Biomedical subjects
Publications and source records attributed to D S Johnson.
In this retrospective study, 36 patients were given oxymetazoline as a first step in treatment for posterior epistaxis. In 75% of the cases, epistaxis was effectively treated with oxymetazoline with no recurrent bleeding. All cases with recurrence resolved with continued administration of oxymetazoline. The results of this study propose a pharmacologic intervention for the treatment of posterior epistaxis.
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Reducing violence is a critical health and economic priority. In Minnesota, as in other parts of the United States, violence is increasingly viewed as a public health problem. Helping people work together to prevent violence is one way that managed care organizations are collaborating with public health to improve the health of communities. In 1994, Blue Cross and Blue Shield of Minnesota worked with community organizations to develop The Minnesota Action Plan to End Gun Violence, a broad-based solution to a community problem: violence in Minnesota. The goal of this initiative was to develop grassroots solutions to violence and to inspire community members to take action. Outcomes of the initiative included: participation by over 1,000 Minnesotans in 12 community violence prevention forums; a widely distributed action plan; Students Stop Guns, a school-based intervention to keep Minnesota schools gun-free; the Governor's Task Force on Violence as a Public Health Problem, which led to a commitment of resources to prevent violence and respond to the victims and consequences of violence, and the Health Care Coalition on Violence, to institutionalize strategies within the Minnesota health care environment. The project's qualitative evaluation resulted in lessons and advice on how to execute a collaborative health improvement initiative. These lessons have been widely shared with Minnesota community health advocates.
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In this study we audited the orthopaedic referrals from the cardiothoracic transplant population at Wythenshawe Hospital, South Manchester. A total of 33 referrals in 29 patients were made during the period of study. The referrals represented 10.3% (33/321) of the transplant population. However, the rate of referral per postoperative year was 37.9/1000, which was of a similar order to that of the general population. The diagnosis at referral was activity related in 24 (72.7%) referrals, with one-half of these being related to some form of sporting activity. Complications of immunosuppression may have contributed in up to 15 (45.4%) of referrals. We believe that musculoskeletal problems after cardiothoracic transplantation do not place an excessive burden on our orthopaedic department and that the pattern of referrals indicates that the transplant programme is a success.
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Although a considerable sum of money has been made available for the introduction of medical audit, many of the indirect costs have not been considered. We have assessed one of these areas, the medical audit meeting, by calculating the cost to Preston Acute Hospitals (PAH) Trust and extrapolating it to England and Wales. A potential cost of Pounds 678,000 per annum to PAH Trust could be reduced to 14 per cent of this figure if current practices were changed. The hidden cost for England and Wales could be up to Pounds 106 million per annum. The cost of medical audit meetings could be dramatically reduced if current practices were modified. This could be done with little detriment to the audit process.
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Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.
Physiological and radioligand binding studies have demonstrated the existence of 5-HT3 receptors in the enteric nervous system. In order to determine if the cloned 5-HT3 receptor subunit, 5-HT3R-A, was expressed in the enteric nervous system of rats, we have performed in situ hybridization with 33P-labeled cRNA antisense probes on sections of rat small intestine. Hybridization was detected in both submucosal and myenteric ganglia of the duodenum, jejunum, and ileum.
The role of serotonin as a neurotransmitter in the vertebrate central and peripheral nervous systems has been extensively studied. In addition to its well-defined role in neurotransmission, serotonin has also been implicated in development. We have used in situ hybridization to localize 5-HT3 receptor mRNA in embryonic rat sections from Embryonic Day 10 (E10) to E18. Expression was first detected in the cranial sensory ganglia starting on E10. Expression was later detected in many regions within the developing CNS. In addition to the cranial sensory ganglia, expression was detected in many regions of the peripheral nervous system including dorsal root, sympathetic, and parasympathetic ganglia, and in the myenteric plexus of the enteric nervous system. Expression was also detected in many nonneuronal cell populations including the choroid plexus, cochlear duct, and olfactory epithelium. Expression in regions of active epithelial-mesenchymal interaction such as the tooth bud, lung, and submandibular gland may indicate a role for 5-HT3 receptors in the process of secondary induction.
The three trimethylammonium salts 3-5 proved to be 100 times more efficient at alkylating DNA than 2 and exhibited DNA alkylation efficiencies identical to that of (+)-CC-1065 (1). In addition, the agents 3 and 4 exhibited DNA alkylation selectivities identical to that of 2. This may be attributed to spatially well-defined stabilizing electrostatic interactions between the positively charged trimethylammonium salt lying on the peripheral face of the agents and the bracketing, negatively charged phosphates located in the DNA backbone that enhance the DNA noncovalent binding affinity without affecting DNA binding or alkylation selectivity. The agent 5 exhibited an altered and more discriminating AT-rich adenine N3 alkylation selectivity than 2-4 that may be attributed to the groove placement of the large trimethylammonium salt.
