Biomedical subjects

J Moss

Publications and source records attributed to J Moss.

At least 19 recordsLinked to original sources

PubMed2006

Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation.

Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, agents that inhibit angiogenesis have important therapeutic implications in numerous malignancies. We examined the effects of methylnaltrexone (MNTX), a peripheral mu opioid receptor antagonist, on agonist-induced human EC proliferation and migration, two key components in angiogenesis. Using human dermal microvascular EC, we observed that morphine sulfate (MS), the active metabolite, morphine-6-glucuronide (M6G), DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkaphalin) and VEGF induced migration which were inhibited by pretreatment with MNTX at therapeutically relevant concentration (0.1 microM). The biologically inactive metabolite morphine-3-glucuronide (M3G) did not affect EC migration. We next examined the mechanism(s) by which MNTX inhibits opioid and VEGF-induced angiogenesis using human pulmonary microvascular EC. MS and DAMGO induced Src activation which was required for VEGF receptor transactivation and opioid-induced EC proliferation and migration. MNTX inhibited MS, DAMGO and VEGF induced tyrosine phosphorylation (transactivation) of VEGF receptors 1 and 2. Furthermore, MS, DAMGO and VEGF induced RhoA activation which was inhibited by MNTX or VEGF receptor tyrosine kinase inhibition. Finally, MNTX or silencing RhoA expression (siRNA) blocked MS, DAMGO and VEGF-induced EC proliferation and migration. Taken together, these results indicate that MNTX inhibits opioid-induced EC proliferation and migration via inhibition of VEGF receptor phosphorylation/transactivation with subsequent inhibition of RhoA activation. These results suggest that MNTX inhibition of angiogenesis can be a useful therapeutic intervention for cancer treatment.

Angiogenesis Inhibitors↗

PubMed2006

Colorectal stenting for colonic obstruction: the indications, complications, effectiveness and outcome--5 year review.

INTRODUCTION: Currently self-expanding metallic stents are being used for palliation and acute decompression of colonic obstruction. The aim of this study is to review our experience of using these metallic stents over a 5-year period. MATERIALS AND METHODS: Case records of 102 patients who had colorectal stenting between 1998 and 2004 were reviewed retrospectively. The indications for colorectal stenting, efficacy of the procedure in relieving the obstruction, complications and clinical outcome were analysed. RESULTS: Ninety-nine patients had malignant disease and in three patients a benign cause of obstruction was demonstrated. All procedures were performed during normal working hours. Stenting was technically successful in 87 patients (85%). A single stent was placed in 80 patients. Seven patients required two stents. Of the successful cases, 67 had stents placed by fluoroscopy alone and 20 by a combined fluoroscopy/endoscopy procedure. Four percent had early complications (within 30 days) which included four perforations. There were late complications (over 30 days) in 9% which included five stent migrations, two blocked stents and one colovesical fistula. Ninety percent (n=76) of the successful patients needed no further radiological or surgical intervention later. Survival ranged from 14 days to 2 years. CONCLUSION: Colorectal stenting when technically successful is an effective procedure for both preoperative and palliative decompression of colonic obstruction.

Aged↗

PubMed2006

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells.

Nitric oxide (NO) may block apoptosis by inhibiting caspases via S-nitrosylation of cysteines. Here, we investigated whether effector caspases might cleave and thereby inhibit endothelial nitric oxide synthase (eNOS). Exposure of eNOS-transfected COS-7 cells and bovine aortic endothelial cells to staurosporine resulted in significant loss of 135-kDa eNOS protein and activity, and appearance of a 60-kDa eNOS fragment; effects were inhibited by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp[OMe]-fluoromethyl ketone (zVAD-fmk). In eNOS-transfected COS-7 cells, staurosporine-induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage coincided with increased eNOS degradation and decreased activity. Loss of eNOS activity was greater than the degree of proteolysis. Incubation of immunoprecipitated eNOS with caspase-3, caspase-6 or caspase-7 resulted in eNOS cleavage. Staurosporine, a general protein kinase inhibitor, also reduced phosphorylation and decreased calmodulin binding, an effect that may explain the reduction in activity. eNOS, therefore, is both an inhibitor of apoptosis and a target of apoptosis-associated proteolysis.

