Middle ear effusion amoxicillin concentrations in acute otitis media.
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Acute Disease↗
Biomedical subjects
C J Harrison
Publications and source records attributed to C J Harrison.
A decision analytic approach to commissioning ambulance cardiac services.
The paper discusses how a decision analytic framework has been used by an English health authority in relation to the commissioning of ambulance cardiac services. Strategies for the management by ambulance personnel of victims of cardiac arrest and persons with acute chest pain of cardiac origin were modelled in a decision-event tree, and a bibliographic database established. The international research literature prior to 1997 was searched in order to derive probability values for the tree. However, after checking whether the subgroupings of results in the papers were in accordance with the variables in the tree, the number of useful papers on acute chest pain was found to be only two. In the almost complete absence of information--even from small observational studies--on the management of the great majority of patients with cardiac symptoms transported by ambulance, the local ambulance service and the main providers of hospital services in the district are now collaborating in field studies of cardiac care in order to improve the inputs into the model.
Algorithms↗
La cage aux fold: asymmetry in the crystal structure of GroEL-GroES-(ADP)7.
The structure of the molecular chaperone GroEL from Escherichia coli in complex with GroES and seven ADP molecules has recently been reported to 3 A resolution. The structure illustrates how the cavity of GroEL is converted from a hydrophobic environment, suitable for binding unfolded polypeptides, to a much larger hydrophilic environment suitable for refolding proteins.
Adenosine Diphosphate↗
A chromosome 14q11/TCR alpha/delta specific yeast artificial chromosome improves the detection rate and characterization of chromosome abnormalities in T-lymphoproliferative disorders.
The rate of detection of chromosome abnormalities in T-cell proliferations is lower than that observed in B-cell malignancies. The former frequently involve the TCR alpha/delta locus at chromosome band 14q11. We have identified a YAC encompassing 70% of the TCR alpha/delta locus, which has been used as a fluorescence in situ hybridization probe to detect chromosome rearrangements involving 14q11, both at metaphase and within interphase nuclei, in patients with a variety of T-lymphoproliferative disorders. Its use allowed detection of previously unsuspected TCR alpha/delta rearrangements in 4/13 (30%) immature T-lineage acute leukemias, including two t(10;14) and 2 minor inversion 14s. It also clarified interpretation of complex chromosome 14 abnormalities in mature T-cell proliferations (T-prolymphocytic leukemia and ataxia telangiectasia). Use of this probe will aid the detection and characterization of abnormalities involving the TCR alpha/delta locus, particularly in cases with normal or complex karyotypes and in those proliferations for which mitoses are difficult to obtain.
Chromosome Aberrations↗
Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK.
The crystal structure of the adenine nucleotide exchange factor GrpE in complex with the adenosine triphosphatase (ATPase) domain of Escherichia coli DnaK [heat shock protein 70 (Hsp70)] was determined at 2.8 angstrom resolution. A dimer of GrpE binds asymmetrically to a single molecule of DnaK. The structure of the nucleotide-free ATPase domain in complex with GrpE resembles closely that of the nucleotide-bound mammalian Hsp70 homolog, except for an outward rotation of one of the subdomains of the protein. This conformational change is not consistent with tight nucleotide binding. Two long alpha helices extend away from the GrpE dimer and suggest a role for GrpE in peptide release from DnaK.
Adenosine Diphosphate↗
Analysis of chromosome 6 deletions in lymphoid malignancies provides evidence for a region of minimal deletion within a 2-megabase segment of 6q21.
Fluorescence in situ hybridization has been used to define deletion breakpoints within chromosome bands 6q16-21 in cases of lymphoid malignancy. Previous evidence suggested that the region might contain a tumour-suppressor gene. Six yeast artificial chromosome probes, each selected using a single marker, were localized to 6q16-21 and the following order was confirmed; D6S330-D6S283-D6S301-D6S447-D6S246-FYN+ ++. Of 32 cases of lymphoid malignancy, 30 showed deletion of D6S246 and, in the two cases in which D6S246 was retained, the adjacent marker, D6S447, was deleted. These observations imply that a region of minimal deletion is located within a 2-megabase segment of 6q21, between D6S447 and D6S246, providing a candidate region for the location of a tumour-suppressor gene.
