Effect of upper respiratory tract infection on AIR inhaled insulin pharmacokinetics and glucodynamics in healthy subjects.

The suitability of employing AIR Inhaled Insulin (AIR Insulin; AIR is a registered trademark of Alkermes) during acute upper respiratory tract infection (URI) has not been determined. Twenty-one healthy, non-diabetic subjects were enrolled in a single-sequence, two-period, euglycemic clamp study. Subjects received a single 12 U-equivalent dose of AIR Insulin before rhinovirus (RV16) inoculation and during symptomatic infection. Spirometry was used to evaluate pulmonary safety. AIR Insulin exposure (the area under the immunoreactive insulin (IRI) concentration vs time curve from time zero until the IRI concentrations returned to the predose baseline value (AUC(0-t'))) and glucodynamic response (total amount of glucose infused (G(tot))) were comparable before and during RV infection (AUC(0-t') 46,300 vs 52,600 pmol min/l, P=0.21; G(tot) 61,800 vs 68,700 mg, P=0.42, respectively). Variability of pharmacokinetic and pharmacodynamic parameters did not change during URI; either did the number or intensity of adverse events. No significant change in forced expiratory volume or forced vital capacity was observed following AIR Insulin administration or during URI. The AIR Insulin system provides similar pharmacokinetic and glucodynamic responses under conditions of an experimentally induced RV infection and is regarded as suitable for use in diabetic patients during URIs.

Production of [17F]CH3F (t1/2=65 s), an improved PET tracer for rCBF measurement.

Production of 17F (t1/2=65 s) in the form of [17F] F2 has been achieved using both the 20Ne(p,alpha)17F and 16O(d,n)17F reactions with 11 MeV protons and 6 MeV deuterons, respectively. Yields have proven suitable for subsequent radiosynthesis of the blood flow tracer, [17F]CH3F (>60 mCi in saline), currently in use for fast repetition human studies of regional cerebral blood flow with positron emission tomography. Thick target yields of 15 mCi /microA for protons and 44 mCi/microA for deuterons have been measured for [17F]F2.

Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure.

BACKGROUND: Use of beta-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation. METHODS AND RESULTS: We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction

Copper-62-pyruvaldehyde bis(N-methyl-thiosemicarbazone) PET imaging in the detection of coronary artery disease in humans.

BACKGROUND: Copper-62 (II)-pyruvaldehyde bis(N(4)-methyl-thiosemicarbazone) (PTSM) has been proposed for cardiac imaging with positron emission tomography (PET). This study evaluated the agreement between Cu-62-PTSM and coronary angiography in the detection of occlusive coronary artery disease. The normalcy rate for Cu-62-PTSM PET in a group of healthy volunteers was also assessed. METHODS AND RESULTS: Forty-five subjects completed the study. Twenty-eight patients underwent stress technetium-99m sestamibi single photon emission computed tomography (SPECT) imaging and cardiac catheterization followed by Cu-62-PTSM rest/dipyridamole stress PET scans, and 17 volunteers underwent Cu-62-PTSM rest/dipyridamole stress PET scans. Cu-62-PTSM myocardial perfusion defects were identified in 100% of patients with 3-vessel disease (n = 8), 100% of patients with 2-vessel disease (n = 9), and 67% of patients with single-vessel disease (n = 6). When considering individual vessels, Cu-62-PTSM perfusion defects were seen in 72% of patients with occlusive disease in the left anterior descending artery territory, 67% in the left circumflex artery territory, and 60% in the right coronary artery territory, respectively. All 17 healthy volunteers had Cu-62-PTSM scans interpreted as normal, for a normalcy rate of 100%. CONCLUSIONS: Perfusion abnormalities are demonstrated by means of Cu-62-PTSM PET in 91% of patients with occlusive coronary artery disease seen at the time of cardiac catheterization, and it shows an excellent normalcy rate of 100%.

An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure.

