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Biomedical subjects

R Howe

Publications and source records attributed to R Howe.

At least 19 recordsLinked to original sources
PubMed2003

Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma.

Secondary myelodysplastic syndrome (sMDS) and acute myelogenous leukemia (AML) have been recognized with increasing frequency following autologous stem cell transplantation (ASCT). A retrospective analysis of 230 consecutive patients with Hodgkin's lymphoma (HL, 64) and non-Hodgkin's lymphoma (NHL, 166) who underwent ASCT was conducted to assess the incidence and risk factors for the development of sMDS/AML. At a median follow up of 41 months (range 0.1-177 months), 10 of 230 patients (4.3%) developed sMDS/AML. The 5-year-actuarial incidence of sMDS/AML was 13.1% and 5-year cumulative incidence by competing risk analysis was 4.2%. The median time to development of sMDS/AML was 39.9 months from the time of ASCT (range 12.1-62.0 months). Complex karyotypes at diagnosis of sMDS/AML included structural anomalies and/or loss of chromosome 5 (eight patients), 7 (five patients), 17 (two patients) and 20 (two patients). All patients subsequently died, at a median of 6.8 months (range 0-39.9) from diagnosis of sMDS/AML. Fluorescent in situ hybridization (FISH) analysis for -5/5q- and -7/7q- were normal in all six patients whose pre-ASCT bone marrow was available for testing. Five of the six had samples available for testing at diagnosis of sMDS/AML and all had abnormal FISH results. By univariate statistical analysis, male gender (P=0.01), prior alkylating agents (mechlorethamine for HL, P=0.001 and cyclophosphamide for NHL, P=0.05) and the number of prior treatment regimens (P=0.04) were significantly associated with the development of sMDS/AML. Given the relatively low incidence rate of sMDS/AML, these analyses are primarily exploratory in nature but provide some insight into relevant risk factors and illustrate the risk of developing sMDS/AML after myeloablative conditioning and ASCT for lymphoma.

Adult↗
PubMed2000

Deeply Penetrating Banded Zonal Flows in the Solar Convection Zone.

Helioseismic observations have detected small temporal variations of the rotation rate below the solar surface that correspond to the so-called "torsional oscillations" known from Doppler measurements of the surface. These appear as bands of slower- and faster-than-average rotation moving equatorward. Here we establish, using complementary helioseismic observations over 4 yr from the GONG network and from the MDI instrument on board SOHO, that the banded flows are not merely a near-surface phenomenon: rather, they extend downward at least 60 Mm (some 8% of the total solar radius) and thus are evident over a significant fraction of the nearly 200 Mm depth of the solar convection zone.

Journal Article↗
PubMed2000

Dynamic variations at the base of the solar convection zone

We have detected changes in the rotation of the sun near the base of its convective envelope, including a prominent variation with a period of 1.3 years at low latitudes. Such helioseismic probing of the deep solar interior has been enabled by nearly continuous observation of its oscillation modes with two complementary experiments. Inversion of the global-mode frequency splittings reveals that the largest temporal changes in the angular velocity Omega are of the order of 6 nanohertz and occur above and below the tachocline that separates the sun's differentially rotating convection zone (outer 30% by radius) from the nearly uniformly rotating deeper radiative interior beneath. Such changes are most pronounced near the equator and at high latitudes and are a substantial fraction of the average 30-nanohertz difference in Omega with radius across the tachocline at the equator. The results indicate variations of rotation close to the presumed site of the solar dynamo, which may generate the 22-year cycles of magnetic activity.

Journal Article↗
PubMed2000

Effects on sleep disturbance of changes in aircraft noise near three airports.

Field measurements were conducted of potential sleep disturbance associated with changes in nighttime aircraft noise exposure near three airports. One study was conducted near Stapleton International Airport (DEN) and Denver International Airport (DIA) in anticipation of the closure of the former and opening of the latter. Sleep behavior was monitored in 57 homes located near runway ends at the two airports. A second study was conducted in the vicinity of DeKalb-Peachtree Airport (PDK), a large general aviation airport that expected increased nighttime flight operations due to the Olympic Games in July and August of 1996. Similar methods of measuring nighttime noise levels and sleep disturbance in the two studies were maintained over the course of 2717 and 686 subject-nights of observations, respectively. No major differences in noise-induced sleep disturbance were observed as a function of changes in nighttime aircraft noise exposure.

