Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/ß dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study.

OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1ß, in patients with knee osteoarthritis (OA). METHOD: This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. RESULTS: A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1ß, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. CONCLUSION: ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.

A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10.

Crouzon craniofacial dysostosis (CFD) is an autosomal dominant craniofacial disorder characterized by premature craniosynostosis, shallow orbits and hypoplastic maxilla. To map the gene responsible, we have used a mapping strategy of testing for linkage to known developmental genes. Analysis of a large kindred established linkage between CFD and three loci (D10S190, D10S209 and D10S216) that span a 13 cM region on chromosome 10q. A maximum pairwise lod score of 4.42 (theta = 0) at D10S190 was obtained and the addition of a second kindred produced a combined pairwise lod score of 5.32 (theta = 0) at the same locus. The developmental gene, PAX2, located within this region, is an attractive candidate gene.

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers.

OBJECTIVES: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. METHODS: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18-65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). RESULTS: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4-5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. CONCLUSIONS: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections.

The vertical profile of winds on Titan.

One of Titan's most intriguing attributes is its copious but featureless atmosphere. The Voyager 1 fly-by and occultation in 1980 provided the first radial survey of Titan's atmospheric pressure and temperature and evidence for the presence of strong zonal winds. It was realized that the motion of an atmospheric probe could be used to study the winds, which led to the inclusion of the Doppler Wind Experiment on the Huygens probe. Here we report a high resolution vertical profile of Titan's winds, with an estimated accuracy of better than 1 m s(-1). The zonal winds were prograde during most of the atmospheric descent, providing in situ confirmation of superrotation on Titan. A layer with surprisingly slow wind, where the velocity decreased to near zero, was detected at altitudes between 60 and 100 km. Generally weak winds (approximately 1 m s(-1)) were seen in the lowest 5 km of descent.

Apparent endocytosis of fluorescein isothiocyanate-conjugated dextran by Saccharomyces cerevisiae reflects uptake of low molecular weight impurities, not dextran.

Concurrent with Riezman's report (Riezman, H. 1985, Cell. 40:1001-1009) that fluid-phase endocytosis of the small molecule Lucifer yellow occurs in the yeast Saccharomyces cerevisiae, Makarow (Makarow, M. 1985. EMBO [Eur. Mol. Biol. Organ.] J. 4:1861-1866) reported the endocytotic uptake of 70-kD FITC-dextran (FD) and its subsequent compartmentation into the yeast vacuole. Samples of FD synthesized and purified here failed to label yeast vacuoles under conditions that allowed labeling using commercial FD. Chromatography revealed that the commercial FD was heavily contaminated with at least three low molecular weight fluorescent compounds. Dialysis was ineffective for removing the contaminants. After purification (Sephadex G25, ethanol extraction), commercial FD was incapable of labeling vacuoles. Extracts of cells labeled with partially purified FD contained FITC, not FD, based on Sephadex and thin layer chromatography. In either the presence or absence of unlabeled 70-kD dextran, authentic FITC (10 micrograms/ml) was an effective labeling agent for vacuoles. The rapid kinetics (0.28 pmol/min per 10(6) cells at pH 5.5) and the pH dependence of FITC uptake suggest that the mechanism of FITC uptake involves diffusion rather than endocytosis. In view of these results, labeling experiments that use unpurified commercial FD should be interpreted with caution.

The VEGA Venus Balloon Experiment.

In June 1985, two instrumented balloons were placed in the atmosphere of Venus as part of the VEGA mission. Each balloon traveled about 30 percent of the way around the planet at a float altitude near 54 kilometers. In situ sensors measured pressure, temperature, vertical wind velocity, cloud particle backscatter, ambient light level, and frequency of lightning. A ground-based network of 20 radio antennas tracked the balloons by very long baseline interferometry (VLBI) techniques to monitor the Venus winds. The history, organization, and principal characteristics of this international balloon experiment are described.

Interior structure and seasonal mass redistribution of Mars from radio tracking of Mars Pathfinder.

Doppler and range measurements to the Mars Pathfinder lander made using its radio communications system have been combined with similar measurements from the Viking landers to estimate improved values of the precession of Mars' pole of rotation and the variation in Mars' rotation rate. The observed precession of -7576 +/- 35 milliarc seconds of angle per year implies a dense core and constrains possible models of interior composition. The estimated annual variation in rotation is in good agreement with a model of seasonal mass exchange of carbon dioxide between the atmosphere and ice caps.

Interferometric observations of an artificial satellite.

Very-long-baseline interferometric observations of radio signals from the TACSAT synchronous satellite, even though extending over only 7 hours, have enabled an excellent orbit to be deduced. Precision in differenced delay and delay-rate measurements reached 0.15 nanosecond ( approximately 5 centimeters in equivalent differenced distance) and 0.05 picosecond per second ( approximately 0.002 centimeter per second in equivalent differenced velocity), respectively. The results from this initial three-station experiment demonstrate the feasibility of using the method for accurate satellite tracking and for geodesy. Comparisons are made with other techniques.

