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Biomedical subjects

Paul Martin

Publications and source records attributed to Paul Martin.

At least 109 records · Page 6Linked to original sources
PubMed2003

c-Jun regulates eyelid closure and skin tumor development through EGFR signaling.

To investigate the function of c-Jun during skin development and skin tumor formation, we conditionally inactivated c-jun in the epidermis. Mice lacking c-jun in keratinocytes (c-jun(Deltaep)) develop normal skin but express reduced levels of EGFR in the eyelids, leading to open eyes at birth, as observed in EGFR null mice. Primary keratinocytes from c-jun(Deltaep) mice proliferate poorly, show increased differentiation, and form prominent cortical actin bundles, most likely because of decreased expression of EGFR and its ligand HB-EGF. In the absence of c-Jun, tumor-prone K5-SOS-F transgenic mice develop smaller papillomas, with reduced expression of EGFR in basal keratinocytes. Thus, using three experimental systems, we show that EGFR and HB-EGF are regulated by c-Jun, which controls eyelid development, keratinocyte proliferation, and skin tumor formation.

Animals↗
PubMed2003

De novo non-alcoholic fatty liver disease following orthotopic liver transplantation.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized clinico-pathologic entity typically associated with obesity, type II diabetes and hyperlipidemia. It has been noted to recur after orthotopic liver transplantation (OLT). We report four patients who developed de novo NAFLD within 3 months of OLT without the typical predisposing factors of diabetes mellitus or obesity. Three of the four patients underwent OLT for hepatitis C-related cirrhosis, and the other for alcoholic cirrhosis. Examination of the liver explants revealed no evidence of steatosis. No surreptitious alcohol use or a drug-induced process could be identified in these patients. Treatment of recurrent hepatitis C infection in one patient with interferon and ribavirin led to sustained suppression of the viral RNA to undetectable levels, but no improvement in histology or liver enzymes. All four patients had histologic evidence of preservation injury on the initial post-OLT biopsies, but the significance of this finding in relationship to the development of NAFLD is unknown. NAFLD can develop without any of the known predisposing conditions after transplantation, and this raises further questions about the pathogenesis of this condition.

Adult↗
PubMed2003

Conversion from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine is safe and cost-effective in patients receiving long-term prophylaxis to prevent hepatitis B recurrence after liver transplantation.

Recurrent hepatitis B infection after liver transplantation was previously frequent and associated with significant allograft failure and mortality. Recurrence rates of hepatitis B were improved with the use of passive immunoprophylaxis with hepatitis B immune globulin, and later, lamivudine monotherapy. Combination prophylaxis with intravenous hepatitis B immune globulin and lamivudine substantially decreased rates of hepatitis B recurrence, but intravenous administration of hepatitis B immune globulin was expensive and associated with significant adverse effects. In the current study, 59 patients receiving primary liver transplantation for chronic hepatitis B infection were prospectively followed up after converting from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine. All patients tolerated intramuscular hepatitis B immune globulin well. At a median follow-up of 511 days after conversion to intramuscular hepatitis B immune globulin, 58 of 59 patients (98.3%) were hepatitis B surface antigen-negative. Twenty-one patients (35.6%) required a median of one supplemental intravenous hepatitis B immune globulin infusion to maintain therapeutic antibody levels. Economic analysis showed an average cost-effectiveness ratio for combination intramuscular hepatitis B immune globulin plus lamivudine of $52,600 per recurrence prevented, which was far below the cost of lamivudine monotherapy and of intravenous hepatitis B immune globulin alone or in combination with lamivudine. These results suggest that intramuscular administration of hepatitis B immune globulin in combination with lamivudine offers a safe, effective, and cost-effective approach to preventing hepatitis B recurrence after orthotopic liver transplantation.

Adult↗
PubMed2003

Hepatitis C-related hepatocellular carcinoma in the United States: influence of ethnic status.

OBJECTIVES: The incidence of hepatocellular carcinoma (HCC) seems to be rising in the United States (US), and considerable variability in the incidence and etiology of HCC has been noted among different racial and ethnic groups in this country. The aim of this study was to evaluate the influence of racial and ethnic status in the viral etiology of HCC in the US. METHODS: Retrospective surveys were conducted at liver transplantation centers in the US. Respondents were asked to review the charts of all patients with HCC seen at their institution for the 2-yr period between July, 1997, and June, 1999, and provide information about the racial and ethnic distribution of cases and their serological status with regard to hepatitis B and C markers. RESULTS: Complete information was available on 691 patients who formed the basis of this study, comprising 59% whites, 14% blacks, 16% Asians, and 11% other racial groups. Of the patients, 107 patients (15.4%) were positive for hepatitis B surface antigen (HBsAg), 322 had antibodies to hepatitis C virus (anti-HCV) (46.5%), 33 (4.7%) had both HBsAg and anti-HCV), and 229 (33.1%) had neither marker present. Clear differences were seen among racial groups. Anti-HCV positivity was the most frequent risk factor in both blacks and whites, whereas HBsAg positivity was the most frequent etiological factor in Asians with HCC. CONCLUSIONS: HCV infection seems to be the major risk factor for HCC in the US, particularly among individuals of white and black ethnicity, whereas hepatitis B remains the main risk factor among patients of Asian ethnicity. These preliminary findings indicate the need for a more detailed study of ethnic variability in the pathogenesis of HCC.