Amino Acid Chloromethyl Ketones↗

PubMed2005

Analysis of the chromosomal region 19q13.4 in two Chinese families with recurrent hydatidiform mole.

BACKGROUND: Familial recurrent hydatidiform mole is an extremely rare autosomal recessive condition in which affected individuals have a predisposition to molar pregnancies that are diploid but biparental, rather than androgenetic, in origin. A gene for this condition has been previously mapped to a 1.1 Mb region of chromosome 19q13.4. However, investigation of further families is needed to refine the location of the specific gene(s) involved. METHODS: We have recently identified two novel Chinese families in which four affected women had recurrent pregnancy loss including 14 complete hydatidiform moles (CHM). Fluorescent microsatellite genotyping was used to determine the origin of CHM in both families. Using a panel of polymorphic microsatellite markers, genotyping and haplotype analysis of the 19q13.4 chromosomal region was performed in both families. RESULTS: Genotyping of CHM from affected individuals confirmed their biparental origin and diagnosis of familial recurrent hydatidiform mole in both families. However, no significant homozygosity for the 19q13.4 candidate region was found in affected members of either family. CONCLUSION: Genotyping and haplotype analysis has shown that a mutation in 19q13.4 is unlikely to be responsible for recurrent CHM in the two Chinese families investigated and provides further evidence to support the hypothesis that, although extremely rare, this condition shows genetic heterogeneity.

China↗

PubMed2005

The association between environmental events and self-injurious behaviour in Cornelia de Lange syndrome.

BACKGROUND: There has been limited empirical research into the environmental causes of self-injury in Cornelia de Lange syndrome. The present study examined the variability of self-injurious behaviour in Cornelia de Lange syndrome across environmental setting events. Additionally, the association between setting events and more specific environmental events was examined. METHOD: A descriptive analysis of observational data on eight children with Cornelia de Lange syndrome aged between 4 and 14 years was carried out. The association between self-injurious behaviour and four environmental setting events and between specific environmental events and setting events was examined using established statistical methods for observational data. RESULTS: Seven out of eight of the participants showed at least one form of self-injurious behaviour that was associated with a particular setting event. The study also demonstrated that the relationship between setting events and environmental events is extremely variable across individuals. CONCLUSIONS: Self-injurious behaviour in some individuals with Cornelia de Lange syndrome is associated with environmental events although the precise nature of the association warrants clarification. Using broad setting events as a methodological tool in isolation provides some insight into the role of specific environmental factors in maintaining self-injurious behaviour but the integrity of setting events must be established.

Adolescent↗

PubMed2005

Select utilization of obese donors in living donor liver transplantation: implications for the donor pool.

Living donor liver transplantation evolved in response to donor shortage. Current guidelines recommend potential living donors (LD) have a body mass index (BMI) <30. With the current obesity epidemic, locating nonobese LD is difficult. From September 1999 to August 2003, 68 LD with normal liver function test (LFTs) and without significant comorbidities underwent donor hepatectomy at our center. Post-operative complications were collected, including wound infection, pneumonia, hernia, fever, ileus, biliary leak, biliary stricture, thrombosis, bleeding, hepatic dysfunction, thrombocytopenia, deep venous thrombosis, pulmonary embolism, difficult to control pain, depression and anxiety. Complication rates for LD with BMI >30 (n = 16) and BMI <30 (n = 52) were compared. The incidence of wound infection increased with BMI, 4% for nonobese and 25% for obese LD (p = 0.024). There were no statistically significant differences for all other complications. No LD died. Recipient survival was 100% with obese LD and 80% with nonobese LD (p = 0.1). Select donors with a BMI >30 may undergo donor hepatectomy with acceptable morbidity and excellent recipient results. Updating current guidelines to include select LD with BMI >30 has the potential to safely increase the donor pool.

