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1.  Can shear-wave elastography predict response to neoadjuvant chemotherapy in women with invasive breast cancer? 
British Journal of Cancer  2013;109(11):2798-2802.
Response of invasive breast cancer to neoadjuvant chemotherapy (NAC) is variable, and prediction of response is imperfect. We aimed to ascertain whether tissue stiffness in breast cancers, as assessed by shear-wave elastography (SWE) before treatment, is associated with response.
We retrospectively compared pre-treatment tumour mean tissue stiffness, with post-treatment Residual Cancer Burden (RCB) scores and its components in 40 women with breast cancer treated by NAC using Pearson's correlation coefficient (CC), a general linear model and multiple linear regression. Subgroup analysis was carried out for luminal, HER2-positive and basal immuno-histochemical subtypes.
Statistically significant correlations were shown between stiffness and RCB scores and between stiffness and percentage tumour cellularity. The correlation between stiffness and percentage cellularity was strongest (CC 0.35 (P<0.0001) compared with CC 0.23 (P=0.004) for the RCB score). The results of a general linear model show that cellularity and RCB score maintain independent relationships with stiffness. By multiple linear regression, only cellularity maintained a significant relationship with stiffness.
Pre-treatment tumour stiffness measured by SWE, has a statistically significant relationship with pathological response of invasive breast cancer to NAC.
PMCID: PMC3844913  PMID: 24169359
shear-wave ultrasound; response; breast cancer; neoadjuvant chemotherapy
3.  The association between different night shiftwork factors and breast cancer: a case–control study 
British Journal of Cancer  2013;109(9):2472-2480.
Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure).
We conducted a population-based case–control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above.
A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97–1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01–1.47) with a statistically significant dose–response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant.
We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose–response relationships.
PMCID: PMC3817316  PMID: 24022188
breast cancer; shiftwork; case–control
5.  Differentiating benign from malignant solid breast masses: value of shear wave elastography according to lesion stiffness combined with greyscale ultrasound according to BI-RADS classification 
British Journal of Cancer  2012;107(2):224-229.
The aim of this study was to assess the performance of shear wave elastography combined with BI-RADS classification of greyscale ultrasound images for benign/malignant differentiation in a large group of patients.
One hundred and seventy-five consecutive patients with solid breast masses on routine ultrasonography undergoing percutaneous biopsy had the greyscale findings classified according to the American College of Radiology BI-RADS. The mean elasticity values from four shear wave images were obtained.
For mean elasticity vs greyscale BI-RADS, the performance results against histology were sensitivity: 95% vs 95%, specificity: 77% vs 69%, Positive Predictive Value (PPV): 88% vs 84%, Negative Predictive Value (NPV): 90% vs 91%, and accuracy: 89% vs 86% (all P>0.05). The results for the combination (positive result from either modality counted as malignant) were sensitivity 100%, specificity 61%, PPV 82%, NPV 100%, and accuracy 86%. The combination of BI-RADS greyscale and shear wave elastography yielded superior sensitivity to BI-RADS alone (P=0.03) or shear wave alone (P=0.03). The NPV was superior in combination compared with either alone (BI-RADS P=0.01 and shear wave P=0.02).
Together, BI-RADS assessment of greyscale ultrasound images and shear wave ultrasound elastography are extremely sensitive for detection of malignancy.
PMCID: PMC3394981  PMID: 22691969
breast; ultrasound; elastography; shear wave; imaging
7.  Trend of Income-related Inequality of Child Oral Health in Australia 
Journal of Dental Research  2010;89(9):959-964.
It is important that we monitor socio-economic inequality in health. Inequality in child oral health has been expected to widen because of widening socio-economic inequality. This study aimed to evaluate trends in income-related inequality in caries experience of Australian children. Cross-sectional studies in 1992/93 and 2002/03 collected data on deciduous caries experience of 5- to 10-year-olds and permanent caries experience of 6- to 12-year-olds. Household composition and income was used to calculate quartiles of equivalized income. Slope Index of Inequality (SII), Concentration Index (CI), and regression-based rate ratios were used to quantify income-related inequality and to evaluate trends. Income-related inequality in caries experience was evident regardless of time and dentition. The three indicators of inequality indicate a significant increase in income-related inequality in child deciduous caries experience during the decade. The income inequality in permanent caries experience did not change significantly. Income inequalities increased in deciduous teeth, but not in permanent teeth, among Australian children.
