Challenges of antibiotic resistance and its surveillance.
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Cross Infection↗
Biomedical subjects
G Webb
Publications and source records attributed to G Webb.
Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1).
OBJECTIVE: To examine whether type II collagen cleavage by collagenase and loss of proteoglycan are excessive in human osteoarthritic (OA) articular cartilage compared with nonarthritic articular cartilage, and whether this can be inhibited by a selective synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1 [MMP-1]). METHODS: Articular cartilage samples were obtained during surgery from 11 patients with OA and at autopsy from 5 adults without arthritis. The articular cartilage samples were cultured in serum-free medium. A collagenase-generated neoepitope, which reflects cleavage of type II collagen, and proteoglycan glycosaminoglycan (GAG), which predominantly reflects aggrecan release, were assayed in culture media. In addition, cultures were performed using either of 2 synthetic MMP inhibitors, both of which inhibited collagenase 2 (MMP-8) and collagenase 3 (MMP-13), but one of which spared collagenase 1. Cultures were also biolabeled with 3H-proline in the presence and absence of these inhibitors to measure collagen synthesis (as tritiated hydroxyproline) and incorporation in articular cartilage. RESULTS: As a group, cleavage of type II collagen by collagenase was significantly increased in OA cartilage samples. In contrast, proteoglycan (GAG) release was not increased. This release of a collagenase-generated epitope was inhibited by both MMP inhibitors in 2 of 5 nonarthritic samples and in 9 of 11 OA cartilage samples. The inhibitor that spared collagenase 1 was generally more effective and inhibited release from 4 of 5 nonarthritic cartilage samples and the same OA cartilage samples. Group analyses revealed that the inhibition of collagenase neoepitope release by both inhibitors was significant in the OA patient cartilage, but not in the nonarthritic cartilage. Proteoglycan loss was unaffected by either inhibitor. Newly synthesized collagen (predominantly, type II) exhibited increased incorporation in OA cartilage, but only in the presence of the inhibitor that arrested collagenase 1 activity. CONCLUSION: These results further indicate that the digestion of type II collagen by collagenase is selectively increased in OA cartilage, and that this can be inhibited in the majority of cases by a synthetic inhibitor that can inhibit collagenases 2 and 3, but not collagenase 1. The results also suggest that in OA, newly synthesized collagen is digested, but in a different manner than that of resident molecules. Proteoglycan release was not increased in OA cartilage and was unaffected by these inhibitors. Inhibitors of this kind may be of value in preventing damage to type II collagen in human arthritic articular cartilage.
Adult↗
Dilation of the pulmonary autograft after the Ross procedure.
OBJECTIVE: Dilation of pulmonary autograft after the Ross procedure is being recognized with increasing frequency. This study was undertaken to examine the extent of this problem and factors that may be associated with it. METHODS: The clinical, operative, and echocardiographic data of 118 patients who underwent the Ross procedure were reviewed. The mean age of 79 men and 39 women was 34 +/- 9 years, range 17 to 57 years. Bicuspid or other congenital aortic valve disease was present in 81% of patients. The pulmonary autograft was sutured as a valve in the subcoronary position in 2 patients, as a root inside of the aortic root in 45, and was used for complete aortic root replacement in 71. Teflon felt was not used to buttress the proximal or the distal anastomosis of the pulmonary autograft. The diameters of the sinuses of Valsalva, aortic anulus, and sinotubular junction were measured early and late after the operation with echocardiography. The mean follow-up was 44 months. RESULTS: The diameter of the sinuses of Valsalva increased from 31.4 +/- 0.4 mm to 33.7 +/- 0.5 mm (P =.01). Analysis of covariance revealed a significant change over time in this diameter, as well as a difference between operative techniques, with replacement of the aortic root being associated with a higher risk of dilation (P =. 0006). In 13 patients the diameter ranged from 40 to 51 mm. The diameter of the aortic anulus decreased in most patients and increased in 15, but there was no interaction between these changes and the operative technique. The diameter of the sinotubular junction increased in patients who had aortic root replacement and decreased in patients who had aortic root inclusion (P =.007). Moderate aortic insufficiency developed in 7 patients, and 3 required replacement of the pulmonary autograft. All patients with moderate aortic insufficiency had dilation of the aortic anulus and/or sinotubular junction. CONCLUSIONS: Dilation of the pulmonary autograft after the Ross procedure may occur because of an intrinsic abnormality of the pulmonary root in patients with congenital aortic valve disease. The technique of aortic root replacement is associated with a higher risk of dilation of the sinuses of Valsalva and sinotubular junction than the technique of aortic root inclusion.
