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M R Howard

Publications and source records attributed to M R Howard.

At least 37 records · Page 2Linked to original sources
PubMed1998

Activity of thalidomide in AIDS-related Kaposi's sarcoma and correlation with HHV8 titre.

A phase II study of thalidomide was conducted to evaluate its efficacy and toxicity in the treatment of cutaneous AIDS-related Kaposi's sarcoma (AIDS-KS). To evaluate whether clinical response is correlated with titre of human herpesvirus 8 (HHV8) DNA in peripheral blood, levels were determined by serial end-point dilution at enrolment and 4-6 weeks later. Seventeen male HIV-seropositive patients with histopathologically diagnosed KS were treated with thalidomide 100mg orally once nightly for 8 weeks. Response evaluation was performed using AIDS Clinical Trials Group (ACTG) criteria and analysis was by intention to treat. Six of 17 patients achieved a partial response (35%: 95% confidence interval 10-61%). Eight patients withdrew (6 owing to toxicity, one to early progression and one to non-compliance). HHV8 DNA load decreased by at least 3log10 to undetectable levels in 3 of the 5 virologically assessable partial responders. This preliminary study demonstrates that thalidomide has activity in the treatment of AIDS-KS and that clinical response is associated with a reduction of HHV8 DNA titre in peripheral blood.

AIDS-Related Opportunistic Infections↗
PubMed1997

Kaposi's sarcoma-associated herpes virus--a new concern for human reproduction?

The detection of the recently discovered Kaposi's sarcoma-associated herpes virus (KSHV) in human immunodeficiency virus-uninfected donor semen and in blood from a normal blood donor has led us to review this new area of health concern, with emphasis on a number of studies conducted into the presence of the virus in semen and the possibility of transmission during assisted conception procedures.

Female↗
PubMed1997

Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors.

OBJECTIVE: To ascertain the prevalence of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, and cytomegalovirus (CMV) DNA in semen was investigated. METHODS: Amplification by nested polymerase chain reaction was used to detect viral DNA sequences in samples from 24 HIV-infected gay men, 15 of them with Kaposi's sarcoma (KS), and 115 healthy donors. RESULTS: Six of the 24 HIV-infected patients had detectable HHV-8 DNA in their semen: three of the 15 patients with KS and three of the nine patients without KS. CMV DNA was detected in 20 semen samples from HIV-infected patients. None of the semen samples from healthy donors had detectable HHV-8 DNA and rates of CMV DNA detection were low (3%). CONCLUSIONS: The study demonstrates the presence of HHV-8 in semen from HIV-infected individuals with, or at risk, of developing KS and the potential for sexual transmission of the virus. We found no evidence of HHV-8 in the semen of HIV-uninfected donors.

Cytomegalovirus↗
PubMed1996

Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex. METHODS: We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay. FINDINGS: 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays. INTERPRETATION: The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.

Adult↗
PubMed1995

Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma.

Kaposi sarcoma-associated herpesvirus (KSHV) is consistently found in biopsy samples from patients with AIDS-related and "classical" Kaposi's sarcoma (KS). Although highly suggestive of a causal role of KSHV in the pathogenesis of KS, this observation does not exclude the possibility that KSHV, like other herpesviruses, is widely distributed and is a mere "passenger" in these lesions. Here we report that KSHV was detectable in peripheral blood mononuclear cells of 24/46 (52%) of KS patients, but in none of 134 blood donors or 26 HIV-uninfected hospital controls. KSHV detection increased with immunosuppression, as shown by a correlation with a reduced number of CD4-positive T-cells. Moreover, KSHV detection in peripheral blood cells of HIV-infected individuals without KS predicted the subsequent appearance of KS lesions. 143 patients who did not have KS at the time of their first (or only) blood sample were followed up for a median of 30 months. Of the 11 who had been KSHV positive 6 developed KS compared with only 12 out of 132 who were KSHV negative. These findings are compatible with a causative role of KSHV in KS. KSHV was rarely detected in sputum and throat swabs of HIV-infected patients, providing a potential explanation for the apparently limited spread of this virus.

AIDS-Related Opportunistic Infections↗
PubMed1995

Bone marrow examination in newly diagnosed Hodgkin's disease: current practice in the United Kingdom.

