Biomedical subjects
D Barrett
Publications and source records attributed to D Barrett.
Synthesis and biological activity of novel macrocyclic antifungals. modification of the tyrosine moiety of the lipopeptidolactone FR901469.
A series of tyrosine-modified derivatives of the macrocyclic lipopeptidolactone FR901469 have been prepared and evaluated for in vitro and in vivo antifungal activity and for hemolytic activity towards red blood cells. Compound 14 displayed significantly reduced hemolytic potential at 1mg/mL and a comparable protective effect to FR901469 in a mouse candidiasis model.
Maturation of extinction behavior in infant rats: large-scale regional interactions with medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex.
The ability to express a behavior during the postnatal period may be related to developmental changes in the recruitment of particular neural systems. Here, we show that developmental changes in the functional interactions involving three cortical regions (the medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex) are associated with maturation of extinction behavior in infant rats. Postnatal day 17 (P17) and P12 pups were trained in a straight-alley runway on an alternating schedule of reward and nonreward [patterned single alternation (PSA)] or on a pseudorandom schedule of partial reinforcement (PRF); the pups were then injected with fluorodeoxyglucose (FDG) and shifted to continuous nonreward (extinction). Handled control groups exposed to the same training environment but not trained on a particular schedule were included. Among P17 pups, extinction proceeded faster in PSA pups relative to PRF pups. No differences were found between P12 groups. FDG uptake, an index of acute changes in functional activity, was quantified in the three cortical regions and 27 other brain regions of interest. A multivariate covariance analysis, seed partial least squares, revealed that functional relationships involving the three cortical regions and large-scale systems of regions throughout the rostrocaudal extent of the brain changed with training in P17 pups. The cortical regions were primarily uncoupled in the younger group. The data suggest that functional maturation of the frontal cortical regions and their interactions with other brain systems are related to the maturational shift in behavior.
Metabolic mapping of brain regions associated with behavioral extinction in preweanling rats.
Fluorodeoxyglucose autoradiography, quantitative image analysis, and a multivariate tool (partial least squares) were used to assess distributed patterns of brain activation in postnatal day 17 and day 12 rat pups engaged in extinction of instrumental behavior. Pups were trained in a straight alley runway on an alternating reward schedule, or on a pseudorandom reward schedule, injected with fluorodeoxyglucose, and then shifted to continuous nonreward (extinction). Another group at each age served as handled controls. Day 17 pups trained on the alternating schedule demonstrated faster extinction rates compared to those trained on the pseudorandom schedule, a phenomenon known as the partial reinforcement extinction effect. No differences were found between day 12 groups. Partial least-squares analysis revealed age-related increases in fluorodeoxyglucose uptake across all three training conditions in the cingulate and frontal cortices, amygdala, midline thalamic nuclei, cerebellum, and in several brainstem regions. Training-related increases common to both age groups were found in the orbital frontal cortex, limbic thalamus, gigantocellular reticular nucleus, the somatosensory system, and cerebellum. Age-dependent training effects were found in the interpositus and medial cerebellar nuclei wherein fluorodeoxyglucose uptake increased in the day 12 alternation and pseudorandom groups relative to controls. Day 12 pups trained on the alternating schedule demonstrated increased uptake in the anterior dorsal thalamus relative to pseudorandom and control pups. Hence, a large-scale neural system comprised by somatosensory, cerebellar, and brainstem regions govern extinction behavior in preweanling rats. Recruitment of limbic structures may allow the older pups to modify extinction behavior based on prior learning.
Monitor: molecules and profiles.
Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.
NF-kappaB and AP-1 gene expression inhibitors.
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Monitor: molecules and profiles.
Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.
Synthesis and biological activity of novel macrocyclic antifungals: acylated conjugates of the ornithine moiety of the lipopeptidolactone FR901469.
A series of acylated analogues of the novel macrocyclic lipopeptidolactone FR901469 has been prepared and evaluated for antifungal and hemolytic activity. Several analogues displayed markedly reduced hemolytic potential and comparable protective effects to the natural product in a mouse model of candidiasis.
Toward a value-based health care system.
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Monitor: molecules and profiles.
Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.
Monitor: molecules and profiles.
Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.
Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C-C bond.
The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C-C bond is described. As a result of these studies, we selected FR21818 (In) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I). no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBP's, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported.
Knee osteoarthritis and obesity.
OBJECTIVES: To assess the risk of knee osteoarthritis (OA) attributable to obesity, and the interactions between obesity and other established causes of the disorder. METHODS: We performed a population-based case-control study in three health districts of England (Southampton, Portsmouth and North Staffordshire). A total of 525 men and women aged 45 y and over, consecutively listed for surgical treatment of primary knee OA, were compared with 525 controls matched by age, sex and family practitioner. RESULTS: Relative to a body mass index (BMI) of 24.0-24.9 kg/m(2), the risk of knee OA increased progressively from 0.1 (95% CI 0.0-0.5) for a BMI<20 kg/m(2) to 13.6 (95% CI 5.1-36.2) for a BMI of 36 kg/m(2) or higher. If all overweight and obese people reduced their weight by 5 kg or until their BMI was within the recommended normal range, 24% of surgical cases of knee OA (95% CI 19-27%) might be avoided. As a risk factor for knee OA obesity interacted more than additively with each of Heberden's nodes, earlier knee injury and meniscectomy. In comparison with subjects of normal weight, without Heberden's nodes, and with no history of knee injury, people with a combination of obesity, definite Heberden's nodes and previous knee injury had a relative risk of 78 (95% CI 17-354). CONCLUSIONS: Our findings give strong support to public health initiatives aimed at reducing the burden of knee OA by controlling obesity. People undergoing meniscectomy or with a history of knee injury might be a focus for targeted advice.
Site-specific structural transformation of the novel antifungal cyclic depsipeptide FR901469: synthesis and biological activity of FR203903.
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Novel amidine conjugates of the ornithine moiety of the macrocyclic antifungal lipopeptidolactone FR901469.
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Value-based partnering in health care.
Many companies are beginning to focus on value in their health care purchasing decisions, and some are going beyond value-based purchasing to value-based partnering. Value-based partnering recognizes the interdependencies among stakeholder groups in the health care system and creates a strategic reason for them to exchange information and create long-term strategic alliances. This article discusses the principles of value-based partnering, impediments to practicing it and its future role in the health care system.
Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease.
Chronic granulomatous disease (CGD) is an inherited disease caused by defects in the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocytes. Genetic lesions in any of 4 components of this antimicrobial enzyme have been detected. Family-specific mutations are found in 3 of 4 forms of CGD due to deficiencies of the gp91-phox, p22-phox, and p67-phox genes. In p47-phox-deficient CGD (autosomal recessive form A47 degrees ) patients, a GT deletion (triangle upGT) at the beginning of exon 2 of the p47-phox gene has been reported in 19 of 20 alleles. This GT deletion is also characteristic for the recently identified p47-phox pseudogenes. To explore a possible link between these findings, a sequence analysis of 28 unrelated, racially diverse A47 degrees CGD patients and 37 healthy individuals was performed. The GT deletion in exon 2 was present on all alleles in 25 patients. Only 3 patients but all healthy individuals contained the GTGT and triangle upGT sequences. A total of 22 patients carried additional pseudogene-specific intronic sequences on all alleles, either only in intron 1 or in intron 1 and intron 2, which lead to different types of chimeric DNA strands. It is concluded that recombination events between the p47-phox gene and its highly homologous pseudogenes result in the incorporation of triangle upGT into the p47-phox gene, thereby leading to the high frequency of GT deletion in A47 degrees CGD patients. (Blood. 2000;95:2150-2156)