Adolescent↗
Results of surgery for aortic root aneurysm in patients with the Marfan syndrome.
OBJECTIVE: To evaluate the results of two operations, aortic valve-sparing and aortic root replacement, in patients with aortic root aneurysm and the Marfan syndrome. METHODS: A retrospective review of 78 consecutive patients with aortic root aneurysm and the Marfan syndrome according to the Gent criteria indicated that 42 patients with normal aortic cusps had an aortic valve-sparing operation, and 36 patients had aortic root replacement (mechanical valve in 25 patients and biological valve in 11). The mean age was similar in both groups, but patients who had aortic root replacement had larger aneurysms, higher grade aortic insufficiency, worse left ventricular function and more cardiac co-morbidity than patients who had aortic valve-sparing operations. The mean follow-up was 41+/-35 months for patients who had aortic valve-sparing, and 65+/-50 months for those who had aortic root replacement. RESULTS: Kaplan-Meyer estimates of survival at 5 years was 100% for patients who had aortic valve-sparing, and 88+/-6% for those who had aortic root replacement (P=0.04). Five patients who had aortic root replacement required seven aortic root re-replacements: three for endocarditis and four for valve failure (biological valves). There have been no reoperations in patients who had aortic valve-sparing operations and annual Doppler echocardiography revealed mild or no aortic insufficiency in 39 patients and moderate aortic insufficiency in three. CONCLUSIONS: These data suggest that aortic valve-sparing operations are safe in patients with the Marfan syndrome and may provide better clinical outcomes than aortic root replacement. Since the size of the aneurysm often determines the feasibility of a valve-sparing procedure, we now recommend surgery when the diameter of the aortic root reaches 50 mm in patients with the Marfan syndrome who have echocardiographically normal aortic valve cusps.
Adolescent↗
Independent factors associated with longevity of prosthetic pulmonary valves and valved conduits.
OBJECTIVE: To evaluate the age dependence of variables predictive of pulmonary valve prosthesis replacement, we conducted the following analysis. METHODS: Retrospective analysis of 945 operations in 726 patients undergoing placement of pulmonary valve prostheses was performed. Age was identified as a strong independent predictor of valve failure. The database was stratified into age-based subsets and predictors of valve replacement were identified within each subset. RESULTS: For the entire cohort, freedom from valve replacement at 5 years was 81%. Younger age was strongly associated with decreased time to valve replacement by multivariable analysis (hazard ratio: 0.71/log-year, P <.001). Other independent factors included diagnosis, type of prosthesis, and time-dependent requirement for pulmonary valve stent placement. Important predictors of valve failure varied among age groups and are as follows: for Age Less Than 3 Months: valve type; for Age 3 Months To Less Than 2 Years: smaller normalized valve prosthesis size; for Age 2 Years To Less Than 13 Years: sex, smaller normalized valve prosthesis size, placement of endovascular stents, and valve type; for Age 13 Years To 65 Years: smaller normalized valve prosthesis size, placement of endovascular stents, and increased number of previous valve placements. CONCLUSION: Age is a dominant risk factor predictive of pulmonary valve prosthesis failure. A significant interaction exists between age and the effects of diagnosis, valve type, and size on prosthetic pulmonary valve longevity.
Adolescent↗
Bridging radiation policy and science.
