Biomedical subjects

Paul Martin

Publications and source records attributed to Paul Martin.

At least 73 records · Page 4Linked to original sources

PubMed2004

Wound healing and inflammation: embryos reveal the way to perfect repair.

Tissue repair in embryos is rapid, efficient and perfect and does not leave a scar, an ability that is lost as development proceeds. Whereas adult wound keratinocytes crawl forwards over the exposed substratum to close the gap, a wound in the embryonic epidermis is closed by contraction of a rapidly assembled actin purse string. Blocking assembly of this cable in chick and mouse embryos, by drugs or by inactivation of the small GTPase Rho, severely hinders the re-epithelialization process. Live studies of epithelial repair in GFP-actin-expressing Drosophila embryos reveal actin-rich filopodia associated with the cable, and although these protrusions from leading edge cells appear to play little role in epithelial migration, they are essential for final zippering of the wound edges together-inactivation of Cdc42 prevents their assembly and blocks the final adhesion step. This wound re-epithelialization machinery appears to recapitulate that used during naturally occurring morphogenetic episodes as typified by Drosophila dorsal closure. One key difference between embryonic and adult repair, which may explain why one heals perfectly and the other scars, is the presence of an inflammatory response at sites of adult repair where there is none in the embryo. Our studies of repair in the PU. 1 null mouse, which is genetically incapable of raising an inflammatory response, show that inflammation may indeed be partly responsible for scarring, and our genetic studies of inflammation in zebrafish (Danio rerio) larvae suggest routes to identifying gene targets for therapeutically modulating the recruitment of inflammatory cells and thus improving adult healing.

Actins↗

PubMed2004

Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: meta-analysis of clinical trials.

BACKGROUND: Numerous reports have appeared on lamivudine use for the treatment of hepatitis B virus (HBV) infection after renal transplantation (RT). However, the efficacy and safety of lamivudine after RT remain unclear. METHODS: The authors evaluated the efficacy and safety of initial lamivudine monotherapy in RT recipients with hepatitis B by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcomes were hepatitis B (HB) e antigen (Ag) and HBV-DNA clearance (as measures of efficacy); the secondary outcomes were biochemical response (as measures of efficacy), dropout rate, and lamivudine resistance (as measures of tolerability). The authors used the random effects model of DerSimonian and Laird, and outcomes were analyzed on an intent-to-treat basis. RESULTS: The authors identified 14 clinical trials (184 patients); all of these were prospective cohort studies. The mean overall estimate for HBV-DNA and HBeAg clearance, alanine aminotransferase normalization, and lamivudine resistance was 91% (95% confidence interval [CI], 86%-96%), 27% (95% CI, 16%-39%), 81% (95% CI, 70%-92%), and 18% (95% CI, 10%-37%), respectively. HBeAg seroconversion rate was assessed in four (28%) trials and ranged between 0% and 46%. The P value was greater than 0.05 for our test of study homogeneity. There was no association between rate of patients who were male patients or had cirrhosis, race, age, lamivudine dose, and HBV-DNA or HBeAg clearance. Increased duration of lamivudine therapy was positively associated with frequency of HBeAg loss (r =0.51, P =0.039) and lamivudine resistance (r =0.620, P =0.019). Only 2 (14%) of 14 studies reported a dropout rate greater than 0%. CONCLUSIONS: Our meta-analysis showed that the majority of RT recipients with hepatitis B had high virologic and biochemical response with lamivudine. Tolerance to lamivudine was good. However, lamivudine resistance was frequent with prolonged therapy, potentially limiting its long-term efficacy after RT.

DNA, Viral↗

PubMed2004

Natural-series radionuclides in traditional aboriginal foods in tropical northern Australia: a review.

This paper gives a review of available information on natural-series radionuclides in traditional Aboriginal foods of northern Australia. Research on this topic has been carried out primarily for radiological impact assessment purposes in relation to uranium mining activities in the region. Many of the studies have concentrated on providing purely concentration data or concentration ratios, although more detailed uptake studies have been undertaken for freshwater mussels, turtles, and water lilies. The most-studied radionuclides are 238U and 226Ra. However, dose estimates based on current data highlight the importance of 210Po, particularly for the natural (nonmining-related) dose. Data on uptake by terrestrial flora and fauna are scarce in comparison with aquatic organisms, and this knowledge gap will need to be addressed in relation to planning for uranium minesite rehabilitation.

Animals↗

PubMed2004

Morphogenesis: shroom in to close the neural tube.

A novel actin-binding protein, Shroom, localises to precisely those cells that will constrict during cranial neural tube closure and appears pivotal in regulating the apical constrictions that drive epithelial foldings in vertebrate embryos.

Actins↗

PubMed2004

The role of actin cables in directing the morphogenesis of the pharyngeal pouches.