Adolescent↗

PubMed2005

Early immune response to the components of the type III system of Pseudomonas aeruginosa in children with cystic fibrosis.

The lungs of patients with cystic fibrosis (CF) are colonized initially by Pseudomonas aeruginosa, which is associated with progressive lung destruction and increased mortality. The pathogenicity of P. aeruginosa is caused by a number of virulence factors, including exotoxin A (ETA) and the type III cytotoxins (ExoS, ExoT, ExoU, and ExoY). P. aeruginosa contacts the plasma membrane to deliver type III cytotoxins through a channel formed by PopB, PopD, and PcrV; ETA enters mammalian cells via receptor-mediated endocytosis. The Wisconsin CF Neonatal Screening Project is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF; the project was the source of serum samples used in this study. Past studies evaluated the longitudinal appearance of antibodies to ETA and elastase and P. aeruginosa infections in patients with CF. The current study characterized the longitudinal appearance of antibodies to components of the type III system in children with CF. Western blot analyses showed that serum antibodies to PopB, PcrV, and ExoS were common. Longitudinal enzyme-linked immunosorbent assays determined that the first detection of antibodies to pooled ExoS/PopB occurred at a time similar to those of detection of antibodies to a P. aeruginosa cell lysate and the identification of oropharyngeal cultures positive for P. aeruginosa. This indicates that children with CF are colonized early with P. aeruginosa expressing the type III system, implicating it in early pathogenesis, and implies that surveillance of clinical symptoms, oropharyngeal cultures, and seroconversion to type III antigens may facilitate early detection of P. aeruginosa infections.

ADP Ribose Transferases↗

PubMed2005

Foci of amorphous/granulofilamentous matrix in the extracellular domain of tumours. 2. Immunohistochemical and immunogold characterization of a fibronectin-rich matrix component.

The term FEAM (foci of extracellular amorphous matrix) has been used for discretely outlined areas of moderately dense material having a filamentous/granular substructure located in the extracellular matrix of tumours. In spite of being widespread in mesenchymal tumours especially, and often abundant, they have received little attention in terms of structure, composition and origin. Mostly, they have been regarded as a variant or a product of lamina ('basement membrane material'). However, they also appear in tumours whose cells should and do lack a lamina, such as giant-cell fibroblastoma and solitary fibrous tumour. This paper describes their fine structure in a variety of predominantly mesenchymal tumours, and documents their composition using light microscope immunostaining and immunogold labelling. Small amounts of type IV collagen and laminin were found focally and inconsistently among the five tumours by light microscope immunostaining, but fibronectin was strongly and consistently identified. Strong fibronectin staining was also identified by immuno-electronmicroscopy. These data suggest that FEAM represent a fibronectin-rich matrix constituent, which might be a common final product of either lamina or the external component of the subplasmalemmal linear density (focal adhesion). There is little support light microscopically for a relationship to immune-complexes or cryoglobulins.

Biomarkers, Tumor↗

PubMed2004

Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson's disease.