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Congresses as Topic↗
Bactericidal activity against coagulase-negative staphylococci is impaired in infants receiving long-term parenteral nutrition.
OBJECTIVE: To examine the role of total parenteral nutrition (TPN) in predisposing infants to infection caused by coagulase-negative staphylococci. SUMMARY BACKGROUND DATA: Total parenteral nutrition is an important means of providing essential nutrients to newborn infants. However, its use has been associated with complications, particularly infection caused by coagulase-negative staphylococci. Recent data suggest that TPN may modulate immune function; however, reports directly indicating impaired immunity against coagulase-negative staphylococci during TPN are limited. METHODS: Study 1 involved 31 infants younger than 4 months who had undergone surgery and were not receiving antibiotics; 20 were receiving TPN and 11 were receiving a normal enteral diet. An in vitro whole blood model was used to measure the host bactericidal activity against coagulase-negative staphylococci. Bacterial killing and phagocytosis were measured after a 45-minute challenge with viable coagulase-negative staphylococci. In study 2, whole blood killing and intracellular killing of coagulase-negative staphylococci were measured in five newborn infants (younger than 2 months) who were receiving long-term TPN (>10 days), five control infants receiving a normal enteral diet, and five healthy adults. RESULTS: In study 1, infants receiving a normal enteral diet showed a high capacity to ingest and kill coagulase-negative staphylococci. In contrast, the blood of infants receiving long-term TPN showed a reduction in coagulase-negative staphylococci phagocytosis and killing. There were significant negative linear correlations between the duration of TPN and killing of coagulase-negative staphylococci and phagocytosis of coagulase-negative staphylococci. In study 2, infants receiving long-term TPN had lower whole blood killing and intracellular killing than infants receiving a normal enteral diet and healthy adult volunteers. These data seem to indicate a neutrophil dysfunction mediated by TPN in infancy. CONCLUSIONS: Host defense mechanisms, including phagocytosis and killing of coagulase-negative staphylococci, are impaired during long-term TPN. The impaired bactericidal activity seems to be related to defective intracellular killing in neutrophils. These findings may explain the high rate of septicemia caused by coagulase-negative staphylococci in infants receiving TPN.
Adult↗
Education Australian physiotherapists: striving for excellence in sport and exercise medicine.
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Australia↗
The interaction of R(+)- or S(-)-2,2'-diamino-1,1'-binaphthalene with a Pd/silica catalyst in tetrahydrofuran.
The interaction of 2,2'-diamino-1,1'-binaphthalene over a Pd/silica catalyst and its interaction with hydrogen in the system and with the solvent tetrahydrofuran, (THF) has been investigated. Three interactions have been identified, i) conversion of amine groups to hydroxy groups, ii) hydrogenation of one or more of the aromatic rings, and iii) reaction between the amine group(s) and the THF solvent.
Catalysis↗
6-oxa isosteres of anacardic acids as potent inhibitors of bacterial histidine protein kinase (HPK)-mediated two-component regulatory systems.
A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.
Anacardic Acids↗
Proteolytic processing in the secretory pathway.
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Animals↗
Arrhythmia and survival in patients >18 years of age after the mustard procedure for complete transposition of the great arteries.
Increasing numbers of patients who underwent Mustard repair as children are now adults. Loss of sinus rhythm, supraventricular arrhythmias, and sudden death have been described in pediatric series. However, little is known about the clinical course of adult patients. This retrospective cohort study examined 86 consecutive adults (age >18 years) who had undergone the Mustard procedure and were referred to an adult congenital cardiac clinic for ongoing follow-up. The incidence and predictors of arrhythmia, congestive heart failure, and death were determined. The median follow-up period was 8 years after age 18 or 23 years after Mustard repair. There were 8 deaths (9%), 2 were sudden. Congestive heart failure (CHF) requiring hospital admission occurred in 9 patients (10%). Pulmonary hypertension and systemic ventricular dysfunction were independent risk factors for death or CHF. Only 29 patients (34%) remained arrhythmia-free. Forty-one patients (48%) had at least 1 episode of supraventricular tachycardia (SVT), with most patients (30, 73%) having atrial flutter. SVT after the age of 18 was associated with CHF. Pulmonary hypertension, systemic ventricular dysfunction, and junctional rhythm before age 18 were independent risk factors for SVT. Pacemakers were implanted in 19 patients (22%); 13 of those were beyond age 18. Thus, adult survivors of the Mustard procedure continue to be at risk for premature death, CHF and supraventricular tachyarrhythmia.
