Determination of the Boltzmann constant with cylindrical acoustic gas thermometry: new and previous results combined.

We report a new determination of the Boltzmann constant kB using a cylindrical acoustic gas thermometer. We determined the length of the copper cavity from measurements of its microwave resonance frequencies. This contrasts with our previous work (Zhang et al 2011 Int. J. Thermophys.32 1297, Lin et al 2013 Metrologia50 417, Feng et al 2015 Metrologia52 S343) that determined the length of a different cavity using two-color optical interferometry. In this new study, the half-widths of the acoustic resonances are closer to their theoretical values than in our previous work. Despite significant changes in resonator design and the way in which the cylinder length is determined, the value of kB is substantially unchanged. We combined this result with our four previous results to calculate a global weighted mean of our kB determinations. The calculation follows CODATA's method (Mohr and Taylor 2000 Rev. Mod. Phys. 72 351) for obtaining the weighted mean value of kB that accounts for the correlations among the measured quantities in this work and in our four previous determinations of kB. The weighted mean k̂B is 1.380 6484(28) × 10-23 J K-1 with the relative standard uncertainty of 2.0 × 10-6. The corresponding value of the universal gas constant is 8.314 459(17) J K-1 mol-1 with the relative standard uncertainty of 2.0 × 10-6.

Interventions for enhancing return to work in individuals with a common mental illness: systematic review and meta-analysis of randomized controlled trials.

Common mental disorders (CMDs) are highly prevalent in the working population, and are associated with long-term sickness absence and disability. Workers on sick leave with CMDs would benefit from interventions that enable them to successfully return to work (RTW). However, the effectiveness of RTW interventions for workers with a CMD is not well studied. The objective of this review is to assess the effectiveness of existing workplace and clinical interventions that were aimed at enhancing RTW. A systematic review of studies of interventions for improving RTW in workers with a CMD was conducted. The main outcomes were proportion of RTW and sick-leave duration until RTW. Randomized controlled trials (RCTs) were identified from Medline/PubMed, PsycINFO, EMBASE, SocINDEX, and Human resource and management databases from January 1995 to 2016. Two authors independently selected studies, assessed risk of bias and extracted data. We pooled studies that we deemed sufficiently homogeneous in different comparison groups and assessed the overall quality of the evidence. We reviewed 2347 abstracts from which 136 full-text articles were reviewed and 16 RCTs were included in the analysis. Combined results from these studies suggested that the available interventions did not lead to improved RTW rates over the control group [pooled risk ratio 1.05, 95% confidence interval (CI) 0.97-1.12], but reduced the number of sick-leave days in the intervention group compared to the control group, with a mean difference of -13.38 days (95% CI -24.07 to -2.69).

Acoustic and microwave tests in a cylindrical cavity for acoustic gas thermometry at high temperature.

Relative primary acoustic gas thermometry (AGT) determines the ratios of thermodynamic temperatures from measured ratios of acoustic and microwave resonance frequencies in a gas-filled metal cavity on isotherms of interest. When measured in a cavity with known dimensions, the frequencies of acoustic resonances in a gas determine the speed of sound, which is a known function of the thermodynamic temperature T. Changes in the dimensions of the cavity are measured using the frequencies of the cavity's microwave resonances. We explored techniques and materials for AGT at high temperatures using a cylindrical cavity with remote acoustic transducers. We used gas-filled ducts as acoustic waveguides to transmit sound between the cavity at high temperatures and the acoustic transducers at room temperature. We measured non-degenerate acoustic modes in a cylindrical cavity in the range 295 K

Tuberculous pericarditis: a diagnostic quandary.

Tuberculous pericarditis is uncommon in the Western world, and can prove a diagnostic quandary in that confirmation of the diagnosis and culture of mycobacteria can be difficult. We present a case of tuberculous pericarditis where endobronchial ultrasound-guided transbronchial needle biopsy of a pathological lymph node provided the diagnosis after other methods of investigation had proved futile.

An unusual infection in an injecting drug user.

Injecting drug users are prone to atypical infections. We present a case of septic thrombophlebitis secondary to Fusobacterium gonidiaformans infection in a heroin user, which demonstrates the frequently unusual nature of pathogens and presentations in this group of patients.

Perturbations From Ducts on the Modes of Acoustic Thermometers.

