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The primary aim of the present study was to determine the impact of acute changes in shear rate patterns, in particular retrograde shear rate, on microvascular function in 15 healthy, young men and women as determined via the post-occlusive near-infrared spectroscopy (NIRS) microvascular reactivity response. Microvascular reactivity, via NIRS-derived measurements of post-occlusion tissue saturation index (TSI%) and total microvascular hemoglobin+myoglobin concentration ([Hb]total), were assessed in each participant before and immediately after exposure to a 30min retrograde shear treatment. Retrograde shear was achieved via a blood pressure cuff placed below the knee inflated to 75mmHg. One leg was exposed to the retrograde shear (Treatment leg) and the contralateral leg served as a non-treatment control. In the Treatment leg, significant increases in retrograde shear rate occurred during the retrograde intervention. Following the intervention, the area under the TSI% post-occlusion response curve, which represents the total microvascular reactivity response, and the absolute peak TSI% response were significantly increased compared to pre-intervention in the Treatment leg, but not the Control leg. The absolute peak [Hb]total response was significantly increased post-intervention in both legs. These results are in contrast to our hypothesis that 75mmHg cuff inflation, designed to increase retrograde shear rate in the femoral artery would negatively affect post-occlusive microvascular reactivity. These data suggest that the current method of increasing retrograde shear rate in the intact human does not adversely impact NIRS derived measurements of microvascular reactivity.

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BACKGROUND: Epinephrine is life-saving in the treatment of anaphylaxis. A limited number of fixed-dose epinephrine formulations are available for out-of-hospital treatment of this disorder. OBJECTIVE: To examine dispensing patterns for epinephrine formulations over 4 consecutive years in a population of 279,638 infants, children, and adolescents (from birth up to but not including the 17th birthday). METHODS: We used the Drug Programs Information Network, an administrative claims database for prescriptions dispensed in ambulatory care settings, developed from real-time computer links with retail pharmacies in the province of Manitoba, Canada. We studied the specific epinephrine formulation dispensed and the precise age of the infant or child at the time it was dispensed. RESULTS: Epinephrine formulations were dispensed for 1.2% of the pediatric population (3,340 children). Boys comprised 59.5% of the recipients. Of all epinephrine formulations, 38.6% were dispensed as EpiPen Jr (0.15 mg), and 57.4% were dispensed as EpiPen (0.3 mg). EpiPen Jr was dispensed for patients ranging in age from 2 months to 16 years, 10 months, inclusive. EpiPen was dispensed for patients ranging in age from 1 year, 8 months to 16 years, 11 months, inclusive. During the 4 years studied, a subgroup of children transitioned from EpiPen Jr to EpiPen auto-injectors at a mean age of 6 years, 6 months +/- 2 years, 8 months (range 1 year, 10 months to 16 years, 11 months). CONCLUSIONS: Both EpiPen Jr and EpiPen auto-injectors were dispensed over almost the entire age range of the pediatric population. Physicians should consider a child's age more carefully when prescribing these auto-injectors. Additional concentrations of epinephrine are needed in these fixed-dose formulations.

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Vascular stenoses were induced in the external iliac arteries of New Zealand white rabbits by a combination of hypercholesterolemic diet and repeat balloon injury. Two-dimensional (2D) and three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) was performed with a specifically designed phased array coil in a 1.5 T system. Enhancement with gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) hexamethylene diamine co-polymer (Nycomed: NC 22181), a blood pool MR contrast agent, was measured after contrast administration and compared with pre-contrast images at the same levels. Vessel diameter measurements were obtained at multiple levels and compared with comparable levels on conventional angiograms of the same animals. Stable enhancement, averaging 227% above baseline, was observed with the 3D TOF MRA over the 40 minutes of this study. Enhancement was not observed with the 2D TOF technique. Measurement of the smallest vessels in this study with 3D TOF MRA was slightly improved following contrast enhancement, although both pre- and post-contrast diameter measurements tended to underestimate the assumed true vessel diameter. Thus, Gd-DTPA hexamethylene diamine co-polymer (Nycomed: NC 22181), a blood pool MR contrast agent, produces significant, stable enhancement with the 3D TOF technique and may improve MRA measurement of small vessels.