Adult↗
PubMed2003

The drugs don't work: expectations and the shaping of pharmacogenetics.

This article examines one particular set of technologies arising from developments in human genetics, those aimed at improving the targeting, design and use of conventional small molecule drugs-pharmacogenetics. Much of the debate about the applications and consequences of pharmacogenetics has been highly speculative, since little or no working technology is yet on the market. This article provides a novel analysis of the development of pharmacogenetics, and the social and ethical issues it raises, based on the sociology of technological expectations. In particular, it outlines how two alternative visions for the development of the technology are being articulated and embedded in a range of heterogeneous discourses, artefacts, actor strategies and practices, including: competing scientific research agendas, experimental technologies, emerging industrial structures and new ethical discourses. Expectations of how pharmacogenetics might emerge in each of these arenas are actively shaping the trajectory of this nascent technology and its potential socio-economic consequences.

Biotechnology↗
PubMed2003

Developments in hepatitis C therapy during 2000-2002.

Hepatitis C virus (HCV) is a human hepatotropic virus with an estimated worldwide prevalence of 170 million cases, including approximately 4 million cases in the US. It is a major cause of liver disease and is the most common indication for liver transplantation in the US. The majority of infected individuals are eligible for therapy. Since it is difficult to predict who will have progressive disease, those with significant inflammation or fibrosis on histologic examination of liver biopsy are generally offered treatment. The following chapter is an overview of the patent literature during 2000-mid-2002, and discusses the potential of various treatment modalities for HCV.

Animals↗
PubMed2003

Mother-to-child transmission of human immunodeficiency virus type 1 in relation to the season in Yaounde, Cameroon.

A public health program to prevent mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) by treatment with nevirapine has been ongoing in Yaounde, Cameroon since January 2000. After 24 months, plasma samples from 119 children born to HIV-1-positive mothers were tested for HIV-1 RNA between six and eight weeks after birth. Thirteen (10.9%) tested positive (95% confidence interval = 5.2-16.7%). Risk factors associated with MTCT in this study were maternal viral load (P < 0.05), low birth weight (chi2 for trend = 8.78, P = 0.01), and birth during the second half of the year. A high correlation was repeatedly observed between rainfall in a given month and the risk of MTCT of HIV-1 in children born three months later (r = 0.634, P < 0.001). Although we cannot rule out other tropical infections related to the rainy season, the role of malaria is highly suspected since the interval of three months we observed between the peaks of rainfall and the rate of transmission is consistent with the Plasmodium life cycle.

Adult↗
PubMed2003

Genetics and Forensics: Making the National DNA Database.

This paper is based on a current study of the growing police use of the epistemic authority of molecular biology for the identification of criminal suspects in support of crime investigation. It discusses the development of DNA profiling and the establishment and development of the UK National DNA Database (NDNAD) as an instance of the 'scientification of police work' (Ericson and Shearing 1986) in which the police uses of science and technology have a recursive effect on their future development. The NDNAD, owned by the Association of Chief Police Officers of England and Wales, is the first of its kind in the world and currently contains the genetic profiles of more than 2 million people. The paper provides a framework for the examination of this socio-technical innovation, begins to tease out the dense and compact history of the database and accounts for the way in which changes and developments across disparate scientific, governmental and policing contexts, have all contributed to the range of uses to which it is put.

Journal Article↗
PubMed2002

Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.

The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation ( 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.

Adolescent↗
PubMed2002

Dynamic analysis of actin cable function during Drosophila dorsal closure.

Throughout development, a series of epithelial movements and fusions occur that collectively shape the embryo. They are dependent on coordinated reorganizations and contractions of the actin cytoskeleton within defined populations of epithelial cells. One paradigm morphogenetic movement, dorsal closure in the Drosophila embryo, involves closure of a dorsal epithelial hole by sweeping of epithelium from the two sides of the embryo over the exposed extraembryonic amnioserosa to form a seam where the two epithelial edges fuse together. The front row cells exhibit a thick actin cable at their leading edge. Here, we test the function of this cable by live analysis of GFP-actin-expressing embryos in which the cable is disrupted by modulating Rho1 signaling or by loss of non-muscle myosin (Zipper) function. We show that the cable serves a dual role during dorsal closure. It is contractile and thus can operate as a "purse string," but it also restricts forward movement of the leading edge and excess activity of filopodia/lamellipodia. Stripes of epithelium in which cable assembly is disrupted gain a migrational advantage over their wild-type neighbors, suggesting that the cable acts to restrain front row cells, thus maintaining a taut, free edge for efficient zippering together of the epithelial sheets.

