Orthopaedic and trauma surgery. Best method of anterior cruciate ligament reconstruction is debated.
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Anterior Cruciate Ligament Injuries↗
Biomedical subjects
D S Johnson
Publications and source records attributed to D S Johnson.
CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.
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.
Alkylating Agents↗
Detection of 5-HT3R-A, a 5-HT3 receptor subunit, in submucosal and myenteric ganglia of rat small intestine using in situ hybridization.
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.
Animals↗
Embryonic expression of the 5-HT3 receptor subunit, 5-HT3R-A, in the rat: an in situ hybridization study.
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.
Animals↗
CC-1065 CBI analogs: an example of enhancement of DNA alkylation efficiency through introduction of stabilizing electrostatic interactions.
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.
Alkylation↗
alpha-Conotoxin ImI exhibits subtype-specific nicotinic acetylcholine receptor blockade: preferential inhibition of homomeric alpha 7 and alpha 9 receptors.
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.
Amino Acid Sequence↗
Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells.
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.
Amino Acid Sequence↗
Methods of applying liquid nitrogen for skin surgery.
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Cryosurgery↗
Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.
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)
Alkylation↗
Reliability of histologic scoring for lupus nephritis: a community-based evaluation.
OBJECTIVE: To determine the reliability of the National Institutes of Health (NIH)-modified semiquantitative histologic scoring system for lupus nephritis. DESIGN: Cross-sectional study, repeated after 8 to 9 months. SETTING: Four community hospitals and one university medical center. PARTICIPANTS: Five pathologists, all experienced in reading renal biopsy specimens, assessed 25 specimens that had been obtained from patients with a clinical diagnosis of systemic lupus erythematosus and showed diffuse proliferative glomerulonephritis. MEASUREMENTS: Biopsy specimens were scored independently and blindly by pathologists for components of nephritis chronicity and activity. Reliability was measured by percentage agreement, intraclass correlation coefficient or kappa statistic, and individual reader effect on the group arithmetic mean. RESULTS: As scored by the readers, the mean chronicity index score varied from 2.3 to 4.8 on a 12-point scale (P = 0.001) and the mean activity index score varied from 5.8 to 11.4 on a 24-point scale (P = 0.0001). Pairs of readers gave scores within 1 point for the chronicity index and within 2 points for the activity index in 50% of cases, and risk group assignments based on chronicity index (three strata) and activity index (two strata) were concordant in 59% and 76% of cases, respectively. Intraclass correlation coefficients for inter-reader agreement were 0.58 for the chronicity index (P < 0.01) and 0.52 for the activity index (P < 0.01). Intrareader agreement was uniformly higher than inter-reader agreement, but mean intraclass correlation coefficients exceeded 0.70 for only 1 of the 10 index components. Repeated readings yielded chronicity index scores that were more than 1 point discordant in 45% of cases and activity index scores that were more than 2 points discordant in 43% of cases. Risk group assignment changed on the basis of chronicity index and activity index in 36% and 21% of cases, respectively. CONCLUSIONS: In a nonreferral setting, the NIH-modified scoring system for lupus nephritis is only moderately reproducible and, if used to prognosticate renal outcome, may result in erroneous predictions of risk for renal failure and response to therapy.
Chronic Disease↗
Evaluation of functional analogs of CC-1065 and the duocarmycins incorporating the cross-linking 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e (C2BI) alkylation subunit.