The pharyngeal arches are separated by endodermal outpocketings, the pharyngeal pouches. These are structures of considerable importance; they are required to segregate the mesenchymal populations of each arch and to induce the formation of arch components, and they generate specific derivatives, including the parathyroid and the thymus. The pharyngeal pouches are first evident as localised sites at which the endoderm contacts the ectoderm, and they then expand along the proximodistal axis to generate the narrow, tight morphology of the mature pouch. We currently have no knowledge of the morphogenetic mechanisms that direct formation of the pharyngeal pouches. Here, in chick, we show that cells within the pharyngeal pouch endoderm have an abundance of apically located actin fibres that are networked within the endodermal sheet, via their insertion into N-cadherin adherens junctions, to form a web of supra-cellular actin cables. Cytochalasin D disruption of these actin structures results in the formation of aberrant pouches that fail to generate their normal slit-like morphology. This suggests that the process of pharyngeal pouch morphogenesis involves the constraining influence of these actin cables that direct expansion, within the pouch, along the proximodistal axis. These results, importantly, provide us with vital insights into how the pharyngeal pouches form their normal morphology. They also give evidence, for the first time, of actin cables functioning as constraints during complex vertebrate morphogenetic episodes.

Actins↗

PubMed2004

Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial.

Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV.

Adult↗

PubMed2004

Hepatitis B: epidemiology and natural history.

Chronic infection with hepatitis B and its sequelae remains a major global health concern. Despite recommendations and implementation of vaccination programs, the health and economic burdens are still significant. People in endemic areas and immigrants from these areas need to be adequately screened and treated. HBeAg-negative chronic hepatitis is increasingly recognized with additional challenges in management. Programs implementing primary prophylaxis strategies such as vaccination of high-risk adult and adolescent groups should continue.

Disease Progression↗

PubMed2004

Treatment of chronic viral hepatitis in patients with renal disease.

In the last several years, numerous studies on the natural history and outcomes of viral hepatitis in dialysis and transplantation have been reported. Despite these, the management of hepatitis C virus or hepatitis B virus-related liver disease in end-stage renal disease continues to be an area of controversy. This article aims to address the current therapeutic options for patients with renal disease and chronic viral hepatitis.

Antiviral Agents↗

PubMed2004

Liver transplantation for hepatitis B.

Recurrent HBV is almost universal post-LT and is accompanied by significant graft and patient loss in the absence of effective immunoprophylaxis. Hepatitis B immunoglobulin (HBIG) monotherapy and lamivudine monotherapy significantly reduce the rate of recurrent hepatitis B, but recurrent hepatitis B still occurs in up to 25% due to the emergence of resistant mutants. Combination administration of HBIG and lamivudine is more efficacious in preventing recurrent hepatitis B, decreasing recurrence rates of hepatitis B to 0-18% in studies. Future studies to determine the optimal dosing regimen and duration of HBIG and lamivudine and to evaluate the efficacy of newer antivirals such as adefovir dipivoxil in preventing recurrent HBV are needed. Treatment of established recurrent hepatitis B remains problematic. Lamivudine has shown promise during the initial treatment period, but is plagued by rapid development of viral resistance with longer treatment duration. Adefovir dipivoxil appears very promising, and further studies are needed to evaluate its efficacy in the post-liver transplant patient. Interferon-alfa's use in the post-liver transplant patient is limited given the availability of the newer antiviral drugs. Famciclovir and ganciclovir have shown some promise in treating recurrent HBV, but have been replaced by newer agents such as lamivudine and adefovir.

Journal Article↗

PubMed2004

Effect of nitric oxide on mucin production in experimental otitis media.

OBJECTIVE: The purpose of this study was to determine the role of nitric oxide (NO) in the pathogenesis of mucoid otitis media (OM) in lipopolysaccharide (LPS)-induced OM. METHODS: OM was induced in chinchillas by injecting S-nitroso-N-acetylpenicillamine (SNAP), LPS, and LPS + SNAP into the superior bullae. Auditory brainstem response thresholds were measured every 24 hours. Samples of middle ear fluid were collected and analyzed for mucin by the periodic acid-Schiff method. At the end of each experiment, temporal bones were harvested for histopathologic study. RESULTS: Mucin concentration was greatest in the LPS + the SNAP group and least in the SNAP-alone group. Auditory brainstem response threshold was highest in the LPS group and lowest in the SNAP group, although not significantly. Histopathology showed the greatest mucosal thickening and inflammation in the LPS + SNAP group. CONCLUSION: The addition of NO in LPS-induced OM increased the mucin concentration in middle ear fluid and increased mucosal thickness and inflammation in middle ear mucosa. SIGNIFICANCE: In the OM disease process, NO may contribute to the pathogenesis of mucoid OM.

Animals↗

PubMed2004

The myth of the biotech revolution.

