ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population.
The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1β, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.


Soil abiotic variables are more important than Salicaceae phylogeny or habitat specialization in determining soil microbial community structure.
Predicting the outcome of interspecific interactions is a central goal in ecology. The diverse soil microbes that interact with plants are shaped by different aspects of plant identity, such as phylogenetic history and functional group. Species interactions may also be strongly shaped by abiotic environment, but there is mixed evidence on the relative importance of environment, plant identity and their interactions in shaping soil microbial communities. Using a multifactor, split-plot field experiment, we tested how hydrologic context, and three facets of Salicaceae plant identity-habitat specialization, phylogenetic distance and species identity-influence soil microbial community structure. Analysis of microbial community sequencing data with generalized dissimilarity models showed that abiotic environment explained up to 25% of variation in community composition of soil bacteria, fungi and archaea, while Salicaceae identity influenced <1% of the variation in community composition of soil microbial taxa. Multivariate linear models indicated that the influence of Salicaceae identity was small, but did contribute to differentiation of soil microbes within treatments. Moreover, results from a microbial niche breadth analysis show that soil microbes in wetlands have more specialized host associations than soil microbes in drier environments-showing that abiotic environment changed how plant identity correlated with soil microbial communities. This study demonstrates the predominance of major abiotic factors in shaping soil microbial community structure; the significance of abiotic context to biotic influence on soil microbes; and the utility of field experiments to disentangling the abiotic and biotic factors that are thought to be most essential for soil microbial communities.


Next-generation sequencing of RNA and DNA isolated from paired fresh-frozen and formalin-fixed paraffin-embedded samples of human cancer and normal tissue.
Formalin-fixed, paraffin-embedded (FFPE) tissues are an invaluable resource for clinical research. However, nucleic acids extracted from FFPE tissues are fragmented and chemically modified making them challenging to use in molecular studies. We analysed 23 fresh-frozen (FF), 35 FFPE and 38 paired FF/FFPE specimens, representing six different human tissue types (bladder, prostate and colon carcinoma; liver and colon normal tissue; reactive tonsil) in order to examine the potential use of FFPE samples in next-generation sequencing (NGS) based retrospective and prospective clinical studies. Two methods for DNA and three methods for RNA extraction from FFPE tissues were compared and were found to affect nucleic acid quantity and quality. DNA and RNA from selected FFPE and paired FF/FFPE specimens were used for exome and transcriptome analysis. Preparations of DNA Exome-Seq libraries was more challenging (29.5% success) than that of RNA-Seq libraries, presumably because of modifications to FFPE tissue-derived DNA. Libraries could still be prepared from RNA isolated from two-decade old FFPE tissues. Data were analysed using the CLC Bio Genomics Workbench and revealed systematic differences between FF and FFPE tissue-derived nucleic acid libraries. In spite of this, pairwise analysis of DNA Exome-Seq data showed concordance for 70-80% of variants in FF and FFPE samples stored for fewer than three years. RNA-Seq data showed high correlation of expression profiles in FF/FFPE pairs (Pearson Correlations of 0.90 +/- 0.05), irrespective of storage time (up to 244 months) and tissue type. A common set of 1,494 genes was identified with expression profiles that were significantly different between paired FF and FFPE samples irrespective of tissue type. Our results are promising and suggest that NGS can be used to study FFPE specimens in both prospective and retrospective archive-based studies in which FF specimens are not available.


Specific alpha 1-, alpha 2-, and beta-responses to norepinephrine in pyruvate-perfused rat kidneys.
We compared the effects of alpha- and beta-adrenergic agonists on vascular resistance, gluconeogenesis (GNG), and electrolyte excretion in pyruvate-perfused rat kidneys. Norepinephrine (NE) (15-60 nM) increased vascular resistance (2-19%) and GNG (42-49%) and decreased fractional excretion of Na (18-34%), Cl (38-48%), and K (13-27%). Prazosin and yohimbine blocked the vasoconstrictor but not the antinatriuretic response. Prazosin revealed an antiphosphaturic and inhibited the gluconeogenic response. Propranolol blocked the effect on Na and Cl (66%) and K excretion (100%). Methoxamine (0.6-1 microM) maximally increased GNG (40-52%) with little effect on vascular resistance (+0-9%) and NaCl excretion (-0-11%). Adding glucose to the perfusate increased methoxamine's effects on electrolyte excretion and vascular resistance. Mercaptopicolinate did not alter methoxamine's effects during pyruvate perfusion. Clonidine (0.1 microM) decreased phosphate excretion without vasoconstriction or antinatriuresis; 0.5-1 microM vasoconstricted and decreased NaCl excretion. Isoproterenol (0.1 microM) vasodilated and decreased Na (25%), Cl (40%), and K excretion (20%). Thus alpha 1- and beta-receptors could account for the effect of NE on GNG and K reabsorption, respectively. Synergism of alpha 1, alpha 2, and beta were required for full antinatriuresis. Glucose increased alpha 1-stimulated vasoconstriction and antinatriuresis. Blocking alpha 1-receptors revealed an alpha 2-like antiphosphaturic response.


The Multiple Applications and Possible Mechanisms of the Hyperbaric Oxygenation Therapy.
Hyperbaric Oxygenation Therapy (HBOT) is used as an adjunctive method for multiple diseases. The method meets the routine treating and is non-invasive, as well as provides 100% pure oxygen (O2), which is at above-normal atmospheric pressure in a specialized chamber. It is well known that in the condition of O2 deficiency, it will induce a series of adverse events. In order to prevent the injury induced by anoxia, the capability of offering pressurized O2 by HBOT seems involuntary and significant. In recent years, HBOT displays particular therapeutic efficacy in some degree, and it is thought to be beneficial to the conditions of angiogenesis, tissue ischemia and hypoxia, nerve system disease, diabetic complications, malignancies, Carbon monoxide (CO) poisoning and chronic radiation-induced injury. Single and combination HBOT are both applied in previous studies, and the manuscript is to review the current applications and possible mechanisms of HBOT. The applicability and validity of HBOT for clinical treatment remain controversial, even though it is regarded as an adjunct to conventional medical treatment with many other clinical benefits. There also exists a negative side effect of accepting pressurized O2, such as oxidative stress injury, DNA damage, cellular metabolic, activating of coagulation, endothelial dysfunction, acute neurotoxicity and pulmonary toxicity. Then it is imperative to comprehensively consider the advantages and disadvantages of HBOT in order to obtain a satisfying therapeutic outcome.


Regulation of Bnip3 death pathways by calcium, phosphorylation, and hypoxia-reoxygenation.
Bnip3 is a proapoptotic member of the Bcl-2 family of death-regulating proteins that promote the intrinsic pathway of programmed cell death. The Bnip3 death program requires membrane insertion through an N-terminal transmembrane domain that directs the protein to mitochondrial and endoplasmic reticular (ER) membranes. We have reported that simulated ischemia induces transcription of the Bnip3 gene, and Bnip3 protein is stabilized by acidosis. Bnip3 programmed death is atypical, with features of both apoptosis and necrosis. Here we demonstrate that hypoxia-reoxygenation and agents that activate protein kinase C, including calcium ionophore, phorbol 12-myristate 13-acetate, and okadaic acid, also induce Bnip3. The molecular size of Bnip3 predicted from the amino acid sequence is 21.5 kDa, but the protein typically migrates in SDS-PAGE as a 31-kDa monomer and 60-kDa dimer. Treatment of cell extracts containing Bnip3 with phosphatase yielded a series of rapidly migrating species, the smallest of which corresponded with the theoretic molecular size of Bnip3. Conversely, treatment of cells with okadaic acid eliminated the rapidly migrating species, suggesting that Bnip3 phosphorylation is a dynamic process. Elevated levels of the phosphoprotein correlated with initiation of Bnip3-dependent death, whereas the dephosphorylated species correlated with extreme acidosis.


Stability of synthetic cathinones in clinical and forensic toxicological analysis-Where are we now?
Understanding the stability of analyzed drugs in biological samples is a crucial part for an appropriate interpretation of the analytical findings. Synthetic cathinones, as psychoactive stimulants, belong to a major class of new psychoactive substances. As they are subject to several degradation pathways, they are known to clinical and forensic toxicologists as unstable analytes in biological samples. When interpreting analytical data of synthetic cathinones in biological samples, analysts must be aware that the concentration of analytes may not accurately reflect the levels at the time they were acquired owing to many factors. This review provides (i) an overview of the current scientific knowledge on the stability of synthetic cathinones and/or metabolites in various human biological samples with a focus on factors that may deteriorate their stability-such as storage temperature, length of storage, matrix, pH, type of preservatives, concentration of analytes, and the chemistry of the analytes-and (ii) possible solutions on how to avoid such degradation. The PubMed database as well as Google Scholar was thoroughly searched to find published studies on the stability of synthetic cathinones since 2007 by searching specific keywords. A total of 23 articles met the inclusion criteria and were included in this review. Synthetic cathinones that carry methylenedioxy or N-pyrrolidine ring showed higher degradation resistance over other substituted groups. Acidification of samples pH plays a crucial role at increasing the stability of cathinones even with analytes that were frequently considered as poorly stable. This review also provides several recommendations for best practice in planning the experimental design, preservation, and storage conditions in order to minimize synthetic cathinones' degradation in human biological samples.