UNLABELLED: Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) and [18F]FDG in patients with stable New York Heart Association functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%. METHODS: Twelve fasting patients underwent dynamic PET studies using [18F]FTHA and FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for [18F]FTHA and FDG. Subsequently, serum free fatty acid and glucose concentrations were used to calculate the myocardial free fatty acid and glucose uptake rates, respectively. Uptake rates were compared with reported values for [18F]FTHA and FDG in subjects with normal left ventricular function. RESULTS: The average Ki for [18F]FTHA was 19.7 +/- 9.3 mL/100 g/min (range, 7.2-36.0 ml/100 g/min). The average myocardial fatty acid use was 19.3 +/- 2.3 mmol/100 g/min. The average Ki for FDG was 1.5 +/- 0.37 mL/100 g/min (range, 0.1-3.3 mL/100 g/min), and the average myocardial glucose use was 12.3 +/- 2.3 mmol/100 g/min. CONCLUSION: Myocardial free fatty acid and glucose use in heart failure can be quantitatively assessed using PET with [18F]FTHA and FDG. Myocardial fatty acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.

Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation.

Interest remains strong for the development of a noninvasive technique for assessment of regional fatty acid oxidation rate in the myocardium. (18)F-labeled 4-thia palmitate (FTP, 16-[(18)F]fluoro-4-thia-hexadecanoic acid) has been synthesized and preliminarily evaluated as a metabolically trapped probe of myocardial fatty acid oxidation for positron emission tomography (PET). The radiotracer is synthesized by Kryptofix 2.2.2/K(2)CO(3) assisted nucleophilic radiofluorination of an iodo-ester precursor, followed by alkaline hydrolysis and by purification by reverse phase high performance liquid chromatography. Biodistribution studies in rats showed high uptake and long retention of FTP in heart, liver, and kidneys consistent with relatively high fatty acid oxidation rates in these tissues. Inhibition of carnitine palmitoyl-transferase-I caused an 80% reduction in myocardial uptake, suggesting the dependence of trapping on the transport of tracer into the mitochondrion. Experiments with perfused rat hearts showed that the estimates of the fractional metabolic trapping rate (FR) of FTP tracked inhibition of oxidation rate of palmitate with hypoxia, whereas the FR of the 6-thia analog 17-[(18)F]fluoro-6-thia-heptadecanoic acid was insensitive to hypoxia. In vivo defluorination of FTP in the rat was evidenced by bone uptake of radioactivity. A PET imaging study with FTP in normal swine showed excellent myocardial images, prolonged myocardial retention, and no bone uptake of radioactivity up to 3 h, the last finding suggesting a species dependence for defluorination of the omega-labeled fatty acid. The results support further investigation of FTP as a potential PET tracer for assessing regional fatty acid oxidation rate in the human myocardium.

Sympathetic overactivity from fenfluramine-phentermine overdose.

A 24-year-old male presented to the emergency department with hyperadrenergic manifestations of fenfluramine-phentermine overdose: tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness. Sedatives, neuromuscular paralytics, adrenergic antagonists, and mechanical ventilation were required to care for the patient. In addition, the patient had self-inflicted 15% TBSA second-degree burns and developed adult respiratory distress syndrome which required continued intubation and mechanical ventilation for 12 days. The patient had split thickness skin grafts for his leg burns on day 11. He was discharged after a 26-day hospital stay. We are unaware of any previously reported cases of fenfluramine-phentermine overdose with such profound degree of sympathetic storm.

Effects on regional brain metabolism of high-altitude hypoxia: a study of six US marines.

Previous studies of brain glucose metabolism in people indigenous to high-altitude environments uncovered two response patterns: Quechuas native to the high Andes of South America sustained modest hypometabolism in most brain regions interrogated, whereas Sherpas, native to the Himalayas and considered by many biologists to be most effectively high-altitude adapted of all humans, showed brain metabolic patterns similar to lowlanders, with no acclimation effects noted. In the present study, the database was expanded to include hypoxia acclimation effects in lowlanders. Positron emission tomography (PET) and [(18)F]-2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMR(glc)) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMR(glc) were found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMR(glc). The observed short-term hypoxia acclimation responses in these lowlanders clearly differ from the long-term hypoxia adaptations found in brain metabolism of people indigenous to high-altitude environments.

Recognition and management of Tillaux fractures in adolescents.

