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Biomedical subjects

C L Nelson

Publications and source records attributed to C L Nelson.

At least 19 recordsLinked to original sources
PubMed2005

Prefrontal cortical modulation of acetylcholine release in posterior parietal cortex.

Attentional processing is a crucial early stage in cognition and is subject to "top-down" regulation by prefrontal cortex (PFC). Top-down regulation involves modification of input processing in cortical and subcortical areas, including the posterior parietal cortex (PPC). Cortical cholinergic inputs, originating from the basal forebrain cholinergic system, have been demonstrated to mediate important aspects of attentional processing. The present study investigated the ability of cholinergic and glutamatergic transmission within PFC to regulate acetylcholine (ACh) release in PPC. The first set of experiments demonstrated increases in ACh efflux in PPC following AMPA administration into the PFC. These increases were antagonized by co-administration of the AMPA receptor antagonist DNQX into the PFC. The second set of experiments demonstrated that administration of carbachol, but not nicotine, into the PFC also increased ACh efflux in PPC. The effects of carbachol were attenuated by co-administration (into PFC) of a muscarinic antagonist (atropine) and partially attenuated by the nicotine antagonist mecamylamine and DNQX. Perfusion of carbachol, nicotine, or AMPA into the PPC did not affect PFC ACh efflux, suggesting that these cortical interactions are not bi-directional. These studies demonstrate the capacity of the PFC to regulate ACh release in the PPC via glutamatergic and cholinergic prefrontal mechanisms. Prefrontal regulation of ACh release elsewhere in the cortex is hypothesized to contribute to the cognitive optimization of input processing.

Acetylcholine↗
PubMed2002

Staphylococcus aureus collagen adhesin contributes to the pathogenesis of osteomyelitis.

To evaluate the role of the Staphylococcus aureus collagen-binding adhesin (Cna) in bone and joint infection, we generated a cna mutant in S. aureus UAMS-1, a strain that was originally isolated from the bone of a patient suffering from osteomyelitis. The mutant (UAMS-237) was unable to bind collagen but bound fibronectin at levels comparable to UAMS-1. The relative virulence of UAMS-1 and UAMS-237 was assessed using a murine model of acute hematogenous osteomyelitis. Specifically, 10(8) colony-forming units (cfu) were introduced into the bloodstream of NIH-Swiss mice via tail-vein injection. After 2 weeks, the left hind limb was harvested and examined histologically for evidence of osteomyelitis and septic arthritis. Osteomyelitis developed in 14 of 20 mice (70%) infected with UAMS-1, but only 1 of 20 (5%) infected with UAMS-237 (p < 0.001). In contrast, septic arthritis was observed in 12 of 20 mice (60%) infected with UAMS-1 and 14 of 20 (70%) infected with UAMS-237 (p < 0.75). These results indicate that Cna is not required to establish joint infection, but does make an important contribution to the ability of S. aureus to establish infection in bone through hematogenous spread.

Adhesins, Bacterial↗
PubMed2001

Using observational data to estimate prognosis: an example using a coronary artery disease registry.

With the proliferation of clinical data registries and the rising expense of clinical trials, observational data sources are increasingly providing evidence for clinical decision making. These data are viewed as complementary to randomized clinical trials (RCT). While not as rigorous a methodological design, observational studies yield important information about effectiveness of treatment, as compared with the efficacy results of RCTs. In addition, these studies often have the advantage of providing longer-term follow-up, beyond that of clinical trials. Hence, they are useful for assessing and comparing patients' long-term prognosis under different treatment strategies. For patients with coronary artery disease, many observational comparisons have focused on medical therapy versus interventional procedures. In addition to the well-studied problem of treatment selection bias (which is not the focus of the present study), three significant methodological problems must be addressed in the analysis of these data: (i) designation of the therapeutic arms in the presence of early deaths, withdrawals, and treatment cross-overs; (ii) identification of an equitable starting point for attributing survival time; (iii) site to site variability in short-term mortality. This paper discusses these issues and suggests strategies to deal with them. A proposed methodology is developed, applied and evaluated on a large observational database that has long-term follow-up on nearly 10 000 patients.

Analysis of Variance↗
PubMed2001

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

Animals↗
PubMed2001

Short-term results of the M2a-taper metal-on-metal articulation.