Biomarkers, Tumor↗
Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study.
Incubation of CML marrow in long-term culture (LTC) conditions may result in selection of normal (Ph-) LTC-initiating cells (LTC-IC) as early as 10 days, and in production of Ph- clonogenic cells and mature end cells within 5 weeks. This was the rationale for using marrow cells from 10-day-old LTC to autograft nine chronic phase CML patients, ineligible for HLA-matched sibling donor transplant, and who were selected on the basis of a pre-transplant screening LTC test. Of the transplanted patients three died; two of graft failure and one of therapy-related toxicity with 97% Ph- cells 16 months following the autograft. The reconstituting haemopoietic cells in the seven engrafted patients were 100% Ph- in four, > or = 90% Ph- in two and 71% Ph- in the seventh, with a duration of complete cytogenetic response of 6-12 months. Three patients reverted to chronic phase and 100% Ph+ haemopoiesis 27-36 months post-autograft. The other three patients remain in continuous haematological remission with 22% Ph- cells in one and complete cytogenetic remission in the other two 3-4 years post-autograft. IFN therapy was generally introduced on the first evidence of recurrence of Ph+ cells or of cytogenetic deterioration. Further strategies to modulate immune surveillance in vivo may improve the outcome of cultured marrow autografts which give an initial and rather prolonged bias towards Ph- haemopoiesis.
Adult↗
Using antibiotic concentrations in middle ear fluid to predict potential clinical efficacy.
BACKGROUND: The effectiveness of an antibiotic in eradicating an infection within an anatomic compartment is related to both its availability (penetration) and the susceptibility of the causative pathogen. Antimicrobial penetration can be assessed by measuring concentrations in serum or tissue. However, to assess antibiotic effectiveness in the treatment of otitis media, both antibiotic concentrations and pathogen profiles in middle ear fluid (MEF) should be considered. Tympanocentesis is required to access fluid in the middle ear compartment. This paper considers data on (MEF) antibiotic concentrations obtained with this procedure. METHODS: Data on MEF antibiotic concentrations were considered in relation to the antibiotic susceptibility profiles of the more common otitis media pathogens. RESULTS: Amoxicillin reaches MEF concentrations that exceed MICs for penicillin-susceptible and penicillin relatively resistant Streptococcus pneumoniae, but not for beta-lactamase-producing Haemophilus influenzae. Several beta-lactamase-stable drugs, e.g. cefixime and amoxicillin/clavulanate, however, achieve MEF concentrations that easily exceed their respective MIC90s for both beta-lactamase-producing and nonproducing H. influenzae but at ordinary doses may not exceed MIC90s for penicillin relatively resistant S. pneumoniae. CONCLUSION: Ongoing observation of organisms and their antibiotic resistance patterns in patients failing initial therapy of acute otitis media indicate that stability to beta-lactamase remains an essential quality for effective second line therapies. However, when possible tympanocentesis with culture is the ideal method of targeting specific therapy for patients failing multiple consecutive antibiotic regimens.
Anti-Bacterial Agents↗
Protection from clinical varicella disease during interferon alpha-2a therapy for chronic active hepatitis B infection.
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Chickenpox↗
Middle ear effusion concentrations of cefixime during acute otitis media with effusion and otitis media with effusion.
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Acute Disease↗
The other effect of intravenously administered respiratory syncytial virus-enriched immune globulin for prophylaxis: less acute otitis media.
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Acute Disease↗
Evaluation of cytogenetic conversion to Ph- haemopoiesis in long-term bone marrow culture for patients with chronic myeloid leukaemia on conventional hydroxyurea therapy, on pulse high-dose hydroxyurea and on interferon-alpha.
