A behavioral approach to instability pathways in financial markets.
We introduce an indicator that aims to detect the emergence of market instabilities by quantifying the intensity of self-organizing processes arising from stock returns' co-movements. In financial markets, phenomena like imitation, herding and positive feedbacks characterize the emergence of endogenous instabilities, which can modify the qualitative and quantitative behavior of the underlying system. The impossibility to formalize ex-ante the dynamic laws that rule the evolution of financial systems motivates the use of a parsimonious synthetic indicator to detect the disruption of an existing equilibrium configuration. Here we show that the emergence of an interconnected sub-graph of stock returns co-movements from a broader market index is a signal of an out-of-equilibrium transition of the underlying system. To test the validity of our approach, we propose a model-free application that builds on the identification of up and down market phases.


Influence of body mass index on outcome of the mechanically ventilated patients.
There are limited data on the impact of body mass index on outcomes in mechanically ventilated patients. Secondary analysis of a cohort including 4698 patients mechanically ventilated. Patients were screened daily for management of mechanical ventilation, complications (acute respiratory distress syndrome, sepsis, ventilator associated pneumonia, barotrauma), organ failure (cardiovascular, respiratory, renal, hepatic, haematological) and mortality in the intensive care unit. To estimate the impact of body mass index on acute respiratory distress syndrome and mortality, the authors constructed models using generalised estimating equations (GEE). Patients were evaluated based on their body mass index: 184 patients (3.7%) were underweight, 1995 patients (40%) normal weight, 1781 patients (35.8%) overweight, 792 patients (15.9%) obese and 216 patients (4.3%) severely obese. Severely obese patients were more likely to receive low tidal volume based on actual body weight but high volumes based on predicted body weight. In obese patients, the authors observed a higher incidence of acute respiratory distress syndrome and acute renal failure. After adjustment, the body mass index was significantly associated with the development of acute respiratory distress syndrome: compared with normal weight; OR 1.69 (95% CI 1.07 to 2.69) for obese and OR 2.38 (95% CI 1.15 to 4.89) for severely obese. There were no differences in outcomes (duration of mechanical ventilation, length of stay and mortality in intensive care unit and hospital) based on body mass index categories. In this cohort, obese patients were more likely to have significant complications but there were no associations with increased mortality.


Electric field assisted surface plasmon-coupled directional emission: an active strategy on enhancing sensitivity for DNA sensing and efficient discrimination of single base mutation.
We have demonstrated the proof-of-principle of electric field assisted surface plasmon-coupled directional emission (E-SPCDE). The combination of SPCDE and electric field control produced a significant synergistic effect to amplify the right signal and suppress the wrong signal intelligently in an active strategy. A novel hairpin structured DNA biosensor based on the quenching and enhancing of fluorescence in SPCDE has been designed. With modulation of the fluorescence coupling efficiency, a high discrimination ratio up to more than 20-fold has been achieved by enhancing the signal of match and suppressing that of mismatch. E-SPCDE has shown a successful application in DNA sensing, eliminating false positives and false negatives in the detection. E-SPCDE should provide an opportunity to create a new generation of miniaturized high-performance sensing platforms especially in chip-based microarrays and to make the manipulation of the nanometer-scale processes more accessible and detectable.


Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine.
Lrig1 is an intestinal stem cell marker important for epithelial homeostasis. However, the position of the Lrig1(+) population in the intestinal crypt has been debated, largely due to discrepant staining patterns using two Lrig1 antibodies. Here, we set out to decipher the differences between these Lrig1 antibodies to clarify their use for Lrig1-related studies. We confirmed that the commercially available Lrig1-R&D antibody stained the bottom third of the colonic crypt, whereas an independently generated Lrig1-VU antibody recognized a subset of anti-Lrig1-R&D(+) cells. Biochemically, we found that anti-Lrig1-VU recognized a non-glycosylated form of Lrig1; in contrast, anti-Lrig1-R&D recognized both glycosylated and non-glycosylated forms of Lrig1. In addition, we generated a reporter mouse (Lrig1-Apple) as an independent readout of Lrig1 transcriptional activity. Flow cytometry of isolated colonic epithelial cells from Lrig1-Apple mice demonstrated anti-Lrig1-R&D recognized mostly RFP-hi cells, while anti-Lrig1-VU recognized cells that were largely RFP-mid. Of note, by qRT-PCR, Lgr5 was expressed in the RFP-hi population, but not in the RFP-mid population. We conclude that anti-Lrig1-R&D appears to recognize all Lrig1(+) cells, while anti-Lrig1-VU recognizes a subpopulation of Lrig1(+) cells.


Improved CCT uniformity of white LED using remote phosphor with patterned sapphire substrate.
The light distribution of a light-emitting diode (LED), using remote phosphor with a patterned sapphire substrate, is evaluated in this study. Three kinds of substrates of the remote phosphors, including planar sapphire (PS), partially patterned sapphire (PPS), and fully patterned sapphire (FPS) are prepared. The LED with the remote phosphor of FPS delivers much better uniformity of the correlated color temperature (CCT) in a far-field pattern than the CCT obtained in the cases of PS and PPS. The results are majorly attributed to the improvement in the scattering ability of the blue light in the FPS; thereby increasing the excitation of the phosphor particles in comparison to the ability of the device assembled with the remote phosphor of PS or PPS.