PMCID: PMC3318073  PMID: 20543094
inequality; caries; children; Australia; trend
9.  How can the principles of complexity science be applied to improve the coordination of care for complex pediatric patients? 
Clinical and technological advances in medicine have resulted in more patients requiring multidisciplinary care and coordination of services. This is particularly challenging in pediatrics, given the dependency of children. Coordination of care is a key ingredient of quality care; when suboptimal, clinical outcomes and satisfaction can suffer. In this article we view coordination of care through the lens of complexity science in an effort to find new solutions to this healthcare challenge.
PMCID: PMC2464825  PMID: 16585105
complexity science; coordination of care; quality improvement; children
10.  Plasmid-Mediated Carbapenem-Hydrolyzing Enzyme KPC-2 in an Enterobacter sp. 
Antimicrobial Agents and Chemotherapy  2004;48(11):4438-4440.
A strain of an Enterobacter sp. with reduced susceptibility to imipenem, which produced a plasmid-mediated class A carbapenem-hydrolyzing enzyme, KPC-2 β-lactamase, was isolated from a patient with sepsis at a Boston hospital. This is the first report of the production of a plasmid-encoded KPC-2 β-lactamase by an Enterobacter sp.
PMCID: PMC525415  PMID: 15504876
13.  TCRβ spectratyping in RA: evidence of clonal expansions in peripheral blood lymphocytes 
Annals of the Rheumatic Diseases  1998;57(5):319-322.
OBJECTIVE—To compare the TCRβ repertoire of peripheral blood CD8 enriched (CD8+) and depleted (CD8−) T cells in rheumatoid arthritis (RA) patients and controls using CDR3 length analysis (spectratyping).
METHODS—CD8+ and CD8− T cells were separated from 14 RA patients and 12 controls, using magnetic beads coated with anti-CD8 monoclonal antibodies. cDNA was prepared as the template for amplification with 22 Vβ-Cβ primer pairs. The products were resolved by electrophoresis in an ABI373 sequencer using GENESCAN software. Expansions were identified as dominant CDR3 lengths, where the area underlying the corresponding peak exceeded the sum of the areas of the two adjacent peaks. This method was validated by sequencing 10 samples displaying dominant peaks. The expansion frequencies in RA patients and controls were compared using the χ2 test statistic.
RESULTS—Dominant peaks were evident in several Vβ families. They were more frequent in RA patients in both the CD8+ subset (RA normalised frequency 10.6; control normalised frequency 8.0; p=0.03) and the CD8− subset (RA normalised frequency 2.9; control normalised frequency 1.5; p=0.02). Sequencing of 10 samples exhibiting dominant peaks revealed an unequivocal clonal expansion in nine (90%).
CONCLUSIONS—RA patients exhibited a significantly increased frequency of T cell expansions both in the CD8+ and CD8− subsets. This phenomenon may reflect the proliferation of autoreactive cells, a non-specific expansion of memory T cells in response to pro-inflammatory cytokines or a defect of T cell regulation that predates the onset of RA and may itself predipose to disease.

 Keywords: rheumatoid arthritis; T cell; clonal expansion
PMCID: PMC1752604  PMID: 9741318
14.  Controversies about extended-spectrum and AmpC beta-lactamases. 
Emerging Infectious Diseases  2001;7(2):333-336.
Many clinical laboratories have problems detecting extended-spectrum beta-lactamases (ESBLs) and plasmid-mediated AmpC beta-lactamases. Confusion exists about the importance of these resistance mechanisms, optimal test methods, and appropriate reporting conventions. Failure to detect these enzymes has contributed to their uncontrolled spread and sometimes to therapeutic failures. Although National Committee for Clinical Laboratory Standards recommendations exist for detecting ESBL- producing isolates of Escherichia coli and Klebsiella spp., no recommendations exist for detecting ESBLs in other organisms or for detecting plasmid-mediated AmpC beta-lactamases in any organisms. Clinical laboratories need to have adequate funding, equipment, and expertise to provide a rapid and clinically relevant antibiotic testing service in centers where these resistance mechanisms are encountered.
