation of Notch signaling recapitulates hyperproliferation of working myocytes but not the conduction system.Collectively, these data suggest that Nkx2-5 regulates the proliferation of atrial working and conduction myocardium in coordination with Notch pathway.
Reduction of oxaluria after an oral course of lactic acid bacteria at high concentration
Authors: Claudio Campieri, Massimo Campieri, Veronica Bertuzzi, Erwin Swennen, Diego Matteuzzi, Sergio Stefoni, Franco Pirovano, Carla Centi, Salvatore Ulisse, Giuseppe Famularo, Claudio De Simone
Journal: Kidney International (2001)
Doxazosin Induces Apoptosis in Cardiomyocytes Cultured In Vitro by a Mechanism That Is Independent of α <sub>1</sub> -Adrenergic Blockade
Authors: José R. González-Juanatey, María J. Iglesias, Carlos Alcaide, Roberto Piñeiro, Francisca Lago
Journal: Circulation (2003)

The alpha1-adrenoceptor-blocking antihypertensive doxazosin has been associated with increased risk of heart failure and is known to induce prostate cell apoptosis. We hypothesized that it might also induce apoptosis in cardiomyocytes.Hoechst dye vital staining and flow cytometry provided evidence that doxazosin induced apoptosis time- and dose-dependently in cardiomyocytes of the HL-1 cell line. TUNEL assays and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) viability test confirmed that doxazosin induced DNA damage and cell death in these cells. MTT tests showed that doxazosin treatment decreased cell viability in primary cultures of neonatal rat cardiomyocytes, and Hoechst dye vital staining demonstrated doxazosin-induced apoptosis in primary cultures of human adult cardiomyocytes. The proapoptotic effect of doxazosin on cardiomyocytes seems not to depend on alpha1 blockade, because it was not modified by cotreatment with alpha- or beta-adrenergic agonists or with the irreversible alpha1-blocker phenoxybenzamine and because doxazosin also decreased the viability of NIH 3T3 cells, which lack alpha1-adrenoceptors. It also does not involve calcineurin, being unaffected by the presence of the calcineurin inhibitors cyclosporin A and FK506. Three other alpha1-blockers were also investigated; prazosin was proapoptotic, like doxazosin, but 5-methylurapidil and terazosin were not.The alpha1-blockers doxazosin and prazosin induce the apoptosis of cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1 blockade and calcineurin.
Cerebral Infusion of AAV9 Vector-encoding Non-self Proteins Can Elicit Cell-mediated Immune Responses
Authors: Agnieszka Ciesielska, Piotr Hadaczek, Gabriele Mittermeyer, Shangzhen Zhou, J Fraser Wright, Krystof S Bankiewicz, John Forsayeth
Journal: Molecular Therapy (2012)

There is considerable interest in the use of adeno-associated virus serotype 9 (AAV9) for neurological gene therapy partly because of its ability to cross the blood–brain barrier to transduce astrocytes and neurons. This raises the possibility that AAV9 might also transduce antigen-presenting cells (APC) in the brain and provoke an adaptive immune response. We tested this hypothesis by infusing AAV9 vectors encoding foreign antigens, namely human aromatic L-amino acid decarboxylase (hAADC) and green fluorescent protein (GFP), into rat brain parenchyma. Over ensuing weeks, both vectors elicited a prominent inflammation in transduced brain regions associated with upregulation of MHC II in glia and associated lymphocytic infiltration. Transduction of either thalamus or striatum with AAV9-hAADC evinced a significant loss of neurons and induction of anti-hAADC antibodies. We conclude that AAV9 transduces APC in the brain and, depending on the immunogenicity of the transgene, can provoke a full immune response that mediates significant brain pathology. We emphasize, however, that these observations do not preclude the use of AAV serotypes that can transduce APC. However, it does potentially complicate preclinical toxicology studies in which non-self proteins are expressed at a level sufficient to trigger cell-mediated and humoral immune responses. There is considerable interest in the use of adeno-associated virus serotype 9 (AAV9) for neurological gene therapy partly because of its ability to cross the blood–brain barrier to transduce astrocytes and neurons. This raises the possibility that AAV9 might also transduce antigen-presenting cells (APC) in the brain and provoke an adaptive immune response. We tested this hypothesis by infusing AAV9 vectors encoding foreign antigens, namely human aromatic L-amino acid decarboxylase (hAADC) and green fluorescent protein (GFP), into rat brain parenchyma. Over ensuing weeks, both vectors elicited a prominent inflammation in transduced brain regions associated with upregulation of MHC II in glia and associated lymphocytic infiltration. Transduction of either thalamus or striatum with AAV9-hAADC evinced a significant loss of neurons and induction of anti-hAADC antibodies. We conclude that AAV9 transduces APC in the brain and, depending on the immunogenicity of the transgene, can provoke a full immune response that mediates significant brain pathology. We emphasize, however, that these observations do not preclude the use of AAV serotypes that can transduce APC. However, it does potentially complicate preclinical toxicology studies in which non-self proteins are expressed at a level sufficient to trigger cell-mediated and humoral immune responses.
Observer variation in examination of knee joints.
Authors: J S Marks, M K Palmer, M J Burke, P Smith
Journal: Annals of the Rheumatic Diseases (1978)

