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David Morgan

Publications and source records attributed to David Morgan.

At least 19 recordsLinked to original sources
PubMed2006

Correlation of stylet activities by the glassy-winged sharpshooter, Homalodisca coagulata (Say), with electrical penetration graph (EPG) waveforms.

Glassy-winged sharpshooter, Homalodisca coagulata (Say), is an efficient vector of Xylella fastidiosa (Xf), the causal bacterium of Pierce's disease, and leaf scorch in almond and oleander. Acquisition and inoculation of Xf occur sometime during the process of stylet penetration into the plant. That process is most rigorously studied via electrical penetration graph (EPG) monitoring of insect feeding. This study provides part of the crucial biological meanings that define the waveforms of each new insect species recorded by EPG. By synchronizing AC EPG waveforms with high-magnification video of H. coagulata stylet penetration in artifical diet, we correlated stylet activities with three previously described EPG pathway waveforms, A1, B1 and B2, as well as one ingestion waveform, C. Waveform A1 occured at the beginning of stylet penetration. This waveform was correlated with salivary sheath trunk formation, repetitive stylet movements involving retraction of both maxillary stylets and one mandibular stylet, extension of the stylet fascicle, and the fluttering-like movements of the maxillary stylet tips. Waveform B1 was ubitquious, interspersed throughout the other waveforms. B1 sub-type B1w was correlated with salivation followed by maxillary tip fluttering. This tip fluttering also occurred before and during B1 sub-type B1s, but was not directly correlated with either the occurrence or frequency of this waveform. Waveform B2 was correlated with sawing-like maxillary stylet movements, which usually occurred during salivary sheath branching. Waveform C was correlated with ingestion. Fluid outflow was also observed as a mechanism to clear the maxillary tips from debris during waveform C. This detailed understanding of stylet penetration behaviors of H. coagulata is an important step toward identifying the instant of bacterial inoculation which, in turn, will be applied to studies of disease epidemiology and development of host plant resistance.

Animals↗
PubMed2006

Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network.

BACKGROUND: Outcome data in young women with ductal carcinoma in situ (DCIS) are rare. The benefits of boost radiotherapy in this group are also unknown. We aimed to assess the effect of boost radiotherapy in young patients with DCIS. METHODS: We included 373 women from 18 institutions who met the following inclusion criteria: having tumour status Tis and nodal status (N)0, age 45 years or younger at diagnosis, and having had breast-conserving surgery. 57 (15%) patients had no radiotherapy after surgery, 166 (45%) had radiotherapy without boost (median dose 50 Gy [range 40-60]), and 150 (40%) had radiotherapy with boost (60 Gy [53-76]). The primary outcome was local relapse-free survival. FINDINGS: Median follow-up was 72 months (range 1-281). 55 (15%) patients had local relapse. Local relapse-free survival at 10 years was 46% (95% CI 24-67) for patients given no radiotherapy, 72% (61-83) for those given radiotherapy without boost, and 86% (78-93) for those given radiotherapy and boost (difference between all three groups, p<0.0001). Age, margin status, and radiotherapy dose were significant predictors of local relapse-free survival. Compared with patients who had no radiotherapy, those who had radiotherapy had a decreased risk of local relapse (without boost, hazard ratio 0.33 [95% CI 0.16-0.71], p=0.004; with boost, 0.15 [0.06-0.36], p<0.0001). INTERPRETATION: In the absence of randomised trials, boost radiotherapy should be considered in addition to surgery for breast-conserving treatment for DCIS.

Adult↗
PubMed2005

Sustained delivery of bioactive cytokine using a dense collagen gel vehicle collagen gel delivery of bioactive cytokine.

