Orbital-flop transition of superfluid 3He in anisotropic silica aerogel.

Superfluid 3He is a paradigm for odd-parity Cooper pairing, ranging from neutron stars to uranium-based superconducting compounds. Recently it has been shown that 3He, imbibed in anisotropic silica aerogel with either positive or negative strain, preferentially selects either the chiral A-phase or the time-reversal-symmetric B-phase. This control over basic order parameter symmetry provides a useful model for understanding imperfect unconventional superconductors. For both phases, the orbital quantization axis is fixed by the direction of strain. Unexpectedly, at a specific temperature Tx, the orbital axis flops by 90∘, but in reverse order for A and B-phases. Aided by diffusion limited cluster aggregation simulations of anisotropic aerogel and small angle X-ray measurements, we are able to classify these aerogels as either "planar" and "nematic" concluding that the orbital-flop is caused by competition between short and long range structures in these aerogels.

Magnetic Susceptibility of Andreev Bound States in Superfluid

Nuclear magnetic resonance measurements of the magnetic susceptibility of superfluid ^{3}He imbibed in anisotropic aerogel reveal anomalous behavior at low temperatures. Although the frequency shift clearly identifies a low-temperature phase as the B phase, the magnetic susceptibility does not display the expected decrease associated with the formation of the opposite-spin Cooper pairs. This susceptibility anomaly appears to be the predicted high-field behavior corresponding to the Ising-like magnetic character of surface Andreev bound states within the planar aerogel structures.

Greener residential environment is associated with increased bacterial diversity in outdoor ambient air.

In urban areas, exposure to greenspace has been found to be beneficial to human health. The biodiversity hypothesis proposed that exposure to diverse ambient microbes in greener areas may be one pathway leading to health benefits such as improved immune system functioning, reduced systemic inflammation, and ultimately reduced morbidity and mortality. Previous studies observed differences in ambient outdoor bacterial diversity between areas of high and low vegetated land cover but didn't focus on residential environments which are important to human health. This research examined the relationship between vegetated land and tree cover near residence and outdoor ambient air bacterial diversity and composition. We used a filter and pump system to collect ambient bacteria samples outside residences in the Raleigh-Durham-Chapel Hill metropolitan area and identified bacteria by 16S rRNA amplicon sequencing. Geospatial quantification of total vegetated land or tree cover was conducted within 500 m of each residence. Shannon's diversity index and weighted UniFrac distances were calculated to measure α (within-sample) and ß (between-sample) diversity, respectively. Linear regression for α-diversity and permutational analysis of variance (PERMANOVA) for ß-diversity were used to model relationships between vegetated land and tree cover and bacterial diversity. Data analysis included 73 ambient air samples collected near 69 residences. Analysis of ß-diversity demonstrated differences in ambient air microbiome composition between areas of high and low vegetated land (p = 0.03) and tree cover (p = 0.07). These relationships remained consistent among quintiles of vegetated land (p = 0.03) and tree cover (p = 0.008) and continuous measures of vegetated land (p = 0.03) and tree cover (p = 0.03). Increased vegetated land and tree cover were also associated with increased ambient microbiome α-diversity (p = 0.06 and p = 0.03, respectively). To our knowledge, this is the first study to demonstrate associations between vegetated land and tree cover and the ambient air microbiome's diversity and composition in the residential ecosystem.

Effect of Magnetic Impurities on Superfluid

It is known that both magnetic and nonmagnetic impurities suppress unconventional superconductivity. Here we compare their effect on the paradigm unconventional superconductor, superfluid ^{3}He, using highly dilute silica aerogel. Switching magnetic to nonmagnetic scattering in the same physical system is achieved by coating the aerogel surface with ^{4}He. We find a marginal influence on the transition temperature itself. However, we have discovered that the A phase, which breaks time reversal symmetry, is strongly influenced, while the isotropic B phase is unchanged. Importantly, this occurs only if the impurities are anisotropically distributed on a global scale.

Non-technical skills of surgeons and anaesthetists in simulated operating theatre crises.

