Specialty and training differences in the reported use of endocarditis prophylaxis at an academic medical center.
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Academic Medical Centers↗
Biomedical subjects
L Thomas
Publications and source records attributed to L Thomas.
The microbiology of postoperative peritonitis.
Postoperative peritonitis carries a higher risk of complications and mortality than does community-acquired disease. Little, however, is known about the specific microbiology of this condition. To gain insight into this problem, the microbiological findings of 67 patients with postoperative peritonitis were compared with those of 68 patients with community-acquired peritonitis. In a comparison of postoperative peritonitis with community-acquired disease, the number of isolates of enterococci (23 versus 6) and Enterobacter species (13 versus 4) were increased and the number of isolates of Escherichia coli (21 versus 42) were reduced. Antibiotic therapy before reintervention increased the number of resistant organisms at relaparotomy (33% versus 8%). The in vitro efficacy of the primary antibiotic or combination of drugs did not affect mortality rates (40% versus 38% after effective and ineffective treatment, respectively). Thus, the microbiology of postoperative peritonitis differs significantly from that of community-acquired disease, and specific antibiotic therapy is required, despite the doubtful impact on survival.
Anti-Bacterial Agents↗
Does bullying cause emotional problems? A prospective study of young teenagers.
OBJECTIVES: To establish the relation between recurrent peer victimisation and onset of self reported symptoms of anxiety or depression in the early teen years. DESIGN: Cohort study over two years. SETTING: Secondary schools in Victoria, Australia. PARTICIPANTS: 2680 students surveyed twice in year 8 (aged 13 years) and once in year 9. MAIN OUTCOME MEASURES: Self reported symptoms of anxiety or depression were assessed by using the computerised version of the revised clinical interview schedule. Incident cases were students scoring >/=12 in year 9 but not previously. Prior victimisation was defined as having been bullied at either or both survey times in year 8. RESULTS: Prevalence of victimisation at the second survey point in year 8 was 51% (95% confidence interval 49% to 54%), and prevalence of self reported symptoms of anxiety or depression was 18% (16% to 20%). The incidence of self reported symptoms of anxiety or depression in year 9 (7%) was significantly associated with victimisation reported either once (odds ratio 1.94, 1.1 to 3.3) or twice (2.30, 1.2 to 4.3) in year 8. After adjustment for availability of social relations and for sociodemographic factors, recurrent victimisation remained predictive of self reported symptoms of anxiety or depression for girls (2.60, 1.2 to 5.5) but not for boys (1.36, 0.6 to 3.0). Newly reported victimisation in year 9 was not significantly associated with prior self report of symptoms of anxiety or depression (1.48, 0.4 to 6.0). CONCLUSION: A history of victimisation and poor social relationships predicts the onset of emotional problems in adolescents. Previous recurrent emotional problems are not significantly related to future victimisation. These findings have implications for how seriously the occurrence of victimisation is treated and for the focus of interventions aimed at addressing mental health issues in adolescents.
Adolescent↗
High-performance liquid chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) after liquid-liquid extraction.
A single HPLC assay was developed for therapeutic drug monitoring of 5 HIV protease inhibitors (indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and a non-nucleoside reverse transcriptase inhibitor (nevirapine) in human plasma. After liquid-liquid extraction in a mixture ethyl acetate-hexane, compounds are separated on a C18 column with a gradient elution of solvent A [acetonitrile and 0.025 M tetramethylammonium perchlorate in 0.2% aqueous trifluoroacetic acid (55:45 (v/v))] and solvent B [methanol and 0.025 M tetramethylammonium perchlorate in 0.2% aqueous trifluoroacetic acid (55:45 (v/v))]. The compounds are detected at various wavelengths: 320 nm (nevirapine), 259 nm (indinavir), 254 nm (amprenavir, nelfinavir, saquinavir) and 239 nm (ritonavir). The intra-day and inter-day precision and accuracy are lower than 15%. The limits of quantitation are 0.05 mg/l (amprenavir), 0.2 mg/l (indinavir, saquinavir, nelfinavir) and 0.4 mg/l (ritonavir, nevirapine). This method which allows to estimate simultaneously plasma levels of protease inhibitors and nevirapine can be used for therapeutic drug monitoring.
Calibration↗
Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling.