OBJECTIVE: The use of cytokines as localized therapeutic agents is limited by the lack of a satisfactory delivery system. The aim of the current investigation was to determine the release kinetics and bioactivity of a simplified cytokine/collagen gel system designed to achieve extended, local delivery of bioactive cytokines at sites of premature cranial suture fusion (craniosynostosis). DESIGN: Cytokine release was determined by ELISA measurements of Tgf-beta3 collected in media. Cytokine bioactivity was determined by measuring the effect of conditioned media, containing released Tgf-beta3, on mink lung epithelial cell proliferation and osteoblast alkaline phosphatase activity. Osteoblast response was evaluated by measuring proliferation of cells cultured on collagen gel containing Tgf-beta3 using an AlamarBlue assay. RESULTS: Gels loaded with 100 and 500 ng of Tgf-beta3 produced a sustained release over 14 days with a pattern of initial large release followed by a gradual reduction in the amount released over the time. The reduced release over time was correlated to the amount initially loaded. Mink lung epithelial cell assay results indicated that Tgf-beta3 released from the collagen gel retained its bioactivity following incorporation into the collagen gel and release into the media. This bioactivity was further illustrated by a decreased alkaline phosphatase activity measured in osteoblasts cultured on the gels loaded with Tgf-beta3. Osteoblast proliferation assays demonstrated that the collagen gel has an inherent inhibitory effect on osteoblast cell number. CONCLUSIONS: This collagen gel/cytokine delivery system can retain and release bioactive cytokine over a prolonged period. These results will allow for better optimization of future in vitro and in vivo studies directed at improving the treatment of craniosynostosis.

Alkaline Phosphatase↗
PubMed2005

Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Alzheimer Disease↗
PubMed2005

Can aesthetic facial reconstruction be judged in black and white?

Aesthetic considerations of the face need to be evaluated in real-life full color. Staged contouring and insetting of a transferred free flap is sometimes required. This consists of debulking, thinning, and reshaping the flap. If the facial area is involved, however, color mismatch of a free flap represents an aesthetic challenge for the reconstructive surgeon, and often is missed with black and white photos. This article reports on a patient in whom a first dorsal metatarsal cutaneous free flap was used to reconstruct a full-thickness defect in the lateral orbit including upper and lower eyelids and outer canthus. The flap resulted in an unacceptable aesthetic outcome consisting of a bulky, hypopigmented deformity. Revisional surgery consisted of debulking the free flap and resurfacing it with a full-thickness skin graft taken from the postauricular area. This resulted in a pleasant, thin, and better color match reconstruction. The advantages of the first web space of foot free flap to the eyelid are well described. The authors are of the opinion that the flap does not match the color of the eyelid region, and therefore suggest that if used, prefabrication or a second procedure is needed. Evaluation of the postoperative results needs to be in color because black and white can mask the final aesthetic result.

Blepharoplasty↗
PubMed2005

Importance of melanin-concentrating hormone receptor for the acute effects of ghrelin.

The hypothalamic peptide melanin-concentrating hormone (MCH) and the gastric hormone ghrelin take part in the regulation of energy homeostasis and stimulate food intake. In the present study, ghrelin was administered centrally to MCH-receptor knockout (MCHr KO) mice. MCHr KO mice and wild type (WT) controls both consumed more food when treated with ghrelin. After ghrelin administration, the serum levels of insulin increased only in WT mice whereas the serum levels of corticosterone increased both in WT and MCHr KO mice. The level of growth hormone (GH) mRNA in the pituitary gland was markedly increased in response to ghrelin injection in the WT mice but was unaffected in the MCHr KO mice. The different ghrelin responses could not be explained by a difference in growth hormone secretagogue receptor expression between MCHr KO and WT mice in the pituitary or hypothalamus. In summary, the MCHr is not required for ghrelin induced feeding. However, the MCHr does play a role for the effect of ghrelin on GH expression in the pituitary and serum insulin levels.

Animals↗
PubMed2005

Activity of flurbiprofen and chemically related anti-inflammatory drugs in models of Alzheimer's disease.