A polyethylene-free, metal-on-metal acetabular system (M2a-taper [Biomet, Inc., Warsaw, IN]) was designed in an effort to improve total hip arthroplasty (THA) longevity. Minimum 2-year follow-up results involving 72 polyethylene liner THAs and 78 metal liner THAs from a multicenter, randomized, controlled, investigational device exemption study are reported. Mean Harris hip scores of 95.54 (polyethylene liner group) and 95.23 (metal liner group) were reported at mean follow-up intervals of 3.29 and 3.23 years. Radiographic evaluation revealed no evidence of early failure. No acetabular components have been revised or are pending revision. No statistically significant differences in the data were calculated between liner types except for the immediate postoperative (P=.0415) and minimum 2-year follow-up (P=.0341) angles of inclination. The M2a-taper metal-on-metal articulation may represent a viable alternative for THA in younger, higher demand patients.

Adolescent↗
PubMed2001

Assessing the clinical and economic burden of coronary artery disease: 1986-1998.

BACKGROUND: The acute phase of coronary artery disease (CAD) is dramatic and receives much attention because of its high mortality and associated treatment cost. However, the acute phase typically resolves within 30 days whereas CAD is a chronic disease, which most patients will live with for more than a decade. We compared the clinical and economic burden of CAD during the acute phase (first 30 days) with that in the postacute phase (31st day through 10 years). METHODS: We included acute coronary syndrome (ACS) patients with significant CAD receiving an initial cardiac catheterization at Duke University Medical Center between 1986 and 1997 with follow-up continuing through 1998. Inpatient medical costs were estimated from ACS clinical trial and economic study data. Costs were adjusted to 1997 values and discounted at 3% per annum. RESULTS: Our study included 9,876 ACS patients (5,557 with an acute myocardial infarction [MI] and 4,319 with unstable angina [UA]). Acute MI patients had higher 30-day mortality than UA patients (5.6% vs. 2.3%, P <0.001). In addition, acute MI and UA patients had significant 10-year unadjusted and adjusted survival differences (both P <0.001). For patients who survived to 30 days, there was no difference in 10-year survival between acute MI and UA patients before adjustment (P = 0.472). After adjustment, however, unstable angina patients who survived to 30 days had greater survival than myocardial infarction patients (P = 0.011). Mean 10-year discounted ACS inpatient medical costs were $45,253 ($23,510 acute phase and $21,819 postacute phase, P = 0.002). Ten year costs for unstable angina patients were $46,423 ($21,824 acute phase and $24,599 postacute phase, P = 0.003); ten year costs for myocardial infarction patients were $44,663 ($24,823 acute phase and $19,840 postacute phase, P <0.001). CONCLUSIONS: We found that the clinical and economic burden of CAD continues long after a patient's acute event has resolved and that postacute CAD cardiac event rates and inpatient medical costs may be higher than previously estimated. With much of all medical costs occurring in the postacute phase, the potential for effective secondary prevention therapies is substantial.

Aged↗
PubMed2001

Treatment of osteonecrosis of the knee.

There are several options for the treatment of patients with osteonecrosis about the knee. Three appear to be the most effective and include conservative treatment for small lesions without evidence of structural collapse, core decompression for relief of pain and possible delay in structural collapse in the patients with steroid-induced osteonecrosis, and either unicompartmental or total knee arthroplasty. Although other modalities have been reported, these three remain the most widely reported and generally offer the greatest success. With better recognition of these problems, longer duration follow-up, and larger patient series, the answers to the best treatment regimen will become better defined.

Adult↗
PubMed2000

Cost effectiveness of early discharge after uncomplicated acute myocardial infarction.

