Sub-Kelvin cooling for two kilopixel bolometer arrays in the PIPER receiver.

The Primordial Inflation Polarization Explorer (PIPER) is a balloon-borne telescope mission to search for inflationary gravitational waves from the early universe. PIPER employs two 32 × 40 arrays of superconducting transition-edge sensors, which operate at 100 mK. An open bucket Dewar of liquid helium maintains the receiver and telescope optics at 1.7 K. We describe the thermal design of the receiver and sub-Kelvin cooling with a continuous adiabatic demagnetization refrigerator (CADR). The CADR operates between 70 and 130 mK and provides ≈10 µW cooling power at 100 mK, nearly five times the loading of the two detector assemblies. We describe electronics and software to robustly control the CADR, overall CADR performance in flightlike integrated receiver testing, and practical considerations for implementation in the balloon float environment.

Antibiotic dosing in obesity: the search for optimum dosing strategies.

Global obesity has nearly doubled and is now a common occurrence in high-income and developing countries. The World Health Organization estimates that more than 1.4 billion adults are obese. Although the prevalence of obesity is increasing over the last decades, pharmacokinetic evaluations are still conducted in individuals with a body weight of approximately 70 kg. Morbid obesity is associated with several pathophysiological changes that can profoundly affect drug distribution and clearance. There are currently no specific dosing recommendations for antibiotics in obese patients, making dosing suggestions primarily based on pharmacokinetic characteristics of the medications and dosing recommendations in other disease states. Understanding of the pharmacokinetic alterations and maximum doses of antibiotics safely used is paramount to appropriate treatment in the obese population.

Optical design of the atacama cosmology telescope and the millimeter bolometric array camera.

The Atacama Cosmology Telescope is a 6 m telescope designed to map the cosmic microwave background simultaneously at 145, 215, and 280 GHz with arcminute resolution. Each frequency will have a 32 by 32 element focal plane array of transition edge sensor bolometers. The telescope and the cold reimaging optics are optimized for millimeter-wave observations with these sensitive detectors. The design of each is described.

Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys.

PURPOSE: The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys. METHODS: Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye. RESULTS: Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident. CONCLUSIONS: The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.

Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys.

Aptamers are oligonucleotide ligands selected, in vitro, to bind a specified target protein. The first aptamer to reach human clinical testing is NX1838, a polyethylene glycol conjugated aptamer that inhibits vascular endothelial growth factor. This paper describes the validation of a high-performance liquid chromatographic anion-exchange method for the determination of NX1838 in plasma. Measurements of intact NX1838 had a coefficient of variation of less than 8% and an accuracy between 107% and 115%. The assay was utilized to determine NX1838 plasma pharmacokinetics in rhesus monkeys following a single 1 mg/kg intravenous or subcutaneous dose. Following intravenous administration, the maximum achieved plasma concentration was 25.5 microg/ml with a terminal half-life of 9.3 h and clearance rate of 6.2 ml/h. After subcutaneous administration, the fraction of the dose absorbed into the plasma compartment was 0.78 with a time to peak concentration (4.9 microg/ml) of 8 to 12 h.

The coronary stress of skiing at high altitude.

Skiing, which may involve strenuous exercise in the cold at high altitude, could place considerable stress on the coronary circulation. To explore this possibility, we obtained by telemetry electrocardiograms on 149 men during recreational skiing at altitudes above 3100 m (10 150 ft). Tachycardia was impressive; heart rate exceeded 80% of predicted maximum in two thirds of the subjects. Five men developed abnormal ST-segment depression during or immediately after exercise. All five were older than 40 years, so in this age group the incidence of ST abnormalities was 5.6%. This is not greater than the incidence among asymptomatic men during submaximal exercise at low altitude. The high level of physical fitness of men who ski may have offset the added stress of cold and hypoxia. Hence, for physically fit older men, mountain skiing does not appear to pose a greater coronary stress than does comparable exercise at low altitude among men of only average physical fitness without known heart disease.

Right ventricular performance during increased afterload impaired by hypercapnic acidosis in conscious dogs.