The knees of 20 patients with rheumatoid arthritis were each examined on two occasions on the same morning by three observers. Assessments were made of joint warmth, synovial thickening, effusion, instability, quadriceps power, bony enlargement, range of movement, and knee circumference, and were graded on a scale of 0-4. Analysis of the results shows close intraobserver agreement for all measurements but considerable interobserver variation for all subjective measurements.
A Piagetian view of imitation
Authors: Harold D. Fishbein
Journal: Behavioral and Brain Sciences (1998)

Byrne &amp; Russon argue that the action and program levels of imitation form two discrete categories, with no intermediate steps. A Piagetian view enlarges our understanding of human and ape imitation by showing the developmental paths that imitation takes in the sensory-motor period of intelligence. It is clear from Piaget's (1945/1962) analysis that the action level of imitation is richly varied and that intermediate steps do occur between the action and program levels.
New Subtype of Spinocerebellar Ataxia With Altered Vertical Eye Movements Mapping to Chromosome 1p32
Authors: Carmen Serrano-Munuera, Marc Corral-Juan, Giovanni Stevanin, Hector San Nicolás, Carles Roig, Jordi Corral, Berta Campos, Laura de Jorge, Carlos Morcillo-Suárez, Arcadi Navarro, Sylvie Forlani, Alexandra Durr, Jaime Kulisevsky, Alexis Brice, Ivelisse Sánchez, Victor Volpini, Antoni Matilla-Dueñas
Journal: JAMA Neurology (2013)

Importance: To provide clinical and genetic diagnoses for patients' conditions, it is important to identify and characterize the different subtypes of spinocerebellar ataxia (SCA). Objective:To clinically and genetically characterize a Spanish kindred with pure SCA presenting with altered vertical eye movements.Design: Family study of ambulatory patients.Electrooculographic and genetics studies were performed in 2 referral university centers.Setting: Primary care institutional center in Spain.Participants: Thirty-six participants from a large Spanish kindred were clinically examined, and 33 family members were genetically examined.Detailed clinical data were obtained from 9 affected relatives.Two ataxic siblings and 2 asymptomatic family members were examined using an enhanced clinical protocol for a follow-up period of 7 years.Main Outcomes and Measures: High-density genomewide single-nucleotide polymorphism arrays, along with microsatellite analysis, and genetic linkage studies were performed.Whole-exome sequencing was used for 2 affected relatives.For most patients, the initial symptoms included falls, dysarthria, or clumsiness followed by a complete cerebellar syndrome.For all 9 affected relatives, we observed altered vertical eye movements, as initial ocular signs for 3 of them and for the 2 asymptomatic family members, all having inherited the risk haplotype.Neuroimaging showed isolated cerebellar atrophy.Results: Initial genome-wide linkage analysis revealed suggestive linkage to chromosome 1p32.Multipoint analysis and haplotype reconstruction further traced this SCA locus to a 0.66-cM interval flanked by D1S200 and D1S2742 (z max =6.539; PϽ .0001).The causative mutation was unidentified by exome sequencing. Conclusions and Relevance:We report a new subtype of SCA presenting in patients as slow progressing ataxia with altered vertical eye movements linked to a 11-megabase interval on 1p32.
Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non–Small-Cell Lung Cancer
Authors: Jin Seuk Kim, Haengbung Lee, Hojoong Kim, Young Mog Shim, Joungho Han, Joobae Park, Duk-Hwan Kim
Journal: Journal of Clinical Oncology (2004)

Purpose To investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARβ2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non–small-cell lung cancer (NSCLC). Patients and Methods We retrospectively analyzed the relationship between RARβ2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARβ2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years. Results SPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARβ2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P = .08) times higher compared to those without RARβ2 methylation. However, for current smokers, hypermethylation of the RARβ2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P = .03). Conclusion Hypermethylation of RARβ2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.
Binding of sulfobromophthalein (BSP) sodium by plasma albumin. Its role in hepatic BSP extraction.
Authors: K J Baker, S E Bradley
Journal: Journal of Clinical Investigation (1966)

When sulfobromophthalein (Bromsulphalein, BSP) sodium was introduced some 40 years ago as a tool for the measurement of liver function, Rosenthal and White (1) reported that solution in serum completely prevented ultrafiltration of the dye through a collodion membrane.They suggested that binding of protein might make BSP and other substances with similar properties, such as bilirubin and rose bengal, more readily available for hepatic removal by preventing their loss in the urine.Although their observation has been repeatedly confirmed (2-7), precise quantitative data referable to BSP concentrations employed in clinical and physiological studies are still lacking.This is so, unfortunately, because the plasma proteins must be diluted 50to 100-fold during examination of the dye-protein interaction by equilibrium dialysis or by ultrafiltration in order to minimize interference by oncotic pressure effects, changing protein concentrations, Gibbs-Donnan equilibria, and various membrane phenomena.To obtain measurable concentrations of BSP, one must work at molar ratios of dye-to-protein far in excess of those ever encountered in zivo.Since saturation of binding sites and alteration in binding capacity may occur at such high ratios, the resulting figures are of somewhat dubious physiological significance.The information available does indicate that after addition to plasma in vitro or by intravenous injection, BSP promptly combines so avidly with albumin that almost none of it is detectable as a "free fraction."Definition of the mechanisms of hepatocellular transport must begin with precise values for the kinetic parameters of the BSP protein interaction to establish whether the initial movement of the dye from the blood to the cells can be accounted for by diffusion of the free frac-*