Disappointing results of combination therapy for HCV?
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Adolescent↗
Biomedical subjects
K O'Donnell
Publications and source records attributed to K O'Donnell.
Chromosome complement of the fungal plant pathogen Fusarium graminearum based on genetic and physical mapping and cytological observations.
A genetic map of the filamentous fungus Fusarium graminearum (teleomorph: Gibberella zeae) was constructed to both validate and augment the draft whole-genome sequence assembly of strain PH-1. A mapping population was created from a cross between mutants of the sequenced strain (PH-1, NRRL 31084, originally isolated from Michigan) and a field strain from Minnesota (00-676, NRRL 34097). A total of 111 ascospore progeny were analyzed for segregation at 235 loci. Genetic markers consisted of sequence-tagged sites, primarily detected as dCAPS or CAPS (n = 131) and VNTRs (n = 31), in addition to AFLPs (n = 66) and 7 other markers. While most markers exhibited Mendelian inheritance, segregation distortion was observed for 25 predominantly clustered markers. A linkage map was generated using the Kosambi mapping function, using a LOD threshold value of 3.5. Nine linkage groups were detected, covering 1234 cM and anchoring 99.83% of the draft sequence assembly. The nine linkage groups and the 22 anchored scaffolds from the sequence assembly could be assembled into four chromosomes, leaving only five smaller scaffolds (59,630 bp total) of the nuclear DNA unanchored. A chromosome number of four was confirmed by cytological karyotyping. Further analysis of the genetic map data identified variation in recombination rate in different genomic regions that often spanned several hundred kilobases.
Chromosome Segregation↗
Improved neurodevelopmental outcomes following long-term high-dose oral acyclovir therapy in infants with central nervous system and disseminated herpes simplex disease.
OBJECTIVE: Infants with neonatal herpes, classified as central nervous system or disseminated disease, have a high incidence of moderate and severe neurologic deficits despite standard acute therapy. STUDY DESIGN: Following completion of parenteral therapy, infants with central nervous system and/or disseminated disease received 2 years of continuous oral acyclovir therapy. Target minimum peak serum acyclovir concentrations were >2 microg/ml for the first three patients, and >3 microg/ml for the subsequent 13 patients. Safety assessments were made every 3 months. We evaluated neurodevelopmental outcomes with Bayley Scales of Infant Development. RESULTS: A total of 16 consecutive herpes simplex virus-infected infants born during 1990 to 2003 received the treatment plan; 13/16 infants had central nervous system disease; 3 had disseminated disease without central nervous system involvement. A total of 69% (11/16) had Bayley scores in the normal range for mental development and 79% (11/14) had motor scores in the normal range. At the final assessment, five children had developmental delays. One child had severe mental delay with normal motor development. Four children had mild mental delays, with severe motor delays in three. All children were independently mobile, without seizure disorder, had normal vision, and had speech development. During the 2-year course of treatment, five children had brief recurrences of dermal lesions, and none had evidence of neurologic deterioration. There were no serious or sustained adverse drug reactions. CONCLUSION: This pilot study reports improved outcomes in a small cohort of infants with a prolonged course of oral acyclovir. A minority of these children exhibited mild or significant developmental delays. Further investigation of this approach to treatment is warranted.
Acyclovir↗
Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C*.
SUMMARY: Treatment of hepatitis C virus (HCV) infection with interferon (IFN)-alpha, as monotherapy or in combination with ribavirin, is associated with significant side-effects including weight loss. The aim of our study was to describe the evolution of body weight during combination antiviral treatment and to examine the possible determinants of weight loss. This was a retrospective analysis of 126 patients who received combination therapy of pegylated IFN-alpha-2b and ribavirin at our unit. Body weight was recorded at each outpatient attendance during treatment and follow-up, and was expressed as a percentage of baseline value. We observed a decline of body weight during treatment. Median (range) weight values at 4, 12, 24, and 48 weeks (expressed as percentage of baseline weight) were 97.7 (91.5-110.2), 95.4 (84.4-109.4), 93.7 (80.8-106.5), and 91.1 (80.1-103.6) respectively. There was no significant association of increased weight loss with age, gender, pretreatment weight, ethnicity, pretreatment histological stage, cumulative IFN dose (adjusted for body weight), HCV genotype or treatment outcome. Median body weight returned to baseline within 6 months of stopping treatment. Patients experience significant weight loss during combination therapy. Those experiencing greater weight losses during therapy did not benefit from improved antiviral response.