Tillaux fractures are relatively uncommon Salter Harris III fractures of the tibia. The importance of recognizing this fracture is that a residual deformity in the joint surface can lead to premature degenerative arthritis. For this reason, it is important that accurate imaging to assess the congruity of the joint, as well as adequate reduction, is obtained. These fractures can occur in adolescents in the 18-month period during which the distal tibial epiphysis is closing. These injuries occur either by lateral rotation of the foot or by medial rotation of the leg on the fixed foot. Closed reduction is sufficient in most cases; however, if a gap of > or = 2 mm of the articular surface remains, open reduction is usually required to adequately reduce the articular surface. Orthopedic injuries are one of the most common reasons children are brought to the emergency department (ED). Most of these injuries are easily managed by splinting, with outpatient orthopedic follow-up. However, certain fractures need closer evaluation and immediate consultation with an orthopedic surgeon. One relatively uncommon fracture that needs special attention is the Tillaux fracture. Paul Jules Tillaux first described this particular fracture in 1892. He performed experiments on cadavers and found that stress to the anterior inferior tibiofibular ligament could lead to this type of avulsion fracture, which today is termed the Tillaux fracture. The distal tibial epiphysis is involved, and the mechanism usually is forced external rotation of the foot in a 12- to 14-year-old adolescent. This fracture only occurs during a certain time of adolescence, owing to the differential growth rate of the epiphysis, and only under certain circumstances. The fracture is of great importance because it involves a major weight-bearing articular surface. A residual deformity of the joint surface can lead to premature degenerative arthritis. We present a patient with a Tillaux fracture to elaborate on the mechanism of injury and to summarize the importance of its recognition and imaging and treatment options.

Air vs ground transport and outcome in trauma patients requiring urgent operative interventions.

OBJECTIVE: To study trauma patients requiring urgent operative interventions to determine whether transport mode was associated with outcome difference. METHODS: Eligible patients were injured adults and children who presented over a 57-month period to the emergency department (ED) at the study hospital (annual ED census 36,000) after air or ground transport from trauma scenes or referring hospitals. Patients included were those whose ED lengths of stay were <60 minutes prior to transfer to an operating room. Data collected included injury severity score (ISS), ED and hospital lengths of stay, and mortality. Continuous data, which were not distributed normally, were analyzed using Wilcoxon nonparametric analysis. Categorical variables were analyzed using chi-square testing. Multivariate logistic regression was used to account for confounding variables and isolate the effects of transport mode on mortality. Alpha for all tests was set at 0.05. RESULTS: 272 patients were eligible for study; 168 air medical and 104 ground transports. No between-group differences were found for ED length of stay, ISS, or mortality. A significantly longer hospital stay was found for air-transported patients. Subgroup analysis of patients with penetrating trauma and ISS of > or =25 revealed mortalities of 28% and 45% for air- and ground-transported patients, respectively; this difference was not statistically significant (p = 0.24), but the study had a power of only 22% to detect a difference at this magnitude. CONCLUSION: This study failed to identify, but had insufficient power to rule out, outcome benefit to air medical transport in a subset of trauma patients requiring urgent operative interventions.

Human biodistribution and dosimetry of the PET perfusion agent copper-62-PTSM.

UNLABELLED: Copper-62-pyruvaldehyde bis(N4-methyl)thiosemicarbazone (PTSM) has been proposed as a generator-produced radiopharmaceutical for perfusion imaging using PET. Several clinical studies have demonstrated the ability of 62Cu-PTSM to quantitate myocardial and cerebral perfusion in humans. Because 62Cu-PTSM is generator-produced, it can be provided to clinical centers without cyclotron availability and, therefore, represents a cost-effective, practical PET perfusion tracer for clinical applications. To assess the safety, time-dependent biodistribution, and whole-body and organ-specific absorbed radiation dose estimates of this tracer, a Phase I study of 62Cu-PTSM was performed using whole-body imaging with PET in 10 healthy volunteers and with the radiopharmaceutical delivered by a compact modular generator unit. METHODS: Five male and five female subjects underwent a series of clinical tests and head-to-midthigh, whole-body PET scans at three time points over 1 hr after intravenous injection of 62Cu-PTSM. Before injection of the tracer, PET transmission scans were performed and used to correct the emission data for attenuation. Final image data were expressed in units of mCi/cc. Using standard organ weights, the percent injected dose per organ was calculated. Biodistribution data were obtained at three different time points and from these data biological half-lives in different organs were determined for calculation of radiation absorbed dose estimates. RESULTS: The liver was seen as the critical organ receiving a dose of 0.0886 rad/mCi. This organ defined the maximum single injected dose at 56 mCi using the limit of 5 rads to a critical organ per study per year. The whole-body dose is 0.0111 rad/mCi, resulting in a 0.622 rad exposure with a maximum single injection dose. Only trace levels of activity were found in the urine, which suggests low levels of urinary excretion and bladder exposure. No significant clinical, electrocardiographic or laboratory abnormalities were seen after the injection of 62Cu-PTSM. CONCLUSION: Copper-62-PTSM is a clinically safe radiopharmaceutical with favorable dosimetry for human studies at injected doses significantly above those projected for use in clinical studies.

Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia.

UNLABELLED: To study the sensitivity of two fatty acid tracers to changes in beta-oxidation, the myocardial retention kinetics of 125I-iodine-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) and 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) were compared in states of oxygen deprivation due to ischemia and hypoxia. METHODS: Nineteen swine were studied by extracorporeal perfusion of the three coronary arteries. Fatty acid beta-oxidation rates were determined by infusion of tritiated palmitate into the left anterior descending artery (LAD) and by measurement of labeled water production in the LAD perfusion bed. After a baseline period of 30 min, animals were divided into three groups and subjected to a 50-min intervention period. For the control group, there was no change in perfusion; for the ischemia group, there was a 60% decrease in LAD perfusion; and for the hypoxia group, the perfusion rate was unchanged, but venous blood was used as the LAD perfusate. Continuous infusion of FTHA and BMIPP into the LAD started 10 min into the intervention period and continued until the end of the intervention period. Retention rates of the two tracers were compared between the LAD and circumflex perfusion beds. RESULTS: No difference in beta-oxidation rate occurred from the baseline to the intervention period in the control group. A 50% reduction in beta-oxidation occurred in the ischemia group, and an 80% reduction occurred in the hypoxia group. No difference in retention of BMIPP or FTHA occurred in the control group. In the ischemia group, reduction in retention of both tracers occurred. However, in the hypoxia group, FTHA uptake was unchanged, whereas BMIPP retention increased compared to the circumflex arterial bed. CONCLUSION: Decreased retention of both BMIPP and FTHA occurred with ischemia, despite the known differences in metabolism of the two tracers. This difference in metabolism was further highlighted in the setting of hypoxia with increased BMIPP uptake. Thus, these results suggest that uptake of both FTHA and BMIPP tracks reduction of fatty acid utilization in myocardial ischemia but fails in tracking reduction of fatty acid oxidation during hypoxia.

Myocardial uptake of the fatty acid analog 14-fluorine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate.

UNLABELLED: The fatty acid tracer 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) is a metabolically trapped tracer of exogenous fatty acid utilization. The objectives of this study were to determine the relationship of FTHA uptake to changes in perfusion and fatty acid oxidation and to confirm the retention of FTHA in the mammalian heart. METHODS: Six pigs with extracorporeal perfusion of the left anterior descending artery (LAD) and cannulation of the LAD vein were studied. The extraction fraction (EF) of FTHA, measured from LAD arterial and venous blood samples, was compared to beta-oxidation rates, determined by water production from tritiated palmitate. After a baseline period, changes in FTHA EF were measured in 15-min periods of hyperemia, control (baseline flow rate) and lactate infusion. After the lactate infusion, FTHA infusion was terminated, and a 15-min washout period was observed. RESULTS: Beta-oxidation rate was unchanged from the baseline period during the hyperemic and control periods. With lactate infusion, the expected myocardial preference for lactate was noted, with a decline in exogenous fatty acid oxidation. Fluorine-18-FTHA EF paralleled the changes in beta-oxidation, with a decrease in EF during lactate infusion. Increase in perfusion was associated with a decrease in FTHA EF, compared to control, such that the product of flow and extraction was maintained. A linear relationship of FTHA EF to fractional tritiated water production was found. Washout analysis confirmed minimal washout of tracer at 15 min after termination of infusion. Organic solvent extraction of tissue samples suggested that the majority of tissue radioactivity was protein-bound. CONCLUSION: In the extracorporeally perfused mammalian heart, FTHA EF declined during suppression of beta-oxidation with lactate infusion and alteration in perfusion without change in fatty acid oxidation rate. The linear relationship of FTHA EF with fractional water production from tritiated palmitate further confirms a correlation of the uptake of FTHA with fatty acid beta-oxidation rate and supports the utility of FTHA in the noninvasive determination of fatty acid oxidation rate. Furthermore, the trapped nature of the tracer may allow the use of graphical analysis for the quantification of beta-oxidation rates.