Adolescent↗
Gene structure, expression and chromosomal localization of murine theta class glutathione transferase mGSTT1-1.
We have isolated and characterized a cDNA and partial gene encoding a murine subfamily 1 Theta class glutathione transferase (GST). The cDNA derived from mouse GSTT1 has an open reading frame of 720 bp encoding a peptide of 240 amino acids with a calculated molecular mass of 27356 Da. The encoded protein shares only 51% deduced amino acid sequence identity with mouse GSTT2, but greater than 80% deduced amino acid sequence identity with rat GSTT1 and human GSTT1. Mouse GSTT1-1 was expressed in Escherichia coli as an N-terminal 6x histidine-tagged protein and purified using immobilized-metal affinity chromatography on nickel-agarose. The yield of the purified recombinant protein from E. coli cultures was approx. 14 mg/l. Recombinant mouse GSTT1-1 was catalytically active towards 1, 2-epoxy-3-(p-nitrophenoxy)propane, 4-nitrobenzyl chloride and dichloromethane. Low activity towards 1-menaphthyl sulphate and 1-chloro-2,4-dinitrobenzene was detected, whereas mouse GSTT1-1 was inactive towards ethacrynic acid. Recombinant mouse GSTT1-1 exhibited glutathione peroxidase activity towards cumene hydroperoxide and t-butyl hydroperoxide, but was inactive towards a range of secondary lipid-peroxidation products, such as the trans-alk-2-enals and trans,trans-alka-2,4-dienals. Mouse GSTT1 mRNA is most abundant in mouse liver and kidney, with some expression in intestinal mucosa. Mouse GSTT1 mRNA is induced in liver by phenobarbital, but not by butylated hydroxyanisole, beta-napthoflavone or isosafrole. The structure of mouse GSTT1 is conserved with that of the subfamily 2 Theta class GST genes mouse GSTT2 and rat GSTT2, comprising five exons interrupted by four introns. The mouse GSTT1 gene was found, by in situ hybridization, to be clustered with mouse GSTT2 on chromosome 10 at bands B5-C1. This region is syntenic with the location of the human Theta class GSTs clustered on chromosome 22q11.2. Similarity searches of a mouse-expressed sequence tag database suggest that there may be two additional members of the Theta class that share 70% and 88% protein sequence identity with mouse GSTT1, but less than 55% sequence identity with mouse GSTT2.
Amino Acid Sequence↗
Morbidity outcome in patients with hypertrophic obstructive cardiomyopathy undergoing cardiac septal myectomy: early-extubation anesthesia versus high-dose opioid anesthesia technique.