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Bis[1-(Ethoxycarbonyl)propyl]5-acetylamino-2,4,6- triiodoisophthalate+ (NC 68183) was designed as a new computed tomography imaging agent. The purpose of this study was to determine the pharmacokinetics and metabolism of NC 68183 in conscious rats and in the isolated perfused rat liver. Animals were i.v. dosed at 69 and 690 mg of iodine/kg. Blood samples were collected at 5, 15, 30, and 60 min, and 7 days after dosing. Tissue samples (liver, kidney, and spleen) were taken at 60 min and 7 days after dosing. NC 68183 was cleared from blood in first order kinetics following an i.v. administration of 69 mg I/kg. The volume of distribution (Vss) at steady state and elimination half-life (t(1/2)) were estimated as 24 ml and 11 min. The clearance of NC 68183 from blood was changed to zero-order kinetics following administration of 690 mg/kg, and its elimination rate was 16 microg I/ml.min. The liver and spleen were the only tissues to have the nanoparticle residue at day 7 following administration. NC 68183 (75 mg of agent, 35 mg of I) was injected into the isolated perfused rat liver system. Bile flow increased from 1.0 to 1.3 microl/min/g liver following administration. The biliary excretion rate maximum was estimated as 11 microg/min/g liver. The metabolite was identified using liquid chromatography/mass spectrometry as a monocarboxylic acid product, which exclusively excreted into the bile in a soluble iodinated metabolite. Pharmacokinetics data suggested that NC 68183 primarily resides in the blood pool following an i.v. administration with a plasma half-life appropriate for blood pool imaging.

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Four rabbits in which atherosclerotic disease was induced by diet and balloon angioplasty underwent conventional angiography and MR angiography (MRA) using a black blood pulse sequence before and 10 minutes after the i.v. injection of a macromolecular contrast agent, NC 100283 (1.0 mmol/kg), a dysprosium diethylenetriaminepentaacetic acid hexamethylenediamine copolymer (Dy-DTPA polymer). Intraluminal signal intensity, apparent wall thickness, and lumen size measurements of the aorta and proximal common iliac arteries on precontrast MRA images were compared with postcontrast images. Aortic lumen diameter measurements on the precontrast and postcontrast MRA studies were compared with lumen diameters from conventional angiograms. Intraluminal signal intensity decreased on postcontrast MRA images compared with precontrast images, with an average loss of signal equal to 29% (P < .05). Apparent wall thickness decreased by 24% (P < .05). Lumen diameter and area were generally larger (average of 15% and 33%, respectively) on postcontrast MRA images than on precontrast images. Aortic lumen diameter measurements from postcontrast MRA agreed closely (95% confidence interval of the mean difference was -.2 to .3 mm), and precontrast MRA images tended to underestimate aortic lumen diameter (95% confidence interval of the mean difference was .3 to .8 mm) compared with conventional angiography. Postcontrast MRA with NC 100283, a macromolecular Dy-DTPA contrast agent, provides more accurate assessment of aortic lumen diameter than precontrast MRA, using conventional angiography as the standard reference.

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OBJECTIVE: Determine elderly inpatient's risk ADRs and characterize the events. DESIGN: This is a post-hoc analysis of a comprehensive inpatient ADR survey. Charts were reviewed every four days on all internal medicine service inpatients (1024 patients over four months). Chart review were enhanced by potential indicators such as nurses' and pharmacists' reports; targeted drug orders; 'now', 'stat', and 'hold' orders; off-service physician consults; incident reports; transfers-to-ICU; and abnormal serum drug concentrations. Potential ADRs were classified according to organ system affected, pharmacological type, severity, and Naranjo causality scale. SETTING: Internal medicine wards of a 350-bed county general hospital. RESULTS: Of 1024 inpatients, 301 were elderly. Overall, 237 patients had an ADR (23%). Elderly patients accounted for 89 (37.5%) of the 237 patients experiencing an ADR. The ADRs experienced by the elderly tended to be more severe (p <0.05) and less idiosyncratic (p <0.05). However, no preferences for organ system (p >0.1) or differences in causality rating (p = 0.25) were detected. When statistically controlled for female gender, renal function and number of drugs, age was no longer a risk factor for ADR occurrence. CONCLUSIONS: The elderly experience more ADRs. However, female gender, decline in renal function and polymedicine are the independent factors that account for the elderly's risk. Furthermore, the elderly's ADRs tend to be more severe and an extension of the drug's pharmacology. Therefore, ADR prevention is both important and possible.