Long-term bone marrow culture (LTBMC) has been used successfully in autologous transplantation in chronic myeloid leukaemia (CML). However, variation between patients in the recovery of Ph- cells in culture limits the application of this procedure to a minority. Treatment that effectively reduces in vivo tumour burden prior to initiation of LTBMC may improve the selection of Ph- cells in culture. To test this hypothesis we evaluated the frequency and degree of cytogenetic conversion to Ph- haemopoiesis in LTBMC from four independent groups of CML patients: Untreated (n = 19); conventional dosage of hydroxyurea (HU) (n = 10); pulse high-dose HU (P-HU) (n = 22) and interferon (IFN)-alpha (n = 12). In this study IFN-alpha therapy resulted in a significantly higher incidence of patients with detectable Ph- clonogenic cells in the marrow (P = 0.01) and with > or = 50% Ph- haemopoiesis in LTBMC as compared to newly diagnosed patients (P = 0.05). Also, sequential culture studies undertaken in 14 CML patients at diagnosis and following the start of pulse highdose HU therapy showed that in eight patients the average proportion of Ph- metaphases detected in LTBMC substantially increased from 1.7% (range 0-7) at diagnosis to levels of 71% (range 14-100) after treatment. Therefore we conclude that the use of IFN or pulse high-dose HU in early stage disease appears to create an opportunity to harvest the marrow for long-term culture (LTC) purging with reduced leukaaemic burden.
Adult↗
Effect of antibody alone and combined with acyclovir on neonatal herpes simplex virus infection in guinea pigs.
Neonatal herpes simplex virus (HSV) infection produces severe disease with unacceptable morbidity and mortality with current antiviral therapies. The effect of therapy with passive anti-HSV antibody and acyclovir was evaluated using a guinea pig model of neonatal HSV. Newborn animals were inoculated intranasally and treated with acyclovir (60 mg/kg/day) or antibody (or both), beginning on days 0, 2, or 3 after HSV-2 inoculation. Acyclovir alone was effective only when begun on day 0, and antibody alone was effective when begun on or before day 2. Only combination therapy was effective on day 3, reducing mortality from 82% (14/17) in controls to 44% (7/16; P < .05). Combined therapy also significantly reduced the duration of skin, eye, and mouth disease and respiratory symptoms but not recurrent disease. These data suggest that addition of antibody therapy to acyclovir may improve the outcome of neonatal HSV disease.
Acyclovir↗
Refined solution structure and dynamics of the DNA-binding domain of the heat shock factor from Kluyveromyces lactis.
The solution structure of the 92 residue (11 kDa) winged helix-turn-helix DNA-binding domain from the kluyveromyces lactis heat shock factor was refined using a total of 932 NOE, 35 phi, 25 chi 1, 5 chi 2 and 44 hydrogen bond restraints. The overall root-mean-square deviation for structured regions was 0.75(+/- 0.15) A. The three-helix bundle and four-stranded beta-sheet are well defined with rmsd of 0.53(+/- 0.10) A and 0.60(+/- 0.17) A, respectively. Helix H2 is underwound and bent near Pro45. The angle between helix H2 and the proposed recognition helix H3 is 96(+/- 6) degrees. Detailed comparisons are made with the X-ray structure of this protein as well as other structural studies on HSF. Overall, the results are consistent with the earlier studies. Differences are related to protein-protein interactions in the crystal and dynamics in solution. Backbone dynamics was investigated via 15N relaxation. The average R1, R2 and NOE values for residues in segments of secondary structure were 1.9(+/- 0.9) s-1, 7.8(+/- 0.9) s-1 and 0.81(+/- 0.05), respectively. The correlation time based on these data was 5.6(+/- 0.4) ns. Motional order parameters were calculated by fitting the relaxation data to one of three models. Low-order parameters were found for residues that comprise the turn between helices H2 and H3 (residues Lys49 to Phe53), and most strikingly, the 16 residue wing (residues Val68 to Arg83). These data are consistent with the lack of long-range NOEs identified in these regions. The data provide a basis for comparison with results of the protein-DNA complex. The relationship between structure and function is discussed.