We examine the perturbations of the modes of an acoustic thermometer caused by circular ducts used either for gas flow or as acoustic waveguides coupled to remote transducers. We calculate the acoustic admittance of circular ducts using a model based on transmission line theory. The admittance is used to calculate the perturbations to the resonance frequencies and half-widths of the modes of spherical and cylindrical acoustic resonators as functions of the duct's radius, length, and the locations of the transducers along the duct's length. To verify the model, we measured the complex acoustic admittances of a series of circular tubes as a function of length between 200 Hz and 10 kHz using a three-port acoustic coupler. The absolute magnitude of the specific acoustic admittance is approximately one. For a 1.4 mm inside-diameter, 1.4 m long tube, the root mean square difference between the measured and modeled specific admittances (both real and imaginary parts) over this frequency range was 0.018. We conclude by presenting design considerations for ducts connected to acoustic thermometers.

Proton pump inhibitor use and progression to major adverse renal events: a competing risk analysis.

BACKGROUND: Proton pump inhibitors (PPIs) are associated with acute tubulointerstitial nephritis and there are reports associating their use with the development of chronic kidney disease (CKD). AIM: To determine if PPI use is associated with major adverse renal events (MARE) in patients with CKD. DESIGN: Observational cohort study comprising patients with CKD attending secondary care renal clinics from 1 January 2006 until 31 December 2016. METHODS: We collated baseline clinical, socio-demographic and biochemical data at start of PPI (PPI group) or study inception (control group). MARE was considered a composite of doubling of creatinine or end-stage renal disease. Association between PPI exposure and progression to MARE was assessed by cause-specific hazards competing risk survival analysis. RESULTS: There were 3824 patients with CKD included in the analyses of whom 1195 were prescribed a PPI. The PPI group was younger (64.8 vs. 67.0 years, P < 0.001), with lower estimated glomerular filtration rate (eGFR) (30 vs. 35 ml/min, P < 0.001) and more proteinuria (64 vs. 48 mg/mmol, P < 0.001). PPI use was associated with progression to MARE on multivariable adjustment (hazard ratio 1.13 [95% confidence interval 1.02-1.25], P = 0.021). Other factors significantly associated with progression to MARE were higher systolic blood pressure, lower eGFR, greater proteinuria, congestive cardiac failure and diabetes. Hypomagnesaemia was more common in the PPI group (39.5 vs. 18.9%, P < 0.001). CONCLUSION: PPI use was associated with progression to MARE, but not death in patients with CKD after adjusting for factors known to predict declining renal function, including lower eGFR, proteinuria and comorbidities. A prospective cohort study is required to validate these findings.

Protein kinase C enhances exocytosis from chromaffin cells by increasing the size of the readily releasable pool of secretory granules.

We have used membrane capacitance measurements to assay Ca2+-triggered exocytosis in single bovine adrenal chromatin cells. Brief application of phorbol ester (PMA) enhances depolarization-evoked exocytosis severalfold while actually decreasing the Ca2+ current. Ca2+ metabolism is unchanged. Three different protocols were used to show that PMA increases the size of the readily releasable pool of secretory granules. PMA treatment leads to a large increase in amplitude, but little change in the time course of the exocytic burst that results from rapid elevation of [Ca2+]i upon photolysis of DMI-Nitrophen. Thus, PKC appears to affect a late step in secretion but not the Ca2+ sensitivity of the final step.

Experience with low-dose valganciclovir prophylaxis in adult liver transplant recipients.

Valganciclovir (VGCV) is considered the agent of choice after organ transplant for cytomegalovirus (CMV) prophylaxis. The purpose of this retrospective study was to determine the effectiveness and safety of a low-dose regimen after liver transplant (OLT). Eighty-five patients who underwent OLT between August 2002 and August 2004 were included. All patient data for the first 12 months after transplant were collected. Patients received VGCV 450 mg once daily for 3 months posttransplant. CMV infection was based on detection of CMV virus or viral proteins in blood. CMV disease was defined by the presence of positive antigenemia/viremia and evidence of clinical symptoms and/or tissue findings. Patients were D+R+ (54%) and D-R+ (29%), D+R-(11%) and D-R-(6%). Overall, CMV infection and disease occurred in 13% (11/85). CMV infection and disease occurred in 7% and 6%, respectively. CMV infection and disease occurred in 44% (D+R-), 13% (D+R+), 4% (D-R+) patients. The mean time to onset of CMV infection and disease was 103 days (14 to 312 days). Overall, 82% of patients received antibody therapy. The most common adverse events associated with VGCV were leukopenia (16%), thrombocytopenia (4%), anemia (<1%), and neurotoxicity (<1%). Low-dose VGCV was not an effective means to prevent CMV infection in high-risk (D+R-) patients, especially those who received antibody induction. High-risk patients may require a high-dose regimen, such as 900 mg daily, and/or a longer period of prophylaxis, and/or reduction in the use of potent antibody treatments after liver transplant.

