Systemic acidemia impairs cardiac function in critically Ill patients.

BACKGROUND: Acidemia, is associated with reduced cardiac function in animals, but no studies showing an effect of acidemia on cardiac function in humans are reported. In the present study, we examined the effect of acidemia on cardiac function assessed with transpulmonary thermodilution technique with integrated pulse contour analysis (Pulse Contour Cardiac Output, PiCCO™) in a large cohort of critically ill patients. METHODS: This was a prospective multicenter observational cross-sectional study of 297 patients from 6 intensive care units in London, England selected from all patients admitted consecutively between May 2018 and March 2019. Measurements of lowest plasma pH and concurrent assessment of cardiac function were obtained. FINDINGS: There was a significant difference between two pH categories (pH ≤ 7.28 vs. pH > 7.28) for the following variables of cardiac function: SVI (difference in means 32.7; 95% CI: 21 to 45 mL/m2; p < 0.001); GEF (18; 95% CI: 11 to 26%; p < 0.001), dPmax (-331; 95% CI: -510 to -153 mmHg/s; p = 0.001), CFI (0.7; 95% CI: 0.2 to 1.3 1/min; p = 0.01) and CPI (0.09; 95% CI: 0.03 to 0.15 W/m2; p < 0.001). However, there was no significant difference in CI (0.13; 95% CI: -0.20 to 0.47 L/min/m2; p = 0.12) between the pH categories. Also, a significant relationship was found between the quantitative pH and the following variables: SVI (132; 95% CI: 77 to 188 mL/m2; p < 0.001), GEF (74.7; 95% CI: 37.1 to 112.4%; p < 0.001), dPmax (-1587; 95% CI: -2361 to -815 mmHg/s; p < 0.001), CFI (3.5; 95% CI: 0.9 to 6.1 /min; p = 0.009), CPI (0.62; 95% CI: 0.36 to 0.88 W/m2; p < 0.001) and CI (regression coefficient 1.96; 95% CI:0.45 to 3.47 L/min/m2; p = 0.01). INTERPRETATION: Acidemia is associated with impaired cardiac function in seriously ill patients hospitalized in the intensive care unit supporting the potential value of early diagnosis and improvement of arterial pH in these patients. FUNDING: The study was partially supported by unrestricted funds from the UCLA School of Medicine.

FTIR imaging detects diet and genotype-dependent chemical composition changes in wild type and mutant C. elegans strains.

This study focuses on the use of Fourier Transform Infrared (FTIR) microspectroscopy to determine chemical changes induced in the nematode Caenorhabditis elegans by supplementation of C. elegans maintenance media (CeMM) by Eicosapentaenoic acid (EPA). Wild-type C. elegans (N2) and mutant strains (tub-1 and fat-3) were grown in CeMM alone, and CeMM supplemented with EPA at 25 or 100 µM. Feeding was performed for 72 h. FTIR imaging was performed in transmission mode on individual worms. The FTIR imaging analysis of wild-type animals revealed the presence of vibrations assigned to unsaturated fatty acids, specifically bands at 3008 cm-1 ([double bond, length as m-dash]C-H, olefinic stretch) and 1744 cm-1 (C[double bond, length as m-dash]O, unsaturated fatty acids). It confirmed previously reported synthesis of unsaturated fatty acids in wild-type C. elegans. For the FTIR spectra of mutant strains, these vibrations were absent or present only as very small shoulder, which indicates that tub-1 and fat-3 synthesize essentially saturated fatty acids as indicated by the presence of -CH2 and C[double bond, length as m-dash]O vibrations. These results are in agreement with previous studies which reported that these mutants have altered lipid compositions. Principal component analysis showed differences in chemical composition between wild-type and mutant strains as well as between mutant strains cultured in normal CeMM and those cultured in CeMM supplemented with EPA. This study demonstrated the usefulness of FTIR microspectroscopy to investigate fat metabolism in C. elegans.

Compact flat-panel gas-gap heat switch operating at 295 K.

Heat switches are devices that can change from a thermally conducting (on-) state to an insulating (off-) state whenever the need arises. They enable adaptive thermal management strategies in which cooling rates are altered either spatially or temporally, leading to a substantial reduction in the energy and mass budget of a large range of systems. State-of-the-art heat switches are only rarely employed in thermal system architectures, since they are rather bulky and have a limited thermal performance (expressed as the heat transfer ratio between the on- and off-state heat conductance). Using selective laser melting additive manufacturing technology, also known as 3D printing, we developed a compact flat-panel gas-gap heat switch that offers superior thermal performance, is simpler and more economic to produce and assemble, contains no moving parts, and is more reliable because it lacks welded joints. The manufactured rectangular panel heat switch has frontal device dimensions of 10 cm by 10 cm, thickness of 3.2 mm and weighs just 121 g. An off heat conductance of 0.2 W/K and on-off heat conductance ratio of 38 is observed at 295 K.

