Faecal concentrations of piperacillin and tazobactam in elderly patients.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
A Brown
Publications and source records attributed to A Brown.
Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor.
Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.
Amidohydrolases↗
A neuropathological study of vascular factors in late-life depression.
OBJECTIVES: Depression is a common psychiatric disorder in late life and it may be associated with vascular disease processes. Although there are clinical and neuroimaging studies lending support to such a "vascular depression" hypothesis there have been no neuropathological studies to directly test this. Postmortem tissue was investigated to determine whether late life depression was associated with atheromatous change in large and medium vessels and microvascular disease in the brain. METHODS: Postmortem tissue was obtained from 20 patients with a history of at least one episode of DSM-IV major depression and 20 control subjects. Standard procedures were carried out to analyze and quantify Alzheimer type pathology (plaques, tangles, Braak staging) and cortical Lewy bodies. Coronary arteries, cerebral vessels, and aorta were rated for atheromatous disease on a 0-3 scale and the four neocortical areas were rated for microvascular disease. RESULTS: The two groups showed no significant differences in age, sex, or postmortem delay. There was a significant increase in atheromatous disease in the depressed group (p=0.023). No differences were found for microvascular disease, either in the brain generally or locally in the frontal lobes. No subject had any significant Alzheimer type or Lewy body pathology. CONCLUSIONS: Neuropathological evidence was found for an excess of atheromatous disease, related to the aortic and cerebral vessels, in late life depression. However, there was no evidence of an increase in microvascular disease. The findings broadly support the vascular depression hypothesis.
Aged↗
Ovulation rate and litter size in gilts immunized against androstenedione and 17alpha-hydroxyprogesterone.
Two experiments were conducted to evaluate the effects of the immunization of gilts against ovarian steroids on ovulation rate and litter size. In Exp. 1, gilts (n = five gilts/treatment) at 165+/-1.6 d of age were immunized against either carrier (Control), androstenedione, or 17alpha-hydroxyprogesterone. Age at puberty and estrous cycle length averaged 208+/-5.5 (P = 0.67) and 20.3+/-2.8 d (P = 0.41), respectively, and were not affected by treatment. The androstenedione- and 17alpha-hydroxyprogesterone immunized gilts had higher (P < 0.02) ovulation rates than Controls (14.2, 14.2, and 11.4+/-0.8, respectively). Total pigs born (P = 0.66) and pigs born live (P = 0.65) for the androstenedione-treated group were not different from Controls. Gestation length was not different (P = 0.36) between any of the treatments and the Controls (115+/-0.9 d). Procedures used in Exp. 2 were similar to those in Exp. 1, except that only Control (n= 18) and 17alpha-hydroxyprogesterone (n = 16) treatments were included and only litter size at farrowing was measured. Total pigs and pigs born live were higher in the 17a-hydroxyprogesterone-treated gilts than in the Controls (12.6 vs 10.5+/-0.6, P < 0.02; and 11.4 vs 9.2+/-0.6; P < 0.01, respectively). Data from this study indicate that litter size in gilts can be increased by immunization against 17alpha-hydroxyprogesterone.
17-alpha-Hydroxyprogesterone↗
Central Australian MVE update, 2001.
Explore the source record for details and available documents.
Australia↗
Biotransformation, excretion kinetics, and tissue distribution of an N-pyrrolo[1,2-c]imidazolylphenyl sulfonamide herbicide in rats.
TY029, an N-pyrrolo[1,2-c]imidazolylphenyl sulfonamide herbicide, controls economically important weeds through inhibition of protoporphyrinogen oxygenase. Due to the potential for exposure to this compound in food and animal feed items, a rat metabolism study was required to define the biotransformation of this compound. Animals were exposed to single 50- and 2-mg/kg doses of TY029 [hydantoin-5-(14)C] by oral gavage. About 90% of the administered dose was excreted within 96 h after oral administration. Excretion plateaued after 48 h, and the cumulative sum of urinary or fecal excretion after 48 h was less than 5% of the orally administered dose. TY029 yielded seven major metabolites. While some metabolites were formed by epimerization around chiral centers, others were generated through hydrolytic bond cleavage and hydroxylations and subsequent oxidation of hydroxyl groups to carboxylic acids. One metabolite, about 6.1% of the dose, was observed only in the urine from low-dose female rats. This metabolite was characterized as a glutamate conjugate of an extensively oxidized analog of TY029. With the exception of the glutamate conjugate, the same metabolites were observed in the excreta of all dose groups. However, the relative ratios of the metabolites were different between various dose groups.
