The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers.

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules

Coronal Emission Measures and Abundances for Moderately Active K Dwarfs Observed by Chandra

We have used Chandra to resolve the nearby 70 Oph (K0 V+K5 V) and 36 Oph (K1 V+K1 V) binary systems for the first time in X-rays. The LETG/HRC-S spectra of all four of these stars are presented and compared with an archival LETG spectrum of another moderately active K dwarf, Epsilon Eri. Coronal densities are estimated from O VII line ratios and emission measure distributions are computed for all five of these stars. We see no substantial differences in coronal density or temperature among these stars, which is not surprising considering that they are all early K dwarfs with similar activity levels. However, we do see significant differences in coronal abundance patterns. Coronal abundance anomalies are generally associated with the first ionization potential (FIP) of the elements. On the Sun, low-FIP elements are enhanced in the corona relative to high-FIP elements, the so-called "FIP effect." Different levels of FIP effect are seen for our stellar sample, ranging from 70 Oph A, which shows a prominent solar-like FIP effect, to 70 Oph B, which has no FIP bias at all or possibly even a weak inverse FIP effect. The strong abundance difference exhibited by the two 70 Oph stars is unexpected considering how similar these stars are in all other respects (spectral type, age, rotation period, X-ray flux). It will be difficult for any theoretical explanation for the FIP effect to explain how two stars so similar in all other respects can have coronae with different degrees of FIP bias. Finally, for the stars in our sample exhibiting a FIP effect, a curious difference from the solar version of the phenomenon is that the data seem to be more consistent with the high-FIP elements being depleted in the corona rather than a with a low-FIP enhancementComment: 35 pages, 8 figures, AASTEX v5.0 plus EPSF extensions in mkfig.sty; accepted by Ap

Is radiographic measurement of distal femoral torsion reliable?

BACKGROUND: Distal femur torsion (DFT) is a crucial parameter in knee replacement surgery. The reference standard for measuring DFT is posterior condylar angle (PCA) measurement using computed tomography (CT). The objective of this study was to assess the feasibility and reliability of a radiographic PCA measurement method. MATERIALS AND METHODS: We studied 125 osteoarthritic knees in 79 patients (42 women and 37 men) with a mean age of 71.6 ± 8.8 years (range 47 to 86 years); 32 knees were aligned, 85 in varus, and eight in valgus. DFT was measured on an antero-posterior (AP) radiograph of the knee in 90° of flexion (known as the seated AP view). The PCA was defined as the angle subtended by the tangent to the posterior condyles and the transepicondylar axis (anatomic PCA [aPCA]) or the line connecting the lateral epicondyle to the medial sulcus (surgical PCA [sPCA]). The PCA was conventionally recorded as positive in the event of external torsion and negative in the event of internal torsion. PCA measurements were performed three times by each of five observers to allow assessments of inter-observer and test-retest reliabilities. RESULTS: aPCA was consistently negative (mean, -6.1 ± 1.6°) (range, 0 to -10°); inter-observer and test-retest reliability were satisfactory (0.54 CONCLUSION: Radiographic measurement of DFT is simple and non-invasive. Measurement reproducibility was satisfactory for aPCA but not for sPCA. aPCA showed marked inter-individual variability and tended to increase when the knee was in valgus. Mean aPCA values were comparable to those reported using CT. In contrast to CT, radiographic DFT measurement can easily be incorporated into the pre- and postoperative work-ups for knee replacement surgery, provided the patient can achieve 90° of knee flexion. LEVEL OF EVIDENCE: Level IV, prospective cohort study

Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage])

BACKGROUND AND PURPOSE—: We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. METHODS—: Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. RESULTS—: Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). CONCLUSIONS—: EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190

A DNA delivery system targeting dendritic cells for use in immunization against malaria: a rodent model

DNA-based vaccination has emerged as a promising method of immunisation since the first demonstration of this technology. Improving the antibody responses is desirable for the protective efficacy and hence broad application of these vaccines. We examined the immunogenicity of a Plasmodium-based DNA vaccine that was targeted to antigen presenting cells by fusion to CTLA4. Fusion proteins comprising the extra-cellular domain of CTLA4, the hinge, CH2 and CH3 domains of human IgG1 and MSP-1 gene fragments were expressed in COS-7 cells. Three of the secreted proteins containing the mouse homologue of CTLA4 were shown to bind differently to the human B7-1 molecule expressed on THP-1 cells. Competition binding assays for two fusion proteins showed that binding was specific. When C57BL/6 mice were immunized with plasmids encoding the fusion proteins, antibodies against two denatured and one non-denatured MSP-1 gene fragments were successfully induced. The usefulness of this strategy in future studies of immunisaton against human malaria is discussed. Keywords: malaria, PbMSP-1, DNA vaccine, dendritic cells, rodent model Tanzania Health Research Bulletin Vol. 7(3) 2005: 142-14

