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Search Results: 1 - 10 of 198871 matches for " David H Small "
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Presenilins and the γ-secretase: still a complex problem
David H Small, David W Klaver, Lisa Foa
Molecular Brain , 2010, DOI: 10.1186/1756-6606-3-7
Abstract: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Typically 5-10% of the population over the age of 65 have dementia, and of these cases, a large percentage have AD [1]. AD is characterised by the presence of proteinaceous deposits in the brain [2]. The extracellular amyloid deposits, which are found in the neuropil (amyloid plaques) and in association with small-medium size cerebral blood vessels (cerebral amyloid angiopathy), are composed of a 4 kDa polypeptide known as the amyloid-β protein (Aβ) which is derived by proteolytic cleavage from a much larger amyloid-β precursor protein (APP) [3]. Aβ displays a spontaneous ability to aggregate into oligomers and larger fibrillar structures, and it is generally thought that the accumulation of oligomeric Aβ is chiefly responsible for the neurodegeneration that occurs in AD [4].For the generation of Aβ, APP is first cleaved on the N-terminal side of the Aβ sequence by the β-site APP cleaving enzyme-1 (BACE1), a transmembrane aspartyl protease [3]. The resulting 99-amino acid residue C-terminal fragment (C99) is then cleaved by the γ-secretase to yield Aβ and a C-terminal APP intracellular domain (AICD) fragment (Fig. 1). The function of the AICD fragment is unclear, although it is thought to have a role in intracellular signalling. For example, AICD may be involved in the regulation of gene transcription, synaptic plasticity and cytoskeletal dynamics [5].The major form of Aβ possesses 40 amino-acid residues (Aβ1-40). However, other minor species are also produced which vary in the C-terminal sequence. Production of a longer 42-residue species (Aβ1-42) is thought to be intimately associated with AD pathogenesis [6]. Aβ1-42 aggregates more readily than Aβ1-40, and increased production of Aβ1-42 may seed aggregation of Aβ1-40 or other Aβ species [4].Approximately 5% of all AD cases are autosomal dominant [7]. Soon after the complete APP sequence was cloned in 1987 [8], it became clear that at le
Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile-Induced colitis following vancomycin withdrawal in mice
Leo R Fitzpatrick, Jeffrey S Small, Wallace H Greene, Kelly D Karpa, Sean Farmer, David Keller
Gut Pathogens , 2012, DOI: 10.1186/1757-4749-4-13
Abstract: The mean stool consistency score in Vehicle/C.difficile/Vanco mice increased from 0.4 (day 10) to a range of 1.1 to 1.4 (days 14 to 17), indicating the recurrence of colitis. On days 13 through 17, the stool consistency scores for the vancomycin/BC30 mice were significantly lower (p< 0.05) than for the vancomycin/vehicle cohort of animals. On day 17, 88.9% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0004). Colonic myeloperoxidase (Units/2 cm colon) was significantly (p < 0.05) reduced from 4.3 ± 0.7 (Vehicle/C.difficile/Vanco) to 2.6 ± 0.2 (BC30/C. Difficle/Vanco). The colonic histology score and Keratinocyte derived-chemokine level in the colon were also lower in BC30 treated mice.In BC30-treated mice, there was evidence of better stool consistency, as well as improved biochemical and histological indices of colitis, following initial treatment of animals with vancomycin.BC30 limited the recurrence of CD-induced colitis following vancomycin withdrawal in mice.Clostridium difficile (C. difficile) infection (CDI) is a very common cause of health-care associated diarrhea and colitis [1]. Moreover, CDI is associated with significant morbidity, as well as