Retinoprotective Effects of Bilberry Anthocyanins via Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Mechanisms in a Visible Light-Induced Retinal Degeneration Model in Pigmented Rabbits.
Excessive visible light exposure can induce damage to retinal cells and contribute to the development or progression of age-related macular degeneration. In this study we created a model of phototoxicity in pigmented rabbits. Furthermore, we investigated the protective effect of bilberry anthocyanin extract (BAE, Table A1) and explored the possible mechanisms of action in this model. The model of light-induced retinal damage was established by the pigmented rabbits exposed to light at 18,000 lx for 2 h, and they were sacrificed on day 7. After administration of BAE at dosages of 250 and 500 mg/kg/day, retinal dysfunction was significantly inhibited in terms of electroretinograms, and the decreased thicknesses of retinal outer nuclear layer and lengths of the outer segments of the photoreceptor cells were suppressed in rabbits with retinal degeneration. BAE attenuated the changes caused by light to certain apoptotic proteins (Bax, Bcl-2, and caspase-3). The extract increased the levels of superoxide dismutase, glutathione peroxidase, and catalase, as well as the total antioxidant capacity, but decreased the malondialdehyde level in the retinal cells. BAE inhibited the light-induced elevation in the levels of proinflammatory cytokines and angiogenic parameters (IL-1β and VEGF). Results showed that visible light-induced retinal degeneration model in pigmented rabbits was successfully established and BAE exhibited protective effects by increasing the antioxidant defense mechanisms, suppressing lipid peroxidation and proinflammatory cytokines, and inhibiting retinal cells apoptosis.


Long-lived localization in magnetic resonance imaging.
The longitudinal nuclear relaxation time, T1, sets a stringent limit on the range of information that can be obtained from magnetic resonance imaging (MRI) experiments. Long-lived nuclear spin states provide a possibility to extend the timescale over which information can be encoded in magnetic resonance. We introduce a strategy to localize an ensemble of molecules for a significantly extended duration (∼30 times longer than T1 in this example), using a spatially selective conversion between magnetization and long-lived singlet order. An application to tagging and transport is proposed.


Tunable mosaic structures in van der Waals layered materials.
Intrinsic mosaic structures composed of distinctive stacking domains separated by domain walls (DWs) show the potential to regulate many outstanding properties of van der Waals layered materials. A comprehensive simulation at the atomic scale is performed to explore how the lattice/twist mismatch and the interlayer interaction influence the mosaic configuration from the incommensurate Moiré pattern to commensurate mosaic structures by adapting a complex amplitude version of the phase field crystal method. It is found that after an incommensurate-commensurate transition occurs, the topology of the mosaic structure indicated by different domain wall (DW) patterns can be drastically changed. An experimentally observed intriguing spiral domain wall (SDW) network is revealed as result of the emergent mixed dislocation driven by minimizing the elastic and interlayer energies in the presence of both lattice and twist mismatches. The transition process from a herringbone domain wall (HBDW) network to a SDW network is also simulated, elucidated by a dislocation reaction and in good agreement with the experimental observations.


Nutritional basis for colonization resistance by human commensal Escherichia coli strains HS and Nissle 1917 against E. coli O157:H7 in the mouse intestine.
Escherichia coli is a single species consisting of many biotypes, some of which are commensal colonizers of mammals and others that cause disease. Humans are colonized on average with five commensal biotypes, and it is widely thought that the commensals serve as a barrier to infection by pathogens. Previous studies showed that a combination of three pre-colonized commensal E. coli strains prevents colonization of E. coli O157:H7 in a mouse model (Leatham, et al., 2010, Infect Immun 77: 2876-7886). The commensal biotypes included E. coli HS, which is known to successfully colonize humans at high doses with no adverse effects, and E. coli Nissle 1917, a human commensal strain that is used in Europe as a preventative of traveler's diarrhea. We hypothesized that commensal biotypes could exert colonization resistance by consuming nutrients needed by E. coli O157:H7 to colonize, thus preventing this first step in infection. Here we report that to colonize streptomycin-treated mice E. coli HS consumes six of the twelve sugars tested and E. coli Nissle 1917 uses a complementary yet divergent set of seven sugars to colonize, thus establishing a nutritional basis for the ability of E. coli HS and Nissle 1917 to occupy distinct niches in the mouse intestine. Together these two commensals use the five sugars previously determined to be most important for colonization of E. coli EDL933, an O157:H7 strain. As predicted, the two commensals prevented E. coli EDL933 colonization. The results support a model in which invading pathogenic E. coli must compete with the gut microbiota to obtain the nutrients needed to colonize and establish infection; accordingly, the outcome of the challenge is determined by the aggregate capacity of the native microbiota to consume the nutrients required by the pathogen.


Detection of a mediator derived from endotoxin-stimulated macrohpages that induces the acute phase serum amyloid A response in mice.
The mechanism by which LPS stimulates an acute phase serum amyloid A (SAA) response in C3H mice has been studied. A factor (SAA inducer) appears in the blood of C3H/HeN (lipopolysaccharide [LPS]-sensitive) mice approximately 1 h after administration of LPS, which, when passively administered, can induce C3H/HeJ mice to produce SAA although they are resistant to the LPS itself. SAA inducer has been detected in the culture medium of LPS treated C3H/HeN macrophages but not spleen cells. Thus, two stages in the induction of the acute phase SAA response are now recognized: a latent period of 2-3 h during which the SAA concentration remains at baseline values and in which SAA inducer appears, and the period of synthesis of SAA which lasts for approoximately 24 h past induction. It is proposed that a macrophage response to LPS is responsible for production of the serum mediator which induces SAA synthesis.


The prevalence of microscopic hematuria in a cohort of women with pelvic organ prolapse.
In 2012, the American Urological Association (AUA) revised its guidelines for microscopic hematuria (MH). We hypothesize that the prevalence of MH is greater in women with pelvic organ prolapse than in the general population. All patients presenting to an outpatient urogynecological center with prolapse between January 2008 and December 2011 were reviewed. Exclusion criteria included: pregnancy, presence of gross hematuria, menses, or urological pathology. MH was defined as ≥3 red blood cells per high power field on one urinalysis specimen with a negative urine culture, and the prevalence of MH was calculated. Statistical analysis was performed. One thousand and forty women with pelvic organ prolapse were included in the analysis. Mean age was 64.1 years (range 20 to 96) and mean parity was 2.7 (range 0 to 12). Two hundred and nine out of 1,040 met the criteria for MH. No cases of urological malignancy were diagnosed in patients who underwent further workup. One hundred and ninety-seven patients with MH (93.4 %) had cystoceles on examination. This is the largest study to investigate MH in women with prolapse based on the new guidelines. The prevalence of MH was 20.1 % in our study population. Cystoscopy, renal function testing, and CT urography are now recommended after one positive urinalysis, regardless of gender or the presence of prolapse. Owing to the low incidence of urological malignancy detected as well as the increased prevalence of MH found in women with prolapse, specific guidelines for the management of MH in this population are needed.