Animals↗
Spectrin ubiquitination and oxidative stress: potential roles in blood and neurological disorders.
This review covers the observations that erythrocyte spectrin has a E2 ubiquitin conjugating enzymatic activity that allows it to transfer ubiquitin to a target site in the alpha-spectrin repeats 20/21. The position of this ubiquitination site suggests that ubiquitination may regulate alpha beta spectrin heterodimer nucleation, spectrin-4.1-actin ternary complex formation, and adducin stimulated spectrin-actin attachment in the mature erythrocyte. In sickle cells, which contain altered redox status (high GSSG/GSH ratio), ubiquitin attachment to the E2 and target sites in alpha-spectrin is greatly diminished. We propose that this attenuated ubiquitination of spectrin may be due to glutathiolation of the E2 active site cysteine leading to diminished ubiquitin-spectrin adduct and conjugate formation. Furthermore we propose that lack of ubiquitin-spectrin complex formation leads to dysregulation of the membrane skeleton in mature SS erythrocytes and may diminish spectrin turnover in SS erythropoietic cells via the ubiquitin proteasome machinery. In hippocampal neurons, spectrin is the major ubiquitinated protein and a component of the cytoplasmic ubiquitinated inclusions observed in Alzheimer's and Parkinson's diseases. The two primary neuronal spectrin isoforms: alpha SpI Sigma*/beta SpI Sigma 2 and alpha SpII Sigma 1/beta SpII Sigma 1 are both ubiquitinated. Future work will resolve whether neuronal spectrins also contain E2-ubiquitin conjugating activity and the molecular basis for formation of ubiquitinated inclusions in neurological disorders.
Amino Acid Sequence↗
Antibiotic resistant N. gonorrhoeae in Trinidad and Tobago.
We tested the susceptibility patterns of 128 N. gonorrhoeae isolates to six antimicrobials; penicillin, tetracycline, spectinomycin, ceftriaxone, ciprofloxacin and azithromycin, and examined whether certain demographic or behavioral factors related to antibiotic use increased the likelihood of infection by a resistant strain. There was a low rate of resistance to penicillin; penicillinase-producing and chromosomal-mediated penicillin resistant gonorrhea were estimated to be 0.8%. A much higher proportion of isolates were resistant to tetracycline (up to 15%). All isolates were sensitive to spectinomycin, ciprofloxacin and ceftriaxone. However, less than 2% of isolates displayed intermediate resistance to both ciprofloxacin and ceftriaxone, and 9% exhibited intermediate resistance to spectinomycin. Patients who had obtained medication before attending the clinic and had taken all of the medication were more likely (p = 0.03) to be infected with a resistant strain of gonococcus. Also, patients who were asked by a clinic doctor to return for a test of cure during an earlier clinic visit, but who did not return were more likely to be infected with a resistant organism (p = 0.006) compared to those who returned at the doctor's request. These findings have important implications for antibiotic use and educational programs in Trinidad and Tobago.
Adolescent↗
The Oxford unicompartmental knee replacement for osteoarthritis.
The Oxford unicompartmental knee replacement is a reliable treatment for medial knee compartment osteoarthritis, provided patients with the correct indications are chosen and the appropriate surgical expertise is available. The Oxford knee has been available since fall 2000 in Canada and since the early 1980's in Europe. The latest version, Phase III, has generated interest since it uses both a minimally invasive surgical technique, as well as a free-floating, fully congruent meniscal bearing. This has the potential for faster recovery of the patient, as well as improved wear characteristics.
Arthroplasty, Replacement, Knee↗
Prevnar(tm): a pneumococcal conjugate vaccine for infants and young children.
Explore the source record for details and available documents.
Canada↗
Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo.