Detection of a Compact Radio Source near the Center of a Gravitational Lens: Quasar Image or Galactic Core?

By use of a new, very sensitive interferometric system, a faint, compact radio source has been detected near the center of the galaxy that acts as the main part of a gravitational lens. This lens forms two previously discovered images of the quasar Q09S7+561, which lies in the direction of the constellation Ursa Major. The newly detected source has a core smaller than 0.002 arc second in diameter with a flux density of 0.6 +/- 0.1 millijansky at the 13-centimeter wavelength of the radio observations. This source could be the predicted third image of the transparent gravitational lens, the central core of the galaxy, or some combination of the two. It is not yet possible to choose reliably between these alternatives.

VEGA Balloon System and Instrumentation.

The VEGA Venus balloon radio transmissions received on Earth were used to measure the motion of the balloons and to obtain the data recorded by onboard sensors measuring atmospheric characteristics. Thus the balloons themselves, the gondolas, the onboard sensors, and the radio transmission system were all components of the experiment. A description of these elements is given, and a few details of data sampling and formatting are discussed.

Thermal structure of the venus atmosphere in the middle cloud layer.

Thermal structure measurements obtained by the two VEGA balloons show the Venus middle cloud layer to be generally adiabatic. Temperatures measured by the two balloons at locations roughly symmetric about the equator differed by about 6.5 kelvins at a given pressure. The VEGA-2 temperatures were about 2.5 kelvins cooler and those of VEGA-1 about 4 kelvins warmer than temperatures measured by the Pioneer Venus Large Probe at these levels. Data taken by the VEGA-2 lander as it passed through the middle cloud agreed with those of the VEGA-2 balloon. Study of individual frames of the balloon data suggests the presence of multiple discrete air masses that are internally adiabatic but lie on slightly different adiabats. These adiabats, for a given balloon, can differ in temperature by as much as 1 kelvin at a given pressure.

Implications of the VEGA Balloon Results for Venus Atmospheric Dynamics.

Both VEGA balloons encountered vertical winds with typical velocities of 1 to 2 meters per second. These values are consistent with those estimated from mixing length theory of thermal convection. However, small-scale temperature fluctuations for each balloon were sometimes larger than predicted. The approximate 6.5-kelvin difference in temperature consistently seen between VEGA-1 and VEGA-2 is probably due to synoptic or planetary-scale nonaxisymmetric disturbances that propagate westward with respect to the planet. There is also evidence from Doppler data for the existence of solar-fixed nonaxisymmetric motions that may be thermal tides. Surface topography may influence atmospheric motions experienced by the VEGA-2 balloon.

Overview of VEGA Venus Balloon in Situ Meteorological Measurements.

The VEGA balloons made in situ measurements of pressure, temperature, vertical wind velocity, ambient light, frequency of lightning, and cloud particle backscatter. Both balloons encountered highly variable atmospheric conditions, with periods of intense vertical winds occurring sporadically throughout their flights. Downward winds as large as 3.5 meters per second occasionally forced the balloons to descend as much as 2.5 kilometers below their equilibrium float altitudes. Large variations, in pressure, temperature, ambient light level, and cloud particle backscatter (VEGA-1 only) correlated well during these excursions, indicating that these properties were strong functions of altitude in those parts of the middle cloud layer sampled by the balloons.

VEGA Balloon Dynamics and Vertical Winds in the Venus Middle Cloud Region.

The VEGA balloons provided a long-term record of vertical wind fluctuations in a planetary atmosphere other than Earth's. The vertical winds were calculated from the observed displacement of the balloon relative to its equilibrium float altitude. The winds were intermittent; a large burst lasted several hours, and the peak velocity was 3 meters per second.

Very long baseline interferometric observations made with an orbiting radio telescope.

An orbiting spacecraft and ground observatories have been used to obtain interferometric observations of cosmic radio sources. The Tracking and Data Relay Satellite System (TDRSS) was used as the orbiting observatory in conjunction with two 64- meter radio telescopes at ground observatories, one in Australia and one in Japan. The quasars 1730-130 (NRAO 530), 1510-089, and 1741-038 were observed at a frequency of 2.3 gigahertz, and a maximum projected baseline of 1.4 earth diameters was achieved. All quasar observations for which valid data were acquired resulted in detected fringes. Many of the techniques proposed for a dedicated very long baseline interferometry observatory in space were used successfully in this experiment.

Determination of Venus Winds by Ground-Based Radio Tracking of the VEGA Balloons.

