The effect of posture on errors in gastric emptying measurements.
Scintigraphic gastric emptying measurements were made with subjects supine and upright using a dual-detector rectilinear scanner. Previously reported variations of the depth of activity during the course of a study were again found with both postures. Although there was no significant mean depth change in the group when upright, some individual variations were substantial. Measurements with a gamma camera demonstrated similar changes of depth of stomach contents with seated subjects. The resulting variations of attenuation of the emergent radiation lead to appreciable errors in the emptying rates determined by unilateral detection. In about half the cases the mean movement of a 99Tcm-labelled solid phase marker exceeded 1 cm; such a movement led to an average 20% error in emptying rate determination by an anterior detector. Depth changes of a liquid marker were less marked, exceeding 0.5 cm in half the subjects; this movement gave rise to an average 6% error when 113Inm was used as the tracer.


Optimal phenotypic adaptation in fluctuating environments.
Phenotypic adaptation is a universal feature of biological systems navigating highly variable environments. Recent empirical data support the role of memory-driven decision making in cellular systems navigating uncertain future nutrient landscapes, wherein a distinct growth phenotype emerges in fluctuating conditions. We develop a simple stochastic mathematical model to describe memory-driven cellular adaptation required for systems to optimally navigate such uncertainty. In this framework, adaptive populations traverse dynamic environments by inferring future variation from a memory of prior states, and memory capacity imposes a fundamental trade-off between the speed and accuracy of adaptation to new fluctuating environments. Our results suggest that the observed growth reductions that occur in fluctuating environments are a direct consequence of optimal decision making and result from bet hedging and occasional phenotypic-environmental mismatch. We anticipate that this modeling framework will be useful for studying the role of memory in phenotypic adaptation, including in the design of temporally varying therapies against adaptive systems.


Dental wear patterns in early modern humans from Skhul and Qafzeh: A response to Luca Fiorenza and Ottmar Kullmer.
It is common knowledge, that in archaic populations teeth could have been used as tools, such behavior can be studied by evaluating occlusal attrition patterns. Fiorenza and Kullmer suggested a digital approach to distinguish between masticatory and non-masticatory wear facets in archaic and modern populations. In their last response to our letter (Fiorenza and Kullmer, 2015), they used comparative modern samples to demonstrate that described para-facets in Skhul and Qafzeh individuals could not have been produced by dental occlusal anomalies and also since they claimed that more than 50% of the sample analyzed in their study are characterized by para-facets, it is highly unlikely to be the result of dental pathologies. What the authors neglected to mention is that misalignment of teeth and/or malocclusion features in the Qafzeh specimens for example are present in 55.5% of the individuals, and therefore, malocclusions should be at least reconsidered as a possible cause for the para-facets formation. Also, dental cross-bite may involve functional shift and mandibular deflection and therefore, should also be considered as a possible cause for untypical occlusal contacts. In the current reply, we indicate the disadvantages of the occlusal fingerprints analysis in archaic fragmented samples.


Estimating thermodynamic expectations and free energies in expanded ensemble simulations: Systematic variance reduction through conditioning.
Markov chain Monte Carlo methods are primarily used for sampling from a given probability distribution and estimating multi-dimensional integrals based on the information contained in the generated samples. Whenever it is possible, more accurate estimates are obtained by combining Monte Carlo integration and integration by numerical quadrature along particular coordinates. We show that this variance reduction technique, referred to as conditioning in probability theory, can be advantageously implemented in expanded ensemble simulations. These simulations aim at estimating thermodynamic expectations as a function of an external parameter that is sampled like an additional coordinate. Conditioning therein entails integrating along the external coordinate by numerical quadrature. We prove variance reduction with respect to alternative standard estimators and demonstrate the practical efficiency of the technique by estimating free energies and characterizing a structural phase transition between two solid phases.


T cell receptor induced intracellular redistribution of type I protein kinase A.
The productive activation of CD4(+) T lymphocytes, leading to proliferation and cytokine secretion, requires precise temporal regulation of intracellular cyclic AMP concentrations. The major effector molecule activated by cyclic AMP in mammalian cells is the cyclic AMP-dependent protein kinase A (PKA). The type I PKA isozyme mediates the inhibitory effects of cyclic AMP on T-cell activation. Using laser scanning confocal microscopy, we demonstrated that the regulation of PKA type I activity involves spatial redistribution of PKA type I molecules following T-cell receptor (TCR) stimulation. In resting T cells, PKA type I was located in membrane proximal regions and distributed equally across the cell. Shortly after antigen engagement, T cells and antigen-presenting cells formed an area of intense contact, known as the immunological synapse. TCR concentrated at the synapse, whereas PKA type I molecules redistributed to the opposite cell pole within 10 min after T-cell stimulation. Type I PKA redistribution was solely dependent on TCR signalling, because we observed the same temporal and spatial distribution after antibody-mediated cross-linking of the TCR-associated CD3 complex. Segregation of TCR and PKA type I molecules was maintained for at least 20 min. Thirty minutes after stimulation, PKA type I partially colocalized with the TCR. After 60 min, PKA type I distribution again approached the resting state. Considering that initial TCR signals lead to increases in intracellular cyclic AMP, PKA type I molecules may be targeted towards localized cyclic AMP accumulations or transported away from these areas, depending on the requirements of the cellular response.


A Comparison of Remote and Bedside Assessment of the National Institute of Health Stroke Scale in Acute Stroke Patients.
Telestroke videoconference for conducting the National Institute of Health Stroke Scale (NIHSS) is recommended when the facility of a direct bedside evaluation by a stroke specialist is not immediately available for hyperacute stroke assessment. However, some NIHSS-telestroke studies inherit systematic bias due to the subjective nature of NIHSS administration. We aimed to evaluate NIHSS telestroke assessment, while implementing measures to minimize subjectivity bias. Ninety stroke patients within 48 h of onset were assessed by 6 stroke neurologists grouped in 15 pairs. Each pair of physicians assessed 6 patients. Patients were allocated through block randomization to a physician pair and order of bedside or remote assessment. Every patient was assessed once at the bedside and once remotely. Remote examination was performed by a neurologist through high-quality videoconferencing (HQ-VTC), assisted by a nurse at the patient's bedside. Kappa coefficients and the number of patients with a cumulative difference of ≤3 NIHSS points were calculated to compare bedside and remote measures. Cumulative difference of ≤3 NIHSS points was observed in 85.6% (95% CI 76.6-92.1%) cases. Therefore, every fifth remote examination may have been inaccurate. Quadratically weighted kappa for total NIHSS score was 0.91 (95% CI 0.87-0.95). Minimal agreements were for commands (k = 0.46), facial palsy (k = 0.43), and ataxia (k = 0.27). Remote assessments were longer than bedside: 8 min (interquartile range, IQR 7-9) vs. 6 (IQR 5-8), p < 0.001. NIHSS-telestroke assessment using HQ-VTC in the acute stroke settings is closely matched with NIHSS-bedside assessment but it's credibility for clinical use needs further evaluation.


Effects of epidemiology learning software on nursing and midwifery students.
Being informed of new methods of teaching and comparing their outcome help teachers use more effective and efficient methods in developing and implementing new training courses. The aim of this study was to examine the efficacy of epidemiology learning software on learning epidemiology courses. This quasi-experimental study included 101 nursing and midwifery students taking epidemiology course in two separate classes. One of the classes was selected as intervention group (taught via software) and another one as the control group. At the end of the semester, scores of the courses were analyzed using covarianceanalysis. After adjusting the effect of grade point average, covariance analysis indicated a significant difference in epidemiology scores between the two groups (p<0.001). The students taught through the software obtained significantly higher scores compared to the students in traditional group. By means of this training software, teachers can use several strategies for presenting lessons and increasing training efficacy, leading to active learning in students.


Lactation pattern and the risk for hormone-related female cancer in Japan: the Ohsaki Cohort Study.
Although breastfeeding is associated with a reduction in the risk for breast cancer, its relationship with another hormone-related female cancer, endometrial cancer, has not been fully investigated. The objective of the present study was to prospectively examine the association between lactation pattern and the risk for incidence of breast cancer and endometrial cancer in Japanese women. We analyzed data for 26 680 women registered in the Ohsaki National Health Insurance Cohort Study, who were 40-79 years old at the baseline. During the 11 years of follow-up, we identified 148 incident cases of breast cancer and 32 incident cases of endometrial cancer. Compared with breastfeeding only, multivariate hazard ratios and 95% confidence intervals for the risk of breast cancer incidence were 1.12 (0.92-1.37) for women who had performed mixed feeding and 1.80 (1.14-2.86) for those who fed their babies only with formula (P-trend=0.014). For endometrial cancer incidence, multivariate hazard ratios and 95% confidence intervals were 1.32 (0.86-2.03) for women who had performed mixed feeding and 3.26 (1.23-8.61) for those who had performed only formula feeding (P-trend=0.018). Our findings appear to raise the possibility that nonbreastfeeding is positively associated with the risks for both breast cancer incidence and endometrial cancer incidence. Confirmation of our findings would require further investigation.


An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity.
Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an approximately 3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.


Toroidal Flux Loss due to Flux Emergence Explains why Solar Cycles Rise Differently but Decay in a Similar Way.
A striking feature of the solar cycle is that at the beginning, sunspots appear around midlatitudes, and over time the latitudes of emergences migrate toward the equator. The maximum level of activity (e.g., sunspot number) varies from cycle to cycle. For strong cycles, the activity begins early and at higher latitudes with wider sunspot distributions than for weak cycles. The activity and the width of sunspot belts increase rapidly and begin to decline when the belts are still at high latitudes. Surprisingly, it has been reported that in the late stages of the cycle the level of activity (sunspot number) as well as the widths and centers of the butterfly wings all have the same statistical properties independent of how strong the cycle was during its rise and maximum phases. We have modeled these features using a Babcock-Leighton type dynamo model and show that the flux loss through magnetic buoyancy is an essential nonlinearity in the solar dynamo. Our Letter shows that the nonlinearity is effective if the flux emergence becomes efficient at the mean-field strength of the order of 10^{4} G in the lower part of the convection zone.