Since heart failure may occur in the setting of lung dysfunction and CO2 retention with only modest increases in cardiac work load, we questioned whether myocardial function is impaired by hypercapnic acidosis. To determine the influence of hypercapnic acidosis on right ventricular function, we measured the effects of acute (2 hours) and chronic (2 weeks) hypercapnic acidosis on right ventricular performance during normal and increased right ventricular afterload in five conscious dogs. Systemic hemodynamic and right ventricular functions were unaltered during normal right ventricular afterload by acute hypercapnic acidosis (PaCO2 = 49 +/- 3 mm Hg, pH = 7.27 +/- 0.003). As right ventricular afterload was increased by progressive balloon occlusion of the right ventricular outflow tract during acute hypercapnic acidosis, the rise (slope) in right ventricular end-diastolic pressure was increased 4-fold (P less than 0.01) over that observed in normocapnic control. Maximum isovolumic right ventricular dP/dt rose (P less than 0.05) comparably with increasing right ventricular afterload during normocapnic control and acute hypercapnic acidosis. Chronic hypercapnic acidosis (PaCO2 = 55 +/- 2 mm Hg, pH = 7.28 +/- 0.01) resulted in systemic vasodilation and increased (P less than 0.05) heart rate and cardiac output during normal right ventricular afterload. As right ventricular afterload was increased during chronic hypercapnic acidosis, the rate of rise in right ventricular end-diastolic pressure was 2-fold (P less than 0.01) above normocapnic control but maximum isovolumic right ventricular dP/dt was unchanged in contrast to normocapnic control and acute hypercapnic acidosis. Moreover, cardiac output fell and stroke work was unchanged with increasing afterload during chronic hypercapnic acidosis. beta-Adrenergic blockade resulted in an increased (P less than 0.01) rate of rise in right ventricular end-diastolic pressure with afterload during normocapnic control and chronic hypercapnic acidosis. We conclude that hypercapnic acidosis results in diminished right ventricular performance during increased right ventricular afterload, evidenced by accentuated rise in right ventricular end-diastolic pressure, and may contribute to the congestive heart failure and edema observed in patients with pulmonary hypertension and CO2 retention.

Cardiac function in goats exposed to carbon monoxide.

To investigate the possibility that prolonged carbon monoxide (CO) exposure would depress myocardial function, six chronically instrumented, unsedated goats were exposed to 160--200 ppm CO for 2 wk, resulting in a mean carboxyhemoglobin saturation of 20%. Cardiac index and stroke volume remained unchanged during and after exposure. Hematocrit and hemoglobin concentration started increasing on the 10th day of exposure, this increase reached statistical significance (P less than 0.05) on the 6th postexposure day. Contractility (Vmax) of the left ventricular myocardium and heart rate were unchanged during exposure to CO, but both were significantly (P less than 0.05) decreased at some time during the 1st wk after removal from CO. If there was a decrease in intrinsic myocardial function during CO exposure, it may have been masked by increased sympathetic activity. The mechanism(s) that might produce the decrease in heart rate and contractility after removal from CO are not obvious. Possible explanations are discussed.

Depressed myocardial function in the goat at high altitude.

To determine if depressed myocardial function contributes to the reported decrease in cardiac performance at high altitude, six chronically instrumented, unsedated goats were studied before, during, and after 2-wk exposure to hypobaric hypoxia (PaO2 44 mmHg). Undistorted ventricular pressure wave form was obtained from a miniature transducer implanted in the left ventricular cavity. The relationship between (dP/dt)/28P and P was extrapolated to obtain Vmax as an index of myocardial function. With beta sympathetic blockade (practolol) and pacing to reproduce heart rates, Vmax was uniformly and significantly depressed (P less than 0.01) during chronic hypoxia, and returned to control values following descent to low altitude. Likewise, stroke volume following saline infusion was decreased at high altitude and returned to control values following descent. Acute relief of hypoxia at high altitude by administration of 100% oxygen by mask did not reverse the depressed Vmax. These findings indicate that chronic hypobaric hypoxia produces a depression of myocardial function which is reversible by chronic but not acute relief of hypoxia.