Aircraft↗
PubMed1996

The Solar Acoustic Spectrum and Eigenmode Parameters

The Global Oscillation Network Group (GONG) project estimates the frequencies, amplitudes, and linewidths of more than 250,000 acoustic resonances of the sun from data sets lasting 36 days. The frequency resolution of a single data set is 0.321 microhertz. For frequencies averaged over the azimuthal order m, the median formal error is 0.044 microhertz, and the associated median fractional error is 1.6 x 10(-5). For a 3-year data set, the fractional error is expected to be 3 x 10(-6). The GONG m-averaged frequency measurements differ from other helioseismic data sets by 0.03 to 0.08 microhertz. The differences arise from a combination of systematic errors, random errors, and possible changes in solar structure.

Journal Article↗
PubMed1996

Differential Rotation and Dynamics of the Solar Interior

Splitting of the sun's global oscillation frequencies by large-scale flows can be used to investigate how rotation varies with radius and latitude within the solar interior. The nearly uninterrupted observations by the Global Oscillation Network Group (GONG) yield oscillation power spectra with high duty cycles and high signal-to-noise ratios. Frequency splittings derived from GONG observations confirm that the variation of rotation rate with latitude seen at the surface carries through much of the convection zone, at the base of which is an adjustment layer leading to latitudinally independent rotation at greater depths. A distinctive shear layer just below the surface is discernible at low to mid-latitudes.

Journal Article↗
PubMed1996

Effects of aircraft overflights on wilderness recreationists.

On-site and telephone opinion surveys were conducted to assess outdoor recreationists' annoyance with aircraft overflights of wilderness areas. Although current technology for measuring noise exposure does not yet permit accurate and cost-effective estimates of dosage-response relationships in outdoor recreational settings, it was nonetheless possible to construct a rough relationship between estimated aircraft noise exposure and annoyance from the data of the on-site study. In the second survey, telephone interviews were administered to another sample of outdoor recreationists within 2 weeks of their return from visits to 12 wilderness areas. The prevalence of aircraft noise-induced annoyance (in any degree) among respondents in all wilderness areas ranged from 5% to 32%. The prevalence of a consequential degree of aircraft noise-induced annoyance among respondents was less than 5% in all wilderness areas combined. Noise-induced annoyance proved to be a more direct measure of the effects of aircraft overflights on recreationists than more global measures such as visit satisfaction or intent to revisit.

Acoustics↗
PubMed1995

Kinetic characteristics of ZENECA ZD5522, a potent inhibitor of human and bovine lens aldose reductase.

Aldose reductase (aldehyde reductase 2) catalyses the conversion of glucose to sorbitol, and methylglyoxal to acetol. Treatment with aldose reductase inhibitors (ARIs) is a potential approach to decrease the development of diabetic complications. The sulphonylnitromethanes are a recently discovered class of aldose reductase inhibitors, first exemplified by ICI215918. We now describe enzyme kinetic characterization of a second sulphonylnitromethane, 3',5'-dimethyl-4'-nitromethylsulphonyl-2-(2-tolyl)acetanilide (ZD5522), which is at least 10-fold more potent against bovine lens aldose reductase in vitro and which also has a greater efficacy for reduction of rat nerve sorbitol levels in vivo (ED95 = 2.8 mg kg-1 for ZD5522 and 20 mg kg-1 for ICI 215918). ZD5522 follows pure noncompetitive kinetics against bovine lens aldose reductase when either glucose or methylglyoxal is varied (K(is) = K(ii) = 7.2 and 4.3 nM, respectively). This contrasts with ICI 215918 which is an uncompetitive inhibitor (K(ii) = 100 nM) of bovine lens aldose reductase when glucose is varied. Against human recombinant aldose reductase, ZD5522 displays mixed noncompetitive kinetics with respect to both substrates (K(is) = 41 nM, K(ii) = 8 nM with glucose and K(is) = 52 nM, K(ii) = 3.8 nM with methylglyoxal). This is the first report of the effects of a sulphonylnitromethane on either human aldose reductase or utilization of methylglyoxal. These results are discussed with reference to a Di Iso Ordered Bi Bi mechanism for aldose reductase, where the inhibitors compete with binding of both the aldehyde substrate and alcohol product. This model may explain why aldose reductase inhibitors follow noncompetitive or uncompetitive kinetics with respect to aldehyde substrates, and X-ray crystallography paradoxically locates an ARI within the substrate binding site. Aldehyde reductase (aldehyde reductase 1) is closely related to aldose reductase. Inhibition of bovine kidney aldehyde reductase by ZD5522 follows uncompetitive kinetics with respect to glucuronate (K(ii) = 39 nM), indicating a selectivity greater than 5-fold for bovine aldose reductase relative to aldehyde reductase.