OBJECTIVE: Anesthetic management of patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing septal myectomy is challenging. The morbidity outcome of early-extubation anesthesia (EEA), or fast tracking, versus high-dose opioid (HDO) anesthesia was studied. DESIGN: Retrospective study. SETTING: University teaching hospital. PARTICIPANTS: One hundred seventy-five cardiac septal myectomy patients (EEA, n = 53; HDO, n = 122). INTERVENTIONS: EEA technique consisted of low-dose fentanyl, 10 to 15 microg/kg; propofol infusion; midazolam; and inhalation agent. HDO technique consisted of fentanyl, 50 to 100 microg/kg, and benzodiazepines, with or without an inhalation agent. Demographic data, preoperative symptoms, and data on anesthesia management and postoperative complications were recorded. MEASUREMENTS AND MAIN RESULTS: There were no differences between the groups (EEA v HDO, respectively) regarding age, sex, preoperative symptoms (dyspnea, 89% v 79%; palpitations, 28% v 26%; angina, 47% v 61%; syncope, 47% v 41%), redo surgery, or combined surgery. Mean +/- standard deviation time to tracheal extubation was 7.2 +/- 5.3 hours in EEA versus 19.4 +/- 10.5 hours in HDO patients (p < 0.0001). Intensive care unit (ICU) stay was significantly shorter in EEA versus HDO patients (2.2 v 3.0 days; p < 0.005), with the trend toward earlier hospital discharge (9.7 v 11.3 days; p = 0.09). There was a high requirement for temporary pacing in both groups immediately postoperatively (EEA, 60% v HDO, 48%; p > 0.08). Permanent pacemaker insertion postoperatively was required in 7 of 53 patients (13%) in the EEA group and 11 of 122 patients (9%) in the HDO group (p > 0.25). Atrial arrhythmias occurred postoperatively in 25% of EEA patients versus 34% of HDO patients (p > 0.08). CONCLUSION: EEA facilitates earlier tracheal extubation by 12 hours in patients with HOCM undergoing septal myectomy, significantly shortening ICU stay by 1 day without increasing perioperative cardiac morbidity or mortality.
Adjuvants, Anesthesia↗
Pregnancy in women with congenital heart defects: what are the risks?
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Adult↗
Isolation and characterisation of a prenylated p-terphenyl metabolite of Aspergillus candidus possessing potent and selective cytotoxic activity; studies on mechanism of action.
We describe the discovery and properties of a prenylated p-terphenyl metabolite of the fungus Aspergillus candidus. The compound (1) possesses potent cytotoxic activity against a range of tumour and other hyper-proliferative cell lines. Cell cycle analysis shows that in mouse keratinocyte (BALB/MK) cells treated with 1, the cell cycle is arrested in early S phase, indicative of an antimetabolite effect. Furthermore, cellular cytotoxicity can be reversed by addition of exogenous pyrimidine but not purine nucleosides to the cell culture medium. It is therefore likely that compound 1 selectively inhibits pyrimidine biosynthesis, and it is this property which accounts for its potent cytotoxic properties.
Animals↗
Novel inhibitors of fungal protein synthesis produced by a strain of Graphium putredinis. Isolation, characterisation and biological properties.
The isolation and structure determination of 6 analogues of the fungal protein synthesis inhibitor GR135402, from Graphium putredinis, is described. The relative potencies of the compounds as protein synthesis inhibitors and as in vitro antifungal agents provide interesting insights into the structure-activity relationships in this series.
Antifungal Agents↗
The value of the MACE (Malone antegrade colonic enema) procedure in adult patients.
BACKGROUND: We report our experience with the Malone antegrade colonic enema (MACE) procedure in adult patients suffering from urinary incontinence and intractable constipation with or without fecal soiling. STUDY DESIGN: Since June 1990, the MACE procedure was initiated in 4 female and 12 male patients 14-54 years old (mean age, 29.9 years) with different pathologic conditions (myelodysplasia, n = 7; anorectal anomaly, n = 3; spinal cord lesion, n = 4; neuropathic disease of unclear cause, n = 2). Three surgical techniques were used: reversed and in situ appendix and tapered ileum). Complex simultaneous urologic continence procedures were performed in nine patients. Two patients had undergone previous operations in the lower urinary tract. RESULTS: After 6.6 years of followup (average, 41.7 months), eight patients (50%) were still using the MACE successfully. They were completely clean day and night and were relieved of symptoms of constipation. Eleven complications related to the MACE procedure occurred in seven patients (44%). Eight patients abandoned the procedure for various reasons. The failure rate was higher in chronically constipated patients without fecal soiling. CONCLUSIONS: The MACE procedure is associated with a high failure rate when used in adults, but it may be possible to identify a subgroup of patients in whom the procedure could be beneficial. Success would depend on overcoming technical problems and difficulties with patient compliance.
Adolescent↗