Association of an NFKB1 intron SNP (rs4648068) with gastric cancer patients in the Han Chinese population.
Hyperactivation of nuclear factor-κB (NF-κB) is associated with various types of tumors. This study investigated the susceptibility of the rs4648068 A/G genotype in the intron region of NFKB1 to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. A hospital-based case-control study of 248 gastric cancer patients and 192 control individuals was conducted in Fudan University Shanghai Cancer Center (Shanghai, China). Single nucleotide polymorphism (SNP) rs4648068 genotype in NFKB1 from blood samples of a total of 440 people was analyzed by polymerase chain reaction-based genotyping. The frequencies of the AA, AG, and GG genotypes of the rs4648068 polymorphism were 31.5%, 47.2%, and 21.3% in the gastric cancer patients and 29.7%, 59.9%, and 10.4% in the control individuals, respectively. We found that the GG genotype was associated with a significantly increased risk of gastric cancer (P = 0.042). Furthermore, among the gastric cancer cases, the rs4648068 GG genotype was associated with high clinical stage (AOR = 2.27, 95% CI: 1.11- 4.66), lymph node involvement (AOR = 2.90, 95% CI = 1.40- 6.03) and serosa invasion (AOR = 2.78, 95% CI = 1.34- 5.75). However, rs4648068 genotypes were not associated with tumor differentiation in gastric cancer patients. Homozygous rs4648068 GG was associated with an increased risk of gastric cancer, especially for the lymph node status and serosa invasion in Han Chinese population.


Use of Ayurveda in the Treatment of Type 2 Diabetes Mellitus.
Ayurveda is an ancient medicine practice that is emerging in the United States as a complementary and alternative treatment for chronic illness. Type 2 diabetes is a chronic illness that has major long-term implications for individuals suffering from the disease as well as the health-care system as a whole. Modifications in diet, exercise, and lifestyle are all important factors in successful treatment of type 2 diabetes and are incorporated into the ancient Indian medicinal practice of Ayurveda.Review Summary: This review summarizes the available evidence for the use of Ayurvedic therapies in the treatment of type 2 diabetes. For the treatment of type 2 diabetes, Ayurvedic practices primarily emphasizes the use of herbal supplements; however, exercise, weight management, and various supplemental procedures are included in Ayurvedic practices. The goal of Ayurvedic practices on the treatment of type 2 diabetes like in Western medicine focuses on bringing the hemoglobin A1c (HbA1c) value into a therapeutic range. Where Ayurveda differs is that it looks at the functionality of a person in the context of striking a balance between the life forces or doshas that each individual possesses. Finally, this article includes a case study received from AyurVAID clinic in Bangalore, India that details the specific Ayurvedic intervention used in a patient, bringing his HbA1c from a level of 11.2 to 5.7 over the course of 9 months. Patients with type 2 diabetes may inquire about current complementary and alternative therapies available for the treatment of their disease. Awareness of such modalities is necessary for effective patient counseling and care. The benefits of offering a wide array of treatment options include possible reduction of HbA1c and of comorbidities with adjunct use of supplements and mind-body practices.


A generalized time-frequency subtraction method for robust speech enhancement based on wavelet filter banks modeling of human auditory system.
We present a new speech enhancement scheme for a single-microphone system to meet the demand for quality noise reduction algorithms capable of operating at a very low signal-to-noise ratio. A psychoacoustic model is incorporated into the generalized perceptual wavelet denoising method to reduce the residual noise and improve the intelligibility of speech. The proposed method is a generalized time-frequency subtraction algorithm, which advantageously exploits the wavelet multirate signal representation to preserve the critical transient information. Simultaneous masking and temporal masking of the human auditory system are modeled by the perceptual wavelet packet transform via the frequency and temporal localization of speech components. The wavelet coefficients are used to calculate the Bark spreading energy and temporal spreading energy, from which a time-frequency masking threshold is deduced to adaptively adjust the subtraction parameters of the proposed method. An unvoiced speech enhancement algorithm is also integrated into the system to improve the intelligibility of speech. Through rigorous objective and subjective evaluations, it is shown that the proposed speech enhancement system is capable of reducing noise with little speech degradation in adverse noise environments and the overall performance is superior to several competitive methods.


Cavity mode emission in weakly coupled quantum dot--cavity systems.
We study the origin of bright leaky-cavity mode emission and its influence on photon statistics in weakly coupled quantum dot - semiconductor cavity systems, which consist of a planar photonic-crystal and several quantum dots. We present experimental measurements that show that when the system is excited above the barrier energy, then bright cavity mode emissions with nonzero detuning are dominated by radiative recombinations of deep-level defects in the barrier layers. Under this excitation condition, the second-order photon autocorrelation measurements reveal that the cavity mode emission at nonzero detuning exhibits classical photon-statistics, while the bare exciton emission shows a clear partial anti-bunching. As we enter a Purcell factor enhancement regime, signaling a clear cavity-exciton coupling, the relative weight of the background recombination contribution to the cavity emission decreases. Consequently, the anti-bunching behavior is more significant than the bare exciton case - indicating that the photon statistics becomes more non-classical. These measurements are qualitatively explained using a medium-dependent master equation model that accounts for several excitons and a leaky cavity mode.


Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls.
Although many children with autism spectrum disorders (ASDs) experience difficulties with anxiety,the manifestation of these difficulties remains unresolved. The current study assessed anxiety in a large population based twin sample, aged 10–15 years. Phenotypic analyses were used to explore anxiety symptoms in children with ASDs, their unaffected co-twins and a control sample. Participants included 146 families from the Twins Early Development Study (TEDS) where one or both children had a suspected ASD. Eighty control families were also included. The Revised Child Anxiety and Depression scale (Chorpita, Yim, Moffitt, Umemoto & Francis, 2000) was completed (self- and parent-report), along with diagnostic and cognitive tests. Children were categorized into four groups (a) ASD (b) Broader Autism Phenotype (BAP: mainly co-twins of children with ASDs, with high subclinical autistic traits) (c) unaffected co-twins (with neither ASDs nor BAP) (d) controls. Children in the ASD and BAP groups scored significantly higher than controls for all parent-rated (although not child-rated) anxiety subscales.There were no significant differences between the ASD and BAP groups for any of the parent-rated anxiety subscales. Compared with controls, unaffected co-twins showed significantly heightened Social Anxiety, Generalized Anxiety,and Panic symptoms. Significant associations were observed between certain anxiety subscales and both IQ and ASD symptoms. For example, greater parent-rated Social Anxiety was associated with higher IQ and increased social and communicative impairments. Significant interrater correlations were observed for anxiety reports in children with ASDs (r = .27–.54; p < .01), their unaffected co-twins (r = .32–.63; p < .01) and controls (r = .23–.43; p < .01)suggesting that children in this sample with and without ASD symptoms were able to report on their anxiety symptoms with some accuracy. These findings support previous reports of heightened anxiety in children with ASDs, at least on parent-reported measures. Unaffected co-twins of children with ASDs also showed increased anxiety, generating questions about the potential etiological overlap between ASDs and anxiety. Progress in this area now depends on more refined anxiety measurement in ASDs and continued investigation of interrater differences.


Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel.
G protein-gated inwardly rectifying potassium channel (GIRK) plays a key role in regulating neurotransmission. GIRK is opened by the direct binding of the G protein βγ subunit (Gβγ), which is released from the heterotrimeric G protein (Gαβγ) upon the activation of G protein-coupled receptors (GPCRs). GIRK contributes to precise cellular responses by specifically and efficiently responding to the Gi/o-coupled GPCRs. However, the detailed mechanisms underlying this family-specific and efficient activation are largely unknown. Here, we investigate the structural mechanism underlying the Gi/o family-specific activation of GIRK, by combining cell-based BRET experiments and NMR analyses in a reconstituted membrane environment. We show that the interaction formed by the αA helix of Gαi/o mediates the formation of the Gαi/oβγ-GIRK complex, which is responsible for the family-specific activation of GIRK. We also present a model structure of the Gαi/oβγ-GIRK complex, which provides the molecular basis underlying the specific and efficient regulation of GIRK.


Omnidirectional flexural invisibility of multiple interacting voids in vibrating elastic plates.
In elasticity, the design of a cloaking for an inclusion or a void to leave a vibrational field unperturbed by its presence, so to achieve its invisibility, is a thoroughly analysed, but still unchallenged, mechanical problem. The 'cloaking transformation' concept, originally developed in electromagnetism and optics, is not directly applicable to elastic waves, displaying a complex vectorial nature. Consequently, all examples of elastic cloaking presented so far involve complex design and thick coating skins. These cloakings often work only for problems of unidirectional propagation, within narrow ranges of frequency, and considering only one cloaked object. Here, a new method based on the concept of reinforcement, achieved via elastic stiffening and mass redistribution, is introduced to cloak multiple voids in an elastic plate. This simple technique produces invisibility of the voids to flexural waves within an extremely broad range of frequencies and thus surpassing in many aspects all existing cloaking techniques. The proposed design principle is applicable in mechanical problems ranging from the micro-scale to the scale of civil engineering. For instance, our results show how to design a perforated load-bearing building wall, vibrating during an earthquake exactly as the same wall, but unperforated, a new finding for seismic protection.


The integrin VLA-4 supports tethering and rolling in flow on VCAM-1.
Selectins have previously been shown to tether a flowing leukocyte to a vessel wall and mediate rolling. Here, we report that an intergrin, VLA-4, can also support tethering and rolling. Blood T lymphocytes and alpha 4 integrin-transfected cells can tether in shear flow, and then roll, through binding of the intergrin VLA-4 to purified VCAM-1 on the wall of a flow chamber. VLA-4 transfectants showed similar tethering and rolling on TNF-stimulated endothelium. Tethering efficiency, rolling velocity, and resistance to detachment are related to VCAM-1 density. Tethering and rolling did not occur on ICAM-1, fibronectin, or fibronectin fragments, and tethering did not require integrin activation or the presence of an alpha 4 cytoplasmic domain. Arrest of rolling cells on VCAM-1 occurred spontaneously, and/or was triggered by integrin activating agents Mn2+, phorbol ester, and mAb TS2/16. These agents, and the alpha 4 cytoplasmic domain, promoted increased resistance to detachment. Together the results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1.


Role of TNF-alpha during central sensitization in preclinical studies.
Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior.


Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes.
A novel brain drug delivery system using cationic bovine serum albumin (CBSA)-conjugated biodegradable polymersomes (CBSA-PO) was prepared, and its intracellular delivery mechanism and brain delivery kinetics were evaluated. Biodegradable poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) was used to prepare the polymersomes, and thiolated CBSA was conjugated with the surface of the polymersome. Transmission electron microscopy and dynamic light scattering showed that the CBSA-PO had a round and vesicle-like shape, with a mean diameter of around 100 nm. Coupling of CBSA with polymersomes was confirmed by X-ray photoelectron spectroscopy. Uptake of CBSA-PO by bEnd.3 cells was significantly higher than that of unconjugated polymersomes, but was inhibited by low temperature, free CBSA, and poly-L-lysine, indicating that endocytosis was energy-driven and absorptive-mediated. Cell viability assays confirmed the good safety profile of biodegradable CBSA-PO. Pharmacokinetic results demonstrated that the polymersomes had long circulation times, and CBSA conjugation on the polymersomes significantly increased the blood-brain barrier permeability surface area product by 3.6-fold and the percentage of injected dose per gram brain (% ID/g brain) by 2.1-fold. Capillary depletion experiments showed that CBSA-PO was distributed into the brain parenchyma in a time-dependent manner, with few polymersomes detected, indicating that conjugation of polymersomes with CBSA significantly improved their transcytosis across the brain-blood barrier. These results suggest that CBSA-PO is a promising drug brain delivery carrier with low toxicity.


Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy.
HIV-associated neurocognitive disorder (HAND) persists in the combination antiretroviral therapy (cART) era and is associated with diminished quality of life. The disorder remains challenging to diagnose given the requirement for comprehensive neuropsychological testing. Blood biomarkers are needed to facilitate the diagnosis of HAND and to gauge neurological response to antiretroviral therapy. We performed a study of plasma neurofilament light chain (NFL) that included 37 HIV-infected and 54 HIV-negative adults. In the univariate mixed-effect model involving HIV-infected participants, there was a statistically significant linear relationship between composite neuropsychological score (NPT-11) and plasma NFL (slope = - 9.9, standard error = 3.0 with 95% confidence interval - 3.2 to - 16.6 and p = 0.008 when testing slope = 0). Similarly, in the multivariate mixed-effect model, higher plasma NFL was significantly associated with worse NPT-11 (slope = - 11.5, standard error = 3.3 with 95% confidence interval - 3.7 to - 19.0 and p = 0.01 when testing slope = 0). The association between NPT-11 and NFL appeared to be driven by the group of individuals off cART. In a subset of participants who had visits before and after 24 weeks on cART (n = 11), plasma NFL declined over time (median = 22.7 versus 13.4 pg/ml, p = 0.02). In contrast, plasma NFL tended to increase over time among HIV-negative participants (median 10.3 versus 12.6 pg/ml, p = 0.065, n = 54). Plasma NFL therefore shows promise as a marker of neuropsychological performance during HIV. Larger studies are needed to determine if NFL could serve as a diagnostic tool for HAND during suppressive cART.


The potential utility of an augmented data collection approach in understanding the journey to care of pregnant women for maternal and perinatal death surveillance and response.
Background: The Maternal and Perinatal Death Surveillance and Response (MPDSR) proposed by the World Health Organization recognises the importance for health systems to understand the reasons underpinning the death of a pregnant woman or her newborn as an essential first step in preventing future similar deaths. Data for the surveillance component of the MPDSR process are typically collected from health facility sources and post-mortem interviews with affected families, though it may be traumatising to them. This brief report aimed to assess the potential utility of an augmented data collection method for mapping journeys of maternal and perinatal deaths, which does not require sourcing additional information from grieving family members. Methods: A descriptive analysis of maternal and perinatal deaths that occurred across 24 public hospitals in Lagos State, Nigeria, between 1 st November 2018 and 30 th October 2019 was conducted. Data on their demographic, obstetric history and complication at presentation, travel to the hospital, and mode of birth were extracted from their hospital records. The extracted travel data was exported to Google Maps, where driving distance and travel time to the hospital for the period of the day of travel were also extracted. Results: Of the 182 maternal deaths, most presented during the week (80.8%), travelled 5-10 km (30.6%) and 10-29 minutes (46.9%), and travelled to the nearest hospital to their places of residence (70.9%). Of the 442 pregnant women who had perinatal deaths, most presented during the week (78.5%), travelled <5 km (26.9%) and 10-29 minutes (38.0%). For both, the least reported travel data was the mode of travel used to care (>90.0%) and the period of the day they travelled (approximately 30.0%). Conclusion: An augmented data collection approach that includes accurate and complete travel data and closer-to-reality estimates of travel time and distance can be beneficial for MPDSR purposes.


Arterial inflammation in patients with HIV.
Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV. Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.


Stroke unit care combined with early supported discharge improves 5-year outcome: a randomized controlled trial.
Early supported discharge (ESD) seems to be a promising alternative to conventional follow-up care after acute stroke. We have previously shown that stroke unit care combined with ESD has beneficial effects on functional outcome and the use of resources for up to 1 year. The aim of this trial was to evaluate outcome after 5 years. We performed a randomized controlled trial with 320 acute stroke patients allocated to ordinary stroke unit care (160 patients) or stroke unit care with ESD (160 patients). The ESD service consisted of a mobile team that co-coordinated hospital discharge and further rehabilitation during 1 month of follow-up in cooperation with the primary health care. Mortality, residence, and functional outcome including modified Rankin scale were registered after 5 years. All assessments were blinded. There was no difference between the groups with modified Rankin scale score ≤2 (P=0.213), but there was a trend toward greater improvement in modified Rankin scale score in the ESD group from onset of stroke (38% versus 30%; P=0.106). More patients were dead or institutionalized in the ordinary stroke unit care group (P=0.032); 158 patients were alive, 84 were in ESD, and 74 were in ordinary stroke unit care. Of the 158 patients alive, a greater proportion were living at home in ESD (86%/70%; P=0.019). Stroke unit care combined with ESD seems to reduce death and institutional care and to improve patients' chances of living at home 5 years after stroke compared to traditional stroke care. There is a trend toward improved functional outcome in the ESD group.