Acetanilides↗
PubMed1995

Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin.

One hundred patients, known to have been excreting Clostridium difficile cytotoxin in faeces, were reviewed retrospectively to determine the response time for treatment with oral metronidazole and vancomycin, and the effect of the additional administration of anti-motility agents. Records were available for 78 patients of whom 58 had received treatment with either metronidazole or vancomycin. Response and relapse rates were similar for the two treatment regimens. However, the mean duration of symptoms was significantly shorter in evaluable patients treated with vancomycin (3.0 days, n = 22) compared with those given metronidazole (4.6 days, n = 28) (Mann-Whitney-U, P < 0.01). No difference in the duration of symptoms, irrespective of antibiotic therapy, was associated with use of anti-motility agents. The increased cost of vancomycin compared with metronidazole for the treatment of C. difficile infection may be justifiable by reductions in the length of stay in hospital or in the need for nursing in isolation facilities, consequent upon a shorter symptomatic response time. Administration of anti-motility agents did not appear to impair response in patients with mild to moderate C. difficile infection.

Adult↗
PubMed1995

Paraneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy.

We analysed the clinical features, course and response to immunosuppressive therapy in 30 patients with autoimmune disorders associated with myelodysplastic syndromes (MDS). 18 patients with MDS developed acute systemic autoimmune disorders. Common manifestations were skin vasculitis (n = 15) and arthritis (n = 11). Seven patients had an acute clinical syndrome of vasculitic skin rash, fever and arthritis with peripheral oedema in three and pulmonary infiltrates in five of these seven patients. Other acute manifestations included pericarditis, pleural effusions, skin ulceration, seizures, myositis and peripheral neuropathy. Chronic or isolated autoimmune manifestations (n = 11) included glomerulonephritis, polyneuropathy, pyoderma gangrenosum, ulcerative colitis and polyarthritis. Classic connective tissue disorders recognized included relapsing polychondritis, polymyalgia rheumatica, Raynaud's syndrome and Sjögren's syndrome. Autoimmune manifestations responded to immunosuppressive therapy (primarily prednisone) in 26/27 patients treated. Furthermore, cytopenias improved substantially in six patients, including complete normalization of peripheral blood counts in two patients with cytogenetic remission in one. Patients with a haematological response to immunosuppressive therapy had improved survival compared with non-responding patients. The autoimmune syndrome was implicated as a primary cause of death in 8/17 patients who died. Autoimmune manifestations may be more common than previously recognized in patients with MDS. Aggressive therapy with immunosuppressive agents in selected patients often controls autoimmune phenomena associated with MDS and may lead to haematological responses in some patients.

Adolescent↗
PubMed1993

Inhibition of aldose reductase by (2,6-dimethylphenylsulphonyl)nitromethane: possible implications for the nature of an inhibitor binding site and a cause of biphasic kinetics.