The DNA alkylation properties and in vitro cytotoxic activity of a series of analogs of CC-1065 and the duocarmycins incorporating the 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C2BI) alkylation subunit are detailed. The C2BI-based agents have been shown to alkylate DNA within the minor groove in a fashion analogous to CC-1065 or duocarmycin. The stereoelectronically-controlled adenine N3 addition to the least substituted cyclopropane carbon occurs with a selectivity that represents a composite of the two enantiomers of the corresponding CBI-based agents. Additional high affinity alkylation sites were detected which were not prominent alkylation sites for either enantiomer of the CBI-based agents. Such sites may represent induced high affinity alkylation sites resulting from DNA cross-linking following complementary strand alkylation at a high affinity alkylation site and each such site detected proved consistent with predicted models of an adenine-adenine cross-linking event. Further, consistent with this interpretation, the C2BI agents were shown to constitute efficient cross-linking agents with DNA cross-linking being observed at the same concentrations as DNA alkylation. In comparison to the parent CBI-based agents, the C2BI-based agents proved to be approximately 100-10,000x less effective at DNA alkylation and 100-10,000x less potent in cytotoxic assays. This is suggested to be the consequence of a significant steric deceleration of the adenine N3 alkylation reaction attributable to the additional 9a-chloromethyl substituent. Consistent with this interpretation, the noncovalent binding constant of C2BI-CDPI2 for poly[dA]-poly[dA]-poly[dT] proved nearly identical to that of CDPI3 under kinetic binding conditions, and prolonged incubation of C2BI-CDPI2 with poly[dA]-poly[dT] (72 h, 25 degrees C) provided covalent complexes with a helix stabilization comparable to that observed with (+)- or (-)-CPI-CDPI2 indicating that the size of the C2BI subunit inhibits but does not preclude productive DNA alkylation.
Alkylation↗
A cross-level units-of-analysis approach to individual differences in skill acquisition.
A recent multiple-stage model posits that the individual-difference factors influencing performance vary depending on skill acquisition stage (P. L. Ackerman, 1989, 1990). In the current study, the authors examine the effect of ability in early skill acquisition and extend earlier research by examining the roles of self-efficacy and task familiarity. Furthermore, learning-curve modeling with multilevel models is used to alleviate prior analytical problems. Subjects (N = 115) performed an air traffic control simulation task. Nonlinear learning-curve parameters were estimated for each subject using a negative exponential model (see D. R. Rogosa & J. B. Willett, 1985). Cognitive ability, self-efficacy, and task familiarity were then used to predict learning-curve parameters: learning-rate constant and asymptotic performance. Results revealed that ability, self-efficacy, and familiarity predicted the learning-rate constant, whereas self-efficacy predicted asymptotic performance.
Adult↗
Intraocular pressure and mechanical ventilation.
Mechanical ventilation increases superior vena cava pressure and should theoretically increase episcleral venous pressure and intraocular pressure (IOP). A Keeler Pulsair Non Contact Tonometer was used to measure the IOP's of six subjects with no history of glaucoma or ocular hypertension. At 30 min of supine mechanical ventilation of tidal volume with low (7 to 15 cm H2O) peak inspiratory pressures, the IOP's were no different than at the end of a 30-min control period of supine spontaneous ventilation. However, using high (60 cm H2O) peak inspiratory pressures for 1 min after tidal volume ventilation, IOP's were 32.7% higher than at the end of the supine spontaneous ventilation control period (p < 0.05). Patients requiring long-term mechanical ventilation at high peak inspiratory pressures may be at increased risk of vision impairment secondary to machine-induced increase of IOP.
Adult↗
Adult respiratory distress syndrome: a consideration with rapid respiratory decompensation in association with preeclampsia.
Adult respiratory distress syndrome, presenting as rapid respiratory decompensation in the setting of preeclampsia at 36 weeks of gestation, was managed by early hemodynamic monitoring with pulmonary artery catheterization. With confirmation of the diagnosis of preeclampsia the patient was delivered promptly; improvement of her respiratory failure was observed within 48 hours. Consideration of adult respiratory distress syndrome in the setting of preeclampsia is discussed, with emphasis on early confirmation of the diagnosis and determination of the precise mechanisms of pulmonary edema.
Adolescent↗
Audit of ranitidine administration in parenteral nutrient solutions.