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Because the health status of a population does not usually respond immediately to interventions, whether social or medical, the ability to analyze change over time is important. Therefore, patterns of change and stability in health status and health care use of Manitoba residents during a 3-year period from 1990 to 1992 were analyzed using the Population-based Health Information System. This article presents summary findings and discusses methodological and policy issues arising from the analyses. A small but significant decrease in premature mortality (the primary health status indicator) was observed in most regions of the province, but two remote, northern regions, those whose residents scored at high socioeconomic risk, remained distinguished for their poor health status. These "poor health" regions also had the highest contact rates with primary caregivers, raising questions about the role of the health care system in improving the health of the population. A persistent increase in surgery was observed in several regions, led by increases in outpatient surgery over and above increases in the elderly population and beyond substitution for inpatient procedures. This trend (not obvious before these analyses) is important as hospitals move to expand their outpatient facilities in response to restraints on inpatient care.

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This article describes the software developed in the process of creating the Population Health Information System. The software can be applied to a range of administrative data and provides standardized data on the health status and health care use of populations by generating population-based rates of discrete events. The standardized approach permits construction of a comprehensive, comparative picture for residents of defined geographic regions. The addition of a user friendly graphic interface will permit regional planners to do their own data analyses and allow out-of-province researchers to adopt the system for their own uses.

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The authors introduce the Population Health Information System, its conceptual framework, and the data elements required to implement such a system in other jurisdictions. Among other innovations, the Population Health Information System distinguishes between indicators of health status (outcomes measures) and indicators of need for health care (socioeconomic measures of risk for poor health). The system also can be used to perform needs-based planning and challenge delivery patterns.

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A population-based approach was used to analyze the utilization patterns of hospital care by Manitoba residents during the fiscal year 1991/1992. Patterns were analyzed for eight administrative regions, with use assigned to the patient's region of residence, regardless of the location of the hospitalization. Regional boundaries consistent with those used for presentation of data on health status and socioeconomic risk permitted integration of findings across the Population Health Information System. Marked differences in acute hospital use were found. Residents of the urban Winnipeg ("good health") region had the lowest rates of use of acute care overall, and northern rural ("poor health") regions had significantly higher rates of use. However, almost one half of hospital days by Winnipeg residents were used in long-stay care (60+ days), while rural residents were more likely to use short-stay hospital care. Despite a concentration of surgical specialists in Winnipeg, there were only small regional differences in overall rates of surgery.

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This article describes the utilization of ambulatory physician services by Manitoba residents during the fiscal year 1991/1992. Care was assigned to the patient's residence in one of eight administrative regions, whether the care was received in or out of the region of residence. Disparities in physician supply across regions did not correspond with differences in the use of services: the Winnipeg region had twice as many physicians per 1000 residents as the largely rural non-Winnipeg regions and was home to most specialists. With their rich supply of physicians, particularly specialists, Winnipeg residents had somewhat higher contact rates (16%), and the province spent 26% more per resident providing physician services, despite the fact that our indicators of health status and socioeconomic risk suggest no increased need for physician services among Winnipeg residents. Despite the concentration of physicians in Winnipeg, there was remarkably good access to physicians across the province, with 78% or more of the residents in every region making at least one contact with a physician during the year. The differences in use between Winnipeg and non-Winnipeg residents were almost entirely accounted for by intensive users, (individuals making eight or more visits per year). Although residents 75 years of age and older (6% of the population) made twice as many visits per capita compared to younger adults, their actual demand on the system was small, accounting for just less than 10% of expenditures on physician services. Population-based health information provides important insight for needs-based planning of physician services.