BACKGROUND: Reducing the length of hospitalizations can reduce short-term costs, but there are few data on the long-term clinical and economic consequences of early discharge. METHODS: Using data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, we identified 22,361 patients with acute myocardial infarction who had an uncomplicated course for 72 hours after thrombolysis. Then, using a decision-analytic model, we examined the cost effectiveness of an additional day of hospitalization in this group. We defined incremental survival attributable to another day of monitored hospitalization, using Kaplan-Meier estimates to determine the rate of resuscitation after cardiac arrest between 72 and 96 hours. Lifetime survival curves for each group in the decision-analytic model were estimated from empirical one-year survival data from GUSTO-1. The costs of key hospital resources (e.g., room and monitoring) were derived from data in the GUSTO-1 cost-effectiveness analysis. RESULTS: Of the patients with an uncomplicated course within 72 hours after thrombolysis, 16 had ventricular arrhythmias during the next 24 hours; 13 of these patients (81 percent) survived for at least 24 hours. On average, another 0.006 year of life per patient could be saved by keeping patients with an uncomplicated course in the hospital another day. At a cost of $624 for hospital and physicians' services, extending the hospital stay by another day would cost $105,629 per year of life saved. In sensitivity analyses, it was found that a fourth day of hospitalization would be economically attractive only if its cost could be reduced by more than 50 percent or if a high-risk subgroup could be identified in which the estimated survival benefit would be doubled. CONCLUSIONS: Hospitalization of patients with uncomplicated myocardial infarction beyond three days after thrombolysis is economically unattractive by conventional standards.

Aged↗
PubMed2000

Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes.

BACKGROUND: In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). METHODS AND RESULTS: We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year. CONCLUSIONS: Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

Angina, Unstable↗
PubMed2000

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release.

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.

Acetylcholine↗
PubMed2000

Systemic and intra-accumbens administration of amphetamine differentially affects cortical acetylcholine release.

The present experiments tested the hypothesis that the amphetamine-induced increase in dopamine release in the nucleus accumbens represents a necessary and sufficient component of the ability of systemically administered amphetamine to stimulate cortical acetylcholine release. The effects of systemic or intra-accumbens administration of amphetamine on accumbens dopamine release and cortical acetylcholine release were assessed simultaneously in awake animals equipped with dialysis probes inserted into the shell of the nucleus accumbens and the medial prefrontal cortex. Additionally, the ability of intra-accumbens administration of dopamine D(1) and D(2) receptor antagonists to attenuate the effects of systemic amphetamine on cortical acetylcholine was tested. The effects of all treatments were assessed in interaction with a stimulus-induced activation of cortical acetylcholine release to account for the possibility that the demonstration of the trans-synaptic effects of accumbens dopamine requires pre-activation of basal forebrain circuits. Systemic amphetamine resulted in increases in basal cortical acetylcholine and accumbens dopamine efflux. Intra-accumbens administration of amphetamine substantially increased accumbens dopamine efflux, but did not significantly affect cortical acetylcholine efflux. Furthermore, intra-accumbens administration of sulpiride or SCH 23390 did not attenuate the systemic amphetamine-induced increase in cortical acetylcholine efflux. Collectively, the present data suggest that increases in accumbens dopamine release are neither sufficient nor necessary for the effects of systemically administered amphetamine on cortical acetylcholine release. The systemic amphetamine-induced increase in cortical acetylcholine may be mediated via multiple, parallel pathways and may not be attributable to a single afferent pathway of the basal forebrain.

Acetylcholine↗
PubMed1999

Primary alveolar cleft bone grafting in unilateral cleft lip and palate: arch dimensions at age 8.

The purpose of this investigation is to determine whether primary alveolar cleft bone grafting in infants with unilateral cleft lip and palate (N = 17) leads to less favorable dental arch dimensions at age 8 when compared with other 8-year-old patients with unilateral cleft lip and palate who received no alveolar bone grafting procedures (N = 49). Dental casts were obtained for the primary grafted group, and arch lengths and widths were digitally recorded with a reflex microscope. These arch dimensions were then compared with the reported data for a nongrafted group and a noncleft group of 8-year-old children. The major findings were: 1) that the dental arches of both cleft groups generally demonstrated a significant diminution in length and width (P < 0.05) compared with the noncleft groups, and 2) that the patients who underwent primary alveolar cleft bone grafting showed no statistically significant difference for any arch dimension (P < 0.05) when compared with the nongrafted group lacking this additional surgical procedure.

Alveolar Process↗
PubMed1999

Primary alveolar cleft bone grafting in unilateral cleft lip and palate: craniofacial form at age 8.