Deep brain stimulation (DBS) is used to treat a variety of severe medically intractable movement disorders, including Parkinson's disease, tremor and dystonia. There have been few studies examining the effect of chronic DBS on the brains of Parkinson's disease patients. Most of these post mortem studies concluded that chronic DBS caused mild gliosis around the lead track and did not damage brain tissue. There have been no similar histopathological studies on brains from dystonic patients who have undergone DBS. In this study, our objective was to discover whether tissue would be attached to DBS electrodes removed from patients for routine clinical reasons. We hoped that by examining explanted DBS electrodes using scanning (SEM) and/or transmission (TEM) electron microscopy we might visualize any attached tissue and thus understand the electrode-human brain tissue interaction more accurately. Initially, SEM was performed on one control DBS electrode that had not been implanted. Then 21 (one subthalamic nucleus and 20 globus pallidus internus) explanted DBS electrodes were prepared, after fixation in 3% glutaraldehyde, for SEM (n = 9) or TEM (n = 10), or both (n = 2), according to departmental protocol. The electrodes were sourced from two patients with Parkinson's disease, one with myoclonic dystonia, two with cervical dystonia and five with primary generalized dystonia, and had been in situ for 11 and 31 months (Parkinson's disease), 16 months (myoclonic dystonia), 14 and 24 months (cervical dystonia) and 3-24 months (primary generalized dystonia). Our results showed that a foreign body multinucleate giant cell-type reaction was present in all TEM samples and in SEM samples, prewashed to remove surface blood and fibrin, regardless of the diagnosis. Some of the giant cells were >100 microm in diameter and might have originated from either fusion of parenchymal microglia, resident perivascular macrophage precursors and/or monocytes/macrophages invading from the blood stream. The presence of mononuclear macrophages containing lysosomes and sometimes having conspicuous filopodia was detected by TEM. Both types of cell contained highly electron-dense inclusions, which probably represent phagocytosed material. Similar material, the exact nature of which is unknown, was also seen in the vicinity of these cells. This reaction was present irrespective of the duration of implantation and may be a response to the polyurethane component of the electrodes' surface coat. These findings may be relevant to our understanding of the time course of the clinical response to DBS in Parkinson's disease and various forms of dystonia, as well as contributing to the design characteristics of future DBS electrodes.

Adult↗

PubMed2004

Phenotypic variability in siblings with type III spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy (SMA) shows substantial phenotypic variability, presenting at a variety of ages from infancy to adult life. Diagnostic difficulties may arise because SMA sometimes produces a dystrophic or myopathic phenotype rather than classical neurogenic abnormalities. Two brothers are described who illustrate this principle and highlight the increasing importance of molecular genetics in investigating patients with neuromuscular diseases. The findings are discussed in the light of recent observations in a mouse model of SMA.

Adolescent↗

PubMed2003

Community context of health system development: implications for health sector reform in Pakistan.

To describe local sociopolitical and organizational factors that influence health system development in Karachi, Pakistan, we conducted participant observation while working with health providers and communities in one urban district to reorient services towards a primary health care district health system. We found that the community characteristics, particularly the diverse socialpolitical and cultural make-up and organizational complexity that involved multiple levels of government, influenced efforts towards collaboration and shaped the development of the health system. We conclude that for effective implementation of health sector reform there is a need to comprehend fully the community context and complexity of existing health service provision.

Community Health Services↗

PubMed2001

Production of beta-defensin-2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein.

We recently showed that FliC of Salmonella enteritidis increased human beta-defensin-2 (hBD-2) expression, and now describe the signaling responsible pathway. FliC increased the intracellular Ca(2+) concentration ([Ca(2+)](in)) in Caco-2 cells. The [Ca(2+)](in) increase induced by FliC was prevented by U73122 and heparin, but not by chelating extracellular Ca(2+) or pertussis toxin. The FliC-induced increase in hBD-2 promoter activity via nuclear factor kappaB (NF-kappaB) was also inhibited by chelation of intracellular Ca(2+) or by U73122. We conclude that FliC increased [Ca(2+)](in) via inositol 1,4,5-trisphosphate, which was followed by up-regulating hBD-2 mRNA expression via an NF-kappaB-dependent pathway.

Caco-2 Cells↗

PubMed2001

Meningiomas in lymphangioleiomyomatosis.