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A population-based approach to monitoring quality of care combining small-area analysis and outcomes assessment is proposed. While adverse outcomes due to poor surgical technique have long been targeted for quality-of-care review, in this study, giving similar attention to adverse outcomes produced by high rates of interventions is proposed. A population-based approach will strengthen traditional review efforts that currently begin and end at the hospital door. Excluded from these reviews have been questions such as the following: Should the procedure have been performed in the first place? Did the benefits outweigh the risks? Were there other patients not operated on who might have benefited more? Traditional approaches can identify less competent hospitals or practitioners: population-based approaches can identify the surgical enthusiasts who may pose equal risks to the populations of the areas they serve. Applying a population-based approach to review of coronary artery bypass graft surgery for Medicare patients in five cities in the United States demonstrates that at least as many deaths could have been prevented by decreasing surgical rates to the U.S. average as by improving the technical quality of care with which the procedure was performed. A similar population-based analysis of complications (as judged by re-admissions within 30 days of surgery) associated with hysterectomy across regions of Manitoba, Canada, is presented. In summary, negligent acts in the delivery of health care in institutions are rare and are difficult to detect because medicine is an inexact science and because adverse outcomes are more likely in high-risk patients, regardless of the quality of care. However, from a population perspective, adverse events are predictable, occur relatively frequently, and are directly related to the frequency of a population's exposure to surgical intervention. Efforts to improve quality of care could be made more effective by including the rates at which populations are exposed to treatments and the technical quality of care delivered.

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This study was a prospective observational study of ADR occurrence and evaluation in adult internal medicine inpatients conducted over a 120-day period. Clinical pharmacists screened for ADRs at a county hospital in Indianapolis, IN. Patient information was reviewed on admission, every four days during hospitalization, and at discharge. ADRs occurring after hospital admission were assessed for causality, severity, pharmacological type (i.e., augmented pharmacology versus idiosyncratic reaction) and affected organ system. Nurse and pharmacist reports, incident reports, physician consults, patient transfers to critical care units, and serum drug concentration reports were additional means of ADR identification. Overall, 23.1% of patients experienced an ADR while 2.6% of the 11,702 drug exposures resulted in an ADR. Patients aged greater than 65 years (29.6% vs. 20.5% for younger patients) and females (26.2% vs. 20% for males) were at higher risk for ADR development (p < 0.05). Length of hospital stay was longer (13.3 days vs. 6.7 days; p < 0.05) and drug exposures more frequent for patients experiencing ADRs (p < 0.001). Furosemide elicited the most ADRs with 36 in 244 patient exposures (14.7%). Diltiazem, enalapril, heparin, trimterene/hydrochlorothiazide combination and captopril were also frequently implicated. ADRs were classified as mild (35.9%), moderate (52.6%), and severe (10.2%). Organ systems most commonly affected were the metabolic/hematologic (32.9%), gastrointestinal (17.8%), genitourinary (11.8%), and cardiovascular (10.5%). Over 30% of events were idiosyncratic reactions. ADR incidence was consistent with previous literature. Many frequently implicated medications were newer agents and the severity of events was less than previously reported.

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This study compared the factor structure and burnout scores obtained on the Maslach Burnout Inventory from 84 pharmacists in Health Maintenance Organizations (HMO) with the normative data for USA pharmacists. Results provided empirical support for the reliability and validity of the inventory to measure burnout within the profession of pharmacy. Values of Cronbach coefficient alpha for subscales of Emotional Exhaustion, Depersonalization, and Personal Accomplishment were similar to those obtained with the normative sample. Factor analysis was conducted to yield the best three-factor solution. Derived factor loadings matched the three hypothesized subscales. On Personal Accomplishment the mean subscale score for HMO pharmacists was significantly higher than the normative score. Given limitations of the small sample, research is indicated to substantiate use of the inventory among HMO pharmacists.

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Liposomes bearing surface-attached antibody (L-Ab) molecules can be used for various purposes including the immunospecific delivery of drugs or other materials to antigenic target cells. In this study, L-Ab were prepared to deliver an anti-human immunodeficiency virus (HIV) drug, dideoxycytidine triphosphate (ddCTP) to human monocyte/macrophages. Cells of the monocyte/macrophage lineage are an important reservoir of HIV-1. A mouse monoclonal antibody IgG2a was labelled with 125I and modified using N succinimidyl-3-(2-pyridyldithio)propionate (SPDP) as a heterobifunctional reagent in order to conjugate with liposomes to produce a covalent bond (thioether). SPDP-modified antibody was incubated with liposomes containing 5 mol% of maleimido phenyl butyrate phosphatidylethanolamine (MPB-PE) at room temperature (21 degrees C) for 24 h. L-Ab were separated from free and aggregated antibodies by centrifugation. L-Ab were characterized by measuring particle size and binding to anti-mouse IgG-sepharose. Ninety five per cent of the liposomal (L-Ab) lipid label was bound to anti-mouse IgG-sepharose, whereas only 7% of plain liposomes were bound, indicating non-specific binding. Uptake of L-Ab was measured in human monocyte/macrophages as a function of time and compared with that of plain liposomes. The uptake increased with time and it was 4-6 times greater than that of plain liposomes although part of that effect may have been due to unreacted MPB groups.