Toll-like receptor 2 (TLR2) and TLR4 play important roles in innate immune responses to various microbial agents. We have previously shown that human dermal endothelial cells (HMEC) express TLR4, but very little TLR2, and respond to LPS, but not to Mycobacterium tuberculosis 19-kDa lipoprotein, unless transfected with TLR2. Here we report that HMEC are unresponsive to several additional biologically relevant TLR2 ligands, including, phenol-soluble modulin (PSM), a complex of three small secreted polypeptides from the skin commensal Staphylococcus epidermidis, soluble tuberculosis factor (STF), and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L). Expression of TLR2 renders HMEC responsive to all these ligands. We further characterized the signaling pathway in response to STF, OspA-L, and PSM in TLR2-transfected HMEC. The TLR2 signaling pathway for NF-kappaB trans-activation shares the IL-1R signaling molecules. Dominant negative constructs of TLR2 or TLR6 inhibit the responses of STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the concept of functional cooperation between TLR2 and TLR6 for all these TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and overexpression of Tollip inhibits NF-kappaB activation in response to TLR2 and TLR4 signaling. Collectively, these findings suggest that there is functional interaction between TLR2 and TLR6 in the cellular response to STF and OspA-L in addition to S. epidermidis (PSM) Ags, and that engagement of TLR2 triggers a signaling cascade, which shares the IL-1R signaling molecules, similar to the TLR4-LPS signaling cascade. Our data also suggest that Tollip may be an important constituent of both the TLR2 and TLR4 signaling pathways.
Adaptor Proteins, Signal Transducing↗
Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia.
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a heritable disorder of the ED-1 gene disrupting the morphogenesis of ectodermal structures. The ED-1 gene product, ectodysplasin-A (EDA), is a tumor necrosis factor (TNF) family member and is synthesized as a membrane-anchored precursor protein with the TNF core motif located in the C-terminal domain. The stalk region of EDA contains the sequence -Arg-Val-Arg-Arg156-Asn-Lys-Arg159-, representing overlapping consensus cleavage sites (Arg-X-Lys/Arg-Arg( downward arrow)) for the proprotein convertase furin. Missense mutations in four of the five basic residues within this sequence account for approximately 20% of all known XLHED cases, with mutations occurring most frequently at Arg156, which is shared by the two consensus furin sites. These analyses suggest that cleavage at the furin site(s) in the stalk region is required for the EDA-mediated cell-to-cell signaling that regulates the morphogenesis of ectodermal appendages. Here we show that the 50-kDa EDA parent molecule is cleaved at -Arg156Asn-Lys-Arg(159 downward arrow)- to release the soluble C-terminal fragment containing the TNF core domain. This cleavage appears to be catalyzed by furin, as release of the TNF domain was blocked either by expression of the furin inhibitor alpha1-PDX or by expression of EDA in furin-deficient LoVo cells. These results demonstrate that mutation of a functional furin cleavage site in a developmental signaling molecule is a basis for human disease (XLHED) and raise the possibility that furin cleavage may regulate the ability of EDA to act as a juxtacrine or paracrine factor.
Amino Acid Sequence↗
Effect of audit and feedback, and reminder messages on primary-care radiology referrals: a randomised trial.
BACKGROUND: Radiological tests are often used by general practitioners (GPs). These tests can be overused and contribute little to clinical management. We aimed to assess two methods of reducing GP requests for radiological tests in accordance with the UK Royal College of Radiologists' guidelines on lumbar spine and knee radiographs. METHODS: We assessed audit and feedback, and educational reminder messages in six radiology departments and 244 general practices that they served. The study was a before-and-after, pragmatic, cluster randomised controlled trial with a 232 factorial design. A random subset of GP patients' records were examined for concordance with the guidelines. The main outcome measure was number of radiograph requests per 1000 patients per year. Analysis was by intention to treat. FINDINGS: The effect of educational reminder messages (ie, the change in request rate after intervention) was an absolute change of -1.53 (95% CI -2.5 to -0.57) for lumbar spine and of -1.61 (-2.6 to -0.62) for knee radiographs, both relative reductions of about 20%. The effect of audit and feedback was an absolute change of -0.07 (-1.3 to 0.9) for lumbar spine of 0.04 (-0.95 to 1.03) for knee radiograph requests, both relative reductions of about 1%. Concordance between groups did not differ significantly. INTERPRETATION: 6-monthly feedback of audit data is ineffective but the routine attachment of educational reminder messages to radiographs is effective and does not affect quality of referrals. Any department of radiology that handles referrals from primary care could deliver this intervention to good effect.
Adult↗
PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic.
PACS-1 is a cytosolic protein involved in controlling the correct subcellular localization of integral membrane proteins that contain acidic cluster sorting motifs, such as furin and human immunodeficiency virus type 1 (HIV-1) NEF: We have now investigated the interaction of PACS-1 with heterotetrameric adaptor complexes. PACS-1 associates with both AP-1 and AP-3, but not AP-2, and forms a ternary complex between furin and AP-1. A short sequence within PACS-1 that is essential for binding to AP-1 has been identified. Mutation of this motif yielded a dominant-negative PACS-1 molecule that can still bind to acidic cluster motifs on cargo proteins but not to adaptor complexes. Expression of dominant-negative PACS-1 causes a mislocalization of both furin and mannose 6-phosphate receptor from the trans-Golgi network, but has no effect on the localization of proteins that do not contain acidic cluster sorting motifs. Furthermore, expression of dominant-negative PACS-1 inhibits the ability of HIV-1 Nef to downregulate MHC-I. These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis.