Adult↗
Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis.
OBJECTIVE: To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by methylated bovine serum albumin (mBSA) and interleukin-1 (IL-1). METHODS: Mice were injected intraarticularly with mBSA on day 0 and subcutaneously with recombinant human IL-1beta on days 0-2. At day 7, knee joints were removed and assessed histologically. Flow cytometry and RNase protection were used to analyze IL-1-dependent events. RESULTS: C57BL/6 (B6), 129/Sv, and (B6 x 129/ Sv)F1 hybrid mice, all H-2b strains, were susceptible to mBSA/IL-1-induced arthritis, whereas C3H/HeJ (H-2k) mice were not. B6 mice lacking T and B cells (RAG1-/-) or major histocompatibility complex (MHC) class II antigens (MHCII-/-), and B6 mice treated with a CD4+ T cell-depleting monoclonal antibody, were resistant to disease. In contrast, B cell-deficient (muMT/ muMT) mice developed arthritis at an incidence and severity similar to that of controls. RelB-deficient (RelB-/-) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity. In B6 mice, flow cytometry demonstrated an IL-1-dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA (mRNA) for the chemokines monocyte chemoattractant protein 1, macrophage inhibitory protein 2 (MIP-2), RANTES, MIP-1alpha, and MIP-1beta, in vivo and in vitro. CONCLUSION: Arthritis induced by mBSA/IL-1 is strain specific and dependent on CD4+ T lymphocytes and at least partially on RelB, but not on B lymphocytes or antibody. IL-1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells. This model of acute monarticular arthritis is particularly suitable for further investigations into cell-mediated immunity in arthritis and the role of IL-1.
Acute Disease↗
Characterization of a human synovial cell antigen: VCAM-1 and inflammatory arthritis.
The contribution of synovial cells to the pathogenesis of rheumatoid arthritis (RA) is only partly understood. Monoclonal antibody (mAb) 1D5 is one of very few mAb ever raised against RA synovial cells in order to study the biology of these cells. Studies on the expression pattern and structural features of the 1D5 Ag suggest that 1D5 recognizes human vascular cell adhesion molecule-1 (VCAM-1), which is an intercellular adhesion molecule. Vascular cell adhesion molecule-1 may be involved in a number of crucial intercellular interactions in RA.
Animals↗
A zinc-containing intraruminal device for prevention of the sporidesmin-induced cholangiopathy of facial eczema in calves.
AIM: To develop and evaluate a zinc-containing intraruminal controlled-release bolus for protection of calves (175-250 kg bodyweight) against facial eczema (FE). METHODS: Boluses releasing zinc, in the form of zinc oxide, at rates ranging from 1.67 to 4.25 g/day were administered to calves which were challenged 4 weeks later with the FE toxin, sporidesmin. The efficacy of the boluses in protecting against sporidesmin-induced cholangiopathy was determined by measuring serum activities of gamma-glutamyltransferase (GGT). RESULTS: A bolus releasing zinc at approximately 4.25 g/day gave excellent protection against sporidesmin toxicity for periods of up to 5 weeks duration. CONCLUSIONS: This zinc-containing intraruminal controlled-release bolus has the potential to markedly reduce the incidence and severity of FE in calves within a 175-250 kg bodyweight range.
Journal Article↗
Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir.
BACKGROUND: Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure. CASE REPORT: A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the development of graft failure. OUTCOME: A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved. CONCLUSION: The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.
Acute Disease↗
Severe inflammatory arthritis and lymphadenopathy in the absence of TNF.
It has been postulated that TNF has a pivotal role in a cytokine cascade that results in joint inflammation and destruction in rheumatoid arthritis (RA). To evaluate this, we examined the response of TNF-deficient (Tnf(-/-)) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by injection of chick type II collagen (CII) in CFA. Tnf(-/-) mice had some reduction in the clinical parameters of CIA and, on histology, significantly more normal joints. However, severe disease was evident in 54% of arthritic Tnf(-/-) joints. Tnf(-/-) mice had impaired Ig class switching, but preserved T cell proliferative responses to CII and enhanced IFN-gamma production. Interestingly, CII-immunized Tnf(-/-) mice developed lymphadenopathy and splenomegaly associated with increased memory CD4(+) T cells and activated lymph node B cells. Acute inflammatory arthritis was also reduced in Tnf(-/-) mice, although again some mice exhibited severe disease. We conclude that TNF is important but not essential for inflammatory arthritis; in each model, severe arthritis could proceed even in the complete absence of TNF. These results call into doubt the concept that TNF is obligatory for chronic autoimmune and acute inflammatory arthritis and provide a rationale for further studies into TNF-independent cytokine pathways in arthritis.
