Organizational ethics and sentinel events: doing the right thing when the worst thing happens.
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Decision Making, Organizational↗
Biomedical subjects
K M Johnson
Publications and source records attributed to K M Johnson.
Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters.
In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications of its structure. In the case of the substituent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In the present study, we report our results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using Ki values rather than IC50 values when making such comparisons of transporter selectivity. One of the most interesting compounds identified in the present work is a 2, 3-diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the 5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy further underscores the versatility of this particular chemical approach to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in nonracemic form.
Animals↗
Regulation of neurotransmitter release by endogenous nitric oxide in striatal slices.
This study sought to determine the potential role of nitric oxide (NO) in N-methyl-D-aspartate (NMDA)-stimulated efflux of [14C] gamma-aminobutyric acid (GABA) and [3H]acetylcholine from striatal slices in vitro. In Mg2+-free buffer, NMDA-stimulated [14C]GABA and [3H]acetylcholine release were inhibited by the guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and, to a lesser extent, by the nitric oxide synthase inhibitor, nitroarginine (N-Arg). Since reversal of catecholamine transporters previously has been implicated in the mechanism underlying NO-induced catecholamine release, we used the GABA transport inhibitor, 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-py ridine-carboxylic acid hydrochloride (NNC-711), to address the role of GABA transport in NArg-sensitive NMDA-induced release. NNC-711 inhibited NMDA-stimulated [14C]GABA efflux by 50%, confirming our previous report that NMDA-stimulated GABA release is partially dependent on reversal of the transporter. The effect of N-Arg in the presence of NNC-711 was similar to its effect in the absence of the transport inhibitor, suggesting that reversal of the transporter is not involved in the NO component of NMDA-stimulated [14C]GABA release. These data suggest that glutamatergic transmission through striatal NMDA receptors is partially mediated through activation of the NO/guanylate cyclase pathway and that this mechanism may contribute to the tetrodotoxin sensitivity of NMDA-induced release of GABA and acetylcholine in the striatum.
Acetylcholine↗
Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex.
In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed.
Animals↗
Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton.
To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)- or (-)-dibenzoyltartaric acid. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35, 428 binding at the dopamine transporter and in the inhibition of [3H]dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (-)-9 was found to be the most potent with a binding affinity of 3 nM. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Although no efforts have presently been made to "optimize" binding affinity at the DAT, the substantive activity found for the n-propyl derivative (-)-9 is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. As a further point of interest, it was found that the cis-disubstituted piperidine (-)-3 is only about 2-fold more potent than its trans isomer (+)-11. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from beta to alpha has been reported to result in a lowering of activity by 30-200-fold. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications.
Animals↗
Gadolinium-bearing red cells as blood pool MRI contrast agents.
Human and rat red blood cells (RBCs) were loaded with gadolinium DTPA dimeglumine using an osmotic pulse technique to create a blood pool contrast agent for MRI. The resulting packed red cells contained 30.9 +/- 3.3 (1 SD) mmol Gd/liter for humans and 24.7 +/- 3.5 (1 SD) mmol Gd/liter for rats. Longitudinal relaxation rate constant of human RBCs increased from 2.0 +/- 0.1 to 145.6 +/- 36.2 s(-1); the transverse relaxation rate constant increased from 6.8 +/- 1.2 to 562 +/- 410 s(-1). For rat RBCs, R1 increased from 1.45 +/- 0.15 to 84.8 +/- 23.9 s(-1); R2 increased from 7.1 +/- 0.64 to 247 +/- 158 s(-1). Affinity for oxygen was slightly reduced (control P50 = 22.3 +/- 2.3 versus experimental P50 = 27.3 +/- 1.3, P < 0.01), as was mechanical deformability. No drop in relaxivities was seen after 5 days of storage. The apparent volume of distribution was 0.0164 +/- 0.003 liter/kg, biologic half-life 4.38 +/- 0.34 h, and total plasma clearance 0.003 +/- 0.0006 liter/kg/h. Compared with Gd-DTPA "free" in the plasma, tissue enhancement from RBCs was initially lower but was much prolonged. Preparation is simple enough to be reproduced by most laboratories.