Adaptor Protein Complex 3↗
Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries.
BACKGROUND: 12-Lipoxygenase (12-LO) products of arachidonate metabolism have growth and chemotactic effects in vascular smooth muscle cells. We have also recently demonstrated increased 12-LO mRNA and protein expression in the neointima of balloon-injured rat carotid arteries. In this study, we evaluated whether 12-LO activation plays a role in neointimal thickening in this rat model by using a specific ribozyme (Rz) directed to rat 12-LO. METHODS AND RESULTS: We designed a chimeric DNA-RNA hammerhead Rz to cleave rat leukocyte-type 12-LO mRNA. This Rz dose-dependently cleaved a 166-nucleotide target 12-LO mRNA substrate in vitro and reduced 12-LO mRNA and protein expression in rat vascular smooth muscle cells. A control mutant Rz (MRz) with a point mutation in the catalytic site was inactive. To test the in vivo efficacy of the 12-LO Rz, the left common carotid arteries of rats were injured with a balloon catheter. The distal half of the injured arteries was treated with Rz or MRz mixed with lipofectin. The proximal half received only lipofectin. Twelve days after injury, intima-to-media ratios were significantly lower in the Rz-treated sections than in untreated sections from the same rat (0.742+/-0.16 versus 1.749+/-0.12, P:<0.001). In contrast, the MRz had no significant effect. CONCLUSIONS: These results indicate the important role of the leukocyte-type 12-LO pathway in restenosis in response to injury.
Analysis of Variance↗
Palladium-catalyzed selective cross-coupling between 2-bromopyridines and aryl bromides.
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Journal Article↗
Bacterial lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4.
In HIV-infected patients, concurrent infections with bacteria and viruses are known to induce HIV replication as assessed by increases in plasma HIV RNA levels. In the present study, we determined the cell surface receptor and molecular mechanisms of enterobacterial LPS-induced HIV transcription. Human dermal microvessel endothelial cells (HMEC) were transfected with an HIV-long terminal repeat (LTR)-luciferase construct and subsequently stimulated with purified bacterial LPS. Our studies demonstrate that human Toll-like receptor 4 (TLR4) mediates LPS-induced NF-kappaB and HIV-LTR activation in HMEC through IL-1 signaling molecules, namely myeloid differentiation protein, IL-1R-associated kinase, TNFR-associated factor, and NF-kappaB-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates LPS-induced HIV transcription as does the use of dominant-negative mutants of the IL-1 signaling molecules. Transfection of HMEC with an HIV-LTR-mutant that lacks the NF-kappaB binding site or pretreatment of cells with chemical inhibitors of the NF-kappaB pathway also blocked LPS-induced HIV-LTR transactivation. These data support the conclusion that TLR4 mediates enterobacterial LPS-induced HIV transcription via IL-1 signaling molecules and NF-kappaB activation plays an important role in HIV-LTR transactivation.
Animals↗
Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation.
Toll-like receptor (TLR) 4 has been identified as the primary receptor for enteric LPS, whereas TLR2 has been implicated as the receptor for Gram-positive and fungal cell wall components and for bacterial, mycobacterial, and spirochetal lipoproteins. Vascular endothelial cell (EC) activation or injury by microbial cell wall components such as LPS is of critical importance in the development of sepsis and septic shock. We have previously shown that EC express predominantly TLR4, and have very little TLR2. These cells respond vigorously to LPS via TLR4, but are unresponsive to lipoproteins and other TLR2 ligands. Here we show that LPS, TNF-alpha, or IFN-gamma induce TLR2 expression in both human dermal microvessel EC and HUVEC. Furthermore, LPS and IFN-gamma act synergistically to induce TLR2 expression in EC, and LPS-induced TLR2 expression is NF-kappaB dependent. LPS and IFN-gamma also up-regulate TLR4 mRNA expression in EC. These data indicate that TLR2 and TLR4 expression in ECs is regulated by inflammatory molecules such as LPS, TNF-alpha, or IFN-gamma. TLR2 and TLR4 molecules may render EC responsive to TLR2 ligands and may help to explain the synergy between LPS and lipoproteins, and between LPS and IFN-gamma, in inducing shock associated with Gram-negative sepsis.
Cell Line↗
Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria.