Degradation of Escherichia coli chromosomal and plasmid DNA in serum.
Incubation of serum-sensitive [3H]thymidine labelled Escherichia coli PC2166 (RSF1030) and E. coli AM1281 (pBR322) harbouring small plasmids (mol. wt 5.5 X 10(6) and 2.6 X 10(6] in serum resulted in killing of 99.9% of the bacteria within 15 min and in the release of 85% of the radioactivity into the medium after 1 h incubation. The fate of chromosomal and plasmid DNA during incubation of the bacteria in serum was analysed by measurement of the amount of DNA-associated radioactivity, by TCA precipitation, by agarose gel electrophoresis and by the capacity of DNA to transform competent acceptor bacteria. Chromosomal DNA and high molecular weight plasmid DNA were rapidly degraded after 1 h incubation of bacteria in serum. However, low molecular weight plasmid DNA was virtually unaffected and remained physicochemically as well as biologically intact during up to 4 h of incubation of bacteria in serum.


A Systematic Review of the Influence of Overweight and Obesity across the Lifespan on Obstacle Crossing during Walking.
This study aimed to systematically review and summarize the available data regarding the influence of overweight and obesity across the lifespan on obstacle crossing during walking. Four databases were systematically searched with no limitation on publication date following the Cochrane Handbook for Systematic Reviews and PRISMA guidelines. Only full-text English-language articles published in a peer-reviewed journal were eligible. They had to compare obstacle crossing during walking by overweight or obese individuals with individuals of normal body weight. Five studies were considered eligible. All the studies assessed kinematics; only one assessed kinetics, but none investigated muscle activity or obstacle contact. Compared to normal individuals crossing obstacles, overweight or obese individuals exhibited lower velocity, shorter step length, lower cadence, and less time spent in single-limb support. They also exhibited increased step width, more time spent in double support, and greater trailing leg ground force reaction and centre of mass acceleration. Overall, the small number of included studies did not allow us to draw any conclusions. However, being overweight or obese seems to have a potentially negative influence on the kinematics of gait parameters due to a tendency to trip, fall, and suffer severe fall-related injuries when negotiating obstacles on foot in real-life environments.


Electroneurography and Advanced Neuroimaging Profile in Pediatric-onset Metachromatic Leukodystrophy.
Metachromatic leukodystrophy (MLD) is a rare autosomal-recessive disorder characterized by demyelination of central and peripheral nervous system. There is scarcity of literature on the electrophysiological aspects of peripheral nerves and the advanced neuroimaging findings in MLD. The aim was to study the nerve conduction parameters and advanced neuroimaging findings in patients with MLD. This study is a retrospective analysis conducted, between 2005 and 2016, of 12 patients who had biochemical, histopathological, or genetic confirmation of MLD and disease onset before 18 years of age. The clinical, electroneurography, and the advanced neuroimaging findings were reviewed and analyzed. The data were presented as percentages or mean ± standard deviation as defined appropriate for qualitative and quantitative variables. Mean age of onset was 4.84 (±4.60) years and seven patients were males. Eight patients had juvenile MLD and four had late infantile MLD. Clinical presentation of psychomotor regression was more common in infantile MLD (75%), whereas gait difficulty (62.5%) and cognitive impairment (37.5%) were more frequent in juvenile MLD. Nerve conduction study (NCS) revealed diffuse demyelinating sensorimotor peripheral neuropathy in 9 (75%) patients. One patient had a rare presentation with conduction blocks in multiple nerves with contrast enhancement of cauda equina. Diffusion restriction involving periventricular and central white matter was seen in five patients and bilateral globus pallidi blooming was noted in three patients. This study highlights the utility of NCS and advanced magnetic resonance imaging sequences in the diagnosis of MLD.


Cell adhesion status-dependent histone acetylation is regulated through intracellular contractility-related signaling activities.
Although histone acetylation is important for epigenetic gene transcription, histone acetylation regulation by extracellular cues has rarely been evidenced. Here, we examined whether and how histone acetylation is regulated by cell adhesion-mediated signaling. Gastric carcinoma cells in suspension showed a higher histone acetylation, compared with fibronectin-adherent cells. This difference was supported by a decreased histone deacetylases activity. Furthermore, trichostatin A (TSA)-mediated histone acetylation was significantly increased only in suspended, but not in fibronectin-adherent, cells. Pharmacological inhibition of intracellular contractility-related myosin light chain kinase or RhoA-kinase (ROCK) or expression of ROCK1 small interfering RNA, dominant negative RhoA, or active Rac1 decreased basal and TSA-mediated histone H3 acetylations in suspended cells,whereas inhibition of calmodulin-dependent protein kinase II or transient overexpression of wild type myosin light chain kinase enhanced the acetylations. Meanwhile, chromatin immunoprecipitation showed higher basal and TSA-enhanced associations of ROCK1 promoter regions with Lys(9)-acetylated histone 3 in suspended cells than in fibronectin-adherent cells and expression of ROCK1 was higher and further increased by TSA treatment in suspension. In addition, phosphorylation of myosin light chain was further increased by TSA in suspension and higher in anchorage-independent cells over adherently growing cells, indicating an inverse relationship between ROCK1 expression-mediated contractility and cell adhesion abilities. Cell adhesion analysis showed that pharmacological activation of intracellular contractility-related signaling activities decreased cell adhesion abilities, whereas inhibition of them increased the adhesion. Taken together, these observations suggest that cell adhesion-related signal transduction regulates histone acetylation, presumably through a close functional linkage between intracellular contractility and histone deacetylases activity/histone acetylation.


[Clinical applications of the neurocutaneous axial flap pedicled with perforating vessels].
To report the operative technique and clinical results of the neurocutaneous vascular axial flap with perforating vessels as its pedicle. An axial skin flap was designed along the axis of small paraneural vessels that was close to a concomitant cutaneous nerve. The cutaneous perforating branches of major arteries were used as the pedicle, which provided a rotation arc for the flap to cover the defects in the distal site of extremities. 43 neurocutaneous vascular axial flaps were transferred, including 13 sural neurocutaneous axial flaps (30 cm x 12 cm to 16 cm x 8 cm) supplied by perforating branches of the peroneal vessel; 9 saphenous neurocutaneous axial flaps (15 cm x 8 cm to 5 cm x 4 cm) with posterior tibial perforators as the pedicle; 8 posterior antebrachial neurocutaneous axial flaps (16 cm x 6 cm to 10 cm x 4 cm) based on the dorsal branch of the anterior interossea vessel and 13 reversed neurocutaneous axial flaps (6.0 cm x 3.5 cm to 2.5 cm x 1.5 cm) on the dorsal hand pedicled with the perforators at the interdigital web space. 42 flaps survived completely. One flap underwent venous congestion with necrosis on the distal one fourth of the flap. The color and texture of the flaps were good. The appearance and functional results were satisfactory as revealed by follow-up for 6 to 24 months. The modified operation combines the advantages of both the perforator flap and the neurocutaneous axial flap, enlarges the size of the flap and extends the scope of reconstruction. The flap is characterized with delicate designation, easy dissection and reliable blood supply. It is a good method in repairing the skin defects of the extremities.


Phytochemical contents and enzyme inhibitory and antioxidant properties of Anethum graveolens L. (dill) samples cultivated under organic and conventional agricultural conditions.
Inhibitory effect of the n-hexane, dichloromethane, ethyl acetate, and ethanol extracts from Anethum graveolens L. (dill) cultivated under organic (AG-O) and conventional (AG-C) conditions was tested against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase at 200 μg mL⁻¹. Their antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylendiamine (DMPD), and nitric oxide (NO) radical scavenging assays as well as ferric ion-chelation capacity, ferric-(FRAP), and phosphomolybdenum-reducing antioxidant power (PRAP). The phytochemical analyses have been performed on both of the plant samples. GC-MS analysis pointed out that α-phellandrene was the main component in both of the essential oils in varying amounts (47.75% for AG-O and 27.94% for AG-C), while oleic acid was the dominant in the fruit oils of two samples (36.39% for AG-O and 53.87% for AG-C). HPLC analysis showed that both of the extracts contained rosmarinic acid as the major phenolic acid. The extracts inhibited BChE at moderate level, while the ethanol extracts exerted remarkable NO scavenging effect. The results emphasize that cultivation conditions may have effect on bioactivity and phytochemical content on plant samples.


Evolutionary programming-based univector field navigation method for past mobile robots.
Most of navigation techniques with obstacle avoidance do not consider the robot orientation at the target position. These techniques deal with the robot position only and are independent of its orientation and velocity. To solve these problems this paper proposes a novel univector field method for fast mobile robot navigation which introduces a normalized two dimensional vector field. The method provides fast moving robots with the desired posture at the target position and obstacle avoidance. To obtain the sub-optimal vector field, a function approximator is used and trained by evolutionary programming. Two kinds of vector fields are trained, one for the final posture acquisition and the other for obstacle avoidance. Computer simulations and real experiments are carried out for a fast moving mobile robot to demonstrate the effectiveness of the proposed scheme.