BACKGROUND: Deficiencies in non-technical skills (NTS) have been increasingly implicated in avoidable operating theatre errors. Accordingly, this study sought to characterize the impact of surgeon and anaesthetist non-technical skills on time to crisis resolution in a simulated operating theatre. METHODS: Non-technical skills were assessed during 26 simulated crises (haemorrhage and airway emergency) performed by surgical teams. Teams consisted of surgeons, anaesthetists and nurses. Behaviour was assessed by four trained raters using the Non-Technical Skills for Surgeons (NOTSS) and Anaesthetists' Non-Technical Skills (ANTS) rating scales before and during the crisis phase of each scenario. The primary endpoint was time to crisis resolution; secondary endpoints included NTS scores before and during the crisis. A cross-classified linear mixed-effects model was used for the final analysis. RESULTS: Thirteen different surgical teams were assessed. Higher NTS ratings resulted in significantly faster crisis resolution. For anaesthetists, every 1-point increase in ANTS score was associated with a decrease of 53·50 (95 per cent c.i. 31·13 to 75·87) s in time to crisis resolution (P < 0·001). Similarly, for surgeons, every 1-point increase in NOTSS score was associated with a decrease of 64·81 (26·01 to 103·60) s in time to crisis resolution in the haemorrhage scenario (P = 0·001); however, this did not apply to the difficult airway scenario. Non-technical skills scores were lower during the crisis phase of the scenarios than those measured before the crisis for both surgeons and anaesthetists. CONCLUSION: A higher level of NTS of surgeons and anaesthetists led to quicker crisis resolution in a simulated operating theatre environment.

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies.

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.

Evaluation and management of cardiac safety using the electrocardiogram in oncology clinical trials: focus on cardiac repolarization (QTc interval).

Non-antiarrhythmic drugs have been reported to prolong the QTc interval and induce potentially fatal ventricular tachyarrhythmias. An increasing number of drugs that are used for treating malignancies are no exception. Therefore, both oncologists and regulators expect sponsors of oncology drugs to evaluate, during the development of the drugs, their effects on the electrocardiogram (ECG), particularly on the QTc interval. In the case of agents that cannot be administered to healthy volunteers, the primary approach is to carry out an intense ECG evaluation, employing robust ECG recordings, during early-phase clinical trials, together with characterization of the concentration-QTc interval relationship, and follow this up with an appropriate intensity of ECG monitoring in the later phases of development. This article describes the broad principles of these approaches, including recommendations for exclusion criteria (relative to baseline QTc interval and to cardiac comorbidity); it also describes methods for conducting ECG monitoring and a proposed scheme for the management of any QTc-related effects that may emerge.

Structure and function of AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) regulates metabolism in response to energy demand and supply. AMPK is activated in response to rises in intracellular AMP or calcium-mediated signalling and is responsible for phosphorylating a wide variety of substrates. Recent structural studies have revealed the architecture of the alphabetagamma subunit interactions as well as the AMP binding pockets on the gamma subunit. The alpha catalytic domain (1-280) is autoinhibited by a C-terminal tail (313-335), which is proposed to interact with the small lobe of the catalytic domain by homology modelling with the MARK2 protein structure. Two direct activating drugs have been reported for AMPK, the thienopyridone compound A769662 and PTI, which may activate by distinct mechanisms.

Pharmacological activators of AMP-activated protein kinase have different effects on Na+ transport processes across human lung epithelial cells.

BACKGROUND AND PURPOSE: AMP-activated protein kinase (AMPK) is activated by metformin, phenformin, and the AMP mimetic, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have completed an extensive study of the pharmacological effects of these drugs on AMPK activation, adenine nucleotide concentration, transepithelial amiloride-sensitive (I(amiloride)) and ouabain-sensitive basolateral (I(ouabain)) short circuit current in H441 lung epithelial cells. EXPERIMENTAL APPROACH: H441 cells were grown on permeable filters at air interface. I(amiloride), I(ouabain) and transepithelial resistance were measured in Ussing chambers. AMPK activity was measured as the amount of radiolabelled phosphate transferred to the SAMS peptide. Adenine nucleotide concentration was analysed by reverse phase HPLC and NAD(P)H autofluorescence was measured using confocal microscopy. KEY RESULTS: Phenformin, AICAR and metformin increased AMPK (alpha1) activity and decreased I(amiloride). The AMPK inhibitor Compound C prevented the action of metformin and AICAR but not phenformin. Phenformin and AICAR decreased I(ouabain) across H441 monolayers and decreased monolayer resistance. The decrease in I(amiloride) was closely related to I(ouabain) with phenformin, but not in AICAR treated monolayers. Metformin and phenformin increased the cellular AMP:ATP ratio but only phenformin and AICAR decreased cellular ATP. CONCLUSIONS AND IMPLICATIONS: Activation of alpha1-AMPK is associated with inhibition of apical amiloride-sensitive Na(+) channels (ENaC), which has important implications for the clinical use of metformin. Additional pharmacological effects evoked by AICAR and phenformin on I(ouabain), with potential secondary effects on apical Na+ conductance, ENaC activity and monolayer resistance, have important consequences for their use as pharmacological activators of AMPK in cell systems where Na+K+ATPase is an important component.

Synthesis and activity of the melanocortin Xaa-d-Phe-Arg-Trp-NH tetrapeptides with amide bond modifications.