Binding Sites↗
Effect of imiquimod as an adjuvant for immunotherapy of genital HSV in guinea-pigs.
Imiquimod, an immunomodulator which upregulates cell-mediated immune responses, was evaluated as an adjuvant for immunotherapy of recurrent genital herpes simplex virus (HSV) infection in guinea-pigs. In two experiments at separate research centres, animals were immunized with HSV glycoprotein and either placebo, 1 or 5 days of imiquimod, or complete Freund's adjuvant, 14 and 35 days after genital HSV-2 infection. Recurrent lesion days were then evaluated from days 15-91. In both experiments, immunization with glycoprotein and imiquimod most effectively reduced recurrence compared with unimmunized controls (53-69%, p < 0.001-0.05). A peak reduction of 70-80% was observed following the second immunization. This reduction was greater than that provided by immunization with glycoprotein and complete Freund's adjuvant in these experiments or those previously reported.
Adjuvants, Immunologic↗
Reduced congenital cytomegalovirus (CMV) infection after maternal immunization with a guinea pig CMV glycoprotein before gestational primary CMV infection in the guinea pig model.
This study evaluated the effects of subunit guinea pig (GP) cytomegalovirus (CMV) immunization on congenital infection. Two 25-micrograms doses of an abundant GPCMV glycoprotein, the gp60-90 complex, plus adjuvant to GPs before pregnancy produced virus-specific humoral (neutralizing and ELISA) and cellular (proliferative and delayed type hypersensitivity) responses. Viral challenge before midgestation resulted in shorter maternal viremia in immunized than in unimmunized dams (3 vs. 17 days). Litters of immunized dams had reduced organ involvement and rates of congenital infection (48% vs. 18%) and increased mean birth weights (74 vs. 99 g). Amplification of DNA extracted from pup blood or organs with primers from the gB gene of GPCMV revealed congenital infection in some pups without detectable CMV by classic culture techniques. These data suggest that induction of preconception immunity to CMV by vaccine could be useful in reducing both the incidence and severity of congenital CMV disease.
Animals↗
Perspectives on newer oral antimicrobials: what do they add?
Since oral antimicrobials have been commercially available, the few select compounds of the 1950s have evolved into an array of choices from the multiple classes currently approved for human use. This proliferation resulted primarily from the need for extended spectrum antimicrobials because of changing resistance patterns among established pathogens and emergence of new pathogens. However, it is not clear that newer oral cephalosporins, fluoroquinolones or macrolides necessarily provide clear advantages over existing drugs for many common or routine infections. Other goals of new drug development include minimizing adverse events and improving convenience. The dilemma facing clinicians is when to use these new or soon to be released compounds. This presentation addresses these and other questions as the elusive search for the ideal oral antimicrobial continues.
Administration, Oral↗
Rational selection of antimicrobials for pediatric upper respiratory infections.
Antibiotic selection is complicated by both emerging resistance to traditional antimicrobials in common community-acquired pathogens and increasing numbers of high potency or extended spectrum antimicrobials. This overview outlines a multistep process for antibiotic choice based on antimicrobial activity and patient acceptance. Understanding the infection (the natural history and most likely pathogens) is necessary for choosing a specific antimicrobial. Choices should be based on knowledge of local trends in and mechanisms of antimicrobial resistance. Candidate drugs should also exceed (at the site of infection) the minimum inhibitory concentration for 90% of strains of each most likely pathogen. Ideally the narrowest spectrum drug satisfying this pharmacodynamic requirement is used. However, inadequate compliance dooms even the most potent antibiotic. Therefore infrequent dosing, palatable taste or form, minimal side effects or lower cost may dictate choosing lower potency or narrower spectrum drugs to gain patient acceptance and thereby reasonable compliance.
Anti-Bacterial Agents↗