Digital health coaching to improve patient preparedness for elective lower limb arthroplasty: a quality improvement project.
Major surgery carries high risks with comorbidities, frailty and health risk behaviours meaning patients are often unprepared for the physiological insult. Since 2018, the Prepwell programme at South Tees Hospitals NHS Foundation Trust has supported patients to improve their preoperative health and fitness. In April 2020, the face-to-face service was suspended due to the pandemic, leading to the team implementing a three-tiered remote digital support pathway, including digital health coaching via a mobile phone application. Patients scheduled for elective lower limb arthroplasty were offered 8 weeks of digital health coaching preoperatively. Following consent, participants were assigned a personal health coach to set individual behaviour change goals supported by online resources, alongside a digitally delivered exercise programme. Participants completed self-assessment questionnaires at Entry to, and Exit from, the programme, with outcome data collected 21 days postoperatively. The primary outcome was the change in Patient Activation Measure (PAM). Fifty-seven of 189 patients (30.2%) consented to referral for digital health coaching. Forty participants completed the 8-week programme. Median PAM increased from 58.1 to 67.8 (p=0.002). Thirty-five per cent of participants were in a non-activated PAM level at Entry, reducing to 15% at Exit with no participants in PAM level 1 at completion. Seventy-one percent of non-activated participants improved their PAM by one level or more, compared with 45% for the whole cohort. Median LOS was 2 days, 1 day less than the Trust's arthroplasty patient population during the study period (unadjusted comparison). Digital health coaching was successfully implemented for patients awaiting elective lower limb arthroplasty. We observed significant improvements in participants' PAM scores after the programme, with the largest increase in participants with lower activation scores at Entry. Further study is needed to confirm the effects of digital health coaching in this and other perioperative groups.


Hormonal correlates of the annual cycle of activity and body temperature in the South-American tegu lizard (Salvator merianae).
Life history transitions and hormones are known to interact and influence many aspects of animal physiology and behavior. The South-American tegu lizard (Salvator merianae) exhibits a profound seasonal shift in metabolism and body temperature, characterized by high daily activity during warmer months, including reproductive endothermy in spring, and metabolic suppression during hibernation in winter. This makes S. merianae an interesting subject for studies of interrelationships between endocrinology and seasonal changes in physiology/behavior. We investigated how plasma concentrations of hormones involved in regulation of energy metabolism (thyroid hormones T4 and T3; corticosterone) and reproduction (testosterone in males and estrogen/progesterone in females) correlate with activity and body temperature (Tb) across the annual cycle of captive held S. merianae in semi-natural conditions. In our initial model, thyroid hormones and corticosterone showed a positive relationship with activity and Tb with independent of sex: T3 positively correlated with activity and Tb, while T4 and corticosterone correlated positively with changes in Tb only. This suggests that thyroid hormones and glucocorticoids may be involved in metabolic transitions of annual cycle events. When accounting for sex-steroid hormones, our sex separated models showed a positive relationship between testosterone and Tb in males and progesterone and activity in females. Coupling seasonal endocrine measures with activity and Tb may expand our understanding of the relationship between animal's physiology and its environment. Manipulative experiments are required in order to unveil the directionality of influences existing among abiotic factors and the hormonal signaling of annual cyclicity in physiology/behavior.


Rare copy number variants are common in young children with autism spectrum disorder.
Several studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions. We performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54 months of age. Pathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability. Our results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.


Renal Denervation Therapy: Can it Contribute to Better Blood Pressure Control in Hypertension?
Although the first results from studies suggested important benefits regarding blood pressure (BP) control in resistant hypertension by the use of diverse systems of renal denervation (RDN) in the setting of resistant hypertension, the Symplicity HTN-3, randomized sham-controlled trial reduced the enthusiasm and led to a more critical approach towards this neuromodulation innovative therapy. Nowadays there is an ongoing research attempt to justify the pathophysiological background of RDN since overdrive of the sympathetic nervous system is one of the key mechanisms leading to the development and progression of the hypertensive and cardiovascular diseases. Future RDN trials based on the clinical findings and gaps from previous works will try to identify those parameters to help identify better BP response, target the most suitable population and conclude whether this interventional approach can contribute to the clinical problem of uncontrolled hypertension.


The structure of the posterolateral aspect of the knee.
The lateral structures of the knee can be divided into three distinct layers. The deepest layer, the lateral part of the capsule, divides into two laminae just posterior to the overlying iliotibial tract. These laminae encompass three ligaments: the lateral collateral, the fabellofibular, and the arcuate ligaments. Three major anatomical variations are seen: reinforcement of the capsule by the arcuate ligament alone (13 per cent), by the fabellofibular ligament alone (20 per cent), and by both ligaments (67 per cent). One can predict which variation will be seen in a given patient from the information provided by a radiograph and by physical examination.


Using a validated transmission model for the optimization of bundled fiber optic displacement sensors.
A variety of intensity-modulated optical displacement sensor architectures have been proposed for use in noncontacting sensing applications, with one of the most widely implemented architectures being the bundled displacement sensor. To the best of the authors' knowledge, the arrangement of measurement fibers in previously reported bundled displacement sensors has not been configured with the use of a validated optical transmission model. Such a model has utility in accurately describing the sensor's performance a priori and thereby guides the arrangement of the fibers within the bundle to meet application-specific performance needs. In this paper, a recently validated transmission model is used for these purposes, and an optimization approach that employs a genetic algorithm efficiently explores the design space of the proposed bundle sensor architecture. From the converged output of the optimization routine, a bundled displacement sensor configuration is designed and experimentally tested, offering linear performance with a sensitivity of -0.066 μm(-1) and displacement measurement error of 223 μm over the axial displacement range of 6-8 mm. It is shown that this optimization approach may be generalized to determine optimized bundle configurations that offer high-sensitivity performance, with an acceptable error level, over a variety of axial displacement ranges. This document has been approved by Los Alamos National Laboratory for unlimited public release (LA-UR 11-03413).


Legal standard of care: a shift from the traditional Bolam test.
An essential component of an action in negligence against a doctor is proof that the doctor failed to provide the required standard of care under the circumstances. Traditionally the standard of care in law has been determined according to the Bolam test. This is based on the principle that a doctor does not breach the legal standard of care, and is therefore not negligent, if the practice is supported by a responsible body of similar professionals. The Bolam principle, however, has been perceived as being excessively reliant upon medical testimony supporting the defendant. The judgment given by the House of Lords in the recent case of Bolitho imposes a requirement that the standard proclaimed must be justified on a logical basis and must have considered the risks and benefits of competing options. The effect of Bolitho is that the court will take a more enquiring stance to test the medical evidence offered by both parties in litigation, in order to reach its own conclusions. Recent case law shows how the court has applied the Bolitho approach in determining the standard of care in cases of clinical negligence. An understanding of this approach and of the shift from the traditional Bolam test is relevant to all medical practitioners, particularly in a climate that is increasingly litigious.


Submillisecond precision of the input-output transformation function mediated by fast sodium dendritic spikes in basal dendrites of CA1 pyramidal neurons.
The ability of cortical neurons to perform temporally accurate computations has been shown to be important for encoding of information in the cortex; however, cortical neurons are expected to be imprecise temporal encoders because of the stochastic nature of synaptic transmission and ion channel gating, dendritic filtering, and background synaptic noise. Here we show for the first time that fast local spikes in basal dendrites can serve to improve the temporal precision of neuronal output. Integration of coactivated, spatially distributed synaptic inputs produces temporally imprecise output action potentials within a time window of several milliseconds. In contrast, integration of closely spaced basal inputs initiates local dendritic spikes that amplify and sharpen the summed somatic potential. In turn, these fast basal spikes allow precise timing of output action potentials with submillisecond temporal jitter over a wide range of activation intensities and background synaptic noise. Our findings indicate that fast spikes initiated in individual basal dendrites can serve as precise "timers" of output action potentials in various network activity states and thus may contribute to temporal coding in the cortex.


Tight focusing of laser beams in a lambda/2-microcavity.
We evaluate the field distribution in the focal spot of the fundamental Gaussian beam as well as radially and azimuthally polarized doughnut beams focused inside a planar metallic sub-wavelength microcavity using a high numerical aperture objective lens. We show that focusing in the cavity results in a much tighter focal spot in longitudinal direction compared to free space and in spatial discrimination between longitudinal and in-plane field components. In order to verify the modeling results we experimentally monitor excitation patterns of fluorescence beads inside the lambda/2-cavity and find them in full agreement to the modeling predictions. We discuss the implications of the results for cavity assisted single molecular spectroscopy and intra-cavity single molecular imaging.


Structure of the Ty3/Gypsy retrotransposon capsid and the evolution of retroviruses.
Retroviruses evolved from long terminal repeat (LTR) retrotransposons by acquisition of envelope functions, and subsequently reinvaded host genomes. Together, endogenous retroviruses and LTR retrotransposons represent major components of animal, plant, and fungal genomes. Sequences from these elements have been exapted to perform essential host functions, including placental development, synaptic communication, and transcriptional regulation. They encode a Gag polypeptide, the capsid domains of which can oligomerize to form a virus-like particle. The structures of retroviral capsids have been extensively described. They assemble an immature viral particle through oligomerization of full-length Gag. Proteolytic cleavage of Gag results in a mature, infectious particle. In contrast, the absence of structural data on LTR retrotransposon capsids hinders our understanding of their function and evolutionary relationships. Here, we report the capsid morphology and structure of the archetypal Gypsy retrotransposon Ty3. We performed electron tomography (ET) of immature and mature Ty3 particles within cells. We found that, in contrast to retroviruses, these do not change size or shape upon maturation. Cryo-ET and cryo-electron microscopy of purified, immature Ty3 particles revealed an irregular fullerene geometry previously described for mature retrovirus core particles and a tertiary and quaternary arrangement of the capsid (CA) C-terminal domain within the assembled capsid that is conserved with mature HIV-1. These findings provide a structural basis for studying retrotransposon capsids, including those domesticated in higher organisms. They suggest that assembly via a structurally distinct immature capsid is a later retroviral adaptation, while the structure of mature assembled capsids is conserved between LTR retrotransposons and retroviruses.


