Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A.

INTRODUCTION: The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A. AIM: To describe the treatment of bleeding episodes with rFVIIIFc in the A-LONG study. METHODS: A-LONG subjects (<1 IU dL-1 endogenous FVIII) were treated with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information recorded for each bleeding episode included type, location and dose to treat the episode. RESULTS: During A-LONG, 757 bleeding episodes occurred during the efficacy period; the majority [456 (60%)] occurred in Arm 3 (episodic treatment). Of 93 subjects in the prophylaxis arms who entered the study with target joints, 43 (60%) in Arm 1 and 11 (52%) in Arm 2 did not experience a target joint bleed. Overall, 98% of bleeding episodes (and 98% of bleeds involving a target joint) resolved with one or two infusions; the median dose per infusion to treat a bleed was 27 IU kg-1 (27 IU kg-1 for target joints). Using population pharmacokinetic simulations, FVIII activity levels were predicted to be below the upper limit of normal (150 IU dL-1 ) in most patients in the event that rFVIIIFc is used to treat a bleeding episode in close proximity to a prophylactic dose. CONCLUSIONS: These findings demonstrate the efficacy of rFVIIIFc for the treatment of acute bleeding episodes in subjects with severe haemophilia A, regardless of treatment regimen.

Transplacental transfer of postpartum inhibitors to factor VIII.

Acquired haemophilia due to antibodies directed against coagulation factor VIII is a well-recognized cause of severe haemorrhage in adults but an uncommon cause of bleeding in children. We present the cases of a mother with a life-threatening postpartum haemorrhage due to an autoantibody to factor VIII and her newborn who developed symptomatic bleeding after a minor surgical intervention as a result of transplacental transfer of the autoantibody. Both patients were treated with infusions of recombinant factor VIIa to control bleeding. The mother required immunosuppressive therapy to decrease inhibitor levels and the infant's levels decreased over time without specific treatment. We also provide a concise review of postpartum haemophilia and transplacental transmission of factor VIII autoantibodies to the neonate--a rare but potentially life-threatening complication of acquired haemophilia in women of childbearing age.

Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system.

Using a cell-based model system of coagulation, we performed a systematic examination of the effect of varying individual procoagulant proteins (over the range of 0-200% of pooled plasma levels) on the characteristics of thrombin generation. The results revealed a number of features unique to the different coagulation factors, as well as common features allowing them to be grouped according to the patterns observed. Variation of those factors contributing to formation of the tenase complex, factor (F)VIII, factor (F)IX and factor (F)XI, primarily affected the rate and peak of thrombin production, but had little to no effect on total thrombin production. The effect of decreased FXI was milder than seen with decreased FVIII or FIX, and more variable between platelet donors. In contrast, varying the concentration of factors that contribute to formation of the prothrombinase complex, prothrombin or factor (F)V (with FV-deficient platelets), significantly affected all three measures of thrombin production: rate, peak and total. Additionally, while no thrombin generation was observed with no factor X, only very small amounts (between 1% and < 10% of normal plasma levels) were required to normalize the measured parameters. Finally, our results with this cell-based system highlight differences in thrombin generation on cell surfaces (platelets) compared with phospholipids, and suggest that platelets contribute more than simply a surface for the generation of thrombin.

Laboratory and field evaluation of measurement methods for one-hour exposures to O3, PM2.5, and CO.

While researchers have linked acute (less than 12-hr) ambient O3, PM2.5, and CO concentrations to a variety of adverse health effects, few studies have characterized short-term exposures to these air pollutants, in part due to the lack of sensitive, accurate, and precise sampling technologies. In this paper, we present results from the laboratory and field evaluation of several new (or modified) samplers used in the "roll-around" system (RAS), which was developed to measure 1-hr O3, PM2.5, and CO exposures simultaneously. All the field evaluation data were collected during two sampling seasons: the summer of 1998 and the winter of 1999. To measure 1-hr O3 exposures, a new active O3 sampler was developed that uses two nitrite-coated filters to measure O3 concentrations. Laboratory chamber tests found that the active O3 sampler performed extremely well, with a collection efficiency of 0.96 that did not vary with temperature or relative humidity (RH). In field collocation comparisons with a reference UV photometric monitor, the active O3 sampler had an effective collection efficiency ranging between 0.92 and 0.96 and a precision for 1-hr measurements ranging between 4 and 6 parts per billion (ppb). The limits of detection (LOD) of this method were 9 ppb-hr for the chamber tests and approximtely 16 ppb-hr for the field comparison tests. PM2.5 and CO concentrations were measured using modified continuous monitors--the DustTrak and the Langan, respectively. A size-selective inlet and a Nafion dryer were placed upstream of the DustTrak inlet to remove particles with aerodynamic diameters greater than 2.5 microm and to dry particles prior to the measurements, respectively. During the field validation tests, the DustTrak consistently reported higher PM2.5 concentrations than those obtained by the collocated 12-hr PM2.5 PEM samples, by approximately a factor of 2. After the DustTrak response was corrected (correction factor of 2.07 in the summer and 2.02 in the winter), measurements obtained using these methods agreed well with R2 values of 0.87 in the summer and 0.81 in the winter. The results showed that the DustTrak can be used along with integrated measurements to measure the temporal and spatial variation in PM2.5 exposures. Finally, during the field validation tests, CO concentrations measured using the Langan were strongly correlated with those obtained using the reference method when the CO levels were above the LOD of the instrument [approximately 1 part per million (ppm)].