Currently, there is an intense debate on the potential use of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). NSAIDs are among the most widely prescribed drugs for the treatment of pain, fever, and inflammation. Their effects are largely attributed to the inhibition of the enzymatic activity of cyclooxygenase (COX)-1 and -2. The apparent activity of this class of drugs stems from one critical pathological process underlying AD and other neurodegenerative disorders, i.e., the presence of chronic neuroinflammation. In fact, prolonged use of NSAIDs is associated with reduced risk of AD. Besides COX inhibition, additional mechanisms could contribute to the potential activity of NSAIDs in AD. For example, several studies show that only a few selected NSAIDs also affect beta-amyloid (Abeta) deposition and metabolism. Among the Abeta-effective NSAIDs, flurbiprofen raised particular interest because of its multiple actions on key AD hallmarks. Studies in cell lines and animal models have shown that flurbiprofen racemate, its R-enantiomer and its nitric oxide (NO)-releasing derivatives, HCT 1026 and NCX 2216, are effective on AD amyloid pathology. Moreover, HCT 1026 and NCX 2216 differentially influence the cellular component of neuroinflammation (i.e., microglia activation) in some experimental settings, i.e., HCT 1026 inhibits the activation of microglia, while NCX 2216 can either enhance or inhibit microglial activation, depending upon the experimental conditions. It is still unclear which effects on microglia will prove most beneficial. Ultimately, clinical studies in AD patients will provide the best information as to whether selected NSAIDs will improve this devastating disease.

Alzheimer Disease↗
PubMed2005

CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide.

Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.

Alzheimer Disease↗
PubMed2004

Simple technique for inverted nipple correction.

Several different techniques have been developed and currently are in use for correction of the inverted nipple. The diversity of techniques indicates the lack of a good, sustainable, and durable solution for this quite common problem. This report discusses a new technique in which two flaps are inserted beneath the nipple through a small tunnel. The advantages of this procedure are its simplicity, the creation of a durable support for the nipple, and the lack of transverse scars in the areola surrounding the nipple. The follow-up period up to 4 years for 11 patients (18 nipples) demonstrates the validity of this technique.

Female↗
PubMed2004

Lovastatin modulation of microglial activation via suppression of functional CD40 expression.

Recent studies have shown that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) possess antiinflammatory and immunomodulatory properties, distinct from their action of lowering serum lipid levels. Moreover, results of epidemiological studies suggest that long-term use of statins is associated with a decreased risk for Alzheimer's disease (AD). Interestingly, lovastatin (one of the most commonly used anticholesterol drugs) treatment of vascular-derived cells has been reported to antagonize activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, and it is well known that the JAK/STAT pathway plays a central role in interferon-gamma (IFN-gamma)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-gamma and amyloid-beta (Abeta) peptide. Moreover, it has been shown that CD40 signaling is critically involved in microglia-related immune responses in the CNS. In this study, we examined the putative role of lovastatin in modulation of CD40 expression and its signaling in cultured microglia. RT-PCR, Western immunoblotting, and flow cytometry data show that lovastatin suppresses IFN-gamma-induced CD40 expression. Additionally, lovastatin markedly inhibits IFN-gamma-induced phosphorylation of JAK/STAT1. Furthermore, lovastatin is able to suppress microglial tumor necrosis factor-alpha, interleukin (IL)-beta1 and IL-6 production promoted either by IFN-gamma or by Abeta peptide challenge in the presence of CD40 cross-linking. To characterize further lovastatin's effect on microglial function, we examined microglial phagocytic capability following CD40 cross-linking. Data reveal that lovastatin markedly attenuates CD40-mediated inhibition of microglial phagocytosis of Abeta. These results provide an insight into the mechanism of the beneficial effects of lovastatin in neurodegenerative disorders, particularly Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed2004

Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation.

Current drug discovery efforts focus primarily on proteins with defined enzymatic or small molecule binding sites. Autoregulatory domains represent attractive alternative targets for small molecule inhibitors because they also occur in noncatalytic proteins and because allosteric inhibitors may avoid specificity problems inherent in active site-directed inhibitors. We report here the identification of wiskostatin, a chemical inhibitor of the neural Wiskott-Aldrich syndrome protein (N-WASP). Wiskostatin interacts with a cleft in the regulatory GTPase-binding domain (GBD) of WASP in the solution structure of the complex. Wiskostatin induces folding of the isolated, unstructured GBD into its autoinhibited conformation, suggesting that wiskostatin functions by stabilizing N-WASP in its autoinhibited state. The use of small molecules to bias conformational equilibria represents a potentially general strategy for chemical inhibition of autoinhibited proteins, even in cases where such sites have not been naturally evolved in a target.

