Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.     

Development of low loss organic-micromachined interconnects on silicon at microwave frequencies

We present the design and development of an ultra-violet (UV) LIGA (a German acronym for electroplating, lithography and molding) micromachining process on silicon substrates at microwave/millimeter wave frequencies. The process employs an ultra-thick negative photoresist SU-8 that can be spin-coated and processed using conventional lithography techniques. Using this process, we have developed micromachined coplanar waveguide (CPW) interconnects on Si substrates. The conductor-backed micromachined CPW on Si (7.2 /spl Omega/-cm) achieves a measured attenuation of 0.18 dB/cm at 20 GHz.     

Phase II trial of paclitaxel and granulocyte colony-stimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study

PURPOSE: Pancreatic cancer is difficult to treat, with most patients surgically unresectable at the time of diagnosis. Radiotherapy and chemotherapy can offer palliation, but more effective therapy is needed. This trial evaluated the effects of an aggressive schedule of paclitaxel given with granulocyte colony-stimulating factor (G-CSF) to patients with advanced pancreatic cancer. PATIENTS AND METHODS: All patients were required to have a histologic diagnosis of pancreatic adenocarcinoma with measurable disease and no prior chemotherapy or radiation therapy. Patients had to have performance status of 0 to 2, pretreatment absolute granulocyte count > or = 1,500/microL, and platelet count greater than or equal to the institutional lower limit of normal. Following pretreatment with dexamethasone, diphenhydramine, and cimetidine, patients received paclitaxel at a dose of 250 mg/m2 by 24-hour infusion on day 1, repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d on days 3 to 18 or until two consecutive absolute neutrophil counts (ANCs) > or = 10,000/microL were obtained. Doses of paclitaxel were modified depending on nadir counts. RESULTS: Forty-five patients were entered onto this study, with six ineligible. For the 39 eligible patients, there was one complete response (CR) and two partial responses (PRs), five stable/no responses, 23 increasing disease, two early deaths, and six patients whose assessment was inadequate to determine response. The response rate was therefore three of 39 or 8% (95% confidence interval [CI], 2% to 21%). The median survival time for the 39 eligible patients was 5 months. The most common toxicities were anemia, leukopenia/granulocytopenia, malaise/fatigue, nausea/vomiting, alopecia, thrombocytopenia, paresthesias, and liver function abnormalities. There was one death due to sepsis. CONCLUSION: Single-agent paclitaxel in this dose and schedule has minimal activity in pancreatic adenocarcinoma patients.     

In vitro studies on the use of clay, clay minerals and charcoal to adsorb bovine rotavirus and bovine coronavirus

Rotaviruses are the leading cause and coronaviruses are the major contributors of acute gastroenteritis in the young of various mammalian and avian species. Despite numerous trials and decades of research, vaccines have limited efficacy particularly for calves. As an alternative method of controlling infection, we have investigated broad spectrum antiviral agents that are not discriminatory among various viruses. This report involves testing a variety of adsorbent agents including charcoal, clay, and clay minerals to adsorb rotavirus and coronavirus in vitro. Results revealed that all the adsorbent agents had good to excellent capability of adsorbing rotavirus and excellent capability of adsorbing coronavirus. Percent adsorptions ranged from 78.74% to 99.89% for rotavirus and 99.99% for coronavirus; while sand (negative control) was < 0.01%. A high affinity binding was present as determined by a low percent desorption (0.06-3.09%). However, the adsorbent bound virus complex retained, and may have actually enhanced, infectivity.     

A 2.2 W, 80 MHz superscalar RISC microprocessor

A 28 mW/MHz at 80 MHz structured-custom RISC microprocessor design is described. This 32-b implementation of the PowerPC architecture is fabricated in a 3.3 V, 0.5 μm, 4-level metal CMOS technology, resulting in 1.6 million transistors in a 7.4 mm by 11.5 mm chip size. Dual 8-kilobyte instruction and data caches coupled to a high performance 32/64-b system bus and separate execution units (float, integer, loadstore, and system units) result in peak instruction rates of three instructions per clock cycle. Low-power design techniques are used throughout the entire design, including dynamically powered down execution units. Typical power dissipation is kept under 2.2 W at 80 MHz. Three distinct levels of software-programmable, static, low-power operation-for system power management are offered, resulting in standby power dissipation from 2 mW to 350 mW. CPU to bus clock ratios of 1×, 2×, 3×, and 4× are implemented to allow control of system power while maintaining processor performance. As a result, workstation level performance is packed into a low-power, low-cost design ideal for notebooks and desktop computers     

A study of solid circulation rate in a circulating fluidized bed

An experimental investigation under cold condition was made to study the effects of some operating/design parameters and non-mechanical L valve configuration on the solid circulation rate in a 4.5 m tall, 0.15 m diameter circulating fluidized bed with riser flow rate varying from 1400 litres/min to 2000 litres/min and bed inventory from 15 kg to 25 kg of sand of average sizes 200 μm, 400 μm and 500 μm. Solid circulation rate was estimated by measuring velocity of sand particle travelling through a vertical Perspex tube section at the bottom of the return leg. It was found to be in the range of 2.8 to 12.3kg/m²s, 0.07 to 9.1kg/m²s and 0.12 to 2.23kg/m²s for sand sizes of 200 μm, 400 μm and 500 μm, respectively for a horizontal L valve. Two mathematical correlations have been developed from the experimental results to predict solid circulation rate as a function of riser flow rate, aeration flow rate, total bed inventory and particle size used.     