In the UK Hodgkin's disease is usually treated by either clinical oncologists or haematologists. A national study of the performance of bone marrow examination in newly diagnosed Hodgkin's disease was undertaken to establish current practice. A total of 620 questionnaires were despatched, and replies were received from 60% of consultants (45% of clinical oncologists and 70% of haematologists). Bone marrow examination was performed in all new cases significantly more often by haematologists than by clinical oncologists (74% vs 40%, P < 0.001). Among haematologists, there was no correlation between the number of new patients seen annually and practice, however clinical oncologists were even less likely to perform routine bone marrow biopsies if they saw more than ten patients per year (P < 0.02). Where bone marrow examination was performed selectively, the most common criteria used were peripheral blood cytopenia and advanced-stage disease. These criteria were applied in the same way by both clinical oncologists and haematologists. Bone marrow biopsy, an invasive and often painful procedure, is currently performed more frequently in Hodgkin's disease than can be recommended on the basis of recent studies in the literature and associated guidelines. There is a significant difference in practice between clinical oncologists and haematologists, and this raises the wider issue of the influence of hospital specialisation on patient management.

Bone Marrow Examination↗
PubMed1995

c-MYC gene abnormalities in high grade and centroblastic-centrocytic non-Hodgkins lymphoma.

Fifty nine cases of high grade and centroblastic-centrocytic (cc) Non Hodgkins Lymphoma (NHL) were investigated for mutations and gross gene rearrangements in the 5' region of the c-MYC gene. Mutations in this region, and the presence of hypermutated c-MYC genes, have been associated with poor prognostic groups. All cases showed normal c-MYC gene organisation on Southern blot analysis indicating absence of gross gene rearrangements. PCR amplification and restriction digest analysis of the exon 1/intron 1 region revealed point mutations in 7 cases. No evidence for hypermutation was found. Mutations were relatively more common in high grade NHL (6/39) than in cc-NHL (1/20). There was no correlation with disease status at presentation or relapse or the presence of extranodal disease. The cc-NHL case with a c-MYC mutation subsequently transformed to high grade disease. These data suggest that hypermutation of the c-MYC gene is a relatively rare event in cc-NHL and high grade NHL and does not contribute to the aetiology in the majority of cases. Mutation of c-MYC in cc-NHL may predict transformation to high grade disease.

Adolescent↗
PubMed1995

A survey of use of unrelated volunteer donor bone marrow transplantation at 46 centres worldwide, 1989-93. International Marrow Unrelated Search and Transplant (IMUST) Study.

Unrelated donor bone marrow transplantation is increasingly used to treat haemopoietic disorders where no HLA-identical sibling is available. The International Marrow Unrelated Search and Transplant Study has collected core data on consecutive unrelated donor BMT (UD-BMT) and HLA-identical sibling donor BMT (ID-BMT) performed in 46 participating centres world-wide between March 1989 and February 1993. Eighteen UD-BMT were performed in the first 6-month period in 14 participating centres, while in the last period there were 103 UD-BMT in 46 centres. The percentage of BMT recipients with the following diagnoses were: bone marrow failure UD-BMT 15% and ID-BMT 11%; AML 13% and 27%; ALL 18% and 17%; CML 48% and 31%; and other diseases 7% and 14%. Thirty-eight per cent of UD-BMT recipients had advanced disease compared with only 23% of ID-BMT recipients. Thirty six per cent of UD-BMT compared with 21% of ID-BMT recipients were under 16 years old. More extreme differences in pre-transplant clinical characteristics between UD and ID-BMT recipients were found when diagnosis and stage of disease were considered together. This survey indicates how UD and ID-BMT are currently used in the treatment of haematological disease; however, longer follow-up is required to assess the value of UD-BMT in the management of patients with bone marrow disorders.

Adolescent↗
PubMed1994

The use of liquid chromatography/thermospray mass spectrometry with on-line ultraviolet diode array and radiochemical detection: characterization of the putative metabolites of U-78875 in female rat faeces.

