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Biomedical subjects

Graeme Currie

Publications and source records attributed to Graeme Currie.

8 recordsLinked to original sources
PubMed2006

Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for persistent infection of hepatocytes. The aim of this study was to determine changes in intrahepatic cccDNA in patients with chronic hepatitis B (CH-B) during 48 weeks of antiviral therapy and its correlation to virological, biochemical, and histological parameters. Twenty-six HBsAg-positive CH-B patients received combination treatment with pegylated interferon alpha-2b (peg-IFN) and adefovir dipivoxil (ADV) for 48 weeks. Paired liver biopsies from before and at the end of treatment were analyzed for intrahepatic HBV-DNA. Median serum HBV-DNA had decreased by -4.9 log10 copies/mL at the end of treatment and was undetectable in 13 individuals (54%). Median intrahepatic total HBV-DNA and cccDNA had decreased by -2.2 and -2.4 log10, respectively. Changes in intracellular HBV-DNA positively correlated with HBsAg serum reduction and were accompanied by a high number of serological responders. Eight of 15 HBeAg-positive patients lost HBeAg, and five developed anti-HBe antibodies during treatment. These eight patients exhibited lower cccDNA levels before and at the end of therapy than did patients without HBeAg loss. Four patients developed anti-HBs antibodies. ALT normalized in 11 patients. The number of HBs-antigen- and HBc-antigen-positive hepatocytes was significantly lower after treatment, suggesting the involvement of cytolytic mechanisms. In conclusion, combination therapy with peg-IFN and ADV led to marked decreases in serum HBV-DNA and intrahepatic cccDNA, which was significantly correlated with reduced HBsAg.

Adenine↗
PubMed2006

Reluctant but resourceful middle managers: the case of nurses in the NHS.

This study counters the widely held view that middle managers have little to contribute to strategic change in health care organizations. In particular, it argues that middle managers with a nursing background that manage clinical activity should be involved in strategic change beyond mere implementation of decisions made by executive management. Constraints upon this are noted - the power of doctors and central government intervention - that means middle managers enact a semiautonomous strategic role. Antecedents for the semiautonomous role are investment in organization and management development, developing lateral organizational structures that allow middle managers to make a contribution to the development, as well as the implementation of strategy and allowing middle managers to interact with other stakeholders outside the confines of the organization.

Humans↗
PubMed2005

Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1.

BACKGROUND/AIMS: Adefovir dipivoxil (10 mg once-daily) was added to antiretroviral therapy including lamivudine in 35 HIV/HBV co-infected patients. METHODS: Parameters evaluated included alanine aminotransferase (ALT), HBV DNA and serological markers, HIV-1 RNA, and CD4+ cell count. RESULTS: Twenty-nine patients (83%) completed 144 weeks. Serum HBV DNA declined from a baseline 9.76 log10 copies/mL (median) to 4.68, 5.24, and 5.90 log10 copies/mL at weeks 48, 96, and 144, respectively (P<0.0001 at all time points). Seven patients (25%) achieved HBV DNA<2.3 log10 copies/mL. No adefovir-associated resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were detected. ALT declined from 81 IU/L (median) at baseline by -16.0, -44.5, and -46.0 IU/L at week 48, 96 and 144, respectively (P=<0.05, respectively), and normalized in 71% of patients (20 of 28) by week 144. Two patients developed antibodies against HB 'e' antigen by week 48. No serious adverse events related to adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable. CONCLUSIONS: Treatment with adefovir dipivoxil for 144 weeks was well tolerated and resulted in significant and sustained reductions in HBV DNA and ALT in HIV/HBV co-infected patients. Efficacy increased with treatment duration, with no loss of viral suppression.

AIDS-Related Opportunistic Infections↗
PubMed2005

Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.

BACKGROUND: Treatment with adefovir dipivoxil for 48 weeks resulted in histologic, virologic, and biochemical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We evaluated the effect of continued therapy as compared with cessation of therapy. METHODS: One hundred eighty-five HBeAg-negative patients with chronic hepatitis B were assigned to receive 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks (ratio, 2:1). After week 48, patients receiving adefovir dipivoxil were again randomly assigned either to receive an additional 48 weeks of the drug or to switch to placebo. Patients originally assigned to placebo were switched to adefovir dipivoxil. Patients treated with adefovir dipivoxil during weeks 49 through 96 were subsequently offered continued therapy. The primary end points were changes in hepatitis B virus (HBV) DNA and alanine aminotransferase levels. RESULTS: Treatment with adefovir dipivoxil resulted in a median decrease in serum HBV DNA of 3.47 log copies per milliliter (on a base-10 scale) at 96 weeks and 3.63 log copies per milliliter at 144 weeks. HBV DNA levels were less than 1000 copies per milliliter in 71 percent of patients at week 96 and 79 percent at week 144. In the majority of patients who were switched from adefovir dipivoxil to placebo, the benefit of treatment was lost (median change in HBV DNA levels from baseline, -1.09 log copies per milliliter; only 8 percent of patients had levels below 1000 copies per milliliter at week 96). Side effects during weeks 49 through 144 were similar to those during the initial 48 weeks. Resistance mutations rtN236T and rtA181V were identified in 5.9 percent of patients after 144 weeks. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, the benefits achieved from 48 weeks of adefovir dipivoxil were lost when treatment was discontinued. In patients treated for 144 weeks, benefits were maintained, with infrequent emergence of viral resistance.