Counterpart analysis can be advantageous for the clinician interested in the underlying determinants of the craniofacial form for any given person. This analysis was performed for a group of patients who underwent primary alveolar cleft bone grafting (N = 18) and a group of patients who did not undergo grafting (N = 19) who were 8 years of age (+/- 6 months). The primary grafting group more frequently noted maxillary retrusion, but of a nonsignificant magnitude. Also, the primary grafting group had greater mean magnitudes of mandibular opening as a compensatory adjustment in some patients, but this could not be generalized to all patients who had underdone primary grafting. The mean magnitude of craniofacial vertical shortening was also greater for some patients who had undergone primary grafting, but it, too, did not exhibit a generalized pattern for all patients who had undergone primary alveolar cleft bone grafting procedures. This study emphasizes the great diversity of craniofacial skeletal adjustments made within each group of patients with unilateral cleft lip and palate and cautions the clinician against generalizations concerning a particular treatment protocol.

Alveolar Process↗
PubMed1999

Primary and revision total hip replacement in patients who are Jehovah's Witnesses.

The Jehovah's Witnesses do not accept allogeneic blood transfusion or certain types of autologous blood transfusion and, therefore, present the orthopaedic surgeon with a challenge in the management of perioperative blood loss. Accepting a patient who is a Jehovah's Witness as a surgical candidate requires the surgeon to be prepared medically to use known techniques to limit red blood cell loss or increase red blood cell mass, to resort to extraordinary means when necessary, and to be prepared philosophically to deal with catastrophic blood loss in a patient who may refuse even potentially life-saving transfusion. Issues pertinent to the management of intraoperative blood loss in the patient who is a Jehovah's Witness require careful delineation and specific treatment guidelines. The authors herein review their past and current experiences in the perioperative blood management of this patient population in an attempt to address this need.

Arthroplasty, Replacement, Hip↗
PubMed1998

Nightly enteral nutrition support of elderly hip fracture patients: a phase I trial.

OBJECTIVE: This non-blinded randomized controlled trial was the first phase of a planned series of investigations designed to test the efficacy of aggressive post-operative enteral nutrition support to decrease the rate of post-operative complications or improve long-term outcomes in specifically defined subgroups of elderly patients who have sustained a hip fracture requiring surgery. METHODS: Eighteen patients (17 males) were randomized to the treatment (eight male subjects) or control groups. The control group (mean age 76.5+/-6.1 years) received standard post-operative care. Subjects in the treatment group (mean age 74.5+/-2.1 years) received 125 cc/hour of nasoenteral tube feedings over 11 hours each night in addition to standard post-operative nutritional care. RESULTS: Both the treatment and control groups had reduced volitional nutrient intakes for the first 7 post-operative days (3,966+/-2,238 vs. 4,263+/-2,916 kJ/day [948+/-535 vs. 1019+/-697 kcal/day], p=0.815), but the treatment subjects had a greater total nutrient intake (7,719+/-2,109 vs. 4,301+/-2,858 kJ/day [1845+/-504 vs. 1028+/-683 kcal], p=0.012). On average, treatment subjects were tube fed for 15.8+/-16.4 days. There was no difference between the groups (treatment vs. controls) in the rate of post-operative life-threatening complications (25 vs. 30%, p=1.00) or in-hospital mortality (0 vs. 30%, p=0.216). Mortality within 6 months subsequent to surgery was lower in the treatment group compared to the controls (0 vs. 50%, p=0.036). DISCUSSION: We conclude that nightly enteral feedings are a safe and effective means of supplementing nutrient intake. The greatest impact of nutrition support may be to reduce mortality.

Aged↗
PubMed1998

An algorithm to optimize perioperative blood management in surgery.

Innovation in surgical blood management has been fueled by patients' perceptions of the risks associated with allogeneic blood transfusions and by surgeons' attitudes toward the use of allogeneic blood. The challenge is to determine the best blood management strategy to implement in the individual patient, particularly in patients with anemia who are at high risk of allogeneic blood transfusion. An algorithm to estimate safe blood loss based on individual patient parameters has been developed. The algorithm uses patient weight, gender, and preoperative hematocrit level to derive the volume of blood loss that can be tolerated while maintaining a target postoperative hematocrit level. Because the margin of safe blood loss can be anticipated, the most appropriate blood conservation option(s) can be implemented and perioperative blood management can be optimized.

Algorithms↗