Immortalization of Syrian hamster embryo cells: probabilistic event or deterministic process.

Previous findings on the induction of immortalization in SHE cells have been explained with the activation/alteration hypothesis which postulates that treatment with a carcinogen results in the induction of a so-called "activated state" which enhances the rate of a probabilistic event in the progeny of the treated cells. This event is supposed to be a mutation. Because it has been recently indicated that in mammalian cells the switching on of signal transduction pathways by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or carcinogens can lead to genetic instability in the progeny of the treated cells, the possibility of an analogy between the induction of genetic instability and induction of immortalization after treatment with TPA was investigated. No effect of TPA was found on the rate of immortalization/cell/generation, not in otherwise untreated cells nor in cells treated with benzo(a)pyrene. TPA was found to enhance the life span of SHE cells. The life span of a culture correlated with its growth rate and its cell density at confluence both in the absence and presence of TPA. These correlations are supposed to reflect a regulation mechanism involved in the program of cellular senescence, and supposedly TPA can partly reverse this program. Treatment with benzo(a)pyrene also interferes with the life span resulting in premature senescence in most of the cells and extension of life span in a small fraction of the cells which subsequently can become immortal. Repeated switching from logarithmic growth to G0 also enhanced life span and rate of immortalization. The findings indicate that the activated state is a disturbance of a differentiation program affecting in SHE cells the program of cellular senescence and that, as an explanation for immortalization, epigenetic alterations causing a deterministic process of dedifferentiation in a subpopulation of the cells appear as plausible or perhaps even more plausible as a probabilistic mutation. This indicates that disturbance of differentiation might be among the causes of genetic instability.

Detecting leaks in gas-filled pressure vessels using acoustic resonances.

We demonstrate that a leak from a large, unthermostatted pressure vessel into ambient air can be detected an order of magnitude more effectively by measuring the time dependence of the ratio p/f(2) than by measuring the ratio p/T. Here f is the resonance frequency of an acoustic mode of the gas inside the pressure vessel, p is the pressure of the gas, and T is the kelvin temperature measured at one point in the gas. In general, the resonance frequencies are determined by a mode-dependent, weighted average of the square of the speed-of-sound throughout the volume of the gas. However, the weighting usually has a weak dependence on likely temperature gradients in the gas inside a large pressure vessel. Using the ratio p/f(2), we measured a gas leak (dM/dt)/M ≈ - 1.3 × 10(-5) h(-1) = - 0.11 yr(-1) from a 300-liter pressure vessel filled with argon at 450 kPa that was exposed to sunshine-driven temperature and pressure fluctuations as large as (dT/dt)/T ≈ (dp/dt)/p ≈ 5 × 10(-2) h(-1) using a 24-hour data record. This leak could not be detected in a 72-hour record of p/T. (Here M is the mass of the gas in the vessel and t is the time.).

Transitioning Youth into Adult Mental Health and Addiction Services: An Outcomes Evaluation of the Youth Transition Project.

The Youth Transition Project was designed to provide youth with mental health and addiction issues with individualized transitional care plans as they transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS). Over an 18-month period, a total of 127 (59.1%) youth were transitioned and seen by an AMHS provider, 41 (19.1%) remained on a waitlist for services and 47 (21.8%) canceled services. The average time to transition was 110 days (SD = 100). Youth exhibited a wide range of diagnoses; 100% of the population was identified as having serious psychiatric problems. Findings demonstrate that the Youth Transition Project has been successful in promoting continuity of care by transitioning youth seamlessly from youth to adult services. Inconsistencies in wait times and service delivery suggest that further model development is needed to enhance the long-term sustainability of the Youth Transition Project.

Electrophysiology of stimulus-secretion coupling in human beta-cells.

Herein, we review the applicability to human beta-cells of an electrophysiologically based hypothesis of the coupling of glucose metabolism to insulin secretion. According to this hypothesis, glucose metabolism leads to the generation of intracellular intermediates (including ATP), which leads to closure of ATP-sensitive K+ channels. Channel closure results in membrane depolarization, the onset of electrical activity, and voltage-dependent Ca2+ entry. The resultant rise in cytosolic Ca2+ leads to Ca(2+)-dependent exocytosis of insulin granules. We found that most of the published experimental evidence for human beta-cells supports this hypothesis. In addition, we present three other emerging lines of evidence in support of this hypothesis for human islet beta-cells: 1) the effects of pHi-altering maneuvers on insulin secretion and electrical activity; 2) preliminary identification of LVA and HVA single Ca2+ channel currents; and 3) validation of the feasibility of Cm measurements to track insulin granule exocytosis. On the basis of this last new line of evidence, we suggest that combinations of Cm measurements and electrical activity/membrane current measurements may help define the roles of diverse electrical activity patterns, displayed by human beta-cells, in stimulus-induced insulin secretion.