The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia.

Recently, high-dose factor VIIa has been used to correct bleeding in patients with various thrombocytopathias including Glanzmann's thrombasthenia, Bernard-Soulier syndrome, and uremia. High-dose factor VIIa is postulated to act on platelets in the absence of tissue factor to activate factors IX and X and thus enhance thrombin generation. This enhanced thrombin generation might help provide hemostasis in patients with thrombocytopathias through several mechanisms. Enhanced thrombin generation would provide a strong signal for recruitment of other platelets. Also, enhanced fibrin deposition might provide mechanisms for bypassing the specific defect in thrombocytopathias. Thus, platelets from a patient with Bernard-Soulier syndrome might associate with fibrin by a glycoprotein IIb-IIIa-mediated mechanism. Also, platelets from a patient with Glanzmann's thrombasthenia might associate with fibrin through von Willebrand factor-mediated interactions with glycoprotein Ib-V-IX. Finally, enhanced thrombin generation on platelets would mean that fewer platelets are required for hemostasis.

The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation.

We used a cell-based, in-vitro model of normal hemostasis and hemophilia to address the question of whether factor (F) X concentration affects the hemostatic response to high-dose activated factor VII (FVIIa). Under conditions designed to mimic normal tissue factor-initiated hemostasis in vivo, we found that only a very small amount of FX -- equivalent to about 3% of the normal plasma level -- was required to support a 'normal' level of thrombin generation. This suggests that, under normal conditions in vivo, the level of FX does not significantly affect hemostatic function. By contrast, in experiments designed to mimic the hemophilic condition, the level of FX had a significant effect on the level of thrombin generated in the presence of high-dose FVIIa. This finding suggests that the plasma level of FX could affect the hemostatic response of hemophilic patients to high-dose FVIIa therapy.

Calibration of sharp cut impactors for indoor and outdoor particle sampling.

A low-flow rate, sharp cut point inertial impaction sampler was developed in 1986 that has been widely used in PM exposure studies in the United States and several other countries. Although sold commercially as the MS&T Area Sampler, this sampler is widely referred to as the Harvard Impactor, since the initial use was at the Harvard School of Public Health. Impactor nozzles for this sampler have been designed and characterized for flows of 4, 10, 20, and 23 L/min and cut points of 1, 2, 5, and 10 microns. An improved method for determining the actual collecting efficiency curve was developed and used for the recent impactor calibrations reported here. It consists of placing a multiplet reduction impactor inline just downstream of the vibrating orifice aerosol generator to remove the multiplets, thus allowing only the singlet particle s to penetrate through to the impactor being calibrated This paper documents the techniques and results of recent nozzle calibrations for this sampler and compares it with other size-selective inertial impactors. In general, the impactors were found to have sharp cutoff characteristics. Particle interstage losses for all of the impactors were very low, with the exception of the 10-micron cut size 20 L/min impactor, which had greater losses due to the higher flow rate. All of the 2.5-micron cut nozzle laboratory calibrations compare favorably to the U.S. Environmental Protection Agency (EPA) WINS-96 fine particle mass (PM2.5) impactor calibration data.

Effects of ozone and other pollutants on the pulmonary function of adult hikers.