CONTEXT: Lymphangioleiomyomatosis (LAM), a cystic lung disease associated with progressive respiratory failure, is found predominantly in women of childbearing age and therefore has been treated with progesterone and other hormonal agents. However, meningiomas have progesterone receptors, and progesterone is believed to be a mitogen for meningioma cells in culture. Since 30% to 40% of patients with tuberous sclerosis complex (TSC) have LAM, we routinely screen patients with LAM for brain lesions found in TSC. OBJECTIVE: To determine the prevalence of meningiomas in women with LAM. DESIGN AND SETTING: Analysis of results from ongoing routine screening protocols initiated in December 1995 at the National Heart, Lung, and Blood Institute. PATIENTS: Two hundred fifty women with sporadic LAM who were referred for screening by magnetic resonance imaging (MRI) and/or computed tomography (CT) of the brain. MAIN OUTCOME MEASURES: Presence of meningiomas on MRI and/or CT scans. RESULTS: Eight women with LAM (3 with and 5 without a diagnosis of TSC) had lesions on MRI scans compatible with meningiomas. Five of the patients had been treated with progesterone. Multiple meningiomas were observed in 2 patients. CONCLUSIONS: Women with LAM appear to have a high prevalence of meningiomas. We recommend that patients with LAM be screened for meningiomas regardless of diagnosis of TSC. In view of the lack of a documented effect of progesterone on progression of lung disease in LAM and the reported mitogenic response of meningiomas to progesterone, we recommend that the drug not be given to LAM patients with an MRI result consistent with diagnosis of meningioma.

Adult↗

PubMed2001

Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare disease, occurring in women, characterized by cystic degeneration of the lungs, abdominal tumors, and proliferation of abnormal smooth muscle cells. Lung function abnormalities consist of impairment of the diffusion capacity (DL(CO)) and airflow obstruction. The objective of this study was to correlate the functional impairment with histologic measures of disease severity to identify predictors of disease outcome. Lung function of 143 patients and lung biopsies of 74 of these patients were reviewed for evidence of airway disease and scoring of disease severity. A positive response to bronchodilators was associated with more severe airflow obstruction, a predominantly solid pattern of LAM lesions in the lung biopsy, and greater rate of decline in expiratory flow. Airway inflammation, present in 61% of the lung specimens, was not associated with reversible airway obstruction and did not correlate with the severity of airflow obstruction. DL(CO) correlated best with the LAM histologic score (LHS), a demonstrated predictor of outcome. We conclude that reversible airway obstruction is found in LAM patients with accelerated loss of lung function and a predominantly solid pattern of LAM lesions. Impairment of DL(CO) correlates with LHS, a predictor of survival and time to lung transplantation.

Adult↗

PubMed2001

beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis.

beta-Arrestins are multifunctional adaptor proteins known to regulate internalization of agonist-stimulated G protein-coupled receptors by linking them to endocytic proteins such as clathrin and AP-2. Here we describe a previously unappreciated mechanism by which beta-arrestin orchestrates the process of receptor endocytosis through the activation of ADP-ribosylation factor 6 (ARF6), a small GTP-binding protein. Involvement of ARF6 in the endocytic process is demonstrated by the ability of GTP-binding defective and GTP hydrolysis-deficient mutants to inhibit internalization of the beta(2)-adrenergic receptor. The importance of regulation of ARF6 function is shown by the ability of the ARF GTPase-activating protein GIT1 to inhibit and of the ARF nucleotide exchange factor, ARNO, to enhance receptor endocytosis. Endogenous beta-arrestin is found in complex with ARNO. Upon agonist stimulation of the receptor, beta-arrestin also interacts with the GDP-liganded form of ARF6, thereby facilitating ARNO-promoted GTP loading and activation of the G protein. Thus, the agonist-driven formation of a complex including beta-arrestin, ARNO, and ARF6 provides a molecular mechanism that explains how the agonist-stimulated receptor recruits a small G protein necessary for the endocytic process and controls its activation.

ADP-Ribosylation Factor 6↗

PubMed2001

Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex.