increased health care costs [2]. The spectrum of C. difficile associated disease (CDAD) ranges from mild antibiotic associated diarrhea to severe and life threatening pseudomembranous colitis [3]. CDAD is caused by the actions of two toxins (toxin A and toxin B), which are produced by pathogenic strains of C. difficile[4,5]. Toxin A results in the activation of three transcription factors (NF- kB, AP1 and CREB). NF-kB (nuclear factor-kappa B) is involved in chemokine production, and also plays a role in colonocyte apoptosis [6,7]. AP-1 (activator protein-1) plays a role in IL-8 production in response to stimulation of colonocytes with toxin A [8]. CREB (Cyclic-AMP Response Binding Protein) is critical for the production of prostaglandin E2 via inducible cyclo
Bacillus Coagulans GBI-30 (BC30) improves indices of Clostridium difficile-Induced colitis in mice
Leo R Fitzpatrick, Jeffrey S Small, Wallace H Greene, Kelly D Karpa, David Keller
Gut Pathogens , 2011, DOI: 10.1186/1757-4749-3-16
Abstract: All mice treated with BC30 survived on study day 13, while two mice treated with vehicle did not survive. On day 12, a significant difference (p = 0.0002) in the percentage of mice with normal stools (66.7%) was found in the BC30/C. difficile group, as compared to the vehicle/C. diffcile group (13.0%). On study day 16, 23.8% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0187). On this day, the stool consistency score for the BC30/C. difficile group (1.1 ± 0.2) was significantly lower (p < 0.05) than for the vehicle/C. difficile cohort (1.9 ± 0.2). BC30 modestly attenuated the colonic pathology (crypt damage, edema, leukocyte influx) that was present following C. difficile infection. Colonic MIP-2 chemokine contents (pg/2 cm colon) were: 10.2 ± 0.5 (vehicle/no C. difficile), 24.6 ± 9.5 (vehicle/C. difficile) and 16.3 ± 4.3 (BC30/C. difficle).The probiotic BC30 improved some parameters of C. difficile-induced colitis in mice. BC30 prolonged the survival of C. diffiicle infected mice. Particularly, this probiotic improved the stool consistency of mice, in this infectious colitis model.Clostridium Difficile (C. difficile) infection can cause nosocomial-related diarrhea [1]. The spectrum of C. difficile-associated disease (CDAD) ranges from mild antibiotic associated diarrhea to severe (or even life threatening) pseudomembranous colitis [1]. CDAD is caused by the actions of two exotoxins (toxin A and toxin B), which are produced by pathogenic strains of C. difficile [2,3].Previous data suggests that toxin A can activate the nuclear factor-kappa B (NF-κB) signal transduction system in monocytes and colonic epithelial cells [4,5]. This activation of NF-κB leads to secretion of a key pro-inflammatory chemokine (IL-8) and subsequently to neutrophil influx into the colonic tissue [4,5]. Neutrophils play a key role in the pathogenesis of CDAD, both in humans and in mice [6].CDAD is often treated successfully with stand
Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice
Hao Cui, Amos C. Hung, David W. Klaver, Toshiharu Suzuki, Craig Freeman, Christian Narkowicz, Glenn A. Jacobson, David H. Small
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023007
Abstract: Background Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice. Methodology/Principal Findings We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPα, C99, C83 and Aβ) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPα and Aβ secretion. Heparin also decreased the level of β-secretase (BACE1) and α-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. Conclusions/Significance The data indicate that heparin and enoxaparin decrease APP processing via both α- and β-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.
TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons
Robert J Gasperini, Xu Hou, Helena Parkington, Harry Coleman, David W Klaver, Adele J Vincent, Lisa C Foa, David H Small
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-19
Abstract: Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones.These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.Protein misfolding is a common feature of many neurodegenerative diseases. In some of these diseases, such as the synucleinopathies and the tauopathies, cytoplasmic proteins aggregate to form intracellular deposits. However, in the amyloidoses, which include Alzheimer's disease (AD), prion diseases and the British and Danish familial dementias, proteinaceous aggregates are observed extracellularly [1-4]. There is increasing evidence that the mechanism of neurotoxicity in these amyloidoses is similar and that it is the conformation of the aggregated protein, rather than its specific amino acid sequence which results in altered membrane permeability to calcium [5]. Therefore, studies on the mechanism of neurotoxicity in one disease may provide insights into the mechanisms involved in other
Simplification to Abacavir/Lamivudine + Atazanavir Maintains Viral Suppression and Improves Bone and Renal Biomarkers in ASSURE, a Randomized, Open Label, Non-Inferiority Trial
David A. Wohl, Laveeza Bhatti, Catherine B. Small, Howard Edelstein, Henry H. Zhao, David A. Margolis, Edwin DeJesus, Winkler G. Weinberg, Lisa L. Ross, Mark S. Shaefer
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096187
Abstract: Objective Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study’s primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients. Design This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥6 months with no history of virologic failure and whose HIV-1 RNA had been ≤75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1:2 to continue current treatment or simplify to ABC/3TC+ATV. Methods The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers. Results After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2–4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3–4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. Conclusions After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol. Trial Registration ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734
‘Jy is die vertolker’: die lewensloop van Adam Small
A Small, H van Vuuren
Tydskrif vir letterkunde , 2012,
Abstract: “Ek het altyd grootgeword tussen die kulture. Ek het nooit kon verstaan dat mense met mekaar kulturele hang-ups kon hê nie” — Adam Small
Gene Expression Profiling of Human Myeloid Leukemic MV4-11 Cells Treated with 5-Aza-2’-deoxycytidine  [PDF]
Kyu-Tae Kim, David Mossman, Donald Small, Rodney J. Scott
Journal of Cancer Therapy (JCT) , 2012, DOI: 10.4236/jct.2012.33025
Abstract: The pyrimidine analog, 5-aza-2’-deoxycytidine (5-aza-dC) is a DNA methyltransferase inhibitor that triggers DNA demethylation leading to the reactivation of epigenetically silenced tumor suppressor genes. To understand the shift in gene expression which mediates the beneficial 5-aza-dC effects in leukemia, we have treated human myeloid derived leukemic cells with 5-aza-dC. Target genes were identified first in MV4-11 cells using a genome-wide gene expression profiling assay to detect differences in treated and untreated cells. From this analysis six genes were identified (HOXA4, HOXD4, HOXA8, HOXD12, CD9 and RGS2) as being significantly different expressed after treatment. To validate microarray data, we performed quantitative PCR on these genes from multiple leukemic cells. The results suggest that these genes are epigenetically regulated indicating that dysregulation of HOXA4, HOXD4, HOXA8, HOXD12, CD9 and RGS2 expression may play an important role in establishing the malignant phenotype in AML.
Star formation history of resolved galaxies. I. The Method
Emma E. Small,David Bersier,Maurizio Salaris
Physics , 2012, DOI: 10.1093/mnras/sts077
Abstract: We present a new method to determine the star formation and metal enrichment histories of any resolved stellar system. This method is based on the fact that any observed star in a colour-magnitude diagram will have a certain probability of being associated with an isochrone characterised by an age t and metallicity [Fe/H] (i.e. to have formed at the time and with the metallicity of that isochrone). We formulate this as a maximum likelihood problem that is then solved with a genetic algorithm. We test the method with synthetic simple and complex stellar populations. We also present tests using real data for open and globular clusters. We are able to determine parameters for the clusters (t, [Fe/H]) that agree well with results found in the literature. Our tests on complex stellar populations show that we can recover the star formation history and age-metallicity relation very accurately. Finally, we look at the history of the Carina dwarf galaxy using deep BVI data. Our results compare well with what we know about the history of Carina.
Toxicity Profiles In Vivo in Mice and Antitumour Activity inTumour-Bearing Mice of Di- and Triorganotin Compounds
M. Gielen,R. Willem,H. Dalil,D. <small.letters>desmall.letters> Vos
Metal-Based Drugs , 1998, DOI: 10.1155/mbd.1998.83
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