Eotaxin is a potent eosinophil chemoattractant that acts selectively through CCR3, which is expressed on eosinophils, basophils, mast cells, and Th2-type T cells. This arm of the immune system is believed to have evolved to control helminthic parasites. We hypothesized that helminths may employ mechanisms to inhibit eosinophil recruitment, to prolong worm survival in the host. We observed that the excretory/secretory products of the hookworm Necator americanus inhibited eosinophil recruitment in vivo in response to eotaxin, but not leukotriene B(4), a phenomenon that could be prevented by the addition of protease inhibitors. Using Western blotting, N. americanus supernatant was shown to cause rapid proteolysis of eotaxin, but not IL-8 or eotaxin-2. N. americanus homogenate was fractionated by gel filtration chromatography, and a FACS-based bioassay measured the ability of each fraction to inhibit the activity of a variety of chemokines. This resulted in two peaks of eotaxin-degrading activity, corresponding to approximately 15 and 50 kDa molecular mass. This activity was specific for eotaxin, as responses to other agonists tested were unaffected. Proteolysis of eotaxin was prevented by EDTA and phenanthroline, indicating that metalloprotease activity was involved. Production of enzymes inactivating eotaxin may be a strategy employed by helminths to prevent recruitment and activation of eosinophils at the site of infection. As such this represents a novel mechanism of regulation of chemokine function in vivo. The existence of CCR3 ligands other than eotaxin (e.g., eotaxin-2) may reflect the evolution of host counter measures to parasite defense systems.
Animals↗
Prenatal cocaine exposure increases sensitivity to the attentional effects of the dopamine D1 agonist SKF81297.
Sensitivity to the attentional effects of SKF81297, a selective full agonist at dopamine D(1) receptors, was assessed in adult rats exposed to cocaine prenatally (via intravenous injections) and controls. The task assessed the ability of the subjects to monitor an unpredictable light cue of either 300 or 700 msec duration and to maintain performance when presented with olfactory distractors. SKF81297 decreased nose pokes before cue presentation and increased latencies and response biases (the tendency to respond to the same port used on the previous trial), suggesting an effect of SKF81297 on the dopamine (DA) systems responsible for response initiation and selection. The cocaine-exposed (COC) and control animals did not differ in sensitivity to the effects of SKF81297 on these measures. In contrast, the COC animals were significantly more sensitive than were controls to the impairing effect of SKF81297 on omission errors, a measure of sustained attention. This pattern of results provides evidence that prenatal cocaine exposure produces lasting changes in the DA system(s) subserving sustained attention but does not alter the DA system(s) underlying response selection and initiation. These findings also provide support for the role of D(1) receptor activation in attentional functioning.
Animals↗
Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.
One of the impediments to the treatment of brain tumors (e.g., gliomas) has been the degree to which they expand, infiltrate surrounding tissue, and migrate widely into normal brain, usually rendering them "elusive" to effective resection, irradiation, chemotherapy, or gene therapy. We demonstrate that neural stem cells (NSCs), when implanted into experimental intracranial gliomas in vivo in adult rodents, distribute themselves quickly and extensively throughout the tumor bed and migrate uniquely in juxtaposition to widely expanding and aggressively advancing tumor cells, while continuing to stably express a foreign gene. The NSCs "surround" the invading tumor border while "chasing down" infiltrating tumor cells. When implanted intracranially at distant sites from the tumor (e.g., into normal tissue, into the contralateral hemisphere, or into the cerebral ventricles), the donor cells migrate through normal tissue targeting the tumor cells (including human glioblastomas). When implanted outside the CNS intravascularly, NSCs will target an intracranial tumor. NSCs can deliver a therapeutically relevant molecule-cytosine deaminase-such that quantifiable reduction in tumor burden results. These data suggest the adjunctive use of inherently migratory NSCs as a delivery vehicle for targeting therapeutic genes and vectors to refractory, migratory, invasive brain tumors. More broadly, they suggest that NSC migration can be extensive, even in the adult brain and along nonstereotypical routes, if pathology (as modeled here by tumor) is present.
Animals↗
Association of educational achievement with pulsatile arterial diameter change of the common carotid artery: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1992.