Retinoids in clinical use.
Retinoids have been investigated for their therapeutic potential for the past 3 decades. They have a reputation for being both beneficial in the treatment of several diseases and detrimental due to toxic and/or teratogenic side effects. The purpose of this review is to highlight retinoids that are currently used in the clinic. We also discuss their mechanisms of action and research strategies to develop new and safer retinoid-based therapies.


Subcellular localization of chicken kidney aryl acylamidase activity.
The intracellular localization of aryl acylamidase (aryl-acylamide amidohydrolase, EC 22.214.171.124) in chicken kidney was investigated. By separation on density gradients of the silica sol Ludox AM, the enzyme was localized in the mitochondrial fraction. This mitochondrial fraction was shown to be substantially free of lysosomal contamination. Subfractionation of the purified mitochondria indicates that the enzyme is located on the outer membrane, can be solubilized, and may be a suitable marker enzyme for kidney mitochondria.


Posttraumatic stress disorder in primary care.
Primary care providers are aware of the importance of identifying depression and anxiety in their patients. The diagnosis of posttraumatic stress disorder (PTSD), however, is less of a priority. Primary care physicians and nurse practitioners in an outpatient facility of a large health maintenance organization administered a psychiatric screening questionnaire to patients whom they suspected had depression or anxiety. Patients with positive results were referred for immediate consultation with a clinical psychologist. One hundred fourteen (38.6%) of the 296 patients referred for consultation met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic criteria for PTSD. The most frequent traumas associated with PTSD were adult domestic violence and childhood abuse. Patients with a diagnosis of PTSD were frequent users of medical services in the 12 months before diagnosis. The majority of patients sought treatment in primary care settings, not mental health settings. Patients with PTSD often visit outpatient primary care settings. Medical providers may identify symptoms of depression or anxiety but may not recognize PTSD because of the high degree of overlap between these conditions, and the lack of familiarity with PTSD diagnostic criteria. We provide screening questions that may help physicians detect PTSD in their practices.


Outcomes of Intradetrusor Onabotulinum Toxin A Therapy in Overactive Bladder Refractory to Sacral Neuromodulation.
Intradetrusor onabotulinum toxin A (BTXA) and sacral neuromodulation (SNM) are effective third-line therapies for overactive bladder (OAB). We aimed to measure the outcomes of BTXA for treatment of OAB refractory to initial SNM and identify patient characteristics associated with these outcomes. This retrospective cohort study included patients who failed to respond to initial SNM treatment for OAB and subsequently received BTXA at a single provider's clinic between January 2013 and December 2016. Treatment successes were defined as patients willing to continue BTXA or who found symptom relief whereas treatment failures discontinued BTXA due to adverse effects or lack of symptom relief. Symptoms and patient-reported outcomes on validated questionnaires were compared before the initial BTXA trial to 2 months after the last BTXA treatment. The SNM failure BTXA groups were also compared to BTXA SNM naïve groups. Of 18 patients who received BTXA after failed SNM treatment, 7 (39%) achieved treatment success. Successfully treated patients demonstrated decreased urinary frequency from a median 11 voids/day pre-BTXA to 8 voids/day with BTXA (P=0.042). Patients whose treatment failed reported increased complaints of a weak urinary stream (P=0.03) and higher frequency of straining to urinate (P=0.016) than the successful treatment group pre-BTXA. Compared to BTXA patients without prior SNM, the odds of failing BTXA after initial SNM were 3.6 times higher (P=0.016). BTXA appears effective for OAB refractory to SNM, although the success rate is lower compared to BTXA patients without SNM exposure.


Increased Angiotensin-Converting Enzyme 2 and Loss of Alveolar Type II Cells in COVID-19-related Acute Respiratory Distress Syndrome.
Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.


MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size.
A central question in the biology of adult stem cells is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Adult muscle stem cells (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle homeostasis and repair. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence and myofiber size. We attenuated MuSK-BMP signaling by deletion of the BMP-binding MuSK Ig3 domain ('ΔIg3-MuSK') and studied the fast TA and EDL muscles. In germ line mutants at 3 months of age SC and myonuclei numbers as well as myofiber size were comparable in ΔIg3-MuSK and WT animals. However, in 5-month-old ΔIg3-MuSK animals SC density was decreased while myofiber size, myonuclear number and grip strength were increased - indicating that SCs had activated and productively fused into the myofibers over this interval. Notably, myonuclear domain size was conserved. Following injury, the mutant muscle fully regenerated with restoration of myofiber size and SC pool to WT levels, indicating that ΔIg3-MuSK SCs maintain full stem cell function. Conditional expression of ΔIg3-MuSK in adult SCs showed that the MuSK-BMP pathway regulates quiescence and myofiber size in a cell autonomous fashion. Transcriptomic analysis revealed that SCs from uninjured ΔIg3-MuSK mice exhibit signatures of activation, including elevated Notch and epigenetic signaling. We conclude that the MuSK-BMP pathway regulates SC quiescence and myofiber size in a cell autonomous, age-dependent manner. Targeting MuSK-BMP signaling in muscle stem cells thus emerges a therapeutic strategy for promoting muscle growth and function in the settings of injury, disease, and aging.


Alteration in cellular viability, pro-inflammatory cytokines and nitric oxide production in nephrotoxicity generation by Amphotericin B: involvement of PKA pathway signaling.
Amphotericin B is one of the most effective antifungal agents; however, its use is often limited owing to adverse effects, especially nephrotoxicity. The purpose of this study was to evaluate the effect of inhibiting the PKA signaling pathway in nephrotoxicity using Amphotericin B from the assessment of cell viability, pro-inflammatory cytokines and nitric oxide (NO) production in LLC-PK1 and MDCK cell lines. Amphotericin B proved to be cytotoxic for both cell lines, as assessed by the mitochondrial enzyme activity (MTT) assay; caused DNA fragmentation, determined by flow cytometry using the propidium iodide (PI) dye; and activated the PKA pathway (western blot assay). In MDCK cells, the inhibition of the PKA signaling pathway (using the H89 inhibitor) caused a significant reduction in DNA fragmentation. In both cells lines the production of interleukin-6 (IL)-6 proved to be a dependent PKA pathway, whereas tumor necrosis factor-alpha (TNF-α) was not influenced by the inhibition of the PKA pathway. The NO production was increased when cells were pre-incubated with H89 followed by Amphotericin B, and this production produced a dependent PKA pathway in LLC-PK1 and MDCK cells lines. Therefore, considering the present study's results as a whole, it can be concluded that the inhibition of the PKA signaling pathway can aid in reducing the degree of nephrotoxicity caused by Amphotericin B.


A sub-maximal occupational aerobic fitness test alternative, when the use of heart rate is not appropriate.
Several emergency response organisations have introduced a minimum aerobic fitness test to predict performance on critical tasks, as well as to help ensure some protection against the cardiovascular stress associated with emergency situations. A popular indirect sub-maximal test of aerobic fitness is the step test; this test relies on the relationship between exercise intensity, heart rate and aerobic capacity. This relationship, and the tests that rely on it, are not valid for individuals who are on prescribed medication (often for high blood pressure) that alter the heart rate response to exercise. The purpose of the work described in this paper was to develop a sub-maximal test of aerobic fitness that did not rely on heart rate. Eighty-four subjects undertook the Tecumseh step test and a six-minute maximal walk test. A Pearson Product correlation of r=- 0.81, P< 0.01 was identified between the distance that an individual could walk in six minutes and their heart rate response to the step test. It is concluded that the walk test offers a valid alternative to the step test for the indirect sub-maximal assessment of aerobic fitness.


[Nordic walking: the prospects of improving the quality of life in the elderly].
The article represents a review of foreign studies of positive effect on health and quality of life of such a new physical activity as Nordic walking. Advantages of Nordic walking for health make this activity very promising for further studies in the group of elderly people and its introduction into the geriatric practice to make elderly people more physically active, to promote healthy life style and proper attitude towards health.


Effects of genome-wide copy number variation on expression in mammalian cells.
There is only a limited understanding of the relation between copy number and expression for mammalian genes. We fine mapped cis and trans regulatory loci due to copy number change for essentially all genes using a human-hamster radiation hybrid (RH) panel. These loci are called copy number expression quantitative trait loci (ceQTLs). Unexpected findings from a previous study of a mouse-hamster RH panel were replicated. These findings included decreased expression as a result of increased copy number for 30% of genes and an attenuated relationship between expression and copy number on the X chromosome suggesting an Xist independent form of dosage compensation. In a separate glioblastoma dataset, we found conservation of genes in which dosage was negatively correlated with gene expression. These genes were enriched in signaling and receptor activities. The observation of attenuated X-linked gene expression in response to increased gene number was also replicated in the glioblastoma dataset. Of 523 gene deserts of size > 600 kb in the human RH panel, 325 contained trans ceQTLs with -log10 P > 4.1. Recently discovered genes, ultra conserved regions, noncoding RNAs and microRNAs explained only a small fraction of the results, suggesting a substantial portion of gene deserts harbor as yet unidentified functional elements. Radiation hybrids are a useful tool for high resolution mapping of cis and trans loci capable of affecting gene expression due to copy number change. Analysis of two independent radiation hybrid panels show agreement in their findings and may serve as a discovery source for novel regulatory loci in noncoding regions of the genome.