The melanocortin receptor (MCR) pathway has been identified as participating in several physiologically important pathways including pigmentation, energy homeostasis, inflammation, obesity, hypertension, and sexual function. All the endogenous MCR agonists contain a core His-Phe-Arg-Trp sequence identified as important for receptor molecular recognition and stimulation. Several structure-activity studies using the Ac-His-d-Phe-Arg-Trp-NH2 tetrapeptide template have been performed in the context of modifying N-terminal 'capping' groups and amino acid constituents. Herein, we report the synthesis and pharmacologic characterization of modified Xaa-d-Phe-Arg-Trp-NH2 (Xaa = His or Phe) melanocortin tetrapeptides (N-site selective methylation, permethylation, or amide bond reduction) at the mouse MC1, MC3, MC4 and MC5 receptors. The modified peptides generated in this study resulted in equipotent or reduced MCR potency when compared with control ligands. The reduced amide bond analog of the Phe-d-Phe-Arg-Trp-NH2 peptide converted its agonist activity into an antagonistic at the central mMC3 and mMC4 receptors involved in the regulation of energy homeostasis, while retaining full agonist activity at the peripheral MC1 and MC5 receptors.

Evaluation of the notification of hepatitis C risk to children who received unscreened blood or blood products.

Parents of children who received blood or blood products between 1984 and 1990 were notified about the potential risk of hepatitis C virus (HCV) infection. Data were collected about knowledge, attitudes and intended behaviours to determine the acceptability of the notification process. Demographic variables that may predict responses to notification were also recorded and analysed. Recipients were sent couriered letters explaining HCV risk, and the survey questionnaire. Sera were screened for HCV antibody and reactive samples confirmed with a recombinant immunoblot assay (RIBA). Four letter recipients were RIBA positive for a prevalence of 1.1% (4/358) in the notification group. Thirty-two percent of respondents did not know their child had been transfused and 58% did not know about the potential risk of HCV infection. Although 90% (165/185) felt the notification was valuable, 65% reported emotional distress (fear, worry, anger, very depressed). Responders were similar to non-responders except for HCV testing rate (76.2% v. 59.8%, p < 0.0002). Parents of children at risk of transfusion-acquired HCV virus approved of notification programs, but experienced some emotional distress. Awareness of transfusion history or risk of HCV was not universal, indicating the need to address notification to individuals, rather than through public education campaigns alone.

Effects of air flow on rat electroolfactogram.

The electroolfactogram (EOG) previously has been used to demonstrate the regional distribution of rat olfactory epithelial odorant responses. Here, we evaluated the effects of airflow parameters on EOGs in two preparations: one where odorants were directly applied to the epithelium (opened preparation) and one where odorants were drawn through the nasal passages by an artificial sniff (closed preparation). EOG rise times served as one measure of odorant access. For isoamyl acetate (but not for limonene), rise times were slower in the lateral recesses of the closed (but not the opened) preparation. Polar odorants (amyl acetate, carvone and benzaldehyde) evoked smaller responses in the closed preparation than in the opened preparation, and these responses were particularly depressed in the lateral regions of the closed preparation. Responses to nonpolar hydrocarbon odorants (limonene and benzene) were equal in the lateral regions of both preparations, but were somewhat depressed in the medial region of the closed preparation. The responses to some polar odorants in the closed preparation were sensitive to changes in airflow parameters. These data suggest that the sorptive properties of the nose contribute substantially to determining the response of the epithelium and act to increase differences produced by inherent receptor mechanisms.

Chemical determinants of the rat electro-olfactogram.

The chemical properties that determine the distribution of the electro-olfactogram were studied after exposure of a large area of the rat olfactory epithelium. Multiple electrodes were placed along the rostral border of endoturbinate IV on the midline of the nasal cavity. This array of electrodes spanned a region containing the four receptor gene expression zones described for the rat. The response to a series of odorants containing only carbon, hydrogen, and oxygen was strongly related to electrode position. For most hydrocarbons, the responses were progressively larger toward the ventral epithelium. The only exceptions were aromatic hydrocarbons, which evoked nearly equal response sizes across the epithelium. Ketones and aldehydes evoked relatively larger dorsal responses than did hydrocarbons with similar structures. Aromatic ketones and aldehydes evoked systematically larger responses from the dorsal part of the epithelium. The response profiles for most odorants were well described by a linear fit to the electrode position along the dorsal-ventral position on the epithelium. However, a few bicyclic odorants and carboxylic acids evoked significantly nonlinear profiles. It is concluded that there is a systematic distribution of odorant sensitivity across this part of the epithelium and that this sensitivity is related to general chemical properties. Other evidence suggests that these properties extend to other parts of the epithelium. This spatial sensitivity of the epithelium to odorants probably contributes to olfactory coding in parallel with the convergence of axons from olfactory sensory neurons expressing the same receptor type.