An audit of the use of ranitidine administered in parenteral nutrient (PN) solutions is reported. Pharmacists at a 747-bed teaching institution developed criteria addressing justification of the use of ranitidine in PN solutions, process indicators for monitoring, and outcome measures. All patients who received ranitidine in their PN solutions between October 29 and November 22, 1989, were included in the study. Data were collected on a standardized form. A total of 23 evaluable patients received ranitidine in PN solutions during the study period. No inappropriate uses of ranitidine were identified. Patients with renal impairment tended to be underdosed. There were no duplicate administrations of ranitidine by the i.v. minibag and PN solution routes. However, on four occasions the PN solution was interrupted for more than six hours; additional ranitidine by i.v. minibag was ordered for only one of these patients. Testing of nasogastric aspirates for pH was not performed in 17 of the 22 patients who needed this test. Gastrointestinal bleeding was observed in two patients, both of whom were not monitored for gastric pH and were underdosed. A program is being developed to promote the safe and effective use of ranitidine administered in PN solutions. An audit of the administration of ranitidine in PN solutions showed that the drug is usually used appropriately at the institution and that most of the patients had positive clinical outcomes.
Evaluation Studies as Topic↗
Characterization of the omega-conotoxin target. Evidence for tissue-specific heterogeneity in calcium channel types.
omega-Conotoxin GVIA (omega-CgTx-VIA) is a 27 amino acid peptide from the venom of the fish-hunting snail, Conus geographus, that blocks voltage-activated Ca channels. The characterization of a biologically active, homogeneous 125I-labeled monoiodinated Tyr22 derivative of omega-conotoxin GVIA and its use in binding and cross-linking studies are described. The 125I-labeled toxin is specifically cross-linked to a receptor protein with an apparent Mr of 135,000. The stoichiometry between omega-conotoxin and nitrendipine binding sites in different chick tissues was determined. Skeletal muscle has a high concentration of [3H]nitrendipine binding sites (greater than 1000 fmol/mg) but no detectable omega-conotoxin sites (less than 7 fmol/mg). Brain microsomes have both binding sites, but omega-conotoxin targets are in excess. These results, combined with recent electrophysiological studies (E. W. McCleskey, A. P. Fox, D. Feldman, L. J. Cruz, B. M. Olivera, R. W. Tsien, and D. Yoshikami, unpublished results), define four types of Ca channels in chick tissues, N, T, Ln (omega sensitive), and Lm (omega insensitive), and are consistent with the hypothesis that the alpha-subunits of certain neuronal Ca2+ channels (Ln, N) are the molecular targets of omega-conotoxin GVIA.
Amino Acid Sequence↗
Adapting disease-specific isolation guidelines to a hospital information system.
The authors modified the Centers for Disease Control's guideline for disease-specific isolation precautions to a hospital computerized information system. Entering a suspected diagnosis selected from the isolation option on computer terminals generated: a printout listing the isolation instructions, infective material(s), and persons who should avoid exposure; an order for the appropriate supplies; a patient charge based on the supplies required; and an option for stopping, changing, or listing the orders. In order to implement this system, both extensive in-service training for nurses and efforts to change ordering practices of physicians were necessary. Prevalence surveys before and after computerization were used to evaluate the new system. Combined surveys showed that isolation was ordered for only 21% of patients when indicated. Failure to isolate was identified as a significant problem. As a consequence, continuous surveillance and consultation of all infected patients were instituted, resulting in isolation orders for 81% when indicated. The computerized disease-specific system has resulted in better and more accurate use of isolation, probably due to in-service education and surveillance efforts.
Centers for Disease Control and Prevention, U.S.↗
A study of neonates' differential responses to three voices, as measured by transcutaneous oxymonitor.
123 newborn infants were tested for changes in arterial oxygen status as an index of response to three voices, one of these being the maternal voice. Male infants responded more than female infants to their mother's voice, but female infants showed a higher response to the other female voice and the male voice. Black infants of each sex responded more than white infants to the maternal voice and to the other female voice. White female infants responded more than black female infants to the male voice.
Black or African American↗