Estradiol Suppresses TLR4-triggered Apoptosis of Decidual Stromal Cells and Drives an Anti-inflammatory TH2 Shift by Activating SGK1.
A pro-inflammatory cytokine profile at the feto-maternal interface may predispose immune maladaptation notably in early miscarriages. We investigated the involvement of estradiol (E2)-activated serum-glucocorticoid regulated kinase 1 (SGK1) in preserving the tolerogenic and pro-survival intrauterine microenvironment beneficial to gestation maintenance. Decidual SGK1 was down-regulated in early miscarriage, consistent with the lower serum E2 concentration seen in pregnancy loss. Lipopolysaccharide (LPS)/Toll-like receptors 4 (TLR4) signaling induced apoptosis and the pro-inflammatory T helper type (TH) 1 response of decidual stromal cells (DSCs) were associated with miscarriage. SGK1 activation was suppressed by LPS/TLR4 signaling and would be rescued by E2 administration via the PI3K signaling pathway in DSCs. SGK1 activation attenuated TLR4-mediated cell apoptosis, while promoting cell viability of DSCs by up-regulating the pro-survival genes BCL2 and XIAP, and enhancing the phosphorylation of FOXO1. Furthermore, E2-induced SGK1 activation reduced the secretion of pro-inflammatory TH1 cytokines, and promoted the generation of TH2 cytokines and elevated IRF4 mRNA and protein levels in LPS-incubated DSCs. Pharmacologic inhibition of SGK1 or suppression by small interfering (si) RNA increased the phosphorylation and nuclear translocation of NF-κB to reverse the pro-TH2 and anti-inflammatory effects of E2 pretreatment, leading to compromised pregnancy. These findings suggest that the E2-mediated SGK1 activation suppressed LPS-mediated apoptosis and promoted the anti-inflammatory TH2 responses in DSCs, ultimately contributing to a successful pregnancy.


Safety and efficacy of drug-induced sleep endoscopy using a probability ramp propofol infusion system in patients with severe obstructive sleep apnea.
Drug-induced sleep endoscopy (DISE) uses sedative-hypnotics to induce moderate obstruction in sleep apnea patients, thereby facilitating anatomic assessment of obstructive physiology. Implementation of DISE with propofol requires a dosing strategy that reliably and efficiently produces obstruction while minimizing oxygen desaturation. The surgeon in a prospective study of transoral robotic resection of the tongue base enrolled 97 patients with obstructive sleep apnea confirmed by polysomnography who failed continuous positive airway pressure. All patients were screened by DISE. Propofol dose was determined using custom software written in MATLAB, which has been previously described. Studies were performed in an operating room with standard monitors and resuscitation equipment. No topical anesthesia was used, and no IV drugs other than propofol were used. All patients received 2 L/min supplemental oxygen via a nasal cannula placed in the mouth. After initiation of propofol sedation, a pediatric bronchoscope was positioned via the naris to observe the velopharynx. The sedation sequence was continued until the clinical end point of obstruction onset was noted. Observation of the pharynx was performed for a sufficient period to obtain images of the anatomic site(s) of obstruction. The infusion was then terminated. Statistical analysis was performed with MATLAB (MathWorks, version 2012b). Comparison of saturation nadirs between DISE and subject sleep studies was performed with both the paired and unpaired Student t test. The subject population was characterized by a median body mass index of 32.1 (interquartile range [IQR] 6.8) kg/m and apnea-hypopnea index of 48 (IQR 32). All patients demonstrated obstruction within the design variables. Obstruction was observed after 236 (±57.9) seconds at an estimated effect-site concentration of 4.2 ± 1.3 mcg/mL. The median saturation nadir during DISE was significantly higher (91.4% (IQR 5.1)) than that during standard sleep studies (81.0% [IQR 11.2], P < 0.0001). Ninety-five percent confidence intervals for correlations between DISE saturation nadir and body mass index, age, apnea-hypopnea index, or administered propofol dose included zero in all cases. A propofol infusion strategy that requires limited experience with propofol dose selection and only 1 pump dosing change reliably produced airway obstruction in patients with severe sleep apnea. Clinical obstruction was achieved faster than target-controlled infusion-based systems for similar procedures reported in the literature. The observed degree of oxygen desaturation in the model system was within a clinically acceptable range.


Efficacy and Safety of Image-Guided Intensity-Modulated Radiation Therapy and Volumetric Modulated Arc Therapy Combined with Paclitaxel Liposomes and Cisplatin for Locally Advanced Stage IIB-IIIB Cervical Cancer: A Retrospective Study at a Single Center.
BACKGROUND This retrospective study aimed to investigate the efficacy and safety of image-guided intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) combined with administration of paclitaxel liposomes and cisplatin for locally advanced stage IIB-IIIB cervical cancer at a single center in China. MATERIAL AND METHODS The clinical data of 126 patients with stage IIB-IIIB cervical cancer treated in our hospital were retrospectively analyzed. The patients were divided into the IMRT group (n=63) and the VMAT group (n=63). The short-term clinical efficacy, the incidence of adverse reactions, the quality-of-life score, and the changes in levels of T-lymphocyte subsets, serum inflammatory factors, and tumor markers were compared pre- and posttreatment between the 2 groups. RESULTS The clinical response rate was 90.5% and 96.8% in the IMRT group and the VMAT group, respectively; the difference was not statistically significant. After treatment, the levels of CD3⁺, CD4⁺, and CD4⁺/CD8⁺ subsets rose significantly, while the CD8⁺ level declined significantly in both groups compared with the pretreatment levels. After treatment, the levels of serum vascular endothelial growth factor, squamous cell carcinoma antigen, interleukin-8, tumor necrosis factor-a, carcinoembryonic antigen, and carbohydrate antigen 125 declined in both groups compared with pretreatment levels. After treatment, the Karnofsky performance scale score rose in both groups, and it was higher in the VMAT group than in the IMRT group. CONCLUSIONS IMRT and VMAT combined with paclitaxel liposomes and cisplatin have similar short-term clinical efficacy and long-term survival rates in the treatment of stage IIB-IIIB cervical cancer.


Curcumol induces RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling in hepatic stellate cells.
It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.


The Amino Acid Transporter OsAAP4 Contributes to Rice Tillering and Grain Yield by Regulating Neutral Amino Acid Allocation through Two Splicing Variants.
Amino acids, which are transported by amino acid transporters, are the major forms of organic nitrogen utilized by higher plants. Among the 19 Amino Acid Permease transporters (AAPs) in rice, only a small number of these genes have been reported to influence rice growth and development. However, whether other OsAAPs are responsible for rice growth and development is unclear. In this study, we demonstrate that OsAAP4 promoter sequences are divergent between Indica and Japonica, with higher expression in the former, which produces more tillers and higher grain yield than does Japonica. Overexpression of two different splicing variants of OsAAP4 in Japonica ZH11 significantly increased rice tillering and grain yield as result of enhancing the neutral amino acid concentrations of Val, Pro, Thr and Leu. OsAAP4 RNA interference (RNAi) and mutant lines displayed opposite trends compared with overexpresing (OE) lines. In addition, exogenous Val or Pro at 0.5 mM significantly promoted the bud outgrowth of lines overexpressing an OsAAP4a splicing variant compared with ZH11, and exogenous Val or Pro at 2.0 mM significantly enhanced the bud outgrowth of lines overexpressing splicing variant OsAAP4b compared with ZH11. Of note, the results of a protoplast amino acid-uptake assay showed that Val or Pro at different concentrations was specifically transported and accumulated in these overexpressing lines. Transcriptome analysis further demonstrated that OsAAP4 may affect nitrogen transport and metabolism, and auxin, cytokinin signaling in regulating rice tillering. Our results suggested that OsAAP4 contributes to rice tiller and grain yield by regulating neutral amino acid allocation through two different splicing variants and that OsAAP4 might have potential applications in rice breeding.


[Comparative analysis of the European and Russian models of medical examination (overview)].
Screening or its synonym medical check-up is the result of a health indicator, representing results of a medical examination and an effective tool of disease prevention. The concept of the term screening in European countries implies active detection of a disease or a premorbidity in people who are considered or consider themselves healthy. Medical check-up is a set of measures that includes preventive medical examination and additional methods of examinations conducted in order to assess the state of health and carried out in relation to certain groups of the population. The study and analysis of the international screening model and experience of its implementation, its role in the system of primary health care, including rehabilitation, is very important in terms of shaping public health at the international level. The article discusses regional trends in screening (medical check-up) and issues related to the conceptual and methodological aspects of medical check-up organization in the context of public health and prevention of risk factors. The data were searched in Scopus Web of Science, MedLine, the Cochrane Library, PubMed.


Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.
To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States. The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review. The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7). The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.