PMCID: PMC2631719  PMID: 11294735
15.  β-Lactamases Responsible for Resistance to Expanded-Spectrum Cephalosporins in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis Isolates Recovered in South Africa 
Although resistance to the expanded-spectrum cephalosporins among members of the family Enterobacteriaceae lacking inducible β-lactamases occurs virtually worldwide, little is known about this problem among isolates recovered in South Africa. Isolates of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis resistant to expanded-spectrum cephalosporins recovered from patients in various parts of South Africa over a 3-month period were investigated for extended-spectrum β-lactamase production. Antibiotic susceptibility was determined by standard disk diffusion and agar dilution procedures. Production of extended-spectrum β-lactamases was evaluated by using the double-disk test, and the β-lactamases were characterized by spectrophotometric hydrolysis assays and an isoelectric focusing overlay technique which simultaneously determined isoelectric points and general substrate or inhibitor characteristics. DNA amplification and sequencing were performed to confirm the identities of these enzymes. The P. mirabilis and E. coli isolates were found to produce TEM-26-type, SHV-2, and SHV-5 extended-spectrum β-lactamases. An AmpC-related enzyme which had a pI of 8.0 and which conferred resistance to cefoxitin as well as the expanded-spectrum cephalosporins was found in a strain of K. pneumoniae. This is the first study which has identified organisms producing different extended-spectrum β-lactamases from South Africa and the first report describing strains of P. mirabilis producing a TEM-26-type enzyme. The variety of extended-spectrum β-lactamases found among members of the family Enterobacteriaceae isolated from major medical centers in South Africa is troubling and adds to the growing list of countries where these enzymes pose a serious problem for antimicrobial therapy.
PMCID: PMC105602  PMID: 9624474
16.  Inhibition of nicotinic responses of bovine adrenal chromaffin cells by the protein kinase C inhibitor, Ro 31-8220. 
British Journal of Pharmacology  1996;119(2):416-422.
1. The effects of the protein kinase C inhibitor, Ro 31-8220, on the responses of cultured bovine adrenal chromaffin cells to nicotine, phorbol 12, 13-dibutyrate (PDBu) and K+ have been investigated. 2. Tyrosine hydroxylase activity was measured in situ in intact cells by measuring 14CO2 evolved following the hydroxylation and rapid decarboxylation of [14C]-tyrosine offered to the cells. Secretion of endogenous adrenaline and noradrenaline was measured by use of h.p.l.c. with electrochemical detection. Cyclic AMP levels were measured in cell extracts by RIA. 3. Ro 31-8220 produced a concentration-dependent inhibition of 300 nM PDBu-stimulated tyrosine hydroxylase activity with an IC50 of < 2 microM and complete inhibition at 10 microM. It had no effect on the responses to forskolin. 4. Ro 31-8220 produced a concentration-dependent inhibition of 5 microM nicotine-stimulated tyrosine hydroxylase activity, adrenaline and noradrenaline secretion and cellular cyclic AMP levels, with an IC50 of about 3 microM and complete inhibition by 10 microM. At concentrations up to 10 microM, Ro 31-8220 had little or no effect on the corresponding responses to 50 mm K+. 5. A structural analogue of Ro 31-8220, bisindolylmaleimide V, that lacks activity as a protein kinase C inhibitor, had no effect up to 10 microM on PDBu-stimulated tyrosine hydroxylase activity or on nicotine-stimulated cyclic AMP levels or noradrenaline secretion and only marginal inhibitory effects on nicotine-stimulated tyrosine hydroxylase activity and adrenaline secretion. 6. A structurally related protein kinase C inhibitor, bisindolylmaleimide I, inhibited PDBu-stimulated tyrosine hydroxylase activity with an IC50 of < 1 microM and complete inhibition by 3 microM, but had essentially no effect on nicotine stimulated tyrosine hydroxylase activity or catecholamine secretion. 7. The results suggest that Ro 31-8220 is not only a protein kinase C inhibitor but is also a potent inhibitor of nicotinic receptor responses in adrenal chromaffin cells by a mechanism unrelated to protein kinase C inhibition. The results are consistent with Ro 31-8220 being a nicotinic receptor antagonist.