Animals↗
Gene genealogies reveal global phylogeographic structure and reproductive isolation among lineages of Fusarium graminearum, the fungus causing wheat scab.
During the past decade, the plant disease called scab or Fusarium head blight of wheat and barley has reached epidemic proportions in North America and elsewhere in the world. Scab is an economically devastating plant disease, not only because it causes significant reduction in seed yields and quality, but also because infested seeds are often contaminated with trichothecene and estrogenic mycotoxins that pose a serious threat to animal health and food safety. To test whether the primary etiological agent of scab, the fungus Fusarium graminearum, is panmictic throughout its range, allelic genealogies were constructed from six single-copy nuclear genes from strains selected to represent the global genetic diversity of this pathogen. Excluding one hybrid strain, all six genealogies recovered the same seven biogeographically structured lineages, suggesting that they represent phylogenetically distinct species among which gene flow has been very limited during their evolutionary history. Parsimony analysis of the combined data set comprising 7,120 aligned nucleotide characters resolved most relationships among the seven lineages of the F. graminearum clade and related fusaria included in the study. Phylogenetic evidence is also presented for introgressive hybridization and intragenic recombination among lineages of the F. graminearum clade in nature.
Biological Evolution↗
Molecular phylogeny of parasitic zygomycota (Dimargaritales, zoopagales) based on nuclear small subunit ribosomal DNA sequences.
We analyzed sequence data of the 18S rDNA gene from representatives of nine mycoparasitic or zooparasitic genera to infer the phylogenetic relationships of these fungi within the Zygomycota. Phylogenetic analyses identified a novel monophyletic clade consisting of the Zoopagales, Kickxellales, Spiromyces, and Harpellales. Analyses also identified a monophyletic mycoparasitic-zooparasitic Zoopagales clade in which Syncephalis, Thamnocephalis, and Rhopalomyces form a sister group to a Piptocephalis-Kuzuhaea clade. Although monophyly of the mycoparasitic Dimargaritales received strong bootstrap and decay index support, phylogenetic relationships of this order could not be resolved because of the unusually high rate of base substitutions within the 18S rDNA gene. Overall, the 18S gene tree topology is weak, as reflected by low bootstrap and decay index support for virtually all internal nodes uniting ordinal and superordinal taxa. Nevertheless, the 18S rDNA phylogeny is mostly consistent with traditional phenotypic-based classification schemes of the Fungi.
Classification↗
Legal conceptions: regulating gametes and gamete donation.
The growing scope of gamete donation and the manipulation of gametes makes it essential to develop a coherent theory of the nature of gametes and the claims which may be made in relation to them. The nature of gametes is ambiguous, they blur the distinctions between persons and property, but the current legal framework which governs gamete donation and manipulation fails to address their status. This leaves unanswered fundamentally important questions about control of processes involving gametes and rights to use or control the gametes themselves and the information which they represent. These are claims which are rooted in the concept of property. A property based analysis highlights the themes of autonomy, personhood and control which lie at the heart of the claims made in relation to gametes and an account based on the notion of property for personhood offers a more coherent justification for recognising claims in gametes and mediating disputes. This perspective exposes the inadequacies and inconsistencies of the legal construction of gametes and the legal regulation of gamete donation. The present legal framework has not sought to develop a coherent construction of gametes, but to constrain the practices of the assisted reproductive technologies (including gamete donation) within a framework which is presented as least damaging to the traditional ideologies of the creation of the family.
Bioethics↗
Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy.
Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.
2-Aminopurine↗
Methodological issues in analyzing psychological test scores in pediatric clinical trials.
Clinical trials to address drug dosing, safety, and efficacy issues in the pediatric population are becoming more common. In some studies, tests of mental ability are administered at regular intervals in drug trials for treatment of children with HIV, certain types of cancer, sickle cell anemia, and diabetes. The test scores are used to examine differences between treatments in efficacy and safety over time. In addition to the well-known problems of analyzing repeated measures with incomplete data profiles, the analyses of these data are complicated by a number of unique features, including that children can be so ill that their raw scores cannot be mapped to a normed scaled score, and that children may be in the studies long enough that they transition between the age-appropriate instruments. These issues are often ignored in data analyses and can potentially cause incorrect conclusions regarding treatment efficacy and safety. This article describes these issues and their possible consequences. A simple approach to determine their impact on the statistical analysis of a particular clinical trial is suggested. The approach is illustrated with data from a Phase III trial in HIV-infected children.