Metabolite-regulated ATP-sensitive K+ channel in human pancreatic islet cells.

In patch-clamped surface cells of human islets, we identified an inwardly rectifying, voltage-independent K+ channel that may be a crucial link between substrate metabolism and depolarization-induced insulin secretion. It is the major channel open at rest. It closes on exposure of the cell to secretagogue concentrations of glucose or other metabolic fuels and oral hypoglycemic sulfonylureas but reopens on addition of either a metabolic inhibitor that prevents substrate utilization or the hyperglycemic sulfonamide diazoxide. Onset of electrical activity coincides with channel closure by the secretagogues. In excised patches, the activity of this channel is inhibited at its cytoplasmic surface by ATP. These results suggest that in humans, as in rodents, 1) rises in cytoplasmic ATP levels during substrate metabolism trigger K+-channel closure and cell depolarization and 2) clinically useful sulfonamides modulate glucose-induced insulin secretion, in part by affecting a readily identifiable resting conductance pathway for K+.

Stimulus-secretion coupling in beta-cells of transplantable human islets of Langerhans. Evidence for a critical role for Ca2+ entry.

With human islets isolated for transplantation, we examined the applicability to humans of a metabolic fuel hypothesis of glucose transduction and a Ca2+ hypothesis of depolarization-secretion coupling, both previously proposed for rodent islet beta-cells. We report that several features of human beta-cell physiology are well accounted for by these hypotheses. With whole-islet perifusion, we demonstrated that insulin secretion induced by glucose, tolbutamide, or elevated K+ is dependent on extracellular Ca2+. Insulin release induced by these secretagogues is enhanced by the dihydropyridine Ca2+ channel agonist BAYk8644 and depressed by the dihydropyridine Ca(2+)-channel antagonist nifedipine. All of the aforementioned secretagogues provoke increases in cytosolic free Ca2+, which are dependent on extracellular Ca2+ and are altered by the dihydropyridine drugs. Individual beta-cells in the islet display diminished resting membrane conductance, graded depolarization, and complex electrical patterns, including bursts of action potentials in response to stimulatory concentrations of glucose or tolbutamide. Individual islet beta-cells display voltage-dependent Ca2+ currents that are activated at membrane potentials traversed during the excursion of the action potential. In most cells, the Ca2+ currents are enhanced by BAYk8644 and depressed by nifedipine at concentrations that have parallel effects on secretagogue-induced increases in cytosolic Ca2+ and insulin secretion. These survey studies should provide the basis for more detailed investigations of the relationship of voltage-dependent ionic currents to electrical activity patterns and of electrical activity patterns to granule exocytosis in single human beta-cells.

The relationship between cAMP, Ca(2)+, and transport of CFTR to the plasma membrane.

The mechanism whereby cAMP stimulates Cl(-) flux through CFTR ion channels in secretory epithelia remains controversial. It is generally accepted that phosphorylation by cAMP-dependent protein kinase increases the open probability of the CFTR channel. A more controversial hypothesis is that cAMP triggers the translocation of CFTR from an intracellular pool to the cell surface. We have monitored membrane turnover in Calu-3 cells, a cell line derived from human airway submucosal glands that expresses high levels of CFTR using membrane capacitance and FM1-43 fluorescence measurements. Using a conventional capacitance measurement technique, we observe an apparent increase in membrane capacitance in most cells that exhibit an increase in Cl(-) current. However, after we carefully correct our recordings for changes in membrane conductance, the apparent changes in capacitance are eliminated. Measurements using the fluorescent membrane marker FM1-43 also indicate that no changes in membrane turnover accompany the activation of CFTR. Robust membrane insertion can be triggered with photorelease of caged Ca(2)+ in Calu-3 cells. However, no increase in Cl(-) current accompanies Ca(2)+-evoked membrane fusion. We conclude that neither increases in cAMP or Ca(2)+ lead to transport of CFTR to the plasma membrane in Calu-3 cells. In addition, we conclude that membrane capacitance measurements must be interpreted with caution when large changes in membrane conductance occur.

Gating of cystic fibrosis transmembrane conductance regulator chloride channels by adenosine triphosphate hydrolysis. Quantitative analysis of a cyclic gating scheme.