Antihyperlipidemic effect of active principle isolated from seed of Eugenia jambolana on alloxan-induced diabetic rabbits.
Diabetes is accompanied by lipid abnormalities, which contribute significantly to cardiovascular morbidity and mortality in diabetic patients. We previously demonstrated the potent antihyperglycemic activity of the active principle (fraction II from Sephadex LH 20 chromatography [LH II]) isolated from ethanolic seed extract of Eugenia jambolana in diabetic rabbits. In the present study, the efficacy of LH II was evaluated for its hypolipidemic activity in alloxan-induced mildly diabetic (MD) and severely diabetic (SD) rabbits. Phytochemical investigation of LH II by various structural spectra showed the presence of saturated fatty acid, Δ(5) lipid, and sterol. Oral administration of LH II (10 mg/kg of body weight) for 21 days resulted in improved glycemic control in both MD and SD rabbits. After treatment with LH II, serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, and the total cholesterol/high-density lipoprotein cholesterol ratio were significantly improved. LH II also resulted in significant (P < .001) improvement in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and levels of total lipids and glycogen in both MD and SD rabbits. Thus, the present study demonstrates that LH II possesses potent hypolipidemic activity and efficacy in both MD and SD rabbits.


Bipolar resistive switching of single gold-in-Ga2O3 nanowire.
We have fabricated single nanowire chips on gold-in-Ga(2)O(3) core-shell nanowires using the electron-beam lithography techniques and realized bipolar resistive switching characteristics having invariable set and reset voltages. We attribute the unique property of invariance to the built-in conduction path of gold core. This invariance allows us to fabricate many resistive switching cells with the same operating voltage by simple depositing repetitive metal electrodes along a single nanowire. Other characteristics of these core-shell resistive switching nanowires include comparable driving electric field with other thin film and nanowire devices and a remarkable on/off ratio more than 3 orders of magnitude at a low driving voltage of 2 V. A smaller but still impressive on/off ratio of 10 can be obtained at an even lower bias of 0.2 V. These characteristics of gold-in-Ga(2)O(3) core-shell nanowires make fabrication of future high-density resistive memory devices possible.


Efficacy of a Semi-Occluded Vocal Tract Exercises-Therapeutic Program in Behavioral Dysphonia: A Randomized and Blinded Clinical Trial.
Semi-occluded vocal tract exercises (SOVTE) may improve the source and filter interaction by changing the acoustic characteristics and the impedance of the vocal tract, both in dysphonic and vocally healthy populations. However, there are a few studies that verify the effects of these exercises in a clinical trial. Thus, this study's purpose was to analyze the effectiveness of the SOVTE-Therapeutic Program (SOVTE-TP) in vocal quality and self-assessment, comparing it with Vocal Function Exercises. Eighteen (eight men; 10 women), ages 18-50, with behavioral dysphonia participated in this randomized and blinded clinical trial. The participants were equally randomized into two groups: Experimental Group and Vocal Function Exercises Group. They were assessed at three moments: before the treatment, after finishing it, and one month after finishing the treatment--follow up. Acoustic measures (ie, fundamental frequency, jitter, shimmer, noise-to-harmonic ratio, cepstral peak-smoothed, alpha ratio, and L1-L0), auditory-perceptual analysis, vocal fatigue index (VFI), self-perceived resonant voice, and vocal handicap index-30 (VHI-30) were measured at all assessment moments. For the two groups, the interventions happened twice per week (four weeks) and lasted 35 minutes. It was applied the repeated-measures ANOVA test (P< 0.05) and Tukey Test. The acoustic measures and auditory-perceptual had no differences between the groups and moments, respectively, which means that SOVTE-TP did not cause any harm. The auditory-perceptual analysis showed a mild deviation of participants' vocal quality. All groups reduced the VFI and VHI-30 scores in M2 and kept these results at M3 also, the vocal economy sensation increased in M2, decreasing slightly in M3. SOVTE-TP has positive effects regarding self-assessment (VFI, VHI, and resonant voice quality) on patients with mild behavioral dysphonia, and it provides the same effects as VFE.


Pyroelectric PVDF sensor modeling of the temporal voltage response to arbitrarily modulated radiation.
Our design of transducer arrays for custom pyroelectric sensors is mainly devoted to IR laser beam characterization and control. It benefits from some of the properties of PVDF film such as low cost, low weight, mechanical flexibility, chemical stability (inert), and compatibility of thick film interconnection technologies on metallized films. By using the temporal characteristics of the source intensity and starting from a standard equivalent one-dimensional model of a multilayer thick-film transducer in the frequency domain, we developed a computer model of the PVDF sensor that determines the temporal response to arbitrarily modulated radiation. The validation of the model accuracy has been carried out with a simulation procedure performed on a PVDF sensor designed for accurate beam alignment of low power laser beams. In this case, an iterative algorithm also was developed to estimate some thermal and physical properties of the front absorbing and the metallization layers that are generally barely known. We present a fitting procedure to determine these properties by using the temporal pyroelectric response to a square wave modulated laser diode that provides a reliable reference signal.


Effects of Independent Component Analysis on Magnetoencephalography Source Localization in Pre-surgical Frontal Lobe Epilepsy Patients.
Objective: Magnetoencephalography source imaging (MSI) of interictal epileptiform discharges (IED) is a useful presurgical tool in the evaluation of drug-resistant frontal lobe epilepsy (FLE) patients. Yet, failures in MSI can arise related to artifacts and to interference of background activity. Independent component analysis (ICA) is a popular denoising procedure but its clinical application remains challenging, as the selection of multiple independent components (IC) is controversial, operator dependent, and time consuming. We evaluated whether selecting only one IC of interest based on its similarity with the average IED field improves MSI in FLE. Methods: MSI was performed with the equivalent current dipole (ECD) technique and two distributed magnetic source imaging (dMSI) approaches: minimum norm estimate (MNE) and coherent Maximum Entropy on the Mean (cMEM). MSI accuracy was evaluated under three conditions: (1) ICA of continuous data (Cont_ICA), (2) ICA at the time of IED (IED_ICA), and (3) without ICA (No_ICA). Localization performance was quantitatively measured as actual distance of the source maximum in relation to the focus (Dmin), and spatial dispersion (SD) for dMSI. Results: After ICA, ECD Dmin did not change significantly (p > 0.200). For both dMSI techniques, ICA application worsened the source localization accuracy. We observed a worsening of both MNE Dmin (p < 0.05, consistently) and MNE SD (p < 0.001, consistently) for both ICA approaches. A similar behaviour was observed for cMEM, for which, however, Cont_ICA seemed less detrimental. Conclusion: We demonstrated that a simplified ICA approach selecting one IC of interest in combination with distributed magnetic source imaging can be detrimental. More complex approaches may provide better results but would be rather difficult to apply in real-world clinical setting. In a broader perspective, caution should be taken in applying ICA for source localization of interictal activity. To ensure optimal and useful results, effort should focus on acquiring good quality data, minimizing artifacts, and determining optimal candidacy for MEG, rather than counting on data cleaning techniques.


Parent conversations about healthful eating and weight: associations with adolescent disordered eating behaviors.
The prevalence of weight-related problems in adolescents is high. Parents of adolescents may wonder whether talking about eating habits and weight is useful or detrimental. To examine the associations between parent conversations about healthful eating and weight and adolescent disordered eating behaviors. Cross-sectional analysis using data from 2 linked multilevel population-based studies. Anthropometric assessments and surveys completed at school by adolescents and surveys completed at home by parents in 2009-2010. Socioeconomically and racially/ethnically diverse sample (81% ethnic minority; 60% low income) of adolescents from Eating and Activity in Teens 2010 (EAT 2010) (n = 2793; mean age, 14.4 years) and parents from Project Families and Eating and Activity in Teens (Project F-EAT) (n = 3709; mean age, 42.3 years). EXPOSURE Parent conversations about healthful eating and weight/size. Adolescent dieting, unhealthy weight-control behaviors, and binge eating. Mothers and fathers who engaged in weight-related conversations had adolescents who were more likely to diet, use unhealthy weight-control behaviors, and engage in binge eating. Overweight or obese adolescents whose mothers engaged in conversations that were focused only on healthful eating behaviors were less likely to diet and use unhealthy weight-control behaviors. Additionally, subanalyses with adolescents with data from 2 parents showed that when both parents engaged in healthful eating conversations, their overweight or obese adolescent children were less likely to diet and use unhealthy weight-control behaviors. Parent conversations focused on weight/size are associated with increased risk for adolescent disordered eating behaviors, whereas conversations focused on healthful eating are protective against disordered eating behaviors.


Expert consensus statement to guide the evidence-based classification of Paralympic athletes with vision impairment: a Delphi study.
Paralympic sports are required to develop evidence-based systems that allocate athletes into 'classes' on the basis of the impact of their impairment on sport performance. However, sports for athletes with vision impairment (VI) classify athletes solely based on the WHO criteria for low vision and blindness. One key barrier to evidence-based classification is the absence of guidance on how to address classification issues unique to VI sport. The aim of this study was to reach expert consensus on how issues specific to VI sport should be addressed in evidence-based classification. A four-round Delphi study was conducted with 25 participants who had expertise as a coach, athlete, classifier and/or administrator in Paralympic sport for VI athletes. The experts agreed that the current method of classification does not fulfil the requirements of Paralympic classification, and that the system should be different for each sport to account for the sports' unique visual demands. Instead of relying only on tests of visual acuity and visual field, the panel agreed that additional tests are required to better account for the impact of impairment on sport performance. There was strong agreement that all athletes should not be required to wear a blindfold as a means of equalising the impairment during competition. There is strong support within the Paralympic movement to change the way that VI athletes are classified. This consensus statement provides clear guidance on how the most important issues specific to VI should be addressed, removing key barriers to the development of evidence-based classification.