Using yeast as a model to study membrane proteins.
Many cellular processes are controlled via either stable or transient protein-protein interactions (PPIs). Protein complexes are 'molecular machines' in which multiple interactive partners carry out various cellular functions. Given that almost a third of the proteome consists of membrane proteins and that more than 50% of currently available drugs are targeted toward them, investigation of membrane protein complexes has taken center stage over the past years. Thus, gaining an in-depth understanding of PPI networks will give us more insight into the functional relationship as well as downstream effectors of protein complexes, hence opening strategies for new drug target definitions. Studying membrane proteins in yeast has recently been applied to many different classes of proteins with diverse functions and structures including membrane transporters. Techniques such as the split-ubiquitin membrane yeast two-hybrid or variants of the protein-fragment complementation assay have been successfully applied to both large-scale genome-wide screens and as smaller-scale PPI studies in a reliable and robust fashion. Yeast-based methods to study membrane PPI in vivo offer a powerful tool for the investigation of protein complexes from various organisms, including mammals. The investigation of global protein maps will serve as a foundation for mechanistic and quantitative studies of poorly characterized gene products and disease-associated proteins. Identification of PPIs is also of great interest for drug discovery as many human diseases result from abnormal PPIs.


Surface-Immobilized Interpolyelectrolyte Complexes Formed by Polyelectrolyte Brushes.
A scaling theory of interaction and complex formation between planar polyelectrolyte (PE) brush and oppositely charged mobile linear PEs is developed. Counterion release is found to be the main driving force for the complexation. An interpolyelectrolyte coacervate complex (IPEC) between the brush and oppositely charged mobile PEs is formed at moderate grafting density and low salt concentration. At higher grafting density mobile chains penetrate the brush, but the brush structure is controlled by the balance between entropic elasticity and nonelectrostatic short-range interactions, as happens in a neutral brush. An increase in salt concentration beyond the theoretically predicted threshold leads to the release of the guest polyions from the brush. For brushes with moderate grafting density, complexation with oppositely charged guest polyions is predicted to trigger lateral microphase separation and formation of the finite-size surface IPEC clusters. Power law dependencies for the cluster dimensions on the brush grafting density, PE length, and salt concentration are provided.


High-resolution optical imaging of functional brain architecture in the awake monkey.
Optical imaging of the functional architecture of cortex, based on intrinsic signals, is a useful tool for the study of the development, organization, and function of the living mammalian brain. This relatively noninvasive technique is based on small activity-dependent changes of the optical properties of cortex. Thus far, functional imaging has been performed only on anesthetized animals. Here we establish that this technique is also suitable for exploring the brain of awake behaving primates. We designed a chronic sealed chamber and mounted it on the skull of a cynomolgus monkey (Macaca fascicularis) over the primary visual cortex to permit imaging through a transparent glass window. Restriction of head position alone was sufficient to eliminate movement noise in awake monkey imaging experiments. High-resolution imaging of the ocular dominance columns and the cytochrome oxidase blobs was achieved simply by taking pictures of the exposed cortex when the awake monkey was viewing video movies alternatively with each eye. Furthermore, the functional maps could be obtained without synchronization of the data acquisition to the animal's respiration and the electrocardiogram. The wavelength dependency and time course of the intrinsic signal were similar in anesthetized and awake monkeys, indicating that the signal sources were the same. We therefore conclude that optical imaging is well suited for exploring functional organization related to higher cognitive brain functions of the primate as well as providing a diagnostic tool for delineating functional cortical borders and assessing proper functions of human patients during neurosurgery.


The Role of the Microbiome in the Developmental Origins of Health and Disease.
Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward this bacterial consortium as a mediator between early lifestyle factors and health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in life. A role of the microbiome in the Developmental Origins of Health and Disease is supported in this collective research. Highlighting the early-life critical window of susceptibility associated with microbiome development, we discuss infant microbial colonization, beginning with the maternal-to-fetal exchange of microbes in utero and up through the influence of breastfeeding in the first year of life. In addition, we review the available disease-specific evidence pointing toward the microbiome as a mechanistic mediator in the Developmental Origins of Health and Disease.


Virus-receptor interactions of coxsackie B viruses and their putative influence on cardiotropism.
Specific virus-receptor interactions are important determinants in the pathogenesis of viral infections, influencing the location and initiation of primary infection as well as the viral spread to other target organs in the postviremic phase. Coxsackieviruses of group B (CVB) specifically interact with at least two receptor proteins, the coxsackievirus-adenovirus receptor (CAR) and the decay-accelerating factor (DAF), and cause a broad spectrum of diseases, including acute and chronic myocarditis. In the human heart, CAR is predominantly expressed in intercalated discs, regions of utmost importance for the functional integrity of the heart. Since DAF is abundantly expressed in epithelial and endothelial cells, interaction of cardiotropic CVB with the DAF coreceptor protein, in addition to CAR, could therefore be advantageous to the virus by enhancing viral entry into the heart.


Segregation of ions at the interface: molecular dynamics studies of the bulk and liquid-vapor interface structure of equimolar binary mixtures of ionic liquids.
The structures of three different equimolar binary ionic liquid mixtures and their liquid-vapor interface have been studied using atomistic molecular dynamics simulations. Two of these binary mixtures were composed of a common cation 1-n-butyl-3-methylimidazolium and varying anions (chloride and hexafluorophosphate in one of the mixtures and chloride and trifluoromethanesulfonate in the other) and the third binary mixture was composed of a common anion, trifluoromethanesulfonate and two imidazolium cations with ethyl and octyl side chains. Binary mixtures with common cations are found to be homogeneous. The anions are preferentially located near the ring hydrogen atoms due to H-bonding interactions. Segregation of ions is observed at the interface with an enrichment of the liquid-vapor interface layer by longer alkyl chains and bigger anions with a distributed charge. The surface composition is drastically different from that of the bulk composition, with the longer alkyl tail groups and bigger anions populating the outermost layer of the interface. The longer alkyl chains of the cations and trifluoromethanesulfonate anions with a smaller charge density show orientational ordering at the liquid-vapor interface.


Integrability-based analysis of the hyperfine-interaction-induced decoherence in quantum dots.
Using the algebraic Bethe ansatz in conjunction with a simple Monte Carlo sampling technique, we study the problem of the decoherence of a central spin coupled to a nuclear spin bath. We describe in detail the full crossover from strong to weak external magnetic field, a limit where a large nondecaying coherence factor is found. This feature is explained by Bose-Einstein-condensate-like physics which also allows us to argue that the corresponding zero frequency peak would not be broadened by statistical or ensemble averaging.


Treatment of cervical incompetence by transabdominal cervicoisthmic cerclage.
Cervical incompetence is a condition traditionally treated by cervical cerclage which in most cases is inserted via the transvaginal route. However the insertion of a transabdominal cervicoisthmic suture is indicated in those patients with recurrent mid-trimester losses due to an incompetent cervix where it is not technically possible to insert a transvaginal suture. Between 1987 and 1996, 12 women at the Royal Women's Hospital, Melbourne were treated with transabdominal cervicoisthmic cerclage (TCC). Eight patients had cerclage in the nonpregnant state, and 4 were pregnant at the time. The completed pregnancies thus far have resulted in 10 surviving infants, a successful pregnancy rate of 69.2%. This compares favourably with a corrected preTCC successful pregnancy rate of only 13%. There were minimal intraoperative complications in our series. Bleeding, chorioamnionitis and premature rupture of the membranes have been reported elsewhere and occurred in 2 of our patients. Our results and a review of the literature confirms that TCC has an important role in carefully-selected patients.


Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas.
Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear. Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB). The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses. Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.


Gender differences in complications following catheter ablation of atrial fibrillation.
Population studies that provide unbiased estimates of gender differences in risk of complications following catheter ablation of atrial fibrillation (AF) are sparse. We sought to evaluate the association of female gender and risk of complications following AF ablation in a nationwide cohort. We identified 35 211 patients (29.5% females) undergoing AF ablations from 2008 to 2017 using national hospitalization data from Australia and New Zealand. The primary outcome was any procedural complication occurring up to 30-days after discharge. Logistic regression was used to adjust for differences in baseline characteristics between sexes. Compared with males, females were older (mean age 64.9 vs. 61.2 years), had higher rates of hypertension (14.0% vs. 11.6%) and haematological disorders (5.3% vs. 3.8%) and experienced a higher rate of procedural complications (6.96% vs. 5.41%) (all P < 0.001). This gender disparity remained significant after adjustment [odds ratio (OR) 1.25 (95% confidence interval 1.14-1.38), P < 0.001] and was driven by an increased risk of vascular injury [OR 1.86 (1.23-2.82), P = 0.003], pericarditis [OR 1.86 (1.16-2.67), P = 0.008], pericardial effusion [OR 1.71 (1.35-2.17), P < 0.001), and bleeding [OR 1.30 (1.15-1.46), P < 0.001]. Notably, the gender difference persisted over time [OR for the most recent period 1.19 (1.003-1.422), P = 0.046] despite a declining complication rate in both men and women. Females undergoing AF ablations experienced a 25% higher risk of procedural complications compared with males, a disparity that has persisted over time despite a falling complication rate. Efforts to reduce this gender disparity should focus on reducing the incidence of pericardial effusion, pericarditis, vascular injury, and bleeding.


Caffeine impairs cerebral and intestinal blood flow velocity in preterm infants.
In adults, a single dose of 250 mg of caffeine may decrease cerebral blood flow by 30%. In preterm infants, caffeine is commonly used for the treatment and prophylaxis of apnea. The purpose of this investigation was to assess effects of caffeine on circulatory parameters in preterm infants. We studied 16 preterm neonates with a mean gestational age (mean +/- standard deviation) of 31 +/- 1.2 weeks (range: 29-33 weeks), birth weight of 1400 +/- 380 g (range: 625-2060 g), and postnatal age of 24 to 72 hours before and 1 and 2 hours after an oral loading dose of 25 mg/kg pure caffeine. We investigated left ventricular output (LVO), cerebral blood flow velocity (BFV) of the internal carotid artery (ICA) and the anterior cerebral artery, and intestinal BFV of the celiac artery and superior mesenteric artery by Doppler sonography. Mean BFV in the ICA decreased significantly 1 (17%) and 2 hours (22%) after caffeine administration. Mean BFV in the anterior cerebral artery showed a reduction of 14% after 2 hours. The mean BFV in the superior mesenteric artery decreased significantly 1 and 2 hours after caffeine administration (30%). Mean BFV in the celiac artery showed a significant reduction of 14% 1 hour after caffeine. No changes were observed in LVO, blood pressure, and heart rate. Oral administration of a high loading dose of caffeine results in marked reduction of cerebral and intestinal BFV, without changing LVO, blood pressure, and heart rate.