Animals↗
The primary interpretation workstation: information beyond image data.
With the advent of picture archival and communication systems (PACS), the importance of design surrounding primary review workstations has become apparent. To help acceptance of filmless medical imaging, workstations must be developed that serve the needs of both radiologists and referring clinicians. This report will discuss integral requirements of workstation design, including information creation, medical management, medical knowledge, and enabling technologies.
Data Display↗
Mechanism of action of rab3A in mossy fiber LTP.
In mossy fiber synapses of the hippocampal CA3 region, LTP is induced by cAMP and requires the synaptic vesicle protein rab3A. In contrast, CA1-region synapses do not exhibit this type of LTP. We now show that cAMP enhances glutamate release from CA3 but not CA1 synaptosomes by (1) increasing the readily releasable pool as tested by hypertonic sucrose; (2) potentiating release evoked by KCl depolarization, which opens voltage-gated Ca2+ channels; and (3) by enhancing Ca2+ action on the secretory apparatus as monitored by the Ca2+-ionophore ionomycin. In rab3A-deficient synaptosomes, forskolin still enhances KCl- and sucrose-induced glutamate release but not ionomycin-induced release. Our results show that cAMP has multiple actions in mossy fiber synapses, of which only the direct activation of the secretory apparatus requires rab3A and functions in mfLTP.
Animals↗
Inner city primary care providers' breast cancer screening knowledge: implications for intervention.
Low income and minority women continue to have relatively low breast cancer screening rates. Since physician recommendation is one of the most important determinants of mammography participation, we aimed to characterize the breast cancer screening knowledge of primary care providers serving a socially disadvantaged population. The study was conducted at the Adult Medicine Clinic of Seattle's county hospital. All attending physicians, resident physicians, and mid-level practitioners were asked to complete a questionnaire in the spring of 1995. Forty-nine of 52 (94%) eligible providers completed the survey. The respondents generally agreed with published guidelines for screening mammography use. In contrast, they had relatively low levels of knowledge about breast cancer risk factors and the effectiveness of other breast cancer screening methods. Additionally, providers tended to over-estimate their breast cancer screening knowledge and skills. For example, 69% believed that they could answer patients' questions about mammography, but only 23% were aware of Medicaid's reimbursement policy for the procedure. For some variables, attending physicians were no more knowledgeable than resident physicians. Our results reinforce the need for increased preventive care training in medical schools and primary care residency programs. Educational programs for providers serving disadvantaged populations might usefully focus on pragmatic issues such as institutional costs and public payer reimbursement policies.
Adult↗
Effects of moderate, central fluid percussion traumatic brain injury on nitric oxide synthase activity in rats.
Experimental traumatic brain injury (TBI) damages cerebral vascular endothelium and reduces cerebral blood flow (CBF). The nitric oxide synthase (NOS) substrate, L-arginine, prevents CBF reductions after TBI, but the mechanism is not known. This study examined the possibility that post-traumatic hypoperfusion is due to reductions in the substrate sensitivity of NOS which are overcome by L-arginine. Isoflurane-anesthetized rats were prepared for TBI (midline fluid-percussion, 2.2 atm), sham-TBI, or no surgery (control), and were decapitated 30 min after injury or sham injury. The brains were removed and homogenized or minced for measurements of crude soluble or cell-dependent stimulated NOS activity, respectively. Baseline arterial oxygen, carbon dioxide, pH, or hemoglobin levels did not differ among control, sham, or TBI groups. Total cortical soluble NOS activity in TBI-treated rats was not significantly different from either untreated or sham groups when 0.45 microM or 1.5 microM L-arginine was added. Also, there were no differences in cell-dependent NOS activity among the three groups stimulated by 300 microM N-methyl-D-aspartate, 50 mM K+, or 10 microM ionomycin. These data suggest that TBI reduces CBF by a mechanism other than altering the substrate specificity or activation of nNOS.
Analysis of Variance↗
Renewed population growth in rural America.