A multi-level, multi-jurisdictional strategy: Transnational tobacco companies' attempts to obstruct tobacco packaging restrictions.
Despite the extensive literature on the tobacco industry, there has been little attempt to study how transnational tobacco companies (TTCs) coordinate their political activities globally, or to theorise TTC strategies within the context of global governance structures and policy processes. This article draws on three concepts from political science - policy transfer, multi-level governance and venue shifting - to analyse TTCs' integrated, global strategies to oppose augmented packaging requirements across multiple jurisdictions. Following Uruguay's introduction of extended labelling requirements, Australia became the first country in the world to require tobacco products to be sold in standardised ('plain') packaging in 2012. Governments in the European Union, including in the United Kingdom and Ireland, adopted similar laws, with other member states due to follow. TTCs vehemently opposed these measures and developed coordinated, global strategies to oppose their implementation, exploiting the complexity of contemporary global governance arrangements. These included a series of legal challenges in various jurisdictions, alongside political lobbying and public relations campaigns. This article draws on analysis of public documents and 32 semi-structured interviews with key policy actors. It finds that TTCs developed coordinated and highly integrated strategies to oppose packaging restrictions across multiple jurisdictions and levels of governance.


Classification of Systemic and Localized Sweating Disorders.
Hyperhidrosis can be subdivided into generalized hyperhidrosis, with increased sweating over the entire body, and focal hyperhidrosis, in which the excessive sweating is restricted to specific parts of the body. Generalized hyperhidrosis may be either primary (idiopathic) or secondary. Secondary generalized hyperhidrosis may be caused by infections such as tuberculosis, hyperthyroidism, endocrine and metabolic disturbances such as pheochromocytoma, neurological disorders, or drugs. Focal hyperhidrosis may also be primary (idiopathic) or secondary. Frey's syndrome is one form of secondary focal hyperhidrosis that occurs during eating together with reddening of the area in front of the ear following parotid gland surgery or injury. Primary focal hyperhidrosis is particularly common on the palms and soles of the feet, in the axilla, and on the head. Anhidrosis may be either congenital/genetic or acquired. Some of the most typical forms of congenital/genetic anhidrosis include hypohidrotic ectodermal dysplasia, congenital insensitivity to pain and anhidrosis, and Fabry disease. Acquired anhidrosis is classified as secondary anhidrosis, which may be due to an underlying disorder such as a neurological disorder, an endocrine or metabolic disturbance, or the effect of drugs, or idiopathic anhidrosis for which the pathology, cause, and mechanism are unknown. Idiopathic anhidrosis is classified into acquired idiopathic generalized anhidrosis (AIGA), idiopathic segmental anhidrosis, and Ross syndrome. AIGA is divided into three categories according to differences in the site of disturbance: (1) sudomotor neuropathy, (2) idiopathic pure sudomotor failure, and (3) sweat gland failure.


Electrophoresis: mathematical modeling and computer simulation.
A mathematical model of electrophoretic separation processes has been developed and adapted for computer simulations. The model is used to predict the characteristic behavior of a variety of electrophoretic techniques from a knowledge of chemical equilibria and physical transport phenomena. The model provides a unifying basis for a rational classification of all electrophoretic processes.


Diabetes mellitus, islet-cell antibodies, and HLA-B8 in a patient with systemic lupus erythematosus.
Evidence that autoimmune mechanisms may provide a possible explanation for the occurrence of some types of diabetes mellitus has included the clinical association of diabetes with other autoimmune conditions and the serologic demonstration of organ-specific antibodies. This article reports the case of a patient with systemic lupus erythematosus accompanied by diabetes and the presence of antibodies to pancreatic islet cells. This represents further evidence that autoimmune activity may play a role in the etiology of diabetes mellitus, which is especially interesting in light of recent HLA antigen studies that show a possible genetic link between the two diseases.


The Hofmeister effect on nanodiamonds: how addition of ions provides superior drug loading platforms.
Colloidal nanodiamonds (NDs) have emerged as highly versatile platforms for the controlled delivery of therapeutics, proteins, DNA, and other assorted biological agents. The most common mechanism of drug loading onto the ND surface depends mainly on electrostatic interactions. Although a few reports have been published on using NaCl salt to increase the drug loading onto NDs, no comprehensive mechanistic study with a wide range of anions and cations has been reported. In this work, the Hofmeister effect of inorganic salts and amino acids with different isoelectric points was employed to understand the mechanism of doxorubicin (DOXH+) loading onto NDs with different sizes. Inorganic salts including NaCl, NaNO3, Na2SO4, KCl, CaCl2, (NH4)2SO4 and amino acids with an isoelectric point above 7 (positively charged at neutral pH) increase the DOXH+ loading onto small size NDs (SNDs, 5-10 nm). On the other hand, amino acids with an isoelectric point below 7 (negatively charged at neutral pH) increase the DOXH+ loading onto large size NDs (LNDs, 80-100 nm).


Assimilation efficiency of PBDE congeners in Chinook salmon.
Polybrominated diphenyl ether (PBDE) flame retardants are environmental contaminants that can accumulate in biota. PBDE accumulation in an organism depends on exposure, assimilation efficiency, and elimination/metabolism. Net assimilation efficiency represents the fraction of the contaminant that is retained in the organism after exposure. In the present study, congener-specific estimates of net PBDE assimilation efficiencies were calculated from dietary exposures of juvenile Chinook salmon. The fish were exposed to one to eight PBDE congeners up to 1500 ng total PBDEs/g food. Mean assimilation efficiencies varied from 0.32 to 0.50 for BDE congeners 28, 47, 99, 100, 153, and 154. The assimilation efficiency of BDE49 was significantly greater than 100%, suggesting biotransformation from higher brominated congeners. Whole body concentrations of BDE49 significantly increased with both exposure to increasing concentrations of BDE99 and decreasing fish lipid levels, implying lipid-influenced debromination of BDE99 to BDE49. Excluding BDE49, PBDE assimilation efficiency was not significantly related to the numbers of congeners in the diets, or congener hydrophobicity, but was greater in foods with higher lipid levels. Estimates of PBDE assimilation efficiency can be used in bioaccumulation models to assess threats from PBDE exposure to Chinook salmon health and recovery efforts, as well as to their predators.


Pooled segregant sequencing reveals genetic determinants of yeast pseudohyphal growth.
The pseudohyphal growth response is a dramatic morphological transition and presumed foraging mechanism wherein yeast cells form invasive and surface-spread multicellular filaments. Pseudohyphal growth has been studied extensively as a model of conserved signaling pathways controlling stress responses, cell morphogenesis, and fungal virulence in pathogenic fungi. The genetic contribution to pseudohyphal growth is extensive, with at least 500 genes required for filamentation; as such, pseudohyphal growth is a complex trait, and linkage analysis is a classical means to dissect the genetic basis of a complex phenotype. Here, we implemented linkage analysis by crossing each of two filamentous strains of Saccharomyces cerevisiae (Σ1278b and SK1) with an S288C-derived non-filamentous strain. We then assayed meiotic progeny for filamentation and mapped allelic linkage in pooled segregants by whole-genome sequencing. This analysis identified linkage in a cohort of genes, including the negative regulator SFL1, which we find contains a premature stop codon in the invasive SK1 background. The S288C allele of the polarity gene PEA2, encoding Leu409 rather than Met, is linked with non-invasion. In Σ1278b, the pea2-M409L mutation results in decreased invasive filamentation and elongation, diminished activity of a Kss1p MAPK pathway reporter, decreased unipolar budding, and diminished binding of the polarisome protein Spa2p. Variation between SK1 and S288C in the mitochondrial inner membrane protein Mdm32p at residues 182 and 262 impacts invasive growth and mitochondrial network structure. Collectively, this work identifies new determinants of pseudohyphal growth, while highlighting the coevolution of protein complexes and organelle structures within a given genome in specifying complex phenotypes.


Detection of aneuploidy in single cells using comparative genomic hybridization.
The ability of comparative genomic hybridization (CGH) to detect aneuploidy following universal amplification of DNA from a single cell, or a small number of cells, was investigated with a view to preimplantation diagnosis following in vitro fertilization, and prenatal diagnosis using fetal erythroblasts obtained from maternal blood. The DNA obtained from lysed single cells was amplified using degenerate oligonucleotide-primed PCR (DOP-PCR). This product was labelled using nick translation and hybridized together with normal reference genomic DNA. The CGH fluorescent ratio profiles obtained could be used to determine aneuploidy with cut-off thresholds of 0.75 and 1.25. Deviation in the profiles in the heterochromatic regions was reduced by using, as a reference sample, normal genomic DNA that had also undergone DOP-PCR. Single cells known to be trisomic for chromosomes 13, 18 or 21 were analysed using this technique. The resolution of CGH with amplified DNA from a single cell is of the order of 40 Mb, sufficient for the diagnosis of trisomy 21, and possibly segmental aneuploidy of equivalent size. These results, and those of others, demonstrate that diagnosis of chromosomal aneuploidy in single cells is possible using CGH with DOP-PCR amplified DNA.