Extending and encoding existing biological terminologies and datasets for use in the reasoned semantic web.
Clinical phenotypes and disease-risk stratification are most often determined through the direct observations of clinicians in conjunction with published standards and guidelines, where the clinical expert is the final arbiter of the patient's classification. While this "human" approach is highly desirable in the context of personalized and optimal patient care, it is problematic in a healthcare research setting because the basis for the patient's classification is not transparent, and likely not reproducible from one clinical expert to another. This sits in opposition to the rigor required to execute, for example, Genome-wide association analyses and other high-throughput studies where a large number of variables are being compared to a complex disease phenotype. Most clinical classification systems and are not structured for automated classification, and similarly, clinical data is generally not represented in a form that lends itself to automated integration and interpretation. Here we apply Semantic Web technologies to the problem of automated, transparent interpretation of clinical data for use in high-throughput research environments, and explore migration-paths for existing data and legacy semantic standards. Using a dataset from a cardiovascular cohort collected two decades ago, we present a migration path - both for the terminologies/classification systems and the data - that enables rich automated clinical classification using well-established standards. This is achieved by establishing a simple and flexible core data model, which is combined with a layered ontological framework utilizing both logical reasoning and analytical algorithms to iteratively "lift" clinical data through increasingly complex layers of interpretation and classification. We compare our automated analysis to that of the clinical expert, and discrepancies are used to refine the ontological models, finally arriving at ontologies that mirror the expert opinion of the individual clinical researcher. Other discrepancies, however, could not be as easily modeled, and we evaluate what information we are lacking that would allow these discrepancies to be resolved in an automated manner. We demonstrate that the combination of semantically-explicit data, logically rigorous models of clinical guidelines, and publicly-accessible Semantic Web Services, can be used to execute automated, rigorous and reproducible clinical classifications with an accuracy approaching that of an expert. Discrepancies between the manual and automatic approaches reveal, as expected, that clinicians do not always rigorously follow established guidelines for classification; however, we demonstrate that "personalized" ontologies may represent a re-usable and transparent approach to modeling individual clinical expertise, leading to more reproducible science.


Zinc finger arrays binding human papillomavirus types 16 and 18 genomic DNA: precursors of gene-therapeutics for in-situ reversal of associated cervical neoplasia.
Human papillomavirus (HPV) types 16 and 18 are the high-risk, sexually transmitted infectious causes of most cervical intraepithelial neoplasias (CIN) or cancers. While efficacious vaccines to reduce the sexual acquisition of these high-risk HPVs have recently been introduced, no virus-targeted therapies exist for those already exposed and infected. Considering the oncogenic role of the transforming (E6 and E7) genes of high-risk HPVs in the slow pathogenesis of cervical cancer, we hypothesize that timely disruption or abolition of HPV genome expression within pre-cancerous lesions identified at screening may reverse neoplasia. We aimed to derive model zinc finger nucleases (ZFNs) for mutagenesis of the genomes of two high-risk HPV (types 16 & 18). Using ZiFiT software and the complete genomes of HPV types16 and 18, we computationally generated the consensus amino acid sequences of the DNA-binding domains (F1, F2, & F3) of (i) 296 & 327 contextually unpaired (or single) three zinc-finger arrays (sZFAs) and (ii) 9 & 13 contextually paired (left and right) three- zinc-finger arrays (pZFAs) that bind genomic DNA of HPV-types 16 and 18 respectively, inclusive of the E7 gene (s/pZFAHpV/E7). In the absence of contextually paired three-zinc-finger arrays (pZFAs) that bind DNA corresponding to the genomic context of the E6 gene of either HPV type, we derived the DNA binding domains of another set of 9 & 14 contextually unpaired E6 gene-binding ZFAs (sZFAE6) to aid the future quest for paired ZFAs to target E6 gene sequences in both HPV types studied (pZFAE6). This paper presents models for (i) synthesis of hybrid ZFNs that cleave within the genomic DNA of either HPV type, by linking the gene sequences of the DNA-cleavage domain of the FokI endonuclease FN to the gene sequences of a member of the paired-HPV-binding ZFAs (pZFAHpV/E7 + FN), and (ii) delivery of the same into precancerous lesions using HPV-derived viral plasmids or vectors. With further optimization, these model ZFNs offer the opportunity to induce target-mutagenesis and gene-therapeutic reversal of cervical neoplasia associated with HPV types 16 & 18.


Peak oxygen uptake in arm ergometry: effects of testing protocol.
The purpose of this investigation was to determine if a new proposed arm ergometer protocol was advantageous in eliciting higher peak oxygen uptake (peak VO2) when compared with two protocols currently referred to in the literature. Ten male subjects were tested on three different exercise protocols; a discontinuous test (DT), a continuous test (CT) and a new proposed jump-max test (JMT). The CT began at a work rate of 33 watts (W) (40 rpm) with the power output (PO) being increased 16 W every 3 minutes. The DT began without resistance on the ergometer flywheel (50 rpm) and the work rate was increased by 25 W every 3 minutes with a 1-minute rest between stages. The JMT began with a 3-minute pretest to determine a PO which elicited a HR of 120 +/- 5 beat min-1. After a 2-minute rest, subjects began exercise at the predetermined work rate (80 rpm) with the PO being increased 20 W each minute of the test. Oxygen uptake was measured minute by minute via open circuit spirometry. Peak VO2 was higher (p less than 0.05) in the JMT (mean +/- SEM = 2.36 +/- 0.06 l.min-1) when compared with either (means +/- SEM = 2.16 +/- 0.07 l.min-1) or the CT (means +/- SEM = 2.04 +/- 0.10 l.min-1). No difference (p greater than 0.05) existed in peak VO2 between the CT and the DT. These data suggest that the proposed JMT may result in a higher measured peak VO2 in subjects when compared with either DT or CT of moderate to long duration.


Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development.
We report our initial investigations into the use of tetraazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of several Zr tetraazamacrocycle complexes, and definitively describe the first crystal structure of zirconium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Zr-DOTA) using single crystal X-ray diffraction analysis. After evaluating several radioactive analogs, we found that 89Zr-DOTA is superior to 89Zr-DFO, the only 89Zr-complex to be used clinically in 89Zr-radiopharmaceutical applications. Finally, we provide a rationale for the unanticipated and extraordinary stability of these complexes in vitro and in vivo. These results may inform the development of safer and more robust immuno-PET agents for precision medicine applications.


Uptake of Diagnostic Tests by Livestock Farmers: A Stochastic Game Theory Approach.
Game theory examines strategic decision-making in situations of conflict, cooperation, and coordination. It has become an established tool in economics, psychology and political science, and more recently has been applied to disease control. Used to examine vaccination uptake in human medicine, game theory shows that when vaccination is voluntary some individuals will choose to "free-ride" on the protection provided by others, resulting in insufficient coverage for control of a vaccine-preventable disease. Here, we use game theory to examine farmer uptake of a new diagnostic ELISA test for sheep scab-a highly infectious disease with an estimated cost exceeding £8M per year to the UK industry. The stochastic game models decisions made by neighboring farmers when deciding whether to adopt the newly available test, which can detect subclinical infestation. A key element of the stochastic game framework is that it allows multiple states. Depending on infestation status and test adoption decisions in the previous year, a farm may be at high, medium or low risk of infestation this year-a status which influences the decision the farmer makes and the farmer payoffs. Ultimately, each farmer's decision depends on the costs of using the diagnostic test vs. the benefits of enhanced disease control, which may only accrue in the longer term. The extent to which a farmer values short-term over long-term benefits reflects external factors such as inflation or individual characteristics such as patience. Our results show that when using realistic parameters and with a test cost around 50% more than the current clinical diagnosis, the test will be adopted in the high-risk state, but not in the low-risk state. For the medium risk state, test adoption will depend on whether the farmer takes a long-term or short-term view. We show that these outcomes are relatively robust to change in test costs and, moreover, that whilst the farmers adopting the test would not expect to see large gains in profitability, substantial reduction in sheep scab (and associated welfare implications) could be achieved in a cost-neutral way to the industry.


A fuzzy adaptive variable structure controller with applications to robot manipulators.
A new adaptive fuzzy control algorithm is developed in this paper, which has a regular fuzzy controller and a supervisory control term. This control algorithm does not require the system model, but has stability assurance for the closed-loop controlled system. The design is simple, in the sense that both the membership functions and the rule base are simple, yet generic. It can be applied to a large class of robotic and other mechanical systems.


[Clinical manifestations of the local effect of protons with an energy of 1000 Mev following irradiation of the hypophysis (experimental)].
In order to study the clinical picture due to inrradiation of the hypophysis by protons with an energy of 1000 Mev with the use of a pendulum technique, the authors examined 30 dogs including 27 with an irradiated hypophysis and 3 control animals during 2 years. The results were verified in autopsies and in histological studies. These examinations demonstrated frequent general cerebral symptoms, focal neurological and hypophysis-endocrinological symptoms as well as frequent lesions of the cranial nerves, epileptic seizures and nonsymptomatic focal brain necrosis. It was also possible to demonstrate a correlation of the clinical traits with the dosage of the irradiation and the time past after irradiation. The report contains corrections for using these data on humans.