Allosteric Site↗
PubMed2004

Comparison of neural network predictors in the classification of tracheal-bronchial breath sounds by respiratory auscultation.

Despite extensive research in the area of identification and discrimination of tracheal-bronchial breath sounds by computer analysis, the process of identifying auscultated sounds is still subject to high estimation uncertainties. Here we assess the performance of the relatively new constructive probabilistic neural network (CPNN) against the more common classifiers, namely the multilayer perceptron (MLP) and radial basis function network (RBFN), in classifying a broad range of tracheal-bronchial breath sounds. We present our data as signal estimation models of the tracheal-bronchial frequency spectra. We have examined the trained structure of the CPNN with respect to the other architectures and conclude that this architecture offers an attractive means with which to analyse this type of data. This is based partly on the classification accuracies attained by the CPNN, MLP and RBFN which were 97.8, 77.8 and 96.2%, respectively. We concluded that CPNN and RBFN networks are capable of working successfully with this data, with these architectures being acceptable in terms of topological size and computational overhead requirements. We further believe that the CPNN is an attractive classification mechanism for auscultated data analysis due to its optimal data model generation properties and computationally lightweight architecture.

Auscultation↗
PubMed2004

A perspective on inversin.

Over the past 5 years, there has been increasing evidence for the role of primary (9+0) cilia in renal physiology and in establishing the left-right axis. The cilia in the renal tract are immotile and thought to have a sensory function. Cilia at the murine embryonic node have a vortical movement that sets up a leftward flow. Inversin, the protein defective in the inv mouse and in patients with type-2 nephronophthisis, localizes to both renal and node primary cilia. However, we present evidence that it is also expressed before the node forms and that its subcellular localization in renal tubular cells is not confined to the cilia. Its role in both the pathway determining left-right axis and renal function remains to be elucidated.

Animals↗
PubMed2004

Histology impacts the outcome of peripheral T-cell lymphomas after high dose chemotherapy and stem cell transplant.

The role of high dose chemotherapy (HDC) and stem cell transplant (SCT) in peripheral T-cell lymphoma (PTCL) was studied in 28 patients, from 1988 to 2002. The aim was to determine if subsets recognized by the REAL/WHO classification have different prognoses. Outcome was compared to 86 patients with diffuse large B-cell lymphoma (DLBCL) transplanted during 1986-2000. The 3-year overall survival (OS) and event free survival (EFS) were 69% and 50%. Patients with anaplastic large cell lymphoma (ALCL) had a better 3-year OS compared to those with non-ALCL histology (86% vs. 47%, P=0.0122). Anaplastic lymphoma kinase (ALK)- positive ALCL patients had a superior EFS compared to ALK-negative ALCL (100% vs. 0; P=0.0228). Patients with cutaneous ALCL (ALK-negative) relapsed, but had an indolent course after SCT. Low International Prognostic Index score at relapse predicted for a better 3-year OS (85% vs. 34%, P=0.0238). When compared to DLBCL, patients with ALCL had a superior OS (86% vs. 36%, P=0.0034) and patients with non-ALCL had a comparable OS. ALCL histology confers better survival compared to non-ALCL and DLBCL histologies. ALK-positive ALCL is associated with the best EFS after relapse with HDC and SCT. The timing of SCT for non-ALCL histology remains to be determined.

Adult↗
PubMed2003

Constructing constrained invariant sets in multiscale continuum systems.

We present a method that we name the constrained invariant manifold method, a visualization tool to construct stable and unstable invariant sets of a map or flow, where the invariant sets are constrained to lie on a slow invariant manifold. The construction of stable and unstable sets constrained to an unstable slow manifold is exemplified in a singularly perturbed model arising from a structural-mechanical system consisting of a pendulum coupled to a viscoelastic rod. Additionally, we extend the step and stagger method [D. Sweet, H. Nusse, and J. Yorke, Phys. Rev. Lett. 86, 2261 (2001)] to calculate a delta pseudoorbit on a chaotic saddle constrained to the slow manifold in order to be able to compute the Lyapunov exponents of the saddle.

Journal Article↗