Metabolic engineering of rice endosperm towards higher vitamin B1 accumulation

Rice is a major food crop to approximately half of the human population. Unfortunately, the starchy endosperm, which is the remaining portion of the seed after polishing, contains limited amounts of micronutrients. Here, it is shown that this is particularly the case for thiamin (vitamin B1). Therefore, a tissue-specific metabolic engineering approach was conducted, aimed at enhancing the level of thiamin specifically in the endosperm. To achieve this, three major thiamin biosynthesis genes, THIC, THI1 and TH1, controlled by strong endosperm-specific promoters, were employed to obtain engineered rice lines. The metabolic engineering approaches included ectopic expression of THIC alone, in combination with THI1 (bigenic) or combined with both THI1 and TH1 (trigenic). Determination of thiamin and thiamin biosynthesis intermediates reveals the impact of the engineering approaches on endosperm thiamin biosynthesis. The results show an increase of thiamin in polished rice up to threefold compared to WT, and stable upon cooking. These findings confirm the potential of metabolic engineering to enhance de novo thiamin biosynthesis in rice endosperm tissue and aid in steering future biofortification endeavours

Low-voltage low-power CMOS analogue circuits for Gaussian and uniform noise generation

IEEE International Symposium on Circuits and Systems, MAY 25-28, 2003, Bangkok, Thailand. (ISI Web of Science)A CMOS analogue circuit for Gaussian noise generution as well as a novel circuitfor transforming Gaussian noise into uniform noise, hoth.designed/or operating with a supply voltoge o/ I . S K arepresented. Both circuits are optimizedfor U 0 . 3 5st~an - dord CMOS technology using an equation-based design methodology based on generic algorithms. Electrical simulations demonstrate that high noise amplinrdes together with reasonable hondwidths can be achieved with relatively low power dissipation. Potential applications include self-calihrution and on-chip self-testing of video-rate analogue-to-digital converter

Evaluation of the Analgesic Efficacy of Undiluted Intraperitoneal and Incisional Ropivacaine for Postoperative Analgesia in Dogs after Major Abdominal Surgery

Recommendations for intraperitoneal (IP) and incisional (INC) administration of local anaesthetics after visceral surgery exist, but evidence is scarce. This prospective, randomized, blinded, controlled, clinical trial compared postoperative pain in dogs undergoing major abdominal surgery. Sixteen client-owned dogs were anaesthetized with a standardized balanced protocol including opioids and received either 2 mg/kg ropivacaine IP (0.27 mL/kg) and a 1 mg/kg INC splash (0.13 mL/kg) or equal volumes of saline. Influence of the treatment on heart rate (HR) and postoperative pain was assessed using the Short Form of the Glasgow Composite Pain Scale (GCPS-SF), a dynamic interactive visual analogue scale (DIVAS) and mechanical nociceptive threshold testing (MNT). Data was tested with mixed ordinal regression and log linear mixed models for 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h after extubation. Rescue analgesia was given to 3/8 dogs after ropivacaine and 0/8 dogs after saline. GCPS-SF and MNT were not different between groups. DIVAS was slightly higher after ropivacaine (odds increased by 5.44 (confidence interval (CI) 1.17–9.96, p = 0.012)), and HR after ropivacaine was 0.76 * that after saline (CI 0.61–0.96, p = 0.02) with no effect of time (p = 0.1). Undiluted ropivacaine IP and INC was not beneficial for postoperative analgesia

Analysis of Multiple Plasmodium falciparum Infections in Tanzanian Children during the Phase III Trial of the Malaria Vaccine SPf66

In the first phase III efficacy trial of the malaria vaccine SPf66 in Africa, MOIs in SPf66- and placebo-vaccinated children were analyzed by polymerase chain reaction-restriction fragment length polymorphism of the Plasmodium falciparum merozoite surface antigen 2 (MSA2). MOIs were significantly reduced in asymptomatic vaccine recipients compared with those in asymptomatic placebo recipients; however, no differences were observed among symptomatic children in the vaccine and control groups. These results show that immunization with SPf66 modulates the course of naturally occurring infections, as reflected by reduced MOIs. In placebo recipients, however, there was a significant negative correlation between numbers of infecting genotypes, as identified by MSA2, and morbidity. Asymptomatic placebo recipients had an average of 5 concurrent infections, whereas children with clinical cases had an average of 3.4 infections. These data provide further evidence that premunition from concurrent infections is important in immunity against clinical malaria. No such effect of multiple infections was found in the vaccinated grou