The metabolites of an anxiolytic drug candidate U-78875 [3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)- imidazo[1,5-alpha]quinoxalin-4(5H)-one; I] were investigated in female rat faecal extracts following a single oral dose of (14C)I. Initial metabolite profiling was performed by high-performance liquid chromatography incorporating homogeneous (i.e. liquid scintillant added post-column) radiochemical detection (radio-HPLC). This indicated the presence of parent drug and one minor metabolite. Because liquid scintillant is incompatible with thermospray interfaces, subsequent analysis by thermospray/HPLC/MS (TSP/LC/MS) incorporated radiochemical detection in heterogeneous (i.e. solid scintillant) mode and ultraviolet (UV) diode array detection. This revealed that the peak thought previously to be parent drug contained two components: a metabolite (major) and parent drug (minor). The UV spectrum and TSP/LC/MS/MS daughter ion analysis led to the proposition of a bisamide structure for the major metabolite. Chemical synthesis was used to confirm this structure. TSP/LC/MS indicated that the molecular weight of the minor metabolite was 16 u higher than the bisamide, suggesting an oxidized analogue. Attempts to obtain a daughter ion spectrum on this minor metabolite proved unsuccessful. On-line radiochemical and UV diode array detection greatly facilitates the TSP/LC/MS characterization of metabolites from studies using radiolabelled drugs.

Animals↗
PubMed1994

Variable detection of myeloid antigens in childhood acute lymphoblastic leukaemia.

AIMS: To determine whether the use of different sources of anti-CD13 and anti-CD33 monoclonal antibodies leads to discrepant results in childhood acute lymphoblastic leukaemia (ALL), which might contribute to the wide variation in the reported incidence of myeloid antigen expressing ALL in childhood. METHODS: Stored leukaemic cells from 10 children with previously defined myeloid positive ALL were examined. A range of commercially available anti-CD13 and anti-CD33 monoclonal antibodies, directly conjugated with phycoerythrin or fluorescein isothyocyanate, or both, was used. Positively reacting cells were detected by flow cytometry. RESULTS: There was a noticeable discordance between the different commercial sources of antibody and between the two fluorochromes in their ability to detect myeloid antigens, as well as variation in the intensity of staining. For CD13, one antibody reacted with eight cases and another with only four. Similarly, CD33 was detected in all 10 cases by one antibody and in only three by another. CONCLUSIONS: The lack of any consistent pattern of results suggests that various commercial antibodies against the same CD antigen might recognise different epitopes and that the number of molecules per cell might vary from case to case. These observations partly explain the variation in reported incidence and the failure to establish the clinical importance of myeloid positivity, and they highlight the importance of standardisation in multicentre studies in which immunophenotypic data are collected.

Antibodies, Monoclonal↗
PubMed1994

In Larrey's shadow: transport of British sick and wounded in the Napoleonic wars.

Dominique Jean Larrey's introduction of a 'flying ambulance' into Napoleons army was a great advance in military surgery. British arrangements for the transport of wounded and sick during the Napoleonic wars fell far short of Larrey's humanitarian vision. The efforts of eminent doctors such as Sir James McGrigor to create a formal ambulance service were frustrated by the army establishment. As a result the sick were often abandoned or carried in local bullock carts. Only sixty years after Waterloo did Britain finally follow Larrey's example and form a field organisation including a trained ambulance corps.

France↗
PubMed1994

A prospective study of factors determining the outcome of unrelated marrow donor searches: report from the International Marrow Unrelated Search and Transplant Study Working Group on behalf of collaborating centres.

Outcomes of searches for unrelated bone marrow donors were analysed to identify factors influencing the probability of identifying an HLA-matched donor and proceeding to an unrelated donor bone marrow transplant (UD-BMT). Between March 1989 and January 1991, 649 unrelated marrow donor searches were entered into the study. Searches were referred from transplant centres in Europe and North America to the Anthony Nolan Research Centre panel and/or the British Bone Marrow and Platelet Donor Panel, two predominantly Caucasian donor registries. Patient immunogenetic and clinical characteristics were documented on study search request forms and search outcomes were monitored at the donor registry. Data were analysed using proportional hazards regression. Major factors predicting favourable search outcomes were patient common Caucasian HLA phenotype and Caucasian ethnic group. Probability of search failure was increased by advanced disease, rare Caucasian HLA phenotype and referral to the smaller registry. Search failure frequently occurred at the mixed lymphocyte reaction stage. This study illustrates the relative roles of clinical, immunogenetic and registry factors in determining the outcome of searches. The information may be used to devise strategies to locate HLA-matched donors for a higher proportion of patients for whom UD-BMT is the preferred treatment.

Adult↗