A global array of 20 radio observatories was used to measure the three-dimensional position and velocity of the two meteorological balloons that were injected into the equatorial region of the Venus atmosphere near Venus midnight by the VEGA spacecraft on 11 and 15 June 1985. Initial analysis of only radial velocities indicates that each balloon was blown westward about 11,500 kilometers (8,000 kilometers on the night side) by zonal winds with a mean speed of about 70 meters per second. Excursions of the data from a model of constant zonal velocity were generally less than 3 meters per second; however, a much larger variation was evident near the end of the flight of the second balloon. Consistent systematic trends in the residuals for both balloons indicate the possibility of a solar-fixed atmospheric feature. Rapid variations in balloon velocity were often detected within a single transmission (330 seconds); however, they may represent not only atmospheric motions but also self-induced aerodynamic motions of the balloon.

Comparative effects of conventional vs. novel hormone replacement therapy on blood pressure in postmenopausal women.

Menopause is commonly characterized by an increase in blood pressure. Higher blood pressure may partially explain the elevated risk for cardiovascular events observed in postmenopausal women. There is a graded relationship between blood pressure and cardiovascular risk which extends to levels of blood pressure well below 140/90 mmHg, the classical established blood pressure limit for the diagnosis of hypertension. Despite this knowledge and the wide availability of consensus treatment guidelines for hypertension, high blood pressure remains untreated or poorly treated in many postmenopausal patients. It is clear that novel and innovative population strategies for lowering blood pressure in postmenopausal women are warranted. Clinical trials suggest that oral estrogen administration may produce either a neutral effect or a small increase in blood pressure in postmenopausal women. Transdermal estrogen administration has not been studied as extensively but may produce a decrease in blood pressure. The mechanisms for the differences observed between oral and transdermal estrogen have not been completely elucidated. Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity that has been developed for hormone therapy as DRSP/17beta-estradiol (DRSP/E2). In several clinical trials, DRSP/E2 has demonstrated a significant antihypertensive effect as well an additive effect when combined with existing antihypertensive therapy. Despite the wide availability of treatment guidelines, a wide array of antihypertensive agents, and the introduction of hormone replacement therapy that can lower blood pressure, optimizing blood pressure control remains a serious issue confronting the physician who cares for the postmenopausal woman.

Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae PEP3 gene was cloned from a wild-type genomic library by complementation of the carboxypeptidase Y deficiency in a pep3-12 strain. Subclone complementation results localized the PEP3 gene to a 3.8-kb DNA fragment. The DNA sequence of the fragment was determined; a 2,754-bp open reading frame predicts that the PEP3 gene product is a hydrophilic, 107-kDa protein that has no significant similarity to any known protein. The PEP3 predicted protein has a zinc finger (CX2CX13CX2C) near its C terminus that has spacing and slight sequence similarity to the adenovirus E1a zinc finger. A radiolabeled PEP3 DNA probe hybridized to an RNA transcript of 3.1 kb in extracts of log-phase and diauxic lag-phase cells. Cells bearing pep3 deletion/disruption alleles were viable, had decreased levels of protease A, protease B, and carboxypeptidase Y antigens, had decreased repressible alkaline phosphatase activity, and contained very few normal vacuolelike organelles by fluorescence microscopy and electron microscopy but had an abundance of extremely small vesicles that stained with carboxyfluorescein diacetate, were severely inhibited for growth at 37 degrees C, and were incapable of sporulating (as homozygotes). Fractionation of cells expressing a bifunctional PEP3::SUC2 fusion protein indicated that the PEP3 gene product is present at low abundance in both log-phase and stationary cells and is a vacuolar peripheral membrane protein. Sequence identity established that PEP3 and VPS18 (J. S. Robinson, T. R. Graham, and S. D. Emr, Mol. Cell. Biol. 11:5813-5824, 1991) are the same gene.

Role of vacuolar acidification in protein sorting and zymogen activation: a genetic analysis of the yeast vacuolar proton-translocating ATPase.

Vacuolar acidification has been proposed to play a key role in a number of cellular processes, including protein sorting, zymogen activation, and maintenance of intracellular pH. We investigated the significance of vacuolar acidification by cloning and mutagenizing the gene for the yeast vacuolar proton-translocating ATPase 60-kilodalton subunit (VAT2). Cells carrying a vat2 null allele were viable; however, these cells were severely defective for growth in medium buffered at neutral pH. Vacuoles isolated from cells bearing the vat2 null allele were completely devoid of vacuolar ATPase activity. The pH of the vacuolar lumen of cells bearing the vat2 mutation was 7.1, compared with the wild-type pH of 6.1, as determined by a flow cytometric pH assay. These results indicate that the vacuolar proton-translocating ATPase complex is essential for vacuolar acidification and that the low-pH state of the vacuole is crucial for normal growth. The vacuolar acidification-defective vat2 mutant exhibited normal zymogen activation but displayed a minor defect in vacuolar protein sorting.