PMCID: PMC1915873  PMID: 8886429
17.  Trovafloxacin, a new fluoroquinolone with potent activity against Streptococcus pneumoniae. 
An in vitro study of the activity of 15 antibacterial agents against 202 recent pediatric isolates of Streptococcus pneumoniae from urban and rural Nebraska and rural Kentucky identified trovafloxacin, ofloxacin, clindamycin, and vancomycin as the most active agents and equally active against both penicillin-susceptible and--resistant strains. In contrast, six beta-lactams, three macrolides, and trimethoprim-sulfamethoxazole were less active overall, especially against penicillin-intermediate and--resistant strains. Trovafloxacin inhibited all strains at a concentration of < or = 0.25 micrograms/ml and was 8- to 16-fold more potent than ofloxacin or ciprofloxacin.
PMCID: PMC163735  PMID: 9021213
18.  Beta-lactamases and detection of beta-lactam resistance in Enterobacter spp. 
Enterobacter spp. are becoming increasingly frequent nosocomial pathogens, and beta-lactam-resistant strains are on the increase, especially among isolates recovered from intensive care units. Therefore, a study was designed to characterize the beta-lactamases produced by 80 isolates of E. cloacae, E. aerogenes, E. taylorae, E. gergoviae, E. sakazakii, E. asburiae, and E. agglomerans by induction studies, spectrophotometric hydrolysis assays, and isoelectric focusing. The ability of broth microdilution and disk diffusion susceptibility tests to detect resistance to 16 beta-lactam antibiotics among these species was also assessed. All species except E. agglomerans, E. gergoviae, and some isolates of E. sakazakii were found to produce a Bush group 1 cephalosporinase that was expressed inducibly or constitutively at high levels. In addition, some strains also produced a Bush group 2 beta-lactamase. In comparisons of broth microdilution and disk diffusion tests, disk diffusion tests failed to detect resistance in 1 of 25 isolates resistant to aztreonam and 2 of 30 isolates resistant to ceftazidime. These results indicate that species of Enterobacter can possess a variety of beta-lactamases that are responsible for beta-lactam resistance in this genus and that the disk diffusion test may occasionally miss resistance in some strains.
PMCID: PMC163656  PMID: 8980751
19.  Protein kinase A and nicotinic activation of bovine adrenal tyrosine hydroxylase. 
British Journal of Pharmacology  1995;114(8):1687-1693.
1. Stimulation of nicotinic cholinoceptors on bovine chromaffin cells increases phosphorylation of three serine residues in tyrosine hydroxylase (TOH) and activates TOH. One of the serines is a target for protein kinase A phosphorylation, and phosphorylation of this serine is adequate alone to cause TOH activation. The role of protein kinase A in nicotinic activation of TOH was therefore investigated. 2. TOH activity was studied in situ in intact, cultured, bovine adrenal chromaffin cells, by measuring 14CO2 evolved following the hydroxylation and rapid decarboxylation of [14C]-tyrosine offered to the cells. 3. Nicotine (5 microM), forskolin (1 microM) and 8-bromo-cyclic AMP (8-Br-cyclic AMP, 1 mM) each increased TOH activity by up to 200% over 10 min. The effect of nicotine was completely abolished by removal of extracellular Ca2+. 4. TOH activation by all three drugs was blocked by H89 (3-20 microM), which inhibits protein kinase A by competing for the ATP binding site on the kinase. Adenosine 3':5'-cyclic monophosphorothioate Rp-diastereomer (Rp-cAMPS) (1 mM), an inhibitor of protein kinase A that competes with cyclic AMP for the regulatory subunit of the kinase, abolished the activation of TOH by nicotine, and reduced that by forskolin and 8-Br-cyclic AMP. Both H89 and Rp-cAMPS inhibited basal TOH activity by 50-80%. 5. A structural analogue of H89, H85 (3-20 microM), which lacks activity as a protein kinase A inhibitor, did not inhibit either the activation of TOH by nicotine (5 microM) or basal TOH activity.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1510372  PMID: 7599937
20.  New variant of TEM-10 beta-lactamase gene produced by a clinical isolate of proteus mirabilis. 
A clinical isolate of Proteus mirabilis was found to produce a new variant of the TEM-10 beta-lactamase gene. This is the first report of TEM-10 production by P. mirabilis and the first report of extended-spectrum beta-lactamase production by an isolate of this species recovered in the United States.