Evaluation of psychological treatment in primary care.
As clinical psychology services to primary care have grown considerably in recent years, several papers have examined the impact of such services. Benefits to patients following contact with the psychologist have been described, but the few studies which have used control groups have -not shown long-lasting effects. However, assessing the global effects of psychological treatment creates several methodological problems, and many of the studies have serious shortcomings in their use of sampling procedures and dependent measures. Clear results are unlikely to emerge from such studies because psychological treatment is not a single entity but encompasses a number of interventions for different types of problem. A more differentiated approach to evaluation is needed to assess the effectiveness of psychological treatment services in primary care.


Mild disintegration of the green microalgae Chlorella vulgaris using bead milling.
In this work, the mild disintegration of the microalgae Chlorella vulgaris for the release of intracellular products has been studied. By means of bead milling the microalgae suspensions were successfully disintegrated at different biomass concentrations (25-145 gDW kg(-1)) over a range of agitator speeds (6-12 m s(-1)). In all cases over 97% of cell disintegration was achieved resulting in a release of water soluble proteins. A clear optimum rate of disintegration and protein release was observed at an agitator speed of 9-10 m s(-1) regardless of the biomass concentration. Selective extraction of water soluble proteins was observed as proteins released sooner than cell disintegration took place. Proteins could be released at 85% lower energy input than for cell disintegration resulting in specific energy consumptions well below 2.5 kWh kgDW(-1).


[Early measurement of intracranial pressure in polytrauma with associated craniocerebral trauma. II: Clinical and therapeutic aspects].
During the time from 1982/83 the intracranial pressure was continuously measured from patients who were polytraumatized and also had severe head injuries. In 53% of these cases the first readings could be obtained within 6 hours after the injury and in 33% first after 12 hours. During the time of evaluation this relationship shifted to earlier implantation. From 27% of these patients the intracranial pressure values fell into a range that instigated immediate therapeutical measures. This proves how important it is to have a direct reading from the intracranial pressure as soon as possible after injury. The aspects of therapy by increased intracranial pressure were discussed.


Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder.
In rodent models of depression, oxidative stress-induced reductions in NO bioavailability contribute to impaired endothelium-dependent dilation. Endothelial dysfunction is evident in major depressive disorder (MDD); however, the molecular mediators remain undefined. We sought to translate preclinical findings to humans by testing the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential modulatory influences of sex, in MDD. Twenty-four treatment-naive, otherwise healthy, young adults with MDD (14 women; 18-23 years) and 20 healthy adults (10 women; 19-30 years) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine, alone and in combination with an NO synthase inhibitor (L-NAME), a superoxide scavenger (Tempol), and an NADPH oxidase inhibitor (apocynin), as well as during perfusion of the endothelium-independent agonist sodium nitroprusside. Tissue oxidative stress markers (eg, nitrotyrosine abundance, superoxide production) were also quantified. Endothelium-dependent dilation was blunted in MDD and mediated by reductions in NO-dependent dilation. Endothelium-independent dilation was likewise attenuated in MDD. In MDD, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation. Acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Expression and activity of oxidative stress markers were increased in MDD. In a subset of adults with MDD treated with a selective serotonin reuptake inhibitor for their depressive symptoms and in remission (n=8; 7 women; 19-37 years), NO-mediated endothelium-dependent dilation was preserved, but endothelium-independent dilation was impaired, compared with healthy adults. Oxidative stress-induced reductions in NO-dependent dilation, as well as alterations in vascular smooth muscle function, directly contribute to microvascular dysfunction in MDD. Strategies targeting vascular oxidative stress may be viable therapeutic options for improving NO-mediated endothelial function and reducing cardiovascular risk in MDD.


Effects of education on self-monitoring of blood pressure based on BASNEF model in hypertensive patients.
Hypertension is one of the most important health problems. Self-monitoring may be an effective method for controlling this disease. The aim of this study is to determine the effectiveness of education on blood pressure self-monitoring in patients with hypertension based on BASNEF model. In this clinical trial, 150 outpatients with hypertension were randomly selected from those referred to private clinics in Yazd, Iran, during 2008. They were divided in two groups. The data were collected by a validated and reliable questionnaire. The implementing educational program was continued for 2 months and the pre-test and post-test had an interval of 2-months. BASNEF model was applied to explain the motivation of a behavior. Descriptive analysis, correlation test and also regression analysis were used to analyze data. The respondents acquired 17.72% of total score for self-monitoring behavior, 47.03% of attitude, 12.37% of subjective norms, 33.46% of intention and 50.95% of enabling factors. After intervention, there were significant increases in self-monitoring behavior (173.31%), attitude (62.60%), subjective norms (54.70%), intention (129.93%) and enabling factors (46.62%) in the intervention group. There was no significant difference between the constructs of BASNEF model in the control group after intervention compared to the baseline values (p > 0.05). The results of this study showed that the level of self-monitoring behavior in the patients was low. Educational programs are helpful and necessary to improve self-monitoring behavior in patients with hypertension.


Assembly and Function of a Bioengineered Human Liver for Transplantation Generated Solely from Induced Pluripotent Stem Cells.
The availability of an autologous transplantable auxiliary liver would dramatically affect the treatment of liver disease. Assembly and function in vivo of a bioengineered human liver derived from induced pluripotent stem cells (iPSCs) has not been previously described. By improving methods for liver decellularization, recellularization, and differentiation of different liver cellular lineages of human iPSCs in an organ-like environment, we generated functional engineered human mini livers and performed transplantation in a rat model. Whereas previous studies recellularized liver scaffolds largely with rodent hepatocytes, we repopulated not only the parenchyma with human iPSC-hepatocytes but also the vascular system with human iPS-endothelial cells, and the bile duct network with human iPSC-biliary epithelial cells. The regenerated human iPSC-derived mini liver containing multiple cell types was tested in vivo and remained functional for 4 days after auxiliary liver transplantation in immunocompromised, engineered (IL2rg-/-) rats.


Magnitude of the CH/pi interaction in the gas phase: experimental and theoretical determination of the accurate interaction energy in benzene-methane.
The accurate CH/pi interaction energy of the benzene-methane model system was experimentally and theoretically determined. In the experiment, mass analyzed threshold ionization spectroscopy was applied to the benzene-methane cluster in the gas phase, prepared in a supersonic molecular beam. The binding energy in the neutral ground state of the cluster, which is regarded as the CH/pi interaction energy for this model system, was evaluated from the dissociation threshold measurements of the cluster cation. The experimentally determined binding energy (D(0)) was 1.03-1.13 kcal/mol. The interaction energy of the model system was calculated by ab initio molecular orbital methods. The estimated CCSD(T) interaction energy at the basis set limit (D(e)) was -1.43 kcal/mol. The calculated binding energy (D(0)) after the vibrational zero-point energy correction (1.13 kcal/mol) agrees well with the experimental value. The effects of basis set and electron correlation correction procedure on the calculated CH/pi interaction energy were evaluated. Accuracy of the calculated interaction energies by DFT methods using BLYP, B3LYP, PW91 and PBE functionals was also discussed.


Butyrolactone autoregulator receptor protein (BarA) as a transcriptional regulator in Streptomyces virginiae.
BarA of Streptomyces virginiae is a specific receptor protein for virginiae butanolides (VBs), a member of the butyrolactone autoregulators of Streptomyces species. Sequencing around the barA gene revealed two novel open reading frames: one upstream, barX, encoding a homolog of AfsA of Streptomyces griseus and another downstream, barB. Northern (RNA) blot analysis for S. virginiae demonstrated that the addition of VB during cultivation switched on the expression of barB. An in vivo expression system in Streptomyces lividans with the use of the xylE reporter gene indicated that BarA in conjunction with VB controlled the barB promoter. Furthermore, the DNA binding ability of BarA was demonstrated in vitro for the first time by means of surface plasmon resonance and a gel-shift assay. Complex formation with VB in vitro resulted in the dissociation of BarA from DNA, thus suggesting that the VB receptor, BarA, is a transcriptional regulator and that the VB signal is transduced to the next step in the signal transduction pathway by modification of the DNA binding ability of BarA.


Design and synthesis of small molecule RhoA inhibitors: a new promising therapy for cardiovascular diseases?
RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ∼200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.


Implementation of a postarrest debriefing tool in a veterinary university hospital.
To describe the use of a postarrest debriefing tool (DBT) within a university teaching hospital and to evaluate user perceptions of the tool. Observational study over a 1-year period and associated hospital clinical personnel survey. University teaching hospital. Qualitative data surrounding the use and utility of the DBT were analyzed, as well as survey results. Forty-four arrests occurred during the study period. Debriefing was performed after 26 of 44 (59%) cardiopulmonary resuscitation (CPR) events, of which 22 of 26 (85%) were recorded using the DBT and four without the DBT. Return of spontaneous circulation did not significantly affect the use of the DBT (p = 0.753). Most events in which debriefing was not performed occurred outside of business hours (13/18; 72%). The most frequent positive debriefing comments related to cooperation/coordination within the team (22/167; 13%). The most frequent negative debriefing comments concerned equipment issues (36/167; 22%). Of the action points generated, 57% (34/60) were directed at equipment use/availability. Teams reported that emergency drugs were appropriately administered in 21 of 22 (95%) cases. In contrast, closed loop communication was reportedly only used during 6 of 22 (27%) events. The hospital survey response rate was 56 of 338 (17%) clinical staff, of whom 37 of 56 (66%) agreed or strongly agreed that debriefing had improved team performance during CPR. Overall, 33 of 56 (60%) staff felt that the DBT had improved the debriefing process at the hospital. However, 3 of 56 (5%) staff members felt that they were unable to state their opinions in a blame-free environment during debriefing. Implementation of a DBT enabled formal identification of strengths and training needs of resuscitation teams, and its implementation was viewed positively by the majority of hospital staff. However, further refinement of the tool and prospective studies evaluating its efficacy in improving outcome are warranted.