Reduced dosage of genes encoding ribosomal protein S18 suppresses a mitochondrial initiation codon mutation in Saccharomyces cerevisiae

A yeast mitochondrial translation initiation codon mutation affecting the gene for cytochrome oxidase subunit III (COX3) was partially suppressed by a spontaneous nuclear mutation. The suppressor mutation also caused cold-sensitive fermentative growth on glucose medium. Suppression and cold sensitivity resulted from inactivation of the gene product of RPS18A, one of two unlinked genes that code the essential cytoplasmic small subunit ribosomal protein termed S18 in yeast. The two S18 genes differ only by 21 silent substitutions in their exons; both are interrupted by a single intron after the 15th codon. Yeast S18 is homologous to the human S11 (70% identical) and the Escherichia coli S17 (35% identical) ribosomal proteins. This highly conserved family of ribosomal proteins has been implicated in maintenance of translational accuracy and is essential for assembly of the small ribosomal subunit. Characterization of the original rps18a-1 missense mutant and rps18a delta and rps18b delta null mutants revealed that levels of suppression, cold sensitivity and paromomycin sensitivity all varied directly with a limitation of small ribosomal subunits. The rps18a-1 mutant was most affected, followed by rps18a delta then rps18b delta. Mitochondrial mutations that decreased COX3 expression without altering the initiation codon were not suppressed. This allele specificity implicates mitochondrial translation in the mechanism of suppression. We could not detect an epitope-tagged variant of S18 in mitochondria. Thus, it appears that suppression of the mitochondrial translation initiation defect is caused indirectly by reduced levels of cytoplasmic small ribosomal subunits, leading to changes in either cytoplasmic translational accuracy or the relative levels of cytoplasmic translation products.     

Mechanical consequences of core drilling and bone-grafting on osteonecrosis of the femoral head

We employed an anatomically realistic three-dimensional finite-element model to explore several biomechanical variables involved in coring or bone-grafting of a segmentally necrotic femoral head. The mechanical efficacy of several variants of these procedures was indexed in terms of their alteration of the stress:strength ratio in at-risk necrotic cancellous bone. For coring alone, the associated structural compromise was generally modest, provided that the tract did not extend near the subchondral plate. Cortical bone-grafting was potentially of great structural benefit for femoral heads in which the graft penetrated deeply into the superocentral or lateral aspect of the lesion, ideally with abutment against the subchondral plate. By contrast, central or lateral grafts that stopped well short of the subchondral plate were contraindicated biomechanically because they caused marked elevations in stress on the necrotic cancellous bone. Calculated levels of stress were relatively insensitive to variations in the diameter of the graft.     

Effect of surface-modifying macromolecules and solvent evaporation time on the performance of polyethersulfone membranes for the separation of chloroform/water mixtures by pervaporation

Polyethersulfone (PES) membranes using different evaporation periods were fabricated by the phase-inversion method. Pervaporation experiments were conducted for chloroform/water mixtures to determine the selectivity of the PES membranes. It was found that chloroform could be concentrated in the permeate from chloroform/water binary feed mixtures by PES membranes prepared using longer evaporation periods, and that the selectivity of PES membranes in pervaporation could be reversed by shorter evaporation periods. This study also showed that by adding surface-modifying macromolecules (SMM) up to 1 wt % into the casting solution, chloroform enrichment in the permeate could be increased by 50%. Chloroform enrichment increased with increasing SMM concentration until an optimal value, after which the enrichment decreased. © 1994 John Wiley & Sons, Inc.     

Effects of aging and schedules of knowledge of results on motor learning

Little research has been conducted on aging and the learning of motor skills. In this study, we examined the effects of different schedules of knowledge of results (KR) on the acquisition and retention of a movement timing task by young adults (20-23 years) and older adults (60-82 years). The results indicated that there were differences between young and older adults in the accuracy and consistency of motor performance when KR was provided. Accuracy effects persisted during a retention interval when KR was no longer provided, although there were no differences in variability. There were no interactions of age with any of the KR-related variables. These findings suggest that the ability to process KR, and the effects of KR on motor learning, are similar in young and older adults. These findings are discussed in terms of age-related issues in movement control and learning processes.