PMCID: PMC162712  PMID: 7625817
21.  Dissociated resistance among fluoroquinolones. 
A panel of 190 clinical isolates of staphylococci, enterococci, Streptococcus pneumoniae, members of the family Enterobacteriaceae, and nonfermentative gram-negative bacilli were examined by agar dilution tests for susceptibility to five quinolones and six nonquinolone agents. Members of the family Enterobacteriaceae and staphylococci were divided into subgroups according to their ciprofloxacin susceptibilities and were analyzed for cross-resistance to OPC-17116, ofloxacin, and temafloxacin. Although the MICs of all quinolones increased with increasing ciprofloxacin resistance, the MICs of OPC-17116, ofloxacin, and temafloxacin tended to increase less than those of ciprofloxacin, indicating that these agents were less affected by the mechanisms of quinolone resistance. An exception to this was the activity of OPC-17116 against highly ciprofloxacin-resistant staphylococci (MIC, > or = 8 micrograms/ml). Some of these staphylococci were equally resistant to OPC-17116, while others were fourfold more susceptible to ciprofloxacin than to OPC-17116. This indicated that in some strains OPC-17116 was more affected than ciprofloxacin by certain mechanisms responsible for high-level resistance. This was paralleled in single-step mutational studies in which 7 of 19 staphylococcal mutants exhibited large decreases in susceptibility to OPC-17116 (128- to 256-fold) but only modest decreases in susceptibility (4- to 16-fold) to the other quinolones. Such mutants were selected only from strains moderately resistant to ciprofloxacin (MIC, > or = 1 microgram/ml). This heterogeneity in the resistance of staphylococci to fluoroquinolones has not been seen previously and suggests that certain mechanisms of resistance in staphylococci affect OPC-17116 to a much greater extent than other quinolones.
PMCID: PMC284690  PMID: 7811025
22.  Use of ketamine in prolonged entrapment. 
This paper discusses the advantages of ketamine analgesia in the management of trapped patients after serious incidents. Four case histories and a review of the literature lead us to the conclusion that ketamine is the drug of choice in these situations.
PMCID: PMC1342430  PMID: 7804588
23.  Read clinical terms and child health. 
Archives of Disease in Childhood  1994;71(3):272-274.
PMCID: PMC1029988  PMID: 7979507
24.  Ceftazidime resistance in Hafnia alvei. 
Two morphotypes of Hafnia alvei differed in their susceptibilities to beta-lactam antibiotics. Both produced an inducible Bush group 1 beta-lactamase. Hyperinducibility of this enzyme was associated with reduced susceptibility in one morphotype.
PMCID: PMC187971  PMID: 8328790
25.  Histamine-induced increases in cyclic AMP levels in bovine adrenal medullary cells. 
British Journal of Pharmacology  1991;104(4):839-846.
1. The effect of histamine on cellular cyclic AMP levels in cultured bovine adrenal medullary cells has been studied. 2. Histamine (0.3-30 microM) increased cyclic AMP levels transiently, with a maximal response after 5 min, a smaller response after 20 min, and no increase seen after 80 or 180 min. The EC50 at 5 min was approximately 2 microM. Histamine had no effect on cyclic AMP release from the cells over 5 min, but increased it after 90 min. 3. The cyclic AMP response to 5 microM histamine was reduced by 45% by 1 microM mepyramine and by almost 30% by 1 microM cimetidine, and was abolished by the combination of both antagonists. Cimetidine at 100 microM did not inhibit the response to histamine more than 1 microM cimetidine. The H3-receptor antagonist, thioperamide (1 microM), had no effect on the response to histamine. 4. The H1-receptor agonist, 2-thiazolyethylamine (5-100 microM) and the H2-receptor agonist, dimaprit (5-100 microM), each induced a cyclic AMP response, and gave more-than-additive responses when combined. The H3 agonist (R) alpha-methylhistamine (100 microM) had no effect either on its own or in combination with either the H1 or the H2 agonist. The response to 100 microM 2-thiazolylethylamine was unaffected by cimetidine (100 microM). 5. The cyclic AMP responses to 5 microM histamine, 100 microM thiazolylethylamine and 100 microM dimaprit were each weakly enhanced in the presence of 1 mM 3-isobutyl-1-methylxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1908824  PMID: 1725765

Results 1-25 (38)