Developmental origins of health and disease: the views of first-time mothers in 5 European countries on the importance of nutritional influences in the first year of life.
The programming concept suggests that poor early nutrition causes an array of medical problems later in life. Public health messages about the implications of programming may not be reaching parents and influencing infant feeding behaviors. The views of new mothers were sought about the extent to which lifelong health is influenced by diet as an infant, rather than by genetic predispositions or lifestyles and behaviors. A questionnaire survey of first-time mothers was undertaken in 5 European countries. A convenience sample of 2071 mothers from England (438), Finland (426), Germany (414), Hungary (389), and Spain (404) self-completed the questionnaire. High proportions of mothers agreed that how an infant is fed affects his or her health over the first year (95.8%) and in subsequent years (88.5%), but the effect of infant feeding decisions on the development of long-term conditions was the least-cited underlying reason. Diet as an infant was rated an extremely/very important influence on adult health by 64% of mothers, equivalent to environmental pollution (63%), but by fewer mothers than were diet and physical activity in childhood/adolescence (79%, 84%) and adulthood (81%, 83%), genetics/inheritance (70%), and exposure to cigarette smoke (81%). Inter- and intracountry differences were observed. Mothers in this study consider diet as an infant to be a less important influence on lifelong health than many lifestyle, behavioral, and environmental factors and genetics. Further dissemination of the implications of programming to consumers may be warranted.


Global increase of p16INK4a in APC-deficient mouse liver drives clonal growth of p16INK4a-negative tumors.
Reduction of β-catenin (CTNNB1) destroying complex components, for example, adenomatous polyposis coli (APC), induces β-catenin signaling and subsequently triggers activation of genes involved in proliferation and tumorigenesis. Though diminished expression of APC has organ-specific and threshold-dependent influence on the development of liver tumors in mice, the molecular basis is poorly understood. Therefore, a detailed investigation was conducted to determine the underlying mechanism in the development of liver tumors under reduced APC levels. Mouse liver at different developmental stages was analyzed in terms of β-catenin target genes including Cyp2e1, Glul, and Ihh using real-time RT-PCR, reporter gene assays, and immunohistologic methods with consideration of liver zonation. Data from human livers with mutations in APC derived from patients with familial adenomatous polyposis (FAP) were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated β-galactosidase activity, and assessing ploidy. A β-catenin activation of hepatocytes does not always result in β-catenin positive but unexpectedly also in mixed and β-catenin-negative tumors. In summary, a senescence-inducing program was found in hepatocytes with increased β-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice). The lack of p16(INK4a) was also detected in liver tumors of mice with triggers other than APC reduction. Epigenetic silencing of p16(Ink4a) in selected liver cells bypassing senescence is a general principle for development of liver tumors with β-catenin involvement in mice independent of the initial stimulus.


Low-tension electrical injury as a cause of atrial fibrillation: a case report.
Electrical injury can cause a variety of cardiac arrhythmias. Atrial fibrillation as a result of such injury is fairly rare, however, and is rarer still in cases of low-tension electrical injury. We present the case of a patient who developed acute atrial fibrillation in association with low-voltage electrical injury, which resolved after the intravenous administration of digoxin.


[Diamond-Blackfan syndrome: pregnancy and heredity].
Diamond-Blackfan syndrome is a rare bone marrow failure involving the erythropoietic lineage and usually diagnosed in the first year of life. About 80% of cases are sporadic but there are examples of recessive and dominant inheritance. Whether the variable pattern of inheritance observed in pedigrees of Diamond-Blackfan syndrome reflects different genetic determinants of the disease remains uncertain. Family studies with use of the newer tools of molecular biology will produce improved insight into the genetic origin of this disease. A review of pregnancy associated Diamond-Blackfan syndrome indicated an increase in pregnancy complications. It appears that pregnancies are usually well tolerated and can be managed with supportive care and blood transfusions.


Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis.
UV irradiation induces apoptosis in U937 human leukemic cells that is accompanied by the activation of both the stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK) signal transduction pathways. The MAPK phosphatase, MKP-1, is capable of inactivating both SAPK and p38 MAPK in vivo. To determine whether MKP-1-mediated inhibition of SAPK and/or p38 MAPK activity provided cytoprotection against UV-induced apoptosis, a U937 cell line conditionally expressing MKP-1 from the human metallothionein IIa promoter was established. Conditional expression of MKP-1 was found to abolish UV-induced SAPK and p38 MAPK activity, and inhibit UV-induced apoptosis as judged by both morphological criteria and DNA fragmentation. MKP-1 was also found to inhibit other biochemical events associated with apoptosis, including activation of caspase-3 and the proteolytic cleavage of the caspase-3 substrate, poly(ADP ribose) polymerase. These findings demonstrate that MKP-1 acts at a site upstream of caspase activation within the apoptotic program. The cytoprotective properties of MKP-1 do not appear to be mediated by its ability to inhibit p38 MAPK because the p38 MAPK specific inhibitor SB203580 had no effect on UV-induced apoptosis in U937 cells. Furthermore, by titrating the level of MKP-1 expression it was found that MKP-1 inhibited UV-induced SAPK activity, DNA fragmentation, and caspase-3 activation in a similar dose-dependent manner. The dual-specificity phosphatase, PAC1, which does not inhibit UV-induced activation of SAPK, did not provide a similar cytoprotection against UV-induced apoptosis. These results are consistent with a model whereby MKP-1 provides cytoprotection against UV-induced apoptosis by inhibiting UV-induced SAPK activity.


A Pilot Observational Cohort Study to Investigate the Effect of Valsalva Maneuver on Internal Jugular Venous Diameter.
Valsalva maneuver (VM) is a technique widely used for acute elevation of blood pressure in humans. It has potential applications in cardiac health prediction and is also a diagnostic tool in cardiovascular, neurology and ENT screening. The jugular venous (JV) diameter increases during the VM procedure and hence it has been widely used to aid central venous catheterization in medical units. In this pilot study, we have quantified the variation in JV diameter response to VM across young and middle-aged populations. The study was conducted on a cohort of 16 males and 11 females, where the JV diameter in baseline, during and post VM intervention were acquired using a B-mode imaging system. The JV diameter measurements were within the ranges specified in earlier literature. The beat-to-beat variability in baseline diameter measurements was found to be between 8% to 20%. In younger population, the average maximum JV diameter during baseline was found to be 9.25 ± 2.61 mm and in middle-aged population it was 12.49 ± 2.65 mm. The average maximum JV diameter in young and middle-aged population during VM was 11.66 ± 2.74 mm and 16.73 ± 3.28 mm respectively. The study findings suggested a statistically significant variation (p < 0.05) between the JV diameter responses from young and middle-aged populations. The JV distensibility decreased significantly during VM in younger cohort (-35%) in comparison with the minimal changes observed in middle-aged population. The study demonstrates the variation in JV diameter and distensibility to VM in young and middle-aged populations.Clinical Relevance- This pilot study reveals the variations in JV diameter in response to VM intervention in young and middle-aged groups which has potential utility in assessing age dependent changes in vasculature.


The variational explicit polarization potential and analytical first derivative of energy: Towards a next generation force field.
A previous article proposed an electronic structure-based polarizable potential, called the explicit polarization (X-POL) potential, to treat many-body polarization and charge delocalization effects in polypeptides. Here, we present a variational version of the X-POL potential, in which the wave function of the entire molecular system is variationally optimized to yield the minimum total electronic energy. This allows the calculation of analytic gradients, a necessity for efficient molecular dynamics simulations. In this paper, the detailed derivations of the Fock matrix and analytic force are presented and discussed. The calculations involve a double self-consistent-field procedure in which the wave function of each fragment is self-consistently optimized in the presence of other fragments, and in addition the polarization of the entire system is self-consistently optimized. The variational X-POL potential has been implemented in the Chemistry at Harvard Molecular Mechanics (CHARMM) package and tested successfully for small model compounds.


A Cell State Monitoring System with Integrated In Situ Imaging and pH Detection.
Cell models are one of the most widely used basic models in biological research, and a variety of in vitro cell culture techniques and models have been developed recently to simulate the physiological microenvironment in vivo. However, regardless of the technique or model, cell culture is the most fundamental but crucial component. As a result, we have developed a cell culture monitoring system to assess the functional status of cells within a biochip. This article focuses on a mini-microscope made from a readily available camera for in situ continuous observation of cell growth within a biochip and a pH sensor based on optoelectronic sensing for measuring pH. With the aid of this monitoring system, scientists can keep an eye on cell growth in real time and learn how the pH of the culture medium affects it. This study offers a new approach for tracking cells on biochips and serves as a valuable resource for enhancing cell culture conditions.