HTT2 promotes plant thermotolerance in Brassica rapa.
Numerous regulatory genes participate in plant thermotolerance. In Arabidopsis, HEAT-INDUCED TAS1 TARGET2 (HTT2) is an important thermotolerance gene that is silenced by ta-siR255, a trans-acting siRNA. ta-siR255 is absent from heading Chinese cabbage (Brassica rapa ssp. pekinensis). Our previous attempt to overexpress the endogenous BrpHTT2 gene of heading Chinese cabbage (B. rapa ssp. pekinensis) failed because of cosuppression. In theory, heading Chinese cabbage can overexpress Arabidopsis HTT2 to improve thermotolerance in the absence of ta-siR255-mediated gene silencing and the weak potential of coexpression. To test the potential application of HTT2 in improving crop thermotolerance, we transferred p35S::HTT2 to heading Chinese cabbage. We tested the leaf electrical conductivity, hypocotyl elongation, and survival percentage of p35S::HTT2 plants subjected to high-temperature (38 °C) and heat-shock (46 °C) treatment. The leaf electrical conductivity of p35S::HTT2 seedlings under high temperature decreased but did negligibly change under heat shock. The hypocotyl length of p35S::HTT2 seedlings increased under high temperature and heat shock. The survival rate of p35S::HTT2 seedlings increased under heat shock. BrpHsfs, a subset of heat-shock factor genes, were upregulated in p35S::HTT2 plants under high-temperature and heat shock conditions. In the field, transgenic plants with HTT2 appeared greener and formed leafy heads earlier than wild-type plants. Exogenous HTT2 increased the survival rates of heat-shocked heading Chinese cabbage by promoting thermotolerance through decreasing electrical conductivity and extending hypocotyl length. Our work provides a new approach to the genetic manipulation of thermotolerance in crops through the introduction of exogenous thermotolerance genes.


SL2-like spliced leader RNAs in the basal nematode Prionchulus punctatus: New insight into the evolution of nematode SL2 RNAs.
Spliced-leader (SL) trans-splicing has been found in all molecularly characterized nematode species to date, and it is likely to be a nematode synapomorphy. Most information regarding SL trans-splicing has come from the study of nematodes from a single monophyletic group, the Rhabditida, all of which employ SL RNAs that are identical to, or variants of, the SL1 RNA first characterized in Caenorhabditis elegans. In contrast, the more distantly related Trichinella spiralis, belonging to the subclass Dorylaimia, utilizes a distinct set of SL RNAs that display considerable sequence diversity. To investigate whether this is true of other members of the Dorylaimia, we have characterized SL RNAs from Prionchulus punctatus. Surprisingly, this revealed the presence of a set of SLs that show clear sequence similarity to the SL2 family of spliced leaders, which have previously only been found within the rhabditine group (which includes C. elegans). Expression of one of the P. punctatus SL RNAs in C. elegans reveals that it can compete specifically with the endogenous C. elegans SL2 spliced leaders, being spliced to the pre-mRNAs derived from downstream genes in operons, but does not compete with the SL1 spliced leaders. This discovery raises the possibility that SL2-like spliced leaders were present in the last common ancestor of the nematode phylum.


Modelling Pb bioaccessibility in soils contaminated by mining and smelting activities.
This investigation was undertaken to identify the most significant parameters that can be used to model the bioaccessibility of lead in contaminated soils. Twenty-five soil samples contaminated by two distinct sources of contamination (mining and smelting areas) were investigated in this work. Edaphic soil properties were determined using the classic techniques. Speciation and solid phase distribution of Pb were determined by sequential fractionation and physical analysis (XRD and SEM-EDX). Bioaccessibility of Pb was measured using the unified BARGE protocol on each soil samples and each residue following the different steps of the sequential extraction procedure. Results showed that Pb speciation varied according to the source of contamination. Pb gastric bioaccessibility ranged from 12% to 86% in mining soils and from 40% to 95% in smelting soils. Soil edaphic properties (pH, CEC, clays content or organic matter content) cannot be used to model Pb bioaccessibility as these parameters could not be extrapolated from on site to another. The differences in Pb bioaccessibility between the 25 soils were better reflected by the nature of the Pb-bearing minerals as characterized by sequential extractions. Soluble, exchangeable and acid-soluble phases could explain from 70 to 98% of Pb bioaccessibility. Consequently, Pb bioaccessibility is extremely sensitive to the Pb-bearing phase distribution. This distribution should be thoroughly evaluated before applying any remedial techniques that would potentially affect Pb speciation in soils.


Medicine.
Advances in hepatitis and immunology illustrate the influence of basic research and technologic innovation in shaping the past, present, and future of medical care.


Reduction of ferrate(VI) and oxidation of cyanate in a Fe(VI)-TiO2-UV-NCO- system.
The aqueous photocatalytic degradation of cyanate (NCO(-)), which is a long-lived neurotoxin formed during the remediation of cyanide in industrial waste streams, was studied in the ferrate(VI)-UV-TiO2-NCO(-) system. Kinetics measurements of the photocatalytic reduction of ferrate(VI) were carried out as a function of [NCO(-)], [ferrate(VI)], [O(2)], light intensity (I(o)), and amount of TiO2 in suspensions at pH 9.0. The photocatalytic reduction rate of ferrate(VI) in the studied system can be expressed as -d[Fe(VI)]/dt=kI(o)(0.5) [NCO(-)] [TiO2]. The rate of photocatalytic oxidation of cyanate with ferrate(VI) was greater than the rate in the analogous system without ferrate(VI). The possibility of involvement of reactive ferrate(V) species for this enhancement was determined by studying the reactivity of ferrate(V) with NCO(-) in a homogeneous solution using a premix pulse radiolysis technique. The rate constant for the reaction of ferrate(V) and NCO(-) in alkaline medium was estimated to be (9.60+/-0.07) x 10(2) M(-1) s(-1), which is much slower than the ferrate(VI) self-decomposition reaction (k approximately 10(7) M(-1) s(-1)). An analysis of the kinetic data in the Fe(VI)-UV-TiO2-NCO(-) system suggests that ferrate(V) is not directly participating in the oxidation of cyanate. Possible reactions in the system are presented to explain results of ferrate(VI) reduction and oxidation of cyanate.


High-throughput drone-based remote sensing reliably tracks phenology in thousands of conifer seedlings.
Phenology is an important indicator of environmental variation and climate change impacts on tree responses. In conifers, monitoring phenology of photosynthesis through remote sensing has been unreliable, because needle foliage varies little throughout the year. This is challenging for modelling ecosystem carbon uptake and monitoring phenology for enhanced breeding (genomic selection) and forest health. Here, we demonstrate that drone-based carotenoid-sensitive spectral indices, such as the Chl/carotenoid index (CCI), can be used to track phenology in conifers by taking advantage of the close relationship between seasonally changing carotenoid levels and the variation of photosynthetic activity. Physiological ground measurements, including photosynthetic pigments and maximum quantum yield of Chl fluorescence, indicated that CCI tracked the variation of photosynthetic activity better than other vegetation indices for 30 white spruce seedlings measured over 1 yr. A machine-learning approach, using CCI derived from drone-based multispectral imagery, was used to model phenology of photosynthesis for the entire pedigree population (6000 seedlings). This high-throughput drone-based phenotyping approach is suitable for studying climate change impacts and environmental variation on the physiological status of thousands of field-grown conifers at unprecedented speed and scale.


Assessment of bony nasolacrimal parameters among Asians.
A case series evaluating racial differences in the nasolacrimal region and quantifying the anterior lacrimal crest thickness and minimum nasolacrimal duct diameter in Asians. Facial or orbital CT scans of 90 consecutive patients were retrospectively reviewed. Evidence of lacrimal fossa tumor or trauma excluded a patient. Using 3-dimensional image software, the thickness of the anterior lacrimal crest, narrowest diameter of the nasolacrimal duct, vertical diameter of the lacrimal sac fossa, frontonasal angle, and inter-frontozygomatic suture distance were measured in axial, sagittal, and coronal planes. Inter- and intraobserver correlation of a sample data proved reliability via intraclass correlation coefficient (0.706-0.917). Southeast Asians had a wider inter-frontozygomatic suture distance than South Asian and Occidental races (p = 0.025). Vertical lacrimal fossa diameter, anterior lacrimal crest thickness, and narrowest nasolacrimal duct diameter did not differ significantly between right and left sides or among ethnic groups. Narrower nasolacrimal duct diameter was significantly associated with decreased inter-frontozygomatic suture distance (p < 0.001), namely in patients with narrower faces. The anterior lacrimal crest thickness was significantly affected by the nasal configuration and thicker in patients with more acute frontonasal angle (p = 0.026). There is no significant difference in nasolacrimal duct diameter among ethnic groups, which may predispose one to nasolacrimal duct obstruction. But, this is significantly associated with inter-frontozygomatic suture distance, suggesting that a wider face is associated with wider nasolacrimal duct diameter. An acute frontonasal angle predicts a thicker anterior lacrimal crest for surgical preparation during dacryocystorhinostomy.