A functional map in rat olfactory epithelium.

Multiple (four or eight) electrode arrays were placed for simultaneous electro-olfactogram (EOG) recordings of responses to a series of odors applied directly to the olfactory epithelium. Three different surfaces of the epithelium were exposed in rats immediately after death by anesthetic overdose. We tested three terpene compounds (carvone, limonene and 1,8-cineole) across the epithelium along the medial surface of the endoturbinate bones. Carvone, a ketone, evoked larger responses dorsally on the epithelium. The largest responses to 1,8-cineole (an ether) were seen in an intermediate-ventral region. The responses to limonene (a hydrocarbon) did not vary greatly across the regions, although they were often larger ventrally. The response distributions deviated from this simple pattern on the caudal part of endoturbinate IV, where the carvone responses were small and the limonene responses were larger. These differences were evident across a substantial concentration range. Similar distributions were seen for these three odors in tests along the dorsal-to-ventral direction across the nasal septum and in the medial-to-lateral direction across the dorsal aspect of one of the endoturbinate bones reaching out into the lateral recess. We argue that the spatial distributions of responses are correlated with the olfactory receptor gene expression zones.

Chronic myelogenous leukemia and porphyria cutanea tarda in a patient with limited systemic sclerosis.

Systemic sclerosis is uncommonly associated with hematologic malignancies. We report the case of a patient who had chronic myelogenous leukemia 3 years after the CREST variant of systemic sclerosis was diagnosed. She also later had porphyria cutanea tarda. The majority of patients who had hematologic malignancies after the diagnosis of systemic sclerosis proved to have either multiple myeloma or chronic lymphocytic leukemia. Hematologic malignancies may be found in patients with systemic sclerosis (either limited or diffuse).

Evidence for the Preemptive Nature of Tomato Race 3 of Xanthomonas campestris pv. vesicatoria in Florida.

ABSTRACT Until recently, tomato race 1 (T1) of Xanthomonas campestris pv. vesicatoria was the only race causing bacterial spot of tomato in Florida. In 1991, tomato race 3 (T3) was first identified in 3 of 13 tomato production fields surveyed. By 1994, T3 was observed in 21 of 28 fields and was the only race identified in 14 fields. In field studies, tomato genotypes with resistance to either T1 or T3 or susceptibility to both were co-inoculated with strains of both races. Lesions on 10 plants in each of three replications for each genotype were sampled three times during the experiment; bacterial isolations were made from each lesion, and tomato race identifications were made for each strain. At the third sampling date, T3 was isolated from 97% of the lesions on the susceptible genotype Walter and the T1-resistant genotype Hawaii 7998, while T3 was isolated from 23% of the lesions and T1 from the remaining 77% on the T3-resistant genotypes PI 128216 and PI 126932. In surface population studies done in growth rooms, suspensions of T1 and T3 were applied alone and in combination to the leaf surfaces of susceptible and resistant genotypes. T1 populations were reduced more than 10-fold when applied in combination with T3, compared with populations that developed when T1 was applied alone. T3 populations were not affected when applied in combination with a T1 strain. In greenhouse studies with the T3-resistant genotype Hawaii 7981, disease was significantly reduced in plants inoculated with T3 in combination with T1, compared with plants inoculated with T1 alone. These results clearly demonstrate the competitive nature of T3 in the presence of T1 and help explain the emergence of T3 as a prevalent race in Florida.

Renal vascular transit time and tubular transit time dispersion for 99Tcm-MAG3.

Renal transit time usually refers to tubular transit time, as introduced by Taplin, but other measures of renal transit have been proposed. Here we examine the vascular transit time (VTT, following Rutland) and the standard deviation of tubular transit time (SDTT, following Britton) in a group of 30 patients having baseline and ACE-inhibitor 99Tcm-MAG3 renography prior to arteriography. A same-day, low-dose/high-dose protocol was used for renography; only the post-captopril dose was high enough to measure VTT. Pre-captopril, the Spearman rank correlation coefficient for SDTT was rho = 0.52 (n = 53 kidneys; P < 0.0002); post-captopril, rho = 0.54 (n = 49 kidneys; P < 0.0002). For VTT, the post-captopril value was rho = 0.24 (n = 30 kidneys; N.S.). For comparison, the same statistics were calculated for Taplin's original measure of transit time: the time from injection to maximum count rate (peak time). Pre-captopril, for peak time, rho was 0.47 (n = 53 kidneys; P < 0.001); post-captopril, rho was 0.39 (n = 50 kidneys, P < 0.01). These findings confirm the diagnostic value of SDTT but not of VTT. SDTT correlated better than peak time with the arteriographic findings.