The true prevalence of pulmonary lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex (TSC) is unknown. The prevalence of LAM, radiological features, and lung function in patients with TSC was measured. The presence of LAM, as defined by the presence of cysts by high-resolution chest computed tomography (HRCT) scan, was determined in patients with TSC without prior pulmonary disease (Group 1). To determine the significance of early detection, severity of disease in screened patients (Group 1) was compared with that in patients with TSC with a prior diagnosis of LAM (Group 2). Forty-eight patients with TSC and no prior history of LAM were screened. Of the 38 females, 13 (34%) had LAM; LAM was absent in males. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients previously known to have LAM, FEV(1) and DL(CO) correlated inversely with severity of disease as assessed by CT scan. The prevalence of LAM in women with TSC was 34%, approximately 10-fold that previously reported, consistent with a large hitherto unrecognized subclinical population of patients at risk for pulmonary complications.

Adult↗

PubMed2001

Nicotinamide adenine dinucleotide (NAD) and its metabolites inhibit T lymphocyte proliferation: role of cell surface NAD glycohydrolase and pyrophosphatase activities.

The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)2) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In vitro, NAD inhibits mitogen-stimulated rat T cell proliferation. To investigate the mechanism of inhibition, the effects of NAD and its metabolites on T cell proliferation were studied using ART2a+ and ART2b+ rat T cells. NAD and ADP-ribose, but not nicotinamide, inhibited proliferation of mitogen-activated T cells independent of ART2 allele-specific expression. Inhibition by P2 purinergic receptor agonists was comparable to that induced by NAD and ADP-ribose; these compounds were more potent than P1 agonists. Analysis of the NAD-metabolizing activity of intact rat T cells demonstrated that ADP-ribose was the predominant metabolite, consistent with the presence of cell surface NAD glycohydrolase (NADase) activities. Treatment of T cells with phosphatidylinositol-specific phospholipase C removed much of the NADase activity, consistent with at least one NADase having a GPI anchor; ART2- T cell subsets contained NADase activity that was not releasable by phosphatidylinositol-specific phospholipase C treatment. Formation of AMP from NAD and ADP-ribose also occurred, a result of cell surface pyrophosphatase activity. Because AMP and its metabolite, adenosine, were less inhibitory to rat T cell proliferation than was NAD or ADP-ribose, pyrophosphatases may serve a regulatory role in modifying the inhibitory effect of ecto-NAD on T cell activation. These data suggest that T cells express multiple NAD and adenine nucleotide-metabolizing activities that together modulate immune function.

ADP Ribose Transferases↗

PubMed2001

Herbal medicines and perioperative care.

CONTEXT: Widespread use of herbal medications among the presurgical population may have a negative impact on perioperative patient care. OBJECTIVES: To review the literature on commonly used herbal medications in the context of the perioperative period and provide rational strategies for managing their preoperative use. DATA SOURCES: The MEDLINE and Cochrane Collaboration databases were searched for articles published between January 1966 and December 2000 using the search terms herbal medicine, phytotherapy, and alternative medicine and the names of the 16 most commonly used herbal medications. Additional data sources were obtained from manual searches of recent journal articles and textbooks. STUDY SELECTION: We selected studies, case reports, and reviews addressing the safety and pharmacology of 8 commonly used herbal medications for which safety information pertinent to the perioperative period was available. DATA EXTRACTION: We extracted safety, pharmacodynamic, and pharmacokinetic information from the selected literature and reached consensus about any discrepancies. DATA SYNTHESIS: Echinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and valerian are commonly used herbal medications that may pose a concern during the perioperative period. Complications can arise from these herbs' direct and pharmacodynamic or pharmacokinetic effects. Direct effects include bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions include potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic herb-drug interactions include increased metabolism of many drugs used in the perioperative period by St John's wort. CONCLUSIONS: During the preoperative evaluation, physicians should explicitly elicit and document a history of herbal medication use. Physicians should be familiar with the potential perioperative effects of the commonly used herbal medications to prevent, recognize, and treat potentially serious problems associated with their use and discontinuation.

Dietary Supplements↗