This chapter documents the fact that "nonmetropolitan America has experienced widespread population gain and net in-migration since 1990. This contrasts with the trend evident through most of this century.... However, this deconcentration has been selective and tempered by economic period effects. Future nonmetropolitan demographic change is likely to be even more dependent on migration because recent rural fertility patterns, together with age structure shifts, have diminished the contribution natural increase can make to rural growth. This increasing dependence on migration, coupled with the greater integration of nonmetropolitan areas into the national and international system, makes rural America increasingly sensitive to national and global economic, political, and social forces."
Americas↗
Endometriosis. The case for early, aggressive treatment.
While the debate rages on regarding how metabolic and immunologic changes fit into the pathophysiology of endometriosis, the clinician must nonetheless make decisions regarding treatment. This article examines the relevant literature, with particular emphasis on immunologic aspects, nonclassic, early and deep disease as well as data on progression, recurrence and effects of treatment, to propose innovations in the management of early-stage disease. All symptomatic early-stage disease should be treated aggressively--even after conservative surgical resection of all apparent endometriosis, adjunct medical treatment in the form of a gonadotropin-releasing hormone agonist should be strongly considered.
Anti-Inflammatory Agents, Non-Steroidal↗
Dopamine neurotoxicity in cortical neurons.
Dopamine (DA), at concentrations greater than 100 microM, has previously been demonstrated to be toxic to mesencephalic, striatal and dorsal root ganglion cell cultures. Pharmacological experiments suggest that DA also may play a role in the cortical neurotoxicity caused by systemic administration of N-methyl-D-aspartate receptor antagonists such as phencyclidine and MK-801. In this study, the potential toxicity of DA in primary cortical cell cultures was determined in vitro. Using calcein and ethidium homodimer fluorescence as a marker for live and dead cells, respectively, we observed that a 24 h treatment with 10-100 microM DA produced a concentration-dependent increase in the number of ethidium homodimer-labelled cells. The cell death induced by 10 microM DA was dramatically reduced by co-administration of either superoxide dismutase and catalase or deferoxamine mesylate, an iron chelator. To verify this observation, the effects of 10 microM DA on the release of cytoplasmic lactate dehydrogenase (LDH) was measured. DA increased LDH release in a manner that was inhibited by both superoxide dismutase/catalase and deferoxamine. Nomifensine potentiated the effect of DA on LDH release, suggesting a protective role for DA uptake in this system. On the other hand, neither D1 nor D2 antagonists were able to prevent DA-induced LDH release. These data suggest that relatively low concentrations of DA can be injurious to cortical neurons through a mechanism that likely involves DA autooxidation and the formation of reactive oxygen species such as superoxide anion and hydroxyl radical. This mechanism may be important in the toxic effects of psychomotor stimulants such as amphetamine. However, the failure of DA receptor antagonists to affect DA-induced injury argues that the effect of DA on cortical neurons in culture does not model the toxic effect of phencyclidine and MK-801 observed in vivo.
Animals↗
Improving cancer pain management in communities: main results from a randomized controlled trial.
The purpose of this randomized controlled community trial is to evaluate the effects of a community intervention utilizing opinion leaders and educational strategies on the cancer pain management knowledge, attitudes, and the practices of physicians and nurses, and cancer pain reported by patients. Six Minnesota communities participated in the study. The three communities randomized to the intervention received educational programs over 15 months. The clinical community opinion leaders participated in a minifellowship, developed community task forces, and interacted with their peers. This strategy was reinforced with community outreach programs, clinical practice guidelines, educational materials, and media events. The primary study end point was patients' pain intensity score. Comparing intervention to control communities, pain prevalence declined slightly, pain management index improved slightly, pain intensity scores increased slightly, patient and family attitude scores did not change, and physicians' and nurses' knowledge and attitude scores improved slightly. None of these changes, however, reached statistical significance. Participation in at least one intervention program improved physicians' and nurses' knowledge and attitude scores that approached statistical significance. Our results suggest that community opinion leaders combined with other educational programs may improve cancer pain management, but this strategy requires further study. The results suggest that more intense intervention application may be effective. Effective strategies to improve cancer pain management remain elusive.