Gating of the cystic fibrosis transmembrane conductance regulator (CFTR) involves a coordinated action of ATP on two nucleotide binding domains (NBD1 and NBD2). Previous studies using nonhydrolyzable ATP analogues and NBD mutant CFTR have suggested that nucleotide hydrolysis at NBD1 is required for opening of the channel, while hydrolysis of nucleotides at NBD2 controls channel closing. We studied ATP-dependent gating of CFTR in excised inside-out patches from stably transfected NIH3T3 cells. Single channel kinetics of CFTR gating at different [ATP] were analyzed. The closed time constant (tauc) decreased with increasing [ATP] to a minimum value of approximately 0.43 s at [ATP] >1.00 mM. The open time constant (tauo) increased with increasing [ATP] with a minimal tauo of approximately 260 ms. Kinetic analysis of K1250A-CFTR, a mutant that abolishes ATP hydrolysis at NBD2, reveals the presence of two open states. A short open state with a time constant of approximately 250 ms is dominant at low ATP concentrations (10 microM) and a much longer open state with a time constant of approximately 3 min is present at millimolar ATP. These data suggest that nucleotide binding and hydrolysis at NBD1 is coupled to channel opening and that the channel can close without nucleotide interaction with NBD2. A quantitative cyclic gating scheme with microscopic irreversibility was constructed based on the kinetic parameters derived from single-channel analysis. The estimated values of the kinetic parameters suggest that NBD1 and NBD2 are neither functionally nor biochemically equivalent.

Bulk viscosity of stirred xenon near the critical point.

We deduce the thermophysical properties of near-critical xenon from measurements of the frequencies and half-widths of the acoustic resonances of xenon maintained at its critical density in centimeter-sized cavities. In the reduced temperature range 1 x 10-3<(T-Tc)/Tc<7 x 10 (-6), we measured the resonance frequency and quality factor (Q) for each of six modes spanning a factor of 27 in frequency. As Tc was approached, the frequencies decreased by a factor of 2.2 and the Q's decreased by as much as a factor of 140. Remarkably, these results are predicted (within +/-2% of the frequency and within a factor of 1.4 of Q) by a model for the resonator and a model for the frequency-dependent bulk viscosity zeta(omega) that uses no empirically determined parameters. The resonator model is based on a theory of acoustics in near-critical fluids developed by Gillis, Shinder, and Moldover [Phys. Rev. E 70, 021201 (2004)]. In addition to describing the present low-frequency data (from 120 Hz to 7.5 kHz), the model for zeta(omega) is consistent with ultrasonic (0.4--7 MHz) velocity and attenuation data from the literature. However, the model predicts a peak in the temperature dependence of the dissipation in the boundary layer that we did not detect. This suggests that the model overestimates the effect of the bulk viscosity on the thermal boundary layer. In this work, the acoustic cavities were heated from below to stir the xenon, thereby reducing the density stratification resulting from Earth's gravity. The stirring reduced the apparent equilibration time from several hours to a few minutes, and it reduced the effective temperature resolution from 60 mK to approximately 2 mK, which corresponds to (T-Tc)/Tc approximately =7 x 10(-6).

Two approaches for addressing electrochemical electrode arrays with reduced external connections.

Although patterning hundreds or thousands of electrochemical electrodes on lab-on-a-chip devices is straightforward and cost-effective using photolithography, easily making connections between hundreds of electrodes and external amplifiers remains a bottleneck. Here we describe two electrode addressing approaches using multiple fluid compartments that can potentially reduce the number of external connections by ~100-fold. The first approach enables all compartments on the device to be filled with solution at the same time, and then each fluid compartment is sequentially electrically activated to make the measurements. The second approach achieves lower measurement noise by sequentially filling recording chambers with solution. We propose an equivalent circuit to explain measurement noise in these recording configurations and demonstrate application of the approaches to measure quantal exocytosis from individual cells. A principle advantage of using these approaches is that they reduce the fraction of the microchip area that needs to be dedicated to making external connections and therefore reduces the cost per working electrode.

'Perforated patch recording' allows long-term monitoring of metabolite-induced electrical activity and voltage-dependent Ca2+ currents in pancreatic islet B cells.

We describe the application of 'perforated patch recording' using the pore-forming antibiotic nystatin, to monitor the electrical activity and underlying ionic currents of rat and human pancreatic islet B cells. We demonstrate that glucose-induced electrical activity is seen even in single B cells during current-clamp recordings lasting hours 'L-type' Ca2+-channel currents can also be monitored over this period of time. This technique may prove useful in examining hormone and neurotransmitter modulation of electrical activity in B cells, while minimizing the effects of cytoplasmic 'wash-out'.