Education is strongly inversely associated with common carotid artery intima-media thickness in the Atherosclerosis Risk in Communities (ARIC) Study. The authors extended the ARIC study of preclinical atherosclerosis by evaluating the cross-sectional association of education with common carotid artery elasticity. This study included 10,091 Black and White men and women aged 45-64 years who were free of clinical coronary heart disease and stroke/transient ischemic attack. Arterial elasticity was assessed by pulsatile arterial diameter change (PADC), derived from phase-locked echo-tracking. The smaller the PADC, the stiffer the artery. Education was categorized into grade school, high school without graduation, high school with graduation, vocational school, some college, and graduate/professional school. PADC was directly associated with educational attainment. The mean PADCs, adjusted for age, height, diastolic diameter, systolic blood pressure, pulse pressure (linear and squared), ethnicity, gender, and smoking status, in successively higher education strata were 402 (standard error (SE) 5), 403 (SE 4), 407 (SE 3), 413 (SE 4), 416 (SE 2), and 417 (SE 4) microm (p = 0.007). To the authors' knowledge, this is the first time such an association has been reported. If arterial dilation impairment precedes arterial wall thickening in the atherosclerotic process, as recent studies on endothelial dysfunction suggest, these results indicate that low socioeconomic status may be associated with early arterial pathophysiologic changes-an effect that appears to be mediated by established cardiovascular disease risk factors.
Anthropometry↗
1H-NMR lipid profiles of human blood platelets; links with coronary artery disease.
Blood platelets are closely involved in the early development of atherosclerosis and in the events that lead to thrombosis, both of which are dominating factors in coronary artery disease (CAD). The aim of the present study was to evaluate the platelet lipid profiles of patients suffering from CAD and explore the possibility of a link between platelet lipids and CAD, using high-resolution high-field proton nuclear magnetic resonance spectroscopy as the analytical tool. The total platelet lipid profiles of healthy volunteers were compared with those of patients presenting with chest pain requiring coronary angiography. Two lipid groups changed significantly: cholesterol increased by 16.5% and total diacylglycerophospholipids decreased by 15.7%. There was also a significant decrease of the ethanolamine-containing phospholipids, by 4.7%; the extent of unsaturation of the fatty acid chains, by 0.2, and increase of the linoleate content of the fatty acid chains, by 1.9%. Our results suggest that platelet lipid abnormalities occur in patients with CAD and these changes may predate the development of overt atherosclerosis.
Blood Platelets↗
Partially unfolded states of beta(2)-microglobulin and amyloid formation in vitro.
Dialysis-related amyloidosis (DRA) involves the aggregation of beta(2)-microglobulin (beta(2)m) into amyloid fibrils. Using Congo red and thioflavin-T binding, electron microscopy, and X-ray fiber diffraction, we have determined conditions under which recombinant monomeric beta(2)m spontaneously associates to form fibrils in vitro. Fibrillogenesis is critically dependent on the pH and the ionic strength of the solution, with low pH and high ionic strength favoring fibril formation. The morphology of the fibrils formed varies with the growth conditions. At pH 4 in 0.4 M NaCl the fibrils are approximately 10 nm wide, relatively short (50-200 nm), and curvilinear. By contrast, at pH 1.6 the fibrils formed have the same width and morphology as those formed at pH 4 but extend to more than 600 nm in length. The dependence of fibril growth on ionic strength has allowed the conformational properties of monomeric beta(2)m to be determined under conditions where fibril growth is impaired. Circular dichroism studies show that titration of one or more residues with a pK(a) of 4.7 destabilizes native beta(2)m and generates a partially unfolded species. On average, these molecules retain significant secondary structure and have residual, non-native tertiary structure. They also bind the hydrophobic dye 1-anilinonaphthalene-8-sulfonic acid (ANS), show line broadening in one-dimensional (1)H NMR spectra, and are weakly protected from hydrogen exchange. Further acidification destabilizes this species, generating a second, more highly denatured state that is less fibrillogenic. These data are consistent with a model for beta(2)m fibrillogenesis in vitro involving the association of partially unfolded molecules into ordered fibrillar assemblies.
Amino Acid Sequence↗
Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling.
Topographic maps are a fundamental feature of sensory representations in nervous systems. The formation of one such map, defined by the connection of ganglion cells in the retina to their targets in the superior colliculus of the midbrain, is thought to depend upon an interaction between complementary gradients of retinal EphA receptors and collicular ephrin-A ligands. We have tested this hypothesis by using gene targeting to elevate EphA receptor expression in a subset of mouse ganglion cells, thereby producing two intermingled ganglion cell populations that express distinct EphA receptor gradients. We find that these two populations form separate maps in the colliculus, which can be predicted as a function of the net EphA receptor level that a given ganglion cell expresses relative to its neighbors.
Animals↗
c-abl is involved in the association of p53 and trk A.
The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
3T3 Cells↗