Cooling a low noise amplifier with a micromachined cryogenic cooler.

The sensitivity of antenna systems increases with increasing active area, but decreases at higher noise figure of the low-noise amplifier (LNA). Cooling the LNA locally results in significant improvement in the gain and in lowering the noise figure of the LNA. Micromachined Joule-Thomson (JT) coolers can provide a cryogenic environment to the LNA. They are attractive because they have no cold moving parts and can be scaled down to match the size and the power consumption of LNAs. The performance of a LNA mounted on a JT microcooler with dimensions of 60.0 × 9.5 × 0.72 mm(3) is reported in this paper. The microcooler is operated with nitrogen gas and the cold-end temperature is controlled at 115 K. The measured net cooling power of the microcooler is about 43 mW when the LNA is not operating. The power dissipation of the LNA is 26 mW, with a supply voltage of 2 V. At room temperature the noise figure of the LNA is 0.83 dB and the gain lies between 17.9 and 13.1 dB, in the frequency range of 0.65 and 1.05 GHz. Upon cooling to 115 K, the noise figure drops to 0.50 dB and the increase in gain varies in the range of 0.6-1.5 dB.

Probing the mechanical properties of brain cancer cells using a microfluidic cell squeezer device.

Despite being invasive within surrounding brain tissues and the central nervous system, little is known about the mechanical properties of brain tumor cells in comparison with benign cells. Here, we present the first measurements of the peak pressure drop due to the passage of benign and cancerous brain cells through confined microchannels in a "microfluidic cell squeezer" device, as well as the elongation, speed, and entry time of the cells in confined channels. We find that cancerous and benign brain cells cannot be differentiated based on speeds or elongation. We have found that the entry time into a narrow constriction is a more sensitive indicator of the differences between malignant and healthy glial cells than pressure drops. Importantly, we also find that brain tumor cells take a longer time to squeeze through a constriction and migrate more slowly than benign cells in two dimensional wound healing assays. Based on these observations, we arrive at the surprising conclusion that the prevailing notion of extraneural cancer cells being more mechanically compliant than benign cells may not apply to brain cancer cells.

Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.

AIM: G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects. METHODS: This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes. RESULTS: JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline. CONCLUSIONS: These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

High frequency pressure oscillator for microcryocoolers.

Microminiature pulse tube cryocoolers should operate at a frequency of an order higher than the conventional macro ones because the pulse tube cryocooler operating frequency scales inversely with the square of the pulse tube diameter. In this paper, the design and experiments of a high frequency pressure oscillator is presented with the aim to power a micropulse tube cryocooler operating between 300 and 80 K, delivering a cooling power of 10 mW. Piezoelectric actuators operate efficiently at high frequencies and have high power density making them good candidates as drivers for high frequency pressure oscillator. The pressure oscillator described in this work consists of a membrane driven by a piezoelectric actuator. A pressure ratio of about 1.11 was achieved with a filling pressure of 2.5 MPa and compression volume of about 22.6 mm(3) when operating the actuator with a peak-to-peak sinusoidal voltage of 100 V at a frequency of 1 kHz. The electrical power input was 2.73 W. The high pressure ratio and low electrical input power at high frequencies would herald development of microminiature cryocoolers.

Electrowetting --a versatile tool for controlling microdrop generation.

Integrating insulator-covered electrodes into a microfluidic flow focusing device (FFD) we demonstrate enhanced flexibility and control of the flow of two non-miscible liquids based on electrowetting (EW). In the parameters space, determined by liquid inlet pressures, we identify a specific region where drops can only be generated and addressed via EW. In this regime we show that the size distribution and the frequency of drop generation can be controlled by the applied voltage and the width of voltage pulses. Moreover it turns out that with EW the drop size and the frequency can be tuned independently. Finally we show that the same drop generation phenomena can also be observed in the presence of surfactants.

A liquid chromatographic method for the simultaneous determination of promethazine and three of its metabolites in plasma using electrochemical and UV detectors.

A new assay method has been developed for the quantitation of promethazine (PMZ) with a sensitivity and reproducibility as good as any previously reported method. This method is also capable of quantitatively determining three metabolites of PMZ (monodemethylated, sulphoxidated, and monodemethylated sulphoxidated PMZ), which has not been previously described. The method uses high-performance liquid chromatography with amperometric and UV detection simultaneously and requires only one extraction step from serum with chloroform. The method uses trifluoperazine as the internal standard. The limit of detection level for PMZ is 1.0 ng/ml when a 0.2-mL specimen of plasma is assayed. A validation study is also conducted for evaluating the recovery, precision, linearity of response, sensitivity, and selectivity of the method.