[Evaluation of the Short-Term Efficacy and Safety of Orelabrutinib Combined with High-Dose Methotrexate in the First-line Treatment of Elderly Patients with High Risk Primary Central Nervous System Lymphoma].
To explore the short-term efficacy and adverse reactions of orelabrutinib combined with high-dose methotrexate (HD-MTX) in the first-line treatment of elderly high-risk primary central nervous system lymphoma (PCNSL), as well as the survival of patients. Twenty-five elderly patients with high-risk primary central nervous system diffuse large B-cell lymphoma admitted to Fujian Provincial Hospital from June 2016 to June 2022 were enrolled in this study, and complete clinical data from all patients were collected retrospectively, and the cut-off for follow-up was December 2022. 15 patients had received temmozolomide combined with HD-MTX regimen for at least four cycles, sequential lenalidomide maintenance therapy, while 10 patients had received orelabrutinib combined with HD-MTX regimen for at least four cycles, sequential orelabrutinib maintenance therapy. The short-term efficacy and adverse reactions of the two groups of patients after treatment were observed. Kaplan-Meier was used to analyze the progression-free survival (PFS) and time to progression (TTP). The objective response rate (ORR) and 2-year median FPS of orelabrutinib combined with HD-MTX regimen group were similar to the temozolomide combined with HD-MTX regimen group (ORR: 100% vs 66.7%; 2-year median PFS: 16 months vs 15 months, P>0.05). The 2-year median TTP of the orelabrutinib+HD-MTX regimen group was better than that of the temozolomide+HD-MTX regimen group (not reached vs 12 months, P<0.05). There were no significant differences in adverse reactions such as gastrointestinal reactions, bone marrow suppression, liver and kidney damage, cardiotoxicity, pneumonia and bleeding between these two groups (P>0.05). For elderly patients with high-risk PCNSL, orelabrutinib combined with HD-MTX has reliable short-term efficacy, good safety, and tolerable adverse reactions, which is worthy of clinical promotion.


Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency, the presence of anti-ADAMTS13 autoantibodies and an open ADAMTS13 conformation with a cryptic epitope in the spacer domain exposed. A detailed knowledge of anti-ADAMTS13 autoantibodies will help identifying pathogenic antibodies and elucidating the cause of ADAMTS13 deficiency. We aimed at cloning anti-ADAMTS13 autoantibodies from iTTP patients to study their epitopes and inhibitory characteristics. We sorted anti-ADAMTS13 autoantibody expressing B cells from peripheral blood mononuclear cells of 13 iTTP patients to isolate anti-ADAMTS13 autoantibody sequences. Ninety-six B cell clones producing anti-ADAMTS13 autoantibodies were identified from which 30 immunoglobulin M (IgM) and 5 IgG sequences were obtained. For this study, we only cloned, expressed and purified the five IgG antibodies. In vitro characterization revealed that three of the five cloned IgG antibodies, TTP73-1, ELH2-1 and TR8C11, indeed recognize ADAMTS13. Epitope mapping showed that antibodies TTP73-1 and TR8C11 bind to the cysteine-spacer domains, while the antibody ELH2-1 recognizes the T2-T3 domains in ADAMTS13. None of the antibodies inhibited ADAMTS13 activity. Given the recent findings regarding the open ADAMTS13 conformation during acute iTTP, we studied if the cloned antibodies could recognize cryptic epitopes in ADAMTS13. Interestingly, all three antibodies recognize cryptic epitopes. In conclusion, we cloned three anti-ADAMTS13 autoantibodies from iTTP patients that recognize cryptic epitopes. Hence, these data nicely fit our recent finding that the conformation of ADAMTS13 is open during acute iTTP.


Computational Insight into the Mechanism of Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols.
The ruthenium(II)-catalyzed α-alkylation reaction of arylmethyl nitriles (phenylacetonitrile) using alcohols (ethanol) in toluene has been extensively investigated by means of SMD-M06-2X/6-311G(d,p)-LANL2dz (LAnL2dz for Ru, 6-311G(d,p) for other atoms) calculations. Detailed mechanistic schemes have been proposed and discussed. The catalytically active Ru(II) complex was generated by the base-induced KCl elimination from the catalyst precursor [(PNPPh)RuHCl(CO)]. The overall Ru(II) catalytic cycle consists of three basic processes: (1) ethanol-to-aldehyde transformation catalyzed by the 16-electron unsaturated ruthenium pincer catalyst; (2) a 16-electron unsaturated ruthenium pincer catalyst catalyzed condensation reaction of arylmethyl nitrile with aldehyde, which leads to PhC(CN)=CHCH3; (3) hydrogenation of PhC(CN)=CHCH3, which leads to the formation of the α-alkylated arylmethyl nitrile product (PhCH(CH2CH3)CN). The DFT results revealed that the rate-determining barrier of the overall reaction was 23.9 kcal/mol of the H-transfer step in the third process. The reaction of PhC(CN)=CHCH3 with the dihydride Ru complex, which is generated in the ethanol-to-aldehyde transformation process, is the more preferable hydrogenation mechanism than hydrogenation of vinyl nitrile-Ru complex by H2. Using alcohol as the reactant not only fulfills the requirement of the borrowing-H strategy but also lowers the barriers of the H-migration steps.


Poly(ester-ether)s: III. assessment of cell behaviour on nanofibrous scaffolds of PCL, PLLA and PDX blended with amorphous PMeDX.
The aim of this paper is to investigate the physico-chemical properties, degradation behaviour and cellular response of electrospun fibre-scaffolds of semi-crystalline PCL, PLLA and PDX blended with amorphous poly(methyl dioxanone) (PMeDX). Electrospun PCL/PMeDX and PLLA/PMeDX blend mats in varying weight ratios of the two components were fabricated and their overall performance was compared with similar composition PDX/PMeDX scaffolds. DSC analysis showed almost no change in crystallization temperature of PCL with increasing PMeDX content and TGA showed a different degradation profile as PMeDX content increased. The appearance of two crystallization peaks for PLLA/PMeDX blends suggested stereocomplex formation. As noted from AFM images, addition of PMeDX caused a change in the width of the lamellae from 14.8 ± 2.9 nm in 100/0 mat to 32.0 ± 11.5 nm in 85/15 mat. Moreover, PCL/PMeDX blend mats show a significant drop in Young's modulus for 93/7, 90/10 and 85/15 compositions compared to 100/0 and 98/2. On the other hand, no clear trend in mechanical properties was observed for espun PLLA/PMeDX mats with increasing PMeDX content. Based on these analyses, it was concluded that PCL and PMeDX were immiscible while miscible blends were obtained with PLLA and PMeDX. Initial degradation of electrospun mats over a period of 5 weeks appears to occur via a surface erosion mechanism. In vitro cell culture studies using HDFs showed that the scaffolds were bioactive and a greater density of viable cells was noted on electrospun PCL/PMeDX and PLLA/PMeDX scaffolds compared to PCL and PLLA mats respectively. HDFs infiltrated through the entire thickness of espun 85/15 PLLA/PMeDX scaffold due to a combination of factors including morphology, porosity, surface characteristics and mechanical properties.


Tracking longitudinal retinal changes in experimental ocular hypertension using the cSLO and spectral domain-OCT.
Involvement of the outer retina is controversial in glaucoma. The aim of this study was to test, first, whether the outer retina is affected in experimental ocular hypertension (OHT) and, second, whether whole retinal thickness can be used as a surrogate marker of glaucomatous change. OHT was surgically induced in 20 Dark Agouti rats. Animals were imaged using a modified Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) at baseline and at 3 and 8 weeks after OHT induction. Measurements were recorded for whole and individual retinal layer thickness in four regions-temporal, superior, nasal, and inferior-around the optic nerve head. Whole retinal thickness in normal eyes was 172.19 ± 5.17 μm, with no significant regional differences. OHT caused a significant reduction in whole retinal thickness and the outer nuclear layer (ONL) at 3 and 8 weeks (P < 0.05), along with the expected thinning of the retinal nerve fiber layer (RNFL). Whole retinal thickness correlated well with RNFL (P = 0.035) and ONL (P ≤ 0.001) changes. Sensitivity of RNFL and ONL to IOP exposure appeared greater at 3 than at 8 weeks. In addition, regional profiles were significantly altered in the ONL and RNFL after OHT induction. Adaptation of the Spectralis OCT enables tracking of structural damage in experimental rat OHT. Here the authors show evidence of glaucomatous damage in the outer retinal layers of this model with significant regional changes and highlight whole retinal thickness in the rat as a useful surrogate marker of inner and outer retinal changes. The authors believe that the OCT data can provide useful information with regard to clinical management.


Photostability of amino acids: photodissociation dynamics of phenylalanine chromophores.
The theoretical prediction of H atom elimination on the excited state of phenol, imidazole and indole, the respective chromophores for the amino acids tyrosine, histidine and tryptophan, and the confirmation of theoretical prediction by experimental observations have a great impact on the explanation of photostability of amino acids upon irradiation with UV photons. On the other hand, no theoretical prediction of the excited state photodissociation dynamics has been made on the other aromatic amino acid, phenylalanine. In this work, photodissociation dynamics for various phenylalanine chromophores, including, phenylethylamine, N-methyl-phenylethylamine, and N-acetyl phenylalanine methyl ester was investigated in a molecular beam at 248 and 193 nm using multimass ion imaging techniques. The major dissociation channel for these compounds is the C-C bond cleavage. However, the photofragment translational energy distribution of phenylethylamine contains two components. The slow component corresponds to the dissociation on the ground state surface after internal conversion, and the fast component represents the dissociation from an excited state with a large exit barrier. The competition between the dissociation on the ground state and on the excited state changes as the size of chromophores increases. Internal conversion to the ground state prior to dissociation becomes the major nonradiative process for large chromophores. This study reveals the size-dependent photostability for these amino acid chromophores.