Actins↗
PubMed2002

A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease.

Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.

Acute Disease↗
PubMed2002

Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children.

Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P <.0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P =.10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P =.23). LFS rates were lower in patients with advanced disease (P <.0001), age 10 years or older (P =.002), or short duration of CR1 (P =.007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.

Adolescent↗
PubMed2002

Effect of endothelin blockade on basal and stimulated forearm blood flow in patients with essential hypertension.

Endothelin receptor antagonism lowers blood pressure in patients with essential hypertension, but the contribution of the endothelin system to increased vascular tone in these patients remains controversial. We used strain-gauge venous plethysmography to measure changes in basal and metabolically stimulated (peak reactive hyperemia [PRH]) forearm blood flow (FBF) induced by continuous intrabrachial infusion of SB 209670, a dual endothelin type A/endothelin type B receptor antagonist (ETRA) in 11 patients with hypertension and 12 healthy age-matched control subjects. In both groups, ETRA caused significant vasodilation (increase in FBF compared with baseline over the last 30 minutes of ETRA infusion: 75+/-12% in control subjects, 40+/-13% in hypertension patients; P<0.01 for both groups). By repeated-measures ANOVA, there was no greater increase in FBF after ETRA in hypertension patients compared with control subjects. In addition, FBF responses to PRH, expressed as percent change from baseline (prePRH), were similar in both groups (control subjects: preETRA, 1381+/-222%; during ETRA, 921+/-178%; and hypertension patients: preETRA, 1232+/-221%: during ETRA, 865+/-285%). We conclude that basal and stimulated vasodilation induced by short-term ETRA infusion in the forearm vasculature of hypertension patients is not increased compared with that of control subjects. An enhanced contribution of the endothelin system to vascular tone in hypertension patients could not be demonstrated using this experimental approach.

Blood Flow Velocity↗
PubMed2002

Immediate early genes krox-24 and krox-20 are rapidly up-regulated after wounding in the embryonic and adult mouse.

Embryos show a remarkable capacity for perfect repair after injury. Wounding of embryonic skin triggers rapid activation of epithelial sweeping and mesenchymal contraction tissue movements that bear striking analogy to several naturally occurring morphogenetic tissue movements, but very little is known about the early molecular signals that might initiate such movements. Here, we describe the rapid and transient up-regulation of two immediate early genes, krox-24 and krox-20, after wounding of the embryonic mouse. Furthermore, we demonstrate that these signals are conserved, but of longer duration, in the neonate and adult wound situation. To further test the roles of these transcription factors in vivo, we performed wound healing studies on embryos lacking either Krox-24 or 20. Despite the dramatic up-regulation of these genes in response to injury, our studies reveal that neither of them on their own is essential for repair.

Age Factors↗
PubMed2002

Epithelial fusions in the embryo.

Morphogenesis in the embryo involves the bending, folding and fusing of epithelial tissues to create the final complex shapes of the various organs and structures in the body. One essential process that occurs frequently during development is the drawing together and fusion of epithelial edges. Drosophila dorsal closure is perhaps the most genetically tractable of this type of movement, and several recent advances have revealed much about the signals regulating the dynamic actin cytoskeletal machineries that underlie the zippering-closed of this hole in the embryonic fly. It is now clear that there are intriguing parallels with more complex morphogenetic tissue movements in vertebrates.

Actins↗
PubMed2002

Structures in focus--filopodia.

Filopodia are thin cell surface extensions filled with tight parallel bundles of actin filaments. They are highly dynamic structures which rapidly extend and retract as well as sweep up and down and from side to side, and can be found at the leading edge of many types of motile cells such as fibroblasts and keratinocytes, as well as the growth cone tips of migrating axons. Cells appear to use filopodia to explore the extracellular matrix (ECM) and surfaces of other cells, identifying appropriate targets for adhesion or in the case of a migrating growth cone, for sensing guidance cues that enable the axon to navigate to it's appropriate target. As well as this sensory role, filopodia have also recently been shown to play an important mechanical role in epithelial adhesion, and are likely to be key players in developmental processes that require migrating epithelial sheets to zipper and fuse to one another. Their dynamic properties as well as their tendency to be damaged or lost after fixation mean they are best analysed using live imaging techniques. As this field improves, the number of tissues in which filopodia are seen to be playing key roles is fast increasing.

Animals↗