Aldose reductase (aldehyde reductase 2, ALR2) is often isolated as a mixture of two forms which are sensitive (ALR2S), or insensitive (ALR2I), to inhibitors. We show that ICI 215918 ((2-6-dimethylphenylsulphonyl)-nitromethane) follows either noncompetitive, or uncompetitive kinetics with respect to aldehyde for ALR2S, or the closely related enzyme, aldehyde reductase (aldehyde reductase 1, ALR1). Similar behaviour is exhibited by two other structural types of aldose reductase inhibitor (ARI), spirohydantoins and acetic acids, when either aldehyde, or NADPH is varied. For ALR2S, we have demonstrated kinetic competition between a sulphonylnitromethane, an acetic acid and a spirohydantoin. Thus, different ARIs probably have overlapping binding sites. Published studies imply that ALR2 follows an ordered mechanism where coenzyme binds first and induces a reversible conformation change (E.NADPH-->E*.NADPH). Reduction of aldehyde appears rate-limited by the step E*.NADP+-->E.NADP+. Spontaneous activation converts ALR2S into ALR2I and increases kcat. This must be associated with acceleration of the rate-determining step. We now propose the following hypothesis to explain characteristics of ARIs. (1) Inhibitors preferentially bind to the E* conformation. (2) The ARI binding site contains residues in common with that for aldehyde substrates. When aldehyde is varied, uncompetitive inhibition arises from association at the site for alcohol product in the E*.NADP+ complex which has little affinity for the substrate. Any competitive inhibition arises from use of the aldehyde site in the E*.NADPH complex. (3) Acceleration of the E*.NADP+-->E.NADP+ step upon activation of ALR2 reduces steady state levels of E* and so decreases sensitivity to ARIs.

Acetates↗
PubMed1993

Cell-mediated immunity in trachomatous scarring. Evidence from a leprosy population.

BACKGROUND: There is limited understanding of the mechanisms that mediate immunity after infection by Chlamydia trachomatis. Since it is known that the clinical course of leprosy is related to cell-mediated immunity and that such immunity contributes to the development of trachomatous conjunctival scarring, the authors examined patients to determine if there might be an association between leprosy status and trachomatous conjunctival scarring. METHODS: Leprosy patients registered at Shashemane Hospital were interviewed, examined, and patients with siblings residing in the vicinity were asked to return for further clinical examination. A subsample of sibships was selected for laboratory evaluation of cell-mediated immunity, measured by lymphocyte proliferative responses in vitro to stimulation by mycobacterial antigens. RESULTS: Conjunctival scarring was less severe in multibacillary leprosy patients (with suppressed cell-mediated immunity) than in their healthy siblings and more severe in paucibacillary leprosy patients (with enhanced cell-mediated immunity) than in their healthy siblings. The mean lymphocyte proliferative responses to mycobacterial antigens were greater in the sibling (whether leprous or healthy) with more severe conjunctival scarring, regardless of type of leprosy. CONCLUSION: The specific cellular immune responses to Mycobacterium leprae and p65 antigen in patients with increased conjunctival scarring provide evidence that early in the course of infection with C. trachomatis, factors related to an individual's cellular response are crucial to the development of conjunctival scarring. A delayed-type hypersensitivity reaction ("reversal reaction") found in paucibacillary leprosy patients could contribute to the increased trachomatous conjunctival scarring in these patients.

Adolescent↗
PubMed1993

Natural and acquired resistance to Leishmania: cellular activation by Leishmania aethiopica of mononuclear cells from unexposed individuals is through the stimulation of natural killer (NK) cells.

Cells from normal non-Leishmania-exposed individuals could respond in vitro by proliferation and interferon-gamma (IFN-gamma) production to Leishmania aethiopica stimulation. The main cell type that appeared to be activated following such stimulation was CD3-, CD16+/56+, i.e. NK cells. Of the few CD3+ cells responding, an involvement of CD8+ cells was evident in the absence of activation of CD4+ cells in normal individuals, while a different feature was observed when patients' cells were investigated. Cells from patients with L. aethiopica infection did not show this NK response, but rather the CD4+ cells were the prominent responding cells. No evidence of the involvement of superantigens or cells utilizing the gamma delta T cell receptor (gamma delta cells) in the response of unexposed individuals was noted.

Adult↗