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OBJECTIVE: To report two cases of suspected immunologic-based hypersensitivity reactions to etoposide therapy. DATA SYNTHESIS: Two cases are presented that differ from the majority of reported hypersensitivity reactions to etoposide. One patient, who tolerated etoposide during his first three-day chemotherapeutic dosage regimen, developed a hypersensitivity reaction to etoposide upon re-exposure to the drug during the first day of a subsequent three-day cycle. Another patient experienced a hypotensive episode on the first day of an initial three-day regimen, which did not recur on the two subsequent days of the cycle. However, when the patient was re-exposed to etoposide four weeks later, he experienced a severe reaction within minutes of drug infusion. Both patients were premedicated with corticosteroids and neither reported prior drug allergies. CONCLUSIONS: Based upon these cases and other literature reports, we believe these reactions primarily represent a type II or immunologic-based hypersensitivity reaction to etoposide.

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Rats were randomly assigned to treatments: (i) no surgery control; (ii) saline control; (iii) 0.25, 0.5, 1.0 or 2.0 micrograms nifedipine kg-1 min-1; or (iv) 5.0 micrograms ritodrine kg-1 min-1. All drug treatments increased the interval between pup deliveries compared with the no surgery and saline controls. Apparent complete tocolysis was observed in 20, 60, 80 and 80% of the animals receiving 0.5, 1.0 or 2.0 micrograms nifedipine kg-1 min-1 or 5.0 micrograms ritodrine kg-1 min-1, respectively. A positive pharmacodynamic relationship was observed for the nifedipine doses. Analysis of pup viability showed no statistically significant difference among treatments. Treatment with 2.0 micrograms nifedipine kg-1 min-1 gave a delay in pup delivery comparable to that with ritodrine.

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We investigated whether semidehydroascorbic acid was an intermediate in norepinephrine synthesis in chromaffin granules and in electron transfer across the chromaffin granule membrane. Semidehydroascorbic acid was measured in intact granules by electron spin resonance. In the presence of intragranular but not extragranular ascorbic acid, semidehydroascorbic acid was formed within granules in direct relationship to dopamine beta-monooxygenase activity. However, semidehydroascorbic acid was not generated when granules were incubated with epinephrine instead of the substrate dopamine, with dopamine beta-monooxygenase inhibitors, without oxygen, and when intragranular ascorbic acid was depleted. Experiments using the impermeant paramagnetic broadening agents [K3 [Cr(C2O4)3].3H2O] and Ni(en)3(NO3)2 provided further evidence that semidehydroascorbic acid was generated only within granules. We also investigated semidehydroascorbic acid formation in the presence of intragranular and extragranular ascorbic acid. Under these conditions, semidehydroascorbic acid was formed on both sides of the granule membrane, and formation was coupled to dopamine beta-monooxygenase activity. These data indicate that dopamine beta-monooxygenase is reduced by single electron transfer from intragranular ascorbic acid, that transmembrane electron transfer occurs by single electron transfer, and that transmembrane electron transfer is directly coupled to formation of intragranular semidehydroascorbic acid via dopamine beta-monooxygenase activity.

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Oxygen-derived active species and superoxide radical in particular are generated and excreted upon granulocyte activation and are instrumental in host defense against bacterial and fungal infections. Associated with the activation of neutrophils is an apparent transitory oxy-radical production. Evidence from independent methods has previously suggested that radical production peaks shortly following neutrophil stimulation and decays within minutes. However, since neutrophil function in the body might reasonably be expected to last beyond the few minutes following stimulation, cessation of the production of oxy-radicals is unexpected. In an attempt to reconcile this discrepancy, the formation kinetics of superoxide by stimulated human neutrophils was reinvestigated by three independent methods: electron spin resonance, chemiluminescence, and ferricytochrome c reduction. The present results demonstrate that under appropriate experimental conditions stimulated neutrophils have the capacity to produce superoxide for several hours. The reasons for the previously reported "apparent" ephemeral nature of oxy-radical formation are discussed.

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