Through a study of cloned nicotinic receptors expressed in Xenopus oocytes, we provide evidence that alpha-conotoxin ImI, a peptide marine snail toxin that induces seizures in rodents, selectively blocks subtypes of nicotinic acetylcholine receptors. alpha-Conotoxin ImI blocks homomeric alpha 7 nicotinic receptors with the highest apparent affinity and homomeric alpha 9 receptors with 8-fold lower affinity. This toxin has no effect on receptors composed of alpha 2 beta 2, alpha 3 beta 2, alpha 4 beta 2, alpha 2 beta 4, alpha 3 beta 4, or alpha 4 beta 4 subunit combinations. In contrast to alpha-bungarotoxin, which has high affinity for alpha 7, alpha 9, and alpha 1 beta 1 gamma delta receptors, alpha-conotoxin ImI has low affinity for the muscle nAChR. Related Conus peptides, alpha-conotoxins MI and GI, exhibit a distinct specificity, strictly targeting the muscle subtype receptor but not alpha 7 or alpha 9 receptors. alpha-Conotoxins thus represent selective tools for the study of neuronal nicotinic acetylcholine receptors.
We report the isolation and functional characterization of a member of the nicotinic acetylcholine receptor subunit gene family, alpha 9. Xenopus oocytes injected with alpha 9 cRNA express a homomeric receptor-channel complex that is activated by acetylcholine. The alpha 9 receptor displays an unusual mixed nicotinic-muscarinic pharmacological profile. The unique properties of the alpha 9 receptor-channel complex closely match those described for the cholinergic receptor present in vertebrate cochlear hair cells. In situ hybridization studies reveal a restricted pattern of alpha 9 gene expression that includes the outer hair cells of the rat cochlea. Our results suggest that the alpha 9 receptor is involved in the cholinergic efferent innervation of cochlear hair cells and thus may modulate the encoding of auditory stimuli.
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A detailed evaluation of the DNA alkylation selectivity of (+)-CC-1065, ent-(-)-CC-1065 and a series of aborted and extended analogs possessing the CPI alkylation subunit is detailed and the refinement of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented. The natural enantiomers bind in the minor groove in the 3'-->5' direction starting from the adenine N3 alkylation site across a 2 base (N-BOC-CPI; i.e. 5'-AA), 3.5 base (CPI-CDPI1/CPI-PDE-I1; i.e. 5'-AAA), 5 base (CC-1065/CPI-CDPI2; i.e. 5'-AAAAA) or 6.5 base (CPI-CDPI3; i.e. 5'-AAAAAA) AT-rich site. In contrast, the unnatural enantiomers bind in the reverse 5'-->3' direction in the minor groove and the binding site necessarily starts at the first 5' base preceding the adenine N3 alkylation site and extends across the alkylation site to the adjacent 3' bases covering an AT-rich site of 2 bases (N-BOC-CPI; e.g., 5'-AA), 5 bases (CC-1065/CPI-CDPI2; eg. 5'-AAAAA), or 6.5 bases (CPI-CDPI3; e.g. 5'-AAAAAA). Notably, the model accommodates the unusual observation that both enantiomers of N-BOC-CPI alkylate the same sites within duplex DNA (5'-AA > 5'-TA) and the required reversed binding orientation of the enantiomeric agents. The reversed binding orientation is required to permit access to the electrophilic cyclopropane and the resulting offset AT-rich alkylation selectivity is the natural consequence of the diastereomeric relationship of the adducts. Three dimensional models of the natural and unnatural enantiomer alkylations are presented which clearly illustrate the offset binding sites. A fundamentally simple model for the CC-1065 DNA alkylation reaction, that accommodates the behavior of both enantiomers, is provided in which the sequence selectivity is derived from the noncovalent binding selectivity of the agents preferentially in the narrower, sterically more accessible AT-rich minor groove, the inherent steric accessibility to the adenine N3 alkylation site that accompanies deep penetration of the agent into the minor groove within an AT-rich site, and the 2 base-pair (N-BOC-CPI), 3.5 base-pair (CPI-PDE-I1/CPI-CDPI1), 5 base-pair (CC-1065/CPI-CDPI2), or 6.5 base-pair (CPI-CDPI3) site size required to permit agent binding in the minor groove at the alkylation site.(ABSTRACT TRUNCATED AT 400 WORDS)