Age Factors↗
Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.
BACKGROUND: In many transplant centres lamivudine is an important component of prophylaxis against, and treatment of, hepatitis B virus (HBV) graft infection. Drug resistant HBV species with specific polymerase mutations may emerge during lamivudine treatment. AIMS: To examine the clinical consequences of graft infection by lamivudine resistant virus. METHODS: The clinical course of four liver transplant patients who developed graft infection with lamivudine resistant virus was reviewed. The response of HBV infection to reduction of immunosuppression and to manipulation of antiviral therapy was assessed. For each patient, serum viral titre was measured and the viral polymerase gene was sequenced at multiple time points. RESULTS: High serum titres were observed following emergence of the lamivudine resistant species. Wild type HBV re-emerged as the dominant serum species after lamivudine withdrawal. All patients developed liver failure, and onset of liver dysfunction was observed when resistant virus was the dominant serum species. In three patients, liver recovery was observed when immunosuppression was stopped and when alternative antivirals were given. Wild type virus appeared to respond to ganciclovir, and to reintroduction of lamivudine. For one patient, introduction of famciclovir was associated with clinical, virological, and histological response. CONCLUSIONS: Failure of lamivudine prophylaxis may identify patients at special risk for the development of severe graft infection. Treatment of graft reinfection should include reduction of immunosuppression, and systematic exposure to alternative antivirals. Viral quantitation and genetic sequencing are essential components of therapeutic monitoring.
Adult↗
Distinct roles for the NF-kappaB1 (p50) and c-Rel transcription factors in inflammatory arthritis.
Rheumatoid arthritis (RA) is a complex disease, with contributions from systemic autoimmunity and local inflammation. Persistent synovial joint inflammation and invasive synovial pannus tissue lead to joint destruction. RA is characterized by the production of inflammatory mediators, many of which are regulated by the Rel/NF-kappaB transcription factors. Although an attractive target for therapeutic intervention in inflammatory diseases, Rel/NF-kappaB is involved in normal physiology, thus global inhibition could be harmful. An alternate approach is to identify and target the Rel/NF-kappaB subunits critical for components of disease. To assess this, mice with null mutations in c-rel or nfkb1 were used to examine directly the roles of c-Rel and p50 in models of acute and chronic inflammatory arthritis. We found c-Rel-deficient mice were resistant to collagen-induced arthritis but had a normal response in an acute, destructive arthritis model (methylated BSA/IL-1 induced arthritis) suggesting c-Rel is required for systemic but not local joint disease. In contrast, p50-deficient mice were refractory to induction of both the chronic and acute arthritis models, showing this subunit is essential for local joint inflammation and destruction. Our data suggest Rel/NF-kappaB subunits play distinct roles in the pathogenesis of inflammatory arthritis and may provide a rationale for more specific therapeutic blockade of Rel/NF-kappaB in RA.
Acute Disease↗
Additive antiviral effects of lamivudine and alpha-interferon in chronic hepatitis B infection.
alpha-Interferon has limited efficacy against chronic hepatitis B virus (HBV) infection. Nucleoside analogues may confer greater benefits, however, it is likely that combination therapies will be required for effective control of this infection. We investigated the antiviral effect of lamivudine and interferon therapy in eight patients with high HBV-DNA levels. Six patients received lamivudine/interferon combination therapy followed, after a 6-month drug-free period, with lamivudine monotherapy. Mean HBV viral load (copies/ml) reduction was significantly greater after 4 months of combination therapy (4.3 x 10(3)) compared to an equivalent period of lamivudine monotherapy (2.9 x 10(2)) (P=0.03). Two patients were given 6 months of lamivudine/interferon combination therapy followed immediately by lamivudine monotherapy. Cessation of interferon in these patients led to a rapid 1-2 log10 increase in HBV viral load. These findings suggest that alpha-interferon has a direct antiviral effect on chronic HBV infection, which may be additive to, or synergistic with lamivudine.
Antiviral Agents↗
Use of pharmacists' cognitive services in home health care assessment.
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Data Collection↗