Iatrogenic acute hyponatraemia in a college athlete.

Hyponatraemia is one of the most common electrolyte abnormalities, leading to significant morbidity and mortality. In the most basic sense, hyponatraemia can be due to sodium loss or fluid excess. The extracellular fluid status is used to clinically divide hyponatraemia into three categories to help to determine both the cause and treatment required. Hyponatraemic patients can be categorised on the basis of their fluid status as hypovolaemic, euvolaemic, or hypervolaemic. Another distinction to make in evaluating hyponatraemia is whether the onset was acute or chronic in nature. The case presented here is iatrogenic acute hypervolaemic hyponatraemia in a college athlete. The patient presented in respiratory distress with an altered mental status after the administration of hypotonic fluids for treatment of muscle cramps. Treatment included intubation, water restriction, and furosemide, to which he responded favourably. Hyponatraemia should be in the differential diagnosis for patients presenting after intravenous fluid administration.

Omeprazole and the development of acute hepatitis.

Omeprazole has been used with increasing frequency for the treatment of conditions such as reflux oesophagitis, peptic ulcer disease, and Zollinger-Ellison syndrome. Several sequelae have been documented in the literature, but there has been limited indication of significant hepatotoxicity. We present a unique case of acute hepatitis secondary to the use of omeprazole that was resolved spontaneously with discontinuation of the drug.

Population density, automated external defibrillator use, and survival in rural cardiac arrest.

OBJECTIVE: To determine whether population density is an independent predictor of survival from out-of-hospital cardiac arrest managed by basic life support (BLS) services using automated external defibrillators (AEDs). METHODS: A retrospective, observational study in Kentucky of 34 BLS services covering 22 counties during the years 1992 to 1994 who used AEDs to treat patients who had out-of-hospital cardiac arrests. RESULTS: Of 311 patients who had out-of-hospital cardiac arrests, 110 (35%) were defibrillated, 46 (15%) were resuscitated to hospital admission, and 19 (6%) survived to hospital discharge. Univariate predictors for survival to hospital discharge were emergency medical services response interval (from call receipt to ambulance arrival) < 8 minutes, defibrillation by the AED, initial rhythm of ventricular fibrillation or ventricular tachycardia (VF/VT), and population density > 100/square mile (sq mi) for the BLS service area (p < 0.001). A forced logistic regression model of survival to hospital discharge, using these 4 factors plus the presence of a witnessed arrest or bystander CPR, demonstrated that population density > 100/sq mi was highly significant (OR 9.4, 95% CI: 1.7 to 51.4, p < 0.01). Stepwise logistic regression models with combinations of these 6 factors found that survival to hospital discharge was best predicted by an initial rhythm of VF/VT (p = 0.004) and population density > 100/sq mi (p = 0.011). CONCLUSIONS: Population density is strongly associated with survival from out-of-hospital cardiac arrest. BLS services within areas with population densities < or = 100/sq mi sustained little benefit from the addition of AEDs to their treatment of patients who had out-of-hospital cardiac arrests.

A rather intense source of fast neutrons for small scale activation.

A thick beryllium target has been developed for installation onto a small proton cyclotron (CTI RDS 112), providing an intense source of fast neutrons for activation purposes. Careful attention was paid to cooling and irradiation geometry, allowing cubic centimeter scale samples to approach the proton beam strike surface to within 5 mm. This proximity assures approximately equal to 10(11) neutron/s passing through the irradiated sample when 20 microgramsA of 11 MeV protons are incident on the beryllium primary target.