Spatial limitations of fast temporal segmentation are best modeled by V1 receptive fields.
The fine temporal structure of events influences the spatial grouping and segmentation of visual-scene elements. Although adjacent regions flickering asynchronously at high temporal frequencies appear identical, the visual system signals a boundary between them. These "phantom contours" disappear when the gap between regions exceeds a critical value (g(max)). We used g(max) as an index of neuronal receptive-field size to compare with known receptive-field data from along the visual pathway and thus infer the location of the mechanism responsible for fast temporal segmentation. Observers viewed a circular stimulus reversing in luminance contrast at 20 Hz for 500 ms. A gap of constant retinal eccentricity segmented each stimulus quadrant; on each trial, participants identified a target quadrant containing counterphasing inner and outer segments. Through varying the gap width, g(max) was determined at a range of retinal eccentricities. We found that g(max) increased from 0.3° to 0.8° for eccentricities from 2° to 12°. These values correspond to receptive-field diameters of neurons in primary visual cortex that have been reported in single-cell and fMRI studies and are consistent with the spatial limitations of motion detection. In a further experiment, we found that modulation sensitivity depended critically on the length of the contour and could be predicted by a simple model of spatial summation in early cortical neurons. The results suggest that temporal segmentation is achieved by neurons at the earliest cortical stages of visual processing, most likely in primary visual cortex.


Zika Virus Targeting in the Developing Brain.
Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems, including microcephaly, cortical thinning, and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice, this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a Type 1 interferon response (IFNR-/-), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS and may target different cells at different stages of brain development.SIGNIFICANCE STATEMENT Zika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second-trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested and initially targeted astrocytes throughout the brain. Infections of the retina were detected in all mice, and infection of CNS visual system nuclei in the brain was common. We find that ZIKV can be transported axonally, thereby enhancing virus spread within the brain. These data suggest that ZIKV infects multiple cell types within the brain and that astrocyte infection may play a more important role in initial infection than previously appreciated.


Prevalence of anal human papillomavirus infection and cytologic abnormalities among HIV-infected and HIV-uninfected men who have sex with men.
Human papillomavirus (HPV) is responsible for 85% of anal cancers. Recently, anal cancer incidence has been increasing, particularly in men who have sex with men (MSM). Cytology may be a useful tool for the detection of anal precancerous lesions. We assessed the prevalence and determinants of anal HPV infection and cytologic abnormalities among HIV-infected and -uninfected MSM. MSM ≥18-year-old attending an STI clinic in Rome (Italy) were enrolled. Anal cytologic samples were collected in PreservCyt (Hologic) using a Dacron swab. The Linear Array HPV Genotyping Test (Roche Diagnostics) was used for the detection and genotyping of 37 mucosal HPV types. Liquid-based cytological slides were obtained using a ThinPrep2000 processor (Hologic). The morphology of the anal pap-test was classified following the Bethesda 2001 guidelines. We enrolled 180 HIV-infected (median age 41 years, IQR 33-47) and 438 HIV-uninfected MSM (median age 32 years, IQR: 27-39). Most of the individuals were Caucasian (92.2% and 97.0%, respectively). HPV prevalence, both overall (93.3% vs 72.4%, p<.001) and by high-risk (HR) HPV types (80.5% vs 56.0%, p<.001), was significantly higher among HIV-infected than HIV-uninfected individuals. HPV-multiple infections were evidenced in 48.2% of the HIV-uninfected and 76.1% of the HIV-infected MSM (p<.001). HPV16 was the most prevalent genotype in both groups (23.3% in HIV-positive and 17.6% in HIV-negative MSM). HPV6 and 84 were the most frequent low-risk types in both cohorts. Anal cytologic abnormalities were found in a significantly higher proportion of HIV-infected MSM (46.1% vs 27.9%, p<.001). H-SILs (high-grade squamous intraepithelial lesions) were exclusively observed among the HIV-infected individuals, although at a low prevalence (1.2%). A high prevalence of anal HPV infection and cytologic abnormalities was evidenced in both populations. Nonetheless, HIV-infected MSM showed a significantly higher rate of HPV infection and abnormal cytology, confirming that HIV-1 infection poses a significant risk for anal HPV infection as well as for anal cellular abnormalities. Screening for anal cancer, which is currently the most frequent non-AIDS-defining cancer in HIV-positive MSM, should be considered for this population. Moreover, vaccination strategies for the prevention of HPV infection should be taken into account.


Glucagon-like peptide-1 receptors in the kidney: impact on renal autoregulation.
Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type 2 diabetes. However, the GLP-1 receptor (GLP-1R) is also present in the kidney, where it influences renal function. The effect of GLP-1 on the kidney varies between humans and rodents. The effect of GLP-1 on kidney function also seems to vary depending on its concentration and the physiological or pathological state of the kidney. In studies with rodents or humans, acute infusion of pharmacological doses of GLP-1 stimulates natriuresis and diuresis. However, the effect on the renal vasculature is less clear. In rodents, GLP-1 infusion increases renal plasma flow and glomerular filtration rate, suggesting renal vasodilation. In humans, only a subset of the study participants exhibits increased renal plasma flow and glomerular filtration rate. Differential status of kidney function and changes in renal vascular resistance of the preglomerular arterioles may account for the different responses of the human study participants. Because renal function in patients with type 2 diabetes is already at risk or compromised, understanding the effects of GLP-1R activation on kidney function in these patients is particularly important. This review examines the distribution of GLP-1R in the kidney and the effects elicited by GLP-1 or GLP-1R agonists. By integrating results from acute and chronic studies in healthy individuals and patients with type 2 diabetes along with those from rodent studies, we provide insight into how GLP-1R activation affects renal function and autoregulation.