This study evaluated the acute effects of ambient ozone (O3), fine particulate matter (PM2.5), and strong aerosol acidity on the pulmonary function of exercising adults. During the summers of 1991 and 1992, volunteers (18-64 years of age) were solicited from hikers on Mt. Washington, New Hampshire. Volunteer nonsmokers with complete covariates (n = 530) had pulmonary function measured before and after their hikes. We calculated each hiker's posthike percentage change in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), the ratio of these two (FEV1/FVC), forced expiratory flow between 25 and 75% of FVC(FEF25-75%), and peak expiratory flow rate (PEFR). Average O3 exposures ranged from 21 to 74 ppb. After adjustment for age,sex, smoking status (former versus never), history of asthma or wheeze, hours hiked, ambient temperature, and other covariates, there was a 2.6% decline in FEV1 [95% confidence interval (CI), 0.4-4.7; p = 0.02] and a 2.2% decline in FVC (CI, 0.8-3.5; p =0.003) for each 50 ppb increment in mean O3. There were consistent associations of decrements in both FVC (0.4% decline; CI,0.2-0.6, p = 0.001) and PEFR (0.8% decline; CI, 0.01-1.6; p = 0.05) with PM2.5 and of decrements in PEFR (0.4% decline; CI, 0.1-0.7; p = 0.02) with strong aerosol acidity across the interquartile range of these exposures. Hikers with asthma or a history of wheeze (n = 40) had fourfold greater responsiveness to ozone than others. With prolonged outdoor exercise, low-level exposures to O3, PM2.5, and strong aerosol acidity were associated with significant effects on pulmonary function among adults. Hikers with a history of asthma or wheeze had significantly greater air pollution-related changes in pulmonary function.

The metropolitan acid aerosol characterization study: results from the summer 1994 Washington, D.C. field study.

An ambient particle monitoring study was conducted in Washington, D.C. during the summer of 1994 as part of the Metropolitan Acid Aerosol Characterization Study (MAACS). Acid aerosol and inhalable (particulate matter with aerodynamic diameters < 10 micron; PM10) and fine (particulate matter with aerodynamic diameters < 2.5 micron; PM2.5) particle samples were collected for 24-hr periods (9 A.M.-9 A.M. EDT) on alternate days at six monitoring sites located throughout the greater Washington, D.C. area. Monitoring sites were located in both urban and rural areas and were generally situated along a southwest to northeast line due to the prevailing winds. Information on site characteristics, including population density and distance from the city center, was also obtained, as were data on meteorological parameters. Results from this study show strong correlations among the particulate measures, PM10, PM2.5, SO4(2-), and H+. These strong correlations resulted from the fact that PM2.5 comprised 77% of PM10, with SO4(2-)-related species accounting for 49% of total PM2.5. PM10, PM2.5, SO4(2-), and H+ concentrations were found to be uniform across the metropolitan Washington area. Spatial variation was found, however, for coarse particles (PM2.5-10) and NH3 concentrations. In our previous Philadelphia study, population density was an important determinant of spatial variation in coarse particles and NH3 concentrations, however, in Washington, D.C., population density was not associated with observed spatial patterns in coarse particle concentrations, but was an important determinant of NH3 concentrations. When data from one site (Reservoir) was excluded from the analysis, population density explained larger percentage of the variability in NH3 levels and became an important determinant of the H+/SO4(2-) ratio as well. Ambient H+ models developed from Philadelphia data were found to predict H+ concentrations in Washington, D.C. reasonably well, representing an improvement over measurements made at a single stationary ambient monitoring site.

Sex ratio variation in the dioecious shrub Oemleria cerasiformis.

Many examples of biased sex ratios are known in natural populations of plants. Proximal causes of these biases are gender diphasy (sex changing), differential mortality between male and female genets, differential rates of clonal growth (numbers of ramets per genet), and differential flowering (differences in flowering frequency or age to maturity). In the western North American shrub Oemleria cerasiformis we determined sex ratios for 60 natural populations and found an excess of males in 56 populations. The male bias was greatest in populations with little recent recruitment. Sampling of young and old plants indicated that males flowered at an earlier age than females, which led to a transient flowering bias in very young plants, and that the genet sex ratio was 1:1 in young mature plants but male biased in old plants, as a result of differential mortality. Examination of dead genets confirmed that mature females have higher mortality rates. Females also have greater reproductive effort and slower growth rates than males. The major cause of biased sex ratios in O. cerasiformis is greater mortality of female plants during their reproductive years, which probably arises directly or indirectly from their greater allocation to reproduction.

Cytogenetic abnormalities in a rare case of giant cell osteogenic sarcoma.

The cytogenetic analysis of a rare, nonirradiated case of giant cell tumor of bone with osteogenic sarcoma transformation is presented for the first time in a 19-year-old female. Telomeric associations involving 4p, 8p, 11p, 14p, 17p, 17q, and 20q were observed. Additionally, monosomy 13, 11p abnormalities and marker chromosomes were identified in tumor cells. Chromosome 11 involvement, particularly 11p translocations and 11p telomeric associations, were frequently observed in the tumor cells obtained from our patient, which suggests that chromosome 11p may play a role in the development of giant cell osteogenic sarcoma.

Anthropometric comparison of mentally retarded males with and without the fragile X syndrome.