Cohort Studies↗
Total-body MR imaging in as little as 18 seconds.
Eighteen human subjects underwent echo-planar magnetic resonance (MR) imaging of the whole body at 1.5 T. A stack of axial images was obtained from the top of the head to the feet with gradient-echo, spin-echo, and inversion-recovery spin-echo pulse sequences by moving the patient table through the magnet isocenter. In all examinations, the subjects tolerated the procedure well and table motion was uniform. Image quality depended on careful setting of the transmit frequency, gain, and shims. Results were easily obtained and reproducible in all cases in as little as 18 seconds.
Adult↗
Lung abscess caused by Legionella micdadei.
We describe a case of lung abscess caused by sporadic infection with Legionella micdadei in a patient with AIDS. L micdadei infection can be very difficult to diagnose because the organism stains only weakly Gram negative, requires special culture media, and is not detectable with some direct fluorescent antibody tests that are directed only at Legionella pneumophila. Since it can stain acid fast, it may be confused with mycobacteria. The abscess was successfully treated using antibiotics and percutaneous catheter drainage.
Acquired Immunodeficiency Syndrome↗
Comparison and reproducibility of visual echocardiographic and quantitative radionuclide left ventricular ejection fractions.
Left ventricular (LV) ejection fraction (EF) is commonly assessed by equilibrium radionuclide angiography and echocardiography. These methods are presumed to be interchangeable for this purpose. This study (1) compares quantification of LVEF by equilibrium radionuclide angiography with visual estimation of LVEF by echocardiography, (2) determines the reproducibility of both methods, and (3) evaluates whether differences in determinations of LVEF are of clinical relevance. Seventy-three clinically stable patients had both equilibrium radionuclide angiography and echocardiography performed within a 4-day period. LVEF by both techniques was compared after blinded analysis by 3 echocardiographers and 3 nuclear technologists. Reproducibility was assessed by blinded repeat analysis after a 1-week interval. The frequency of differences in repeat assessments of EF that the authors considered to be of potential clinical relevance (i.e., difference > or = 10% EF units) was assessed for both techniques. Correlation of LVEF determined by both methods was good (r = 0.81, SEE = 3.5) but with substantial differences in individual patients (limits of agreement, 23.6%). Intra- and inter-observer reproducibility was good for both methods, but better for radionuclide LVEF than for echocardiographic LVEF. Limits of agreement were substantially better for radionuclide LVEF than for echocardiographic LVEF (1.8% to 3.6% versus 13.4% to 17.4%, respectively). Clinically relevant differences did not occur on repeat processing of equilibrium radionuclide angiography. In contrast, potentially clinically relevant differences occurred in 8% to 26% of studies on repeat analysis of echocardiography. Thus, LVEF determined by equilibrium radionuclide angiography and echocardiography show good agreement. Both methods provide clinically valuable measurements for LV function. However, when a precisely reproducible measurement is required for patient management decisions, equilibrium radionuclide angiography is the method of choice.
Adult↗
Glutamate receptor activation induces carrier mediated release of endogenous GABA from rat striatal slices.
The regulation of striatonigral and striatopallidal GABAergic neurons by glutamatergic afferents is thought to play a critical role in normal basal ganglia function. Here we report that in striatal slices about 17% of K(+)-induced endogenous GABA release was Ca(2+)-independent and this could be blocked by a GABA transport inhibitor. Activation of N-methyl-D-aspartate (NMDA)- and quisqualate-sensitive receptors induced endogenous GABA efflux only in the presence of a GABA transaminase inhibitor; this efflux was inhibited by 60-80% with a GABA transport inhibitor. NMDA-induced GABA release was blocked by phencyclidine, Mg2+ and CGS 19755. Quisqualate-induced GABA release was blocked completely by a combination of the metabotropic antagonist, L-AP3 and CNQX, a non-NMDA receptor antagonist. These data indicate that excitatory amino acid agonists-induced GABA release is distinct from that induced by high K+ depolarization.
Animals↗