Metastatic breast cancer: the potential of miRNA for diagnosis and treatment monitoring.
Breast cancer affects approximately 12 % women worldwide and results in 14 % of all cancer-related fatalities. Breast cancer is commonly categorized into one of four main subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) positive and basal), indicating molecular characteristics and informing treatment regimes. The most severe form of breast cancer is metastasis, when the tumour spreads from the breast tissue to other parts of the body. Significantly, the primary tumour subtype affects rates and sites of metastasis. Currently, up to 5 % of patients present with incurable metastasis, with an additional 10-15 % of patients going on to develop metastasis within 3 years of diagnosis. MicroRNAs (miRNAs) are short 21-25 long nucleotides that have been shown to significantly affect gene expression. Currently, >2000 miRNAs have been identified and significantly, specific miRNAs have been found associated with diseases states. Importantly, miRNAs are found circulating in the blood, presenting an opportunity to use these circulating disease-related miRNAs as biomarkers. Clearly, the identification of circulating miRNA specific to metastatic breast cancer presents a unique opportunity for early disease identification and for monitoring disease burden. Currently however, few groups have identified miRNA associated with metastatic breast cancer. Here, we review the literature surrounding the identification of metastatic miRNA in breast cancer patients, highlighting key areas where miRNA biomarker discovery could be beneficial, identifying key concepts, recognizing critical areas requiring further research and discussing potential problems.


Meeting the health needs of older people with intellectual disabilities: exploring the experiences of residential social care staff.
Older people with intellectual disabilities often experience high levels of health needs and multiple morbidities but they may be supported by residential care staff with little or no previous experience of identifying and meeting health needs. Little is known regarding how they undertake this health-related role and this exploratory study seeks to address this gap. A purposive sample of 14 managers of supported living accommodation in Wales were interviewed in 2014 to determine their experiences of supporting tenants in relation to age-related health needs. The semi-structured interviews were transcribed and thematically analysed. Three of the emerging themes are reported in this paper: meeting health needs, the consequences of ageing and relationships. Findings indicate that residential care staff support older people with intellectual disabilities with complex and multiple health needs: they monitor health status, support access to healthcare, provide additional support arising from changing health needs and advocate for tenants in the context of healthcare. However, their role is often not understood by healthcare professionals. The importance of staff having a long-term relationship with those they support was identified as being important to identifying any health-related changes. The need to develop effective relationships with healthcare staff was also noted. It is concluded that there is a need for better understanding among health staff of the role of residential social care workers and for further research regarding health-related communication.


Carcinoma of the penis metastasizing to the dorsal spine. A case report.
Carcinoma of the penis tends to have a predictable route of spread by direct invasion and by regional lymphatic involvement to the inguinal group of lymph nodes. Blood-borne distant spread is rare, last to occur, and is seen in 1-3% of cases. Metastasis to the spine is even rarer. We encountered one such case who presented with spinal metastasis, as documented by the whole body bone scan, and this was later followed by involvement of the inguinal nodes. This case is unique in its site of metastatic presentation as well as its pattern of presentation.


Correlation of Short Leukocyte Telomeres and Oxidative Stress with the Presence and Severity of Lung Cancer Explored by Principal Component Analysis.
Lung cancer (LC) is the second most common malignancy and leading cause of cancer death. The potential "culprit" for local and systemic telomere shortening in LC patients is oxidative stress. We investigated the correlation between the peripheral blood leukocyte (PBL) telomere length (TL) and the presence/severity of LC and oxidative stress, and its usefulness as LC diagnostic marker. PBL TL was measured in 89 LC patients and 83 healthy subjects using the modified Cawthon RTq-PCR method. The relative PBL TL, found to be a potential diagnostic marker for LC with very good accuracy (P < 0.001), was significantly shorter in patients compared to the control group (CG) (P < 0.001). Significantly shorter telomeres were found in patients with LC TNM stage IV than in patients with stages I-III (P = 0.014), in patients without therapy compared to those on therapy (P = 0.008), and in patients with partial response and stable/progressive disease compared to those with complete response (P = 0.039). The total oxidant status (TOS), advanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB) and C-reactive protein (CRP) were significantly higher in patients compared to CG (P < 0.001) and correlated negatively with TL in both patients and CG (P < 0.001). PCA showed a relation between PAB and TL, and between the EGFR status and TL. Oxidative stress and PBL telomere shortening are probably associated with LC development and progression.


Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads.
Prions cause transmissible infectious diseases in humans and animals and have been found to be transmissible by blood transfusion even in the presymptomatic stage. However, the concentration of prions in body fluids such as blood and urine is extremely low; therefore, direct diagnostic tests on such specimens often yield false-negative results. Quantitative preanalytical prion enrichment may significantly improve the sensitivity of prion assays by concentrating trace amounts of prions from large volumes of body fluids. Here, we show that beads conjugated to positively charged peptoids not only captured PrP aggregates from plasma of prion-infected hamsters, but also adsorbed prion infectivity in both the symptomatic and preclinical stages of the disease. Bead absorbed prion infectivity efficiently transmitted disease to transgenic indicator mice. We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions. The reliable and sensitive detection of prions in plasma will enable a wide variety of applications in basic prion research and diagnostics.


Low-density lipoprotein apheresis therapy with a direct hemoperfusion column: a Japanese multicenter clinical trial.
Low-density lipoprotein (LDL) apheresis has been applied to patients with familial hypercholesterolemia (FH) with coronary artery disease (CAD). To examine the efficacy and safety of a new type of LDL adsorption column (KLD01, Kaneka, Osaka, Japan), which deals with whole blood without separating plasma, the new system was evaluated in a multicenter trial. The present study included 33 FH patients with CAD (24 males, 9 females, 57 +/- 13 years) who were treated five times with a mean interval of 2.12 +/- 0.60 weeks between treatments. We studied the removal efficacies for serum LDL cholesterol, Lipoprotein(a) (Lp(a)) and triglyceride, the times for the preparation of the system and for treatment, symptoms, and the biochemical data. The scheduled treatments were completed by 31 patients. Serum levels of LDL cholesterol, Lp(a) and triglycerides were all significantly reduced with KLD01; 61.5 +/- 6.2%, 72.4 +/- 5.9% and 69.5 +/- 9.7%, respectively. The times for both setting up the column system (26 +/- 7 min) and treatment (138 +/- 20 min) were shorter with KLD01 than conventional methods. Adverse reactions occurred in eight cases (17 episodes), but the patients fully recovered immediately after each apheresis therapy session. We conclude that the new type of LDL adsorption column, one that deals with whole blood, is a promising apheresis therapy for FH patients in view of its efficacy, reduced time for treatment, and safety.


Endoscopic pituitary surgery: a systematic review and meta-analysis.
Surgery on the pituitary gland is increasingly being performed through an endoscopic approach. However, there is little published data on its safety and relative advantages over traditional microscope-based approaches. Published reports are limited by small sample size and nonrandomized study design. A meta-analysis allows for a description of the impact of endoscopic surgery on short-term outcomes. The authors performed retrospective review of data from their institution as well as a systematic review of the literature. The pooled data were analyzed for descriptive statistics on short-term outcomes. Nine studies (821 patients) met inclusion criteria. Overall, the pooled rate of gross tumor removal was 78% (95% CI 67-89%). Hormone resolution was achieved in 81% (95% CI 71-91%) of adrenocorticotropic hormone secreting tumors, 84% (95% CI 76-92%) of growth hormone secreting tumors, and 82% (95% CI 70-94%) of prolactin secreting tumors. The pooled complication rates were 2% (95% CI 0-4%) for CSF leak and 1% (95% CI 0-2%) for permanent diabetes insipidus. There were 2 deaths reported in the literature that were both related to vascular injury, giving an overall mortality rate of 0.24%. The results of this meta-analysis support the safety and short-term efficacy of endoscopic pituitary surgery. Future studies with long-term follow-up are required to determine tumor control.


Odds ratio vs risk ratio in randomized controlled trials.
Use of odds ratio (OR) in randomized controlled trials (RCTs) has been criticized because it overestimates the effect size, if incorrectly interpreted as risk ratio (RR). To what extent does this make a difference in the context of clinical research is unclear. We, therefore, aimed to address this issue considering its importance in evidence-based practice of medicine. We reviewed 580 RCTs published in the New England Journal of Medicine between January 2004 and June 2014 and identified 107 RCTs that reported unadjusted RR (n = 76) or OR (n = 31) for the primary outcome. For studies reporting ORs, we calculated RRs, and vice versa, using Stata software. The percentage of divergence between the reported and calculated effect size estimates was analyzed. None of the RCTs showed a statistically significant result becoming insignificant or vice versa depending on the effect size estimate. OR exaggerated the RR in 62% of the RCTs. The percentage of overestimation was > 50% in 28 RCTs and > 100% in 13 RCTs. The degree of overestimation was positively correlated with the prevalence of outcomes (spearman's rho = 0.84 and 0.66, p < 0.001). Use of OR instead of RR in RCTs does not change the qualitative inference of results. However, the use of OR can markedly exaggerate the effect size in RCTs if misinterpreted as RR and, hence, has the potential to mislead clinicians.