An anthropometric survey of 41 variables (weight, height, 10 linear, 4 breadth, 22 craniofacial, 2 skinfold, and testicular volume), including multivariate discriminant analysis, was undertaken on 110 mentally retarded males (39 with and 71 without the fra(X) syndrome). The mean Z scores of the fra(X) syndrome males fell between -2.00 and 8.38 for bizygomatic diameter and testicular volume, respectively, and the range of the mean Z scores of the non-fra(X) males was from -2.64 to 2.26 for hand breadth and testicular volume, respectively. There was a statistically significant difference (P less than .05) between fra(X) and non-fra(X) males for 18 measurements (weight, height, 7 linear, 2 breadth, 5 craniofacial, 1 skinfold, and testicular volume), with the greater measurements (excluding bizygomatic diameter) found in fra(X) males. Sitting height, knee-buttock length, middle finger length, and hand length were negatively correlated (P less than .05) with age, whereas bizygomatic diameter, ear length, and ear width were positively correlated (P less than .05) with age and head circumference, head length, and outer canthal distance were positively correlated (P less than .05) with fra(X) chromosome expression in the fra(X) males. Triceps and subscapular skinfold thicknesses were negatively correlated (P less than .05) with age, whereas ankle breadth, ear length, ear width, and nose length were positively correlated (P less than .05) in the non-fra(X) males. Discriminant analysis of 34 fra(X) and 71 non-fra(X) males resulted in a discriminant function based on 6 of 17 anthropometric variables and age.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome lesions which could be interpreted as "fragile sites" on the distal end of Xq.

Chromosome lesions which could be interpreted as "fragile sites" on the distal end of the long arm of the X chromosome were identified during a cytogenetic study of 160 mentally retarded adult males with no apparent cause of their mental retardation and one normal adult female with a family history of fra (X) syndrome. Peripheral blood samples were cultured in either M199 or RPMI 1640 medium with FUdR or BrdU. Metaphases were examined for chromosome lesions or fragile sites on the distal end of Xq and 3 distinct sites were observed: Xq26, Xq27.2, and Xq27.3. Other chromosome lesions at Xq28 were observed and interpreted as nonspecific telomeric structural changes. Chromosome lesions were observed in cells from 14 of the 161 individuals. These included: 5 patients with an Xq26 site, 2 with the recently reported Xq27.2 site, 4 with the Xq27.3 site (characteristic of the fra (X) syndrome), 2 with nonspecific telomeric structural changes, and one individual with 2 lesions (a nonspecific telomeric structural change and an Xq26 site). Additional research is necessary to determine the frequency and clinical significance, if any, of lesions occurring in this region of the X chromosome and to distinguish among heritable fragile sites, constitutive fragile sites, and nonspecific telomeric structural changes.

Temporomandibular joint ankylosis following mastoiditis: report of a case.

A case of TMJ ankylosis following otitis media and mastoiditis is described and its treatment presented. The infectious etiology of ankylosis is reviewed, with emphasis on mastoid infections. Theories are presented as to the possible mechanisms by which such infections can spread into the glenoid fossa.

Memory error. Developing a new nursing diagnosis.

It is recommended that memory error, the inability to encode, maintain, or retrieve information, be identified as a nursing diagnosis. Two different types of memory error, forgetting to take a medication at the scheduled time and being unable to remember whether a medication has already been taken, are discussed in terms of nursing diagnosis and intervention.

Rhinolith: unusual appearance on panoramic radiograph.

This case report describes an unusual radiopaque lesion that was an incidental finding on a routine panoramic radiograph. The location of the rhinolith gave it the appearance of being within the maxillary sinus. The position of any lesion seen on a panoramic radiograph should be confirmed by other radiologic studies.

The physiological basis of intracranial pressure change with progressive epidural brain compression. An experimental evaluation in cats.

Sequential cerebrospinal fluid (CSF) pressure-volume studies were carried out in seven cats during the expansion at a constant rate of an epidural balloon. The same studies were performed in three control cats. Beginning after 20 minutes of inflation and continuing to the point of pupillary dilatation there was a progressive increase in the pressure-volume index (volume required to change intracranial pressure (ICP) by tenfold). During the course of balloon inflation, there was also a progressive increase in CSF elastance (instantaneous ICP change per unit change in CSE volume). At the point of pupillary dilatation there was a marked, abrupt increase in the pressure-volume index and an equally dramatic decrease in CSF elastance. The CSF outflow resistance increased to a variable extent during balloon inflation. The plot of the CSF pressure versus balloon volume (the mass lesion pressure-volume curve) was of the classical configuration with an initial relatively flat segment and a final steep segment. A hypothesis is presented that interprets the shape of the mass lesion pressure-volume curve in terms of changes occurring in the elastic properties of the tissues surrounding the CSF space and the volume of the CSF space. It is proposed that this hypothesis will explain most of the commonly observed variations in CSF pressure. Confusion regarding the ICP-volume relationships has arisen because of lack of specificity regarding which anatomical spaces are being perturbed.