Adenine↗
PubMed2004

SMP-1, a member of a new family of small myristoylated proteins in kinetoplastid parasites, is targeted to the flagellum membrane in Leishmania.

The mechanisms by which proteins are targeted to the membrane of eukaryotic flagella and cilia are largely uncharacterized. We have identified a new family of small myristoylated proteins (SMPs) that are present in Leishmania spp and related trypanosomatid parasites. One of these proteins, termed SMP-1, is targeted to the Leishmania flagellum. SMP-1 is myristoylated and palmitoylated in vivo, and mutation of Gly-2 and Cys-3 residues showed that both fatty acids are required for flagellar localization. SMP-1 is associated with detergent-resistant membranes based on its recovery in the buoyant fraction after Triton X-100 extraction and sucrose density centrifugation and coextraction with the major surface glycolipids in Triton X-114. However, the flagellar localization of SMP-1 was not affected when sterol biosynthesis and the properties of detergent-resistant membranes were perturbed with ketoconazole. Remarkably, treatment of Leishmania with ketoconazole and myriocin (an inhibitor of sphingolipid biosynthesis) also had no affect on SMP-1 localization, despite causing the massive distension of the flagellum membrane and the partial or complete loss of internal axoneme and paraflagellar rod structures, respectively. These data suggest that flagellar membrane targeting of SMP-1 is not dependent on axonemal structures and that alterations in flagellar membrane lipid composition disrupt axoneme extension.

Amino Acid Sequence↗
PubMed2004

Lanreotide effect on splanchnic blood flow in healthy subjects: effect of the rate of infusion.

BACKGROUND: Somatostatin is a naturally occurring peptide advocated for the management of hemodynamic complications of chronic liver diseases. The route of administration (bolus application or constant infusion) has been a question of debate. AIM: Our aim was to explore the effects of the somatostatin analog lanreotide, given as a bolus injection or continuous infusion, on food-stimulated hemodynamics in humans. METHODS: Twelve healthy subjects (6 men and 6 women) were studied in a double-blind, double-dummy, randomized, crossover study. After a baseline period of 60 minutes, each subject received either a placebo bolus injection and an intravenous infusion of 100 microg/h lanreotide over a period of 8 hours or a placebo infusion over a period of 8 hours and an 800-microg lanreotide bolus injection. Simultaneously, a liquid test meal (Ensure Plus, 6.3 kJ/mL; Abbott Laboratories, Abbott Park, Ill) was perfused intraduodenally at 3 mL/min over a period of 8 hours. Diastolic blood pressure, heart rate, and superior mesenteric arterial and portal venous volume flows were measured at regular intervals by use of echo-Doppler technology. Plasma lanreotide levels were determined at defined intervals. RESULTS: Lanreotide as a 100-microg/h infusion for 8 hours was bioequivalent with lanreotide as an 800-microg bolus injection (mean area under the plasma concentration-time curve [AUC] extrapolated to infinity [AUC( infinity )], 1844.3 ng.min/L versus 1971.0 ng.min/L; AUC(infinity) ratios, 0.99; confidence interval, 0.95-1.02), and clearance was identical (479.2 mL/min versus 413.4 mL/min, P >.05). As expected, significant differences were observed in maximum plasma concentrations (75.58 ng/mL versus 4.85 ng/mL, P <.001) after infusion and bolus injections, respectively. Lanreotide at 100 microg/h over a period of 8 hours was well tolerated and abolished food-stimulated splanchnic hyperemia in both the superior mesenteric artery and the portal vein (mean AUC above baseline values [AUC(ab)], 37.25 L/min.min and 0.51 L/min.min, respectively). In contrast, the same dose of lanreotide given as a bolus injection only temporarily blunted postprandial hyperemia (mean AUC(ab) for superior mesenteric artery, 251.4 L/min.min, P <.001; mean AUC(ab) for portal vein, 194.95 L/min.min, P <.001), and subjects had significantly more side effects. CONCLUSION: On the basis of tolerability and hemodynamic effects, an intravenous infusion of lanreotide seems superior to a bolus injection of the same dose.

Adult↗
PubMed2003

Murine serpin 2A is a redox-sensitive intracellular protein.

Murine serpin 2A is expressed at high levels in haemopoietic progenitors and down-regulated on differentiation. When it is constitutively expressed in the multipotent haemopoietic cell line, FDCP-Mix, it causes a delay in differentiation and increased clonogenic potential. The serpin is also dramatically up-regulated on T-cell activation. It has an unusual reactive site Cys-Cys sequence, a unique C-terminal extension and lacks a typical cleavable N-terminal signal sequence. In spite of these features, the protein is not a member of the ovalbumin-serpin family, but is instead most closely related to human antichymotrypsin. We have shown that the serpin is intracellular with prominent nuclear localization. Transverse urea gradient gels and CD studies show that the protein undergoes the stressed-relaxed conformational change typical of inhibitory serpins. However, we have not detected complex-forming activity with a set of proteases. Thermal denaturation studies also show that the protein has decreased structural stability under reducing conditions, although it lacks disulphide bonds within the core of the molecule. Our results show that serpin 2A is an intracellular protein with the potential to mediate its biological effects via interaction with non-protease intracellular targets. Furthermore, the results presented suggest a model whereby the serpin interactions could be modulated by redox conditions or conformational change induced by cleavage of the reactive-site loop.

Animals↗