Serum S100A12 and S100B proteins are independent predictors of the presence and severity of obstructive sleep apnea
Obstructive sleep apnea (OSA) is associated with serious cardiometabolic risks. Early diagnosis and treatment compliance are important. For this purpose, research is being carried out on biomarkers associated with the pathogenesis of the disease. We aimed to investigate whether serum S100A12 and S100B proteins could be used as biochemical markers in OSA patients to determine disease presence and severity. A total of 60 (16 women, 44 men) patients with OSA and 50 (20 women, 30 men) controls were enrolled in this cross-sectional study. Each subject included in the study underwent full-night polysomnography (PSG). The presence and severity of OSA was assessed with the apnea–hypopnea index (AHI). In the OSA group, 17 cases were mild, 18 were moderate, and 25 were severe.The serum levels of S100A12 and S100B were measured using the enzyme-linked immunosorbent assay (ELISA) technique. These protein levels were compared using Student's t-test in the patient and control groups. Spearman's rho correlation coefficients and corresponding P-values were calculated to determine the correlations between these protein levels and polysomnographic parameters. For evaluating the association between OSA and biomarkers, as well as possible confounding factors with S100A12 and S100B, we employed multiple linear regression analyses for the patients with OSA Serum levels of S100A12 and S100B were higher in patients than those in controls (P = 0.01 and P = 0.005, respectively), and a significant correlation was determined between S100A12 and S100B values and AHI (P = 0.0001; P = 0.0001), sleep time with SpO2 < 90% (P = 0.032; P = 0.01), minimum SpO2 during sleep (P = 0.019; P = 0.007), and oxygen desaturation index (ODI) (P = 0.001; P = 0.0001). In the linear regression analysis, AHI was independently related with both S100A12 (P < 0.0001) and S100B (P = 0.011). Receiving operating curves (ROC) identified patients with OSA: AUC for S100A12 = 0.643; AUC for S100B = 0.655 (P < 0.05). Serum levels of S100B and S100A proteins have high diagnostic performance in OSA and are independent predictors of OSA presence and severity.


Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity.
In this report, sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, is shown to activate tight-junction-associated protein Zonula Occludens-1 (ZO-1), which in turn plays a critical role in regulating endothelial chemotaxis and barrier integrity. After S1P stimulation, ZO-1 was redistributed to the lamellipodia and cell-cell junctions via the S1P1/G(i)/Akt/Rac pathway. Similarly, both endothelial barrier integrity and cell motility were significantly enhanced in S1P-treated cells through the G(i)/Akt/Rac pathway. Importantly, S1P-enhanced barrier integrity and cell migration were abrogated in ZO-1 knockdown cells, indicating ZO-1 is functionally indispensable for these processes. To investigate the underlying mechanisms, we demonstrated that cortactin plays a critical role in S1P-induced ZO-1 redistribution to the lamellipodia. In addition, S1P significantly induced the formation of endothelial tight junctions. ZO-1 and alpha-catenin polypeptides were colocalized in S1P-induced junctional structures; whereas, cortactin was not observed in these regions. Together, these results suggest that S1P induces the formation of two distinct ZO-1 complexes to regulate two different endothelial functions: ZO-1/cortactin complexes to regulate chemotactic response and ZO-1/alpha-catenin complexes to regulate endothelial barrier integrity. The concerted operation of these two ZO-1 complexes may coordinate two important S1P-mediated functions, i.e. migration and barrier integrity, in vascular endothelial cells.


Contrast-detail characteristic evaluations of several display devices.
The contrast-detail characteristic of a display system is a powerful tool for evaluating displayed image quality. It takes into account the physical properties of the display, the psychophysical aspects of the observer, and the viewing conditions. It is a more sensitive measurement of the displayed image quality than a simple Society of Motion Picture and Television (SMPTE) pattern. Yet, it is relatively simple to measure and requires no special equipment or analysis tools. In this presentation, the results of the evaluation of several cathode ray tube (CRT) monitors and a digital projector will be presented. Contrast-detail characteristics of these display devices were measured under various gamma and display settings. The results show excellent intraobserver and interobserver variance (<1 step on the grayscale). Extraneous light, such as room lighting, affects the contrast threshold more severely at low background levels more than at high background. Gamma settings on graphics adapters affect the shapes of the contrast-detail curve for all display types. Gamma settings of approximately 2.0 result in a better contrast threshold for both high and low background brightness. The results show complex differences in contrast-detail characteristics for different display types. The digital projector display not only has significantly worse performance than CRT monitors, but also is affected more by extraneous light. High-brightness monitors with optimal monitor and graphics adapter settings have better performance than color or low-brightness monitors. However, under some settings, the performance of high-brightness monitors is not always better at all object sizes and background levels.


Assessment of the potential reproductive toxicity of long-term exposure of adult male rats to low-dose formaldehyde.
Formaldehyde (FA), a ubiquitous environmental pollutant, is extensively used in hospitals, laboratories and many industrial settings. Previous studies have showed that short-term, high-dose FA exposure is toxic to male reproduction of mammals. In this paper, we evaluated the male reproductive toxicity of long-term, low-dose formaldehyde exposure in rats, and explored the potential mechanisms. A total of 30 Sprague-Dawley male rats were randomly allotted to three groups, rats were exposed to FA at a dose of 0 (control), 0.5, 2.46 mg/m³ respectively by inhalation for consecutive 60 days. The results indicated that the reproductive toxicity of FA is dose-dependent. Testicular, epididymal structure and function in rats of 0.5 mg/m³ FA exposure group showed no obvious difference compared with those in control group. However, sperm quantity and quality, testicular seminiferous tubular diameter, the activities of superoxide dismutase and glutathione peroxidase was significantly decreased whereas the level of malondialdehyde was significantly increased in rats of 2.46 mg/m³ FA exposure group compared with those in control group. Moreover, histopathological results showed atrophy of seminiferous tubules, decreases of spermatogenic cells and the lumina were oligozoospermic in testes of 2.46 mg/m³ FA exposure rats. In conclusion, the level of 0.5 mg/m³ can be considered as a safe level for FA exposure, but long-term FA exposure at a dose of 2.46 mg/m³ has a harmful effect on male reproduction by inducing oxidative stress in male rats.


Effect of Gallium Substitution on Lithium-Ion Conductivity and Phase Evolution in Sputtered Li7-3 xGa xLa3Zr2O12 Thin Films.
Replacing the liquid electrolyte in conventional lithium-ion batteries with thin-film solid-state lithium-ion conductors is a promising approach for increasing energy density, lifetime, and safety. In particular, Li7La3Zr2O12 is appealing due to its high lithium-ion conductivity and wide electrochemical stability window. Further insights into thin-film processing of this material are required for its successful integration into solid-state batteries. In this work, we investigate the phase evolution of Li7-3 xGa xLa3Zr2O12 in thin films with various amounts of Li and Ga for stabilizing the cubic phase. Through this work, we gain valuable insights into the crystallization processes unique to thin films and are able to form dense Li7-3 xGa xLa3Zr2O12 layers stabilized in the cubic phase with high in-plane lithium-ion conductivities of up to 1.6 × 10-5 S cm-1 at 30 °C. We also note the formation of cubic Li7La3Zr2O12 at the relatively low temperature of 500 °C.


Controlled trial of oxygen in uncomplicated myocardial infarction.
Two-hundred consecutive patients thought to have suffered a myocardial infarction were admitted to a randomised, double-blind controlled trial of oxygen or air administered by MC mask throughout the first 24 hours in hospital. Forty-three patients in whom myocardial infarction was not subsequently confirmed were excluded from the analysis. The remaining air and oxygen groups were comparable except for a significantly higher PaO2 and serum aspartate aminotransferase level in the oxygen group. There was no significant difference in mortality, incidence of arrhythmias, use of analgesics, or systolic time intervals between the two groups, although a higher incidence of sinus tachycardia was found in those given oxygen. There appears to be no evidence of benefit from the routine administration of oxygen in uncomplicated myocardial infarction.


Health-related quality of life in patients with multiple myeloma participating in a multidisciplinary rehabilitation program.
Patients with multiple myeloma (MM) report high symptom burden and functional disabilities resulting in impaired health-related quality of life (HRQoL). Effective evidence-based rehabilitation guidelines are needed for patients with MM to improve HRQoL. The primary aim of this study was to investigate HRQoL in patients with rehabilitation needs living their everyday life. Patients with MM in remission attended a 12-week multidisciplinary rehabilitation program including a 5-day residential course, home-based exercise and a 2-day follow-up course. The patients were referred by the treating haematologist and completed a booklet of validated HRQoL questionnaires at baseline and before arriving for the 2-day follow-up course. The proportion of participants with moderate to severe symptoms and functional problems were assessed at the two time points and multivariate logistic regression was used to investigate explaining factors of impaired HRQoL at baseline. Ninety-two patients participated with a follow-up compliance rate of 90%. Median age was 67 years and median time since diagnosis was 26 months (ranged 5 months to 15.6 years). The most frequently reported symptoms were global quality of life, role functioning, fatigue, pain, peripheral neuropathy and physical functioning. Pain and fatigue were both highly coherent with impairment in physical functioning and those two symptoms explained most HRQoL impairments. Overall, the participants reported no change in HRQoL after the 12-week rehabilitation program. The study supports the need for an evidence-based guideline for rehabilitation and palliative care to patients with MM in remission living their everyday life.


Ambulatory blood pressure monitoring: coming of age in nephrology.
The number of patients undergoing ambulatory blood pressure monitoring (ABPM) and the number of publications using this technique to evaluate the risks and effects of high blood pressure on target organs has been increasing, and dramatically so, in the last 5 years. Much of this growth has centered on the role of the blood pressure load (the percentage of systolic or diastolic readings above a preset value during a specific time period) and the changes in blood pressures levels that occur, with sleep. Although many studies are focused on the interaction between blood pressure (as assessed by ABPM) and the heart, interest is growing in the application of ABPM to the practice of nephrology. This paper discusses some of the technical aspects of ABPM, followed by a review of five areas of clinical research using ABPM, and which are relevant to renal medicine: microalbuminuria, renal function, renovascular hypertension, dialysis (hemodialysis and continuous ambulatory peritoneal dialysis), and transplantation. Despite a general lack of reimbursement for performance of the ABPM procedure, the growth in its usage and the willingness of clinicians to withhold or alter therapy on the basis of ABPM readings is testimony to its clinical value in the management of hypertension.