The free ceramide content of rat liver mitochondria was found to be 1.7 nmol/mg protein and outer membranes contained a three-fold higher concentration than inner membranes. The mitochondrial content in neutral glycolipids was 0.6 nmol/mg protein. The long-chain bases found in free ceramides were d18:1 sphingosine, d18:0 3-ketosphinganine and t21:1 phytosphingosine in increasing order. In contrast, 3-ketosphinganine was the only base of glucosylceramide and lactosylceramide of inner membranes, whereas d18:1 sphingosine was the major long-chain base of glucosylceramide of outer membranes.
Animals↗
Extensive coumarin-induced skin necrosis in a patient with acquired protein C deficiency.
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Acenocoumarol↗
The prevalence of urinary tract infections in patients with gestational diabetes mellitus.
Microbiologic evidence of urinary tract infection was studied in 447 pregnant women with (n = 149) or without (control group, n = 298) gestational diabetes mellitus after mid-pregnancy. Laboratory investigations included chemical analysis, microscopic examination and culture of a clean midstream voided urine specimen. Nineteen women (4.2%) had asymptomatic bacteriuria (7 study, 12 control, P=0.7). Of these, 7 (38%) developed symptomatic infection despite treatment with antibiotics (2 study, 5 control, P=0.7) and 6 (31%) had recurrent bacteriuria later in pregnancy (3 study, 3 control, P=0.3). Twelve more women (2.6%) had symptomatic infection (5 study, 7 control, P=0.5), 7 had acute cystitis (3 study, 4 control, P=0.5) and 5 had acute pyelonephritis (2 study, 3 control, P=0.7). Escherichia coli was the commonest pathogen, accounting for 22 (71%) infection episodes. Gestational diabetes mellitus was not associated with increased risk of urinary tract infections nor of maternal and perinatal morbidity as a result of infection.
Adult↗
Pulsed dose rate brachytherapy in head and neck cancers. Feasibility study of a French cooperative group.
PURPOSE: To prospectively evaluate the feasibility of pulsed dose rate (PDR) brachytherapy to mimic the continuous low dose rate (cLDR) iridium wire technique in head and neck carcinomas. MATERIALS AND METHODS: A series of 30 patients were included from June 1995 to May 1998. The primaries were located in the oral cavity (four T1, seven T2 and two T3), the velotonsillar arch (eight T1 and eight T2) and the posterior wall (one T3). Thirteen were irradiated by exclusive brachytherapy (dose, > or =45 Gy). The PDR delivered 0.5 Gy/pulse, one pulse/h, day and night, to mimic cLDR irradiation. RESULTS: The implantation was feasible for all the patients, usually easy and of good quality. The mean duration/pulse was 13 min, with a mean source activity of 171 mCi. Patient tolerance was poor in nine cases. Sixteen patients could receive the whole PDR treatment with a total ranging from 30 to 120 pulses without any problem. Seven had short breakdowns (< or =6 h). Seven had definitive breakdowns, but could end the irradiation by manual afterloading of iridium 192 wires. The radioprotection was better (or complete), except for one patient. Most of the breakdowns were related to kinking or flattering of the tube. CONCLUSIONS: PDR is feasible in head and neck carcinomas, but necessitates improvement of the quality and control of the plastic tubes.
Brachytherapy↗
Gestational diabetes screening of a multiethnic, high-risk population using glycated proteins.
In populations with a high incidence of gestational diabetes (GDM), any form of oral glucose testing for screening or diagnosis excessively strains the health care system. We investigated the value of glycated proteins as potential screening tests in 430 pregnant women, i.e. protein corrected fructosamine (cFRUC) and hemoglobin A1c (HbA(1c)) both alone and in combination for a GDM diagnosis confirmed by the 'gold standard' 100-g oral glucose tolerance test (OGTT). Two cut-off values were used for each test, the upper to rule in and the lower to rule out GDM. At the lower cut-off values for cFRUC of 210 micromol/l and HbA(1c) of 5%, the sensitivities achieved were 92.2 and 92.1% while the negative predictive values were 88.9 and 86.9%, respectively. The upper cut-off values did not achieve acceptable positive predictive values to be useful for ruling in GDM. Screening of our multiethnic, high-risk pregnant population with a combination of cFRUC and HbA(1c) on a single fasting sample would have avoided the cumbersome OGTT (by ruling out GDM) in 37.9% women with only a 3.9% misclassification rate. This potentially simpler approach, though not universally applicable, would be clinically useful and more acceptable to patients in selected high-risk populations.
Adolescent↗
[Standards, options and recommendations for the initial management of patients with malignant ovarian epithelial tumors (abridged version) ].
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Biomarkers, Tumor↗