The existence of a medicinal 'biotech revolution' has been widely accepted and promoted by academics, consultants, industry and government. This has generated expectations about significant improvements in the drug discovery process, healthcare and economic development that influence a considerable amount of policy-making. Here we present empirical evidence, from a variety of indicators, that shows that a range of outputs have failed to keep pace with increased research and development spending. Rather than producing revolutionary changes, medicinal biotechnology is following a well-established pattern of slow and incremental technology diffusion. Consequently, many expectations are wildly optimistic and over-estimate the speed and extent of the impact of biotechnology, suggesting that the assumptions underpinning much contemporary policymaking need to be rethought.

Attitude to Health↗

PubMed2004

A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.

BACKGROUND AND AIMS: Chronic hepatitis B is an important public health problem worldwide and in the United States. A treatment algorithm for chronic hepatitis B virus (HBV) infection was developed by a panel of US hepatologists based on new developments in the understanding of the virology of HBV, availability of more sensitive molecular diagnostic testing, and advantages and disadvantages of currently approved therapies. METHODS: This algorithm is based on available evidence, but where data are lacking, the panel relied on clinical experience and consensus expert opinion. RESULTS: Serum HBV DNA can be detected at levels as low as 100-1000 copies/mL by using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible. The threshold level of HBV DNA for determination of candidacy for therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3) copies/mL, respectively. CONCLUSIONS: Interferon alfa-2b, lamivudine, and adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost. Studies are under way to explore the safety and efficacy of combination therapy, which may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance.

Algorithms↗

PubMed2004

Integrating pharmacogenetics into society: in search of a model.

There has been considerable scientific, corporate and policy interest in the more effective use of genetics in both drug development and delivery. Pharmacogenetics - the study of the relationship between an individual's genetic makeup and response to medicinal drugs - has attracted global interest, but will it live up to its promise? Looking beyond the hype that has accompanied much of the commentary in the area, the future of pharmacogenetics will depend on how competing interests and options are resolved.

Animals↗

PubMed2004

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.

Adenine↗

PubMed2004

HBV infection in patients with end-stage renal disease.

Controlling the spread of hepatitis B virus (HBV) infection in dialysis units has been one of major triumphs in the management of end-stage renal disease. However, HBV incidence and prevalence rates remain high in dialysis patients in less-developed countries, and HBV within dialysis units continues to spread in the industrialized world. Overall response rates to HBV vaccination are lower in dialysis patients than in the nondialysis population. Lamivudine is effective in the treatment of HBV infection in the dialysis setting. Presence of hepatitis B surface antigen (HbsAg) has a negative impact on patient survival after renal transplantation. Several issues remain unanswered with regard to the management of HBV infection in dialysis patients, including the management of lamivudine resistance and the optimal timing and duration of antiviral therapy. Liver biopsy prior to renal transplantation is crucial in order to identify and exclude patients with advanced fibrosis or even cirrhosis.

Antiviral Agents↗

PubMed2004

Hepatitis C infection associated with renal disease and chronic renal failure.

Screening of blood products and attention to stricter infection control measures in hemodialysis units have reduced the incidence of hepatitis C virus (HCV) infection among dialysis patients. HCV can be transmitted via transplanted organs. Renal transplantation may accelerate the course of liver disease, which has an impact on patient and graft survival. Interferon (IFN) alfa monotherapy has produced promising results during treatment but disappointing long-term results in patients with HCV-associated glomerulonephritis. Dialysis patients with HCV infection respond well to IFN-based therapy, and there appears to be clinical benefit in clearing HCV in renal transplantation candidates. Larger prospective trials are required to fully determine the role of IFN in these patient groups, including the potential use of IFN plus ribavirin and pegylated IFNs. IFN therapy in renal transplantation patients is not recommended because of potential graft rejection.

Graft Rejection↗

PubMed2004

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Adolescent↗

PubMed2004

Tailored medicine: whom will it fit? The ethics of patient and disease stratification.

A key selling point of pharmacogenetics is the genetic stratification of either patients or diseases in order to target the prescribing of medicine. The hope is that genetically 'tailored' medicines will replace the current 'one-size-fits-all' paradigm of drug development and usage. This paper is concerned with the relationship between difference and justice in the use of pharmacogenetics. This new technology, which facilitates the identification and use of difference, has, we shall argue, the potential to lead to injustice either by the inappropriate use of difference or through the inappropriate failure to use difference. We build on empirical data from a detailed study of the range of options for the development of pharmacogenetics to present a consideration of the ethical issues that surround patient and disease stratification. In it we explore the ways in which the use of pharmacogenetics may lead to the creation of new, genetically stratified, forms of difference and new forms of injustice based on these divisions. We also examine the ways in which existing forms of difference and social stratification may interact with the use of pharmacogenetics. In conclusion, we suggest how an understanding of these ethical issues could usefully inform future policy discussions.

Clinical Trials as Topic↗