The gene for alternative oxidase-2 (AOX2) from Arabidopsis thaliana consists of five exons unlike other AOX genes and is transcribed at an early stage during germination.
We investigated the expressions of genes for alternative oxidase (AOX1a, AOX1b, AOX1c and AOX2) and genes for cytochrome c oxidase (COX5b and COX6b) during germination of Arabidopsis thaliana, and examined oxygen uptakes of the alternative respiration and the cytochrome respiration in imbibed Arabidopsis seeds. A Northern blot analysis showed that AOX2 mRNA has already accumulated in dry seeds and subsequently decreased, whereas accumulation ofAOX1a mRNA was less abundant from 0 hours to 48 hours after imbibition and then increased. The increase of the capacity of the alternative pathway appeared to be dependent on the expressions of both AOX2 and AOX1a. On the other hand, steady-state mRNA levels of COX5b and COX6b were gradually increased during germination, and the capacity of the cytochrome pathway was correlated with the increase of expressions of the COX genes. Antimycin A, the respiratory inhibitor, strongly increased the expression of AOX1a but had no effect on the expression of AOX2. A 5'RACE analysis showed that AOX2 consists of five exons, which is different from the case of most AOX genes identified so far. Analysis of subcellular localization of AOX2 using green fluorescent protein indicated that the AOX2 protein is imported into the mitochondria.


[The dynamic state of the concentrations of copper and histidine, and the complex effects of histidine and copper on the formation of lipid peroxidation in sera of undernourished young women].
First, we observed that copper and histidine levels were increased in the sera of undernourished women. The objective of this study was to clarify the reason for the increase in copper and histidine. Furthermore, we tried to determine the compound(s) to which the increased copper was binding, and examined the effect of the increased copper and histidine on lipid peroxidation. We investigated young women's diets and took blood samples, and the contents of histidine in the sera were determined by HPLC. The contents of copper were determined by flameless atomic absorption spectroscopy. The subjects were classified into three groups according to the concentration of histidine in the sera. The contents of copper and lipid peroxide in the sera were compared among the high histidine group and the other groups. We also examined the ability of the complexes to prevent LDL oxidation induced by copper, using an in vitro assay. The contents of lipid peroxide were lower in the high histidine group than in the other groups. Furthermore, the complexes of histidine and copper inhibited the formation of peroxidized lipids in an in vitro assay. These results indicate that histidine masks copper, reducing oxidation reaction. They also suggest that the complexes are suited for plasma antioxidation, preventing oxidative modification of lipids in the sera of undernourished women. The increased histidine appeared to be an effective trap for active oxygen.


Investigation of the phenylalkylamine binding site in hKv1.3 (H399T), a mutant with a reduced C-type inactivated state.
To screen for residues of hKv1.3 important for current block by the phenylalkylamine verapamil, the inactivated-state-reduced H399T mutant was used as a background for mutagenesis studies. This approach was applied mainly to abolish the accumulation in the inactivated blocked state, recovery from which in the wild type is normally slow. Substitution of amino acids in the S6 transmembrane helix indicated a heavy disruption of verapamil block by the A413C mutation, reducing the IC(50) from 2.4 to 267 microM. Subsequent scanning for verapamil moieties essential for current block was performed by application of derivatives with altered side groups. Neither the removal of the nitrile or the methyl group nor the addition of a methoxy group resulted in major variations of IC(50) values for hKv1.3 (H399T) current block. However, disruption of current block by A413C was 4- to 10-fold less pronounced for derivatives lacking the 4-methoxy group of the (3,4-dimethoxyphenyl)ethylmethyl-amino part (devapamil) or all four methoxy groups (emopamil), respectively. Emopamil displayed a Hill coefficient of 2 for hKv1.3 (H399T/A413C) instead of 1 for hKv1.3 (H399T) current block. These results might indicate that the alteration of Ala413 modulates the access of phenylalkylamines to their binding site depending on the occupancy of the phenyl rings with methoxy groups. A computer-based docking model shows a subset of docked PAA conformations, with a spatial proximity between the (4-methoxyphenyl)ethyl-methyl-amino group and Ala413. The PAA binding site might therefore include a binding pocket for the aromatic ring of the ethyl-methyl-amino part in an S6-S6 interface gap.


Weed hygiene practices in rural industries and public land management: Variable knowledge, patchy implementation, inconsistent coordination.
Weed management science and practice largely focuses on eradicating, containing and reducing existing weed populations; the focus is on plants in situ. More recently, the redefinition of biosecurity to include weeds has seen greater attention paid to preventing the introduction of weeds to previously uninfested areas within countries. Thus weed hygiene has come to the fore, with a growing number of publications recommending a diverse range of practices to minimise the spread of weeds across farm, regional and state boundaries. Yet little is known about the uptake of weed hygiene practices. The aim of this paper is to evaluate the extent to which best practice weed hygiene is being implemented on, across and along private and public lands. Telephone interviews were conducted with 54 private and public land managers, weed contractors, and agricultural transport operators in New South Wales, Australia. Vehicle hygiene was commonly undertaken across all stakeholder groups when it was consistent with other goals, requirements or norms. Other practices, such as sequencing harvesting from least to most weedy paddocks or including weed hygiene clauses in contracts were often known, but rarely practiced because of the onerous labour and financial costs or concerns about social etiquette. Individual commitment to weed hygiene efforts were also undermined by intra and inter-organisational coordination challenges. Public debate and assessment are needed on the benefits and costs to society of weed hygiene compared to in situ weed control to determine where best to invest limited time and resources.


Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin.
Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps. Because of the solubilizing and hydration effects of sugars, it was thought that glycosylation of insulin could inhibit fibril formation and lead to a more stable formulation. Since enzymatic glycosylation results in heterogeneous products, we developed a novel chemical strategy to produce a homogeneous glycoinsulin (disialo-glycoinsulin) in excellent yield (∼60%). It showed a near-native binding affinity for insulin receptors A and B in vitro and high glucose-lowering effects in vivo, irrespective of the route of administration (s.c. vs i.p.). The glycoinsulin retained insulin-like helical structure and exhibited improved stability in human serum. Importantly, our disialo-glycoinsulin analogue does not form fibrils at both high concentration and temperature. Therefore, it is an excellent candidate for clinical use in insulin pumps.


Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial.
Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use. This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 μg, levonorgestrel [LV] 150 μg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 μg BID from Days 1 through 4 and at 10 μg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period. Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial. The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. ClinicalTrials.gov: NCT00254800.


Annual summary of vital statistics: 2012-2013.
The number of births in the United States declined by 1% between 2012 and 2013, to a total of 3 932 181. The general fertility rate also declined 1% to 62.5 births per 1000 women, the lowest rate ever reported. The total fertility rate was down by 1% in 2013 (to 1857.5 births per 1000 women). The teenage birth rate fell to another historic low in 2013, 26.5 births per 1000 women. Birth rates also declined for women 20 to 29 years, but the rates rose for women 30 to 39 and were unchanged for women 40 to 44. The percentage of all births that were to unmarried women declined slightly to 40.6% in 2013, from 40.7% in 2012. In 2013, the cesarean delivery rate declined to 32.7% from 32.8% for 2012. The preterm birth rate declined for the seventh straight year in 2013 to 11.39%; the low birth weight (LBW) rate was essentially unchanged at 8.02%. The infant mortality rate was 5.96 infant deaths per 1000 live births in 2013, down 13% from 2005 (6.86). The age-adjusted death rate for 2013 was 7.3 deaths per 1000 population, unchanged from 2012. Crude death rates for children aged 1 to 19 years declined to 24.0 per 100 000 population in 2013, from 24.8 in 2012. Unintentional injuries and suicide were, respectively, the first and second leading causes of death in this age group. These 2 causes of death jointly accounted for 45.7% of all deaths to children and adolescents in 2013.


In-mold patterning and actionable axo-somatic compartmentalization for on-chip neuron culture.
Oriented neuronal networks with controlled connectivity are required for many applications ranging from studies of neurodegeneration to neuronal computation. To build such networks in vitro, an efficient, directed and long lasting guidance of axons toward their target is a pre-requisite. The best guidance achieved so far, however, relies on confining axons in enclosed microchannels, making them poorly accessible for further investigation. Here we describe a method providing accessible and highly regular arrays of axons, emanating from somas positioned in distinct compartments. This method combines the use of a novel removable partition, allowing soma positioning outside of the axon guidance patterns, and in-mold patterning (iMP), a hybrid method combining chemical and mechanical cell positioning clues applied here for the first time to neurons. The axon guidance efficiency of iMP is compared to that of conventional patterning methods, e.g. micro-contact printing (chemical constraints by a poly-l-lysine motif) and micro-grooves (physical constraints by homogeneously coated microstructures), using guiding tracks of different widths and spacing. We show that iMP provides a gain of 10 to 100 in axon confinement efficiency on the tracks, yielding mm-long, highly regular, and fully accessible on-chip axon arrays. iMP also allows well-defined axon guidance from small populations of several neurons confined at predefined positions in μm-sized wells. iMP will thus open new routes for the construction of complex and accurately controlled neuronal networks.


Leaf trait variability between and within subalpine grassland species differs depending on site conditions and herbivory.
Plant traits are commonly used to predict ecosystem-level processes, but the validity of such predictions is dependent on the assumption that trait variability between species is greater than trait variability within a species-the robustness assumption. Here, we compare leaf trait intraspecific and interspecific variability depending on geographical differences between sites and 5 years of experimental herbivore exclusion in two vegetation types of subalpine grasslands in Switzerland. Four leaf traits were measured from eight herbaceous species common to all 18 sites. Intraspecific trait variability differed significantly depending on site and herbivory. However, the amount and structure of variability depended on the trait measured and whether considering leaf traits separately or multiple leaf traits simultaneously. Leaf phosphorus concentration showed the highest intraspecific variability, while specific leaf area showed the highest interspecific variability and displayed intraspecific variability only in response to herbivore exclusion. Species identity based on multiple traits was not predictable. We find intraspecific variability is an essential consideration when using plant functional traits as a common currency not just species mean traits. This is particularly true for leaf nutrient concentrations, which showed high intraspecific variability in response to site differences and herbivore exclusion, a finding which suggests that the robustness assumption does not always hold.


Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.


Major pollutants in soils of abandoned agricultural land contaminated by e-waste activities in Hong Kong.
Polycyclic aromatic hydrocarbon (PAH), polychlorinated biphenyl (PCB), polybrominated diphenyl ether (PBDE) compounds and five heavy metals (cadmium, copper, chromium, lead, and zinc) were determined in soil samples collected from six sites of abandoned agricultural land affected by electronic-waste: e-waste dismantling workshop [EW (DW)], e-waste open burning site [EW (OBS)], e-waste storage [EW (S)], and agricultural (A) in the New Territories, Hong Kong. Persistent organic pollutants (POPs) and heavy metals were detected in all soil samples. EW (DW) contained the highest concentrations of PAHs, Cr, Cu, and Zn, whereas EW (OBS) had the highest concentrations of PCBs, PBDEs, Cd, and Pb. PAH at EW (DW) and EW (OBS) and PCB concentrations at EW (OBS) exceeded the target values of the New Dutch list, whereas Cd, Cu, Cr, Pb, and Zn levels exceeded the Chinese legislation for the protection of agricultural production and safeguarding of human health, by 3-11 times at EW (OBS) and 5-8 times at EW (DW). Lead at EW (OBS) and EW (DW) and Cr at EW (DW) greatly exceeded the Canadian Soil Quality Guidelines by 46 and 20 times and 27 times, respectively. Concentrations of POPs and heavy metals at EW (DW) and EW (OBS) were significantly higher than at EW (S) and A. It was concluded that e-waste activities led to increases of toxic chemicals at these abandoned agricultural land, which would hinder the redevelopment of the land.


Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma.
Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR-Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type-specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.


Galectin-3 mediates IL-4-induced survival and differentiation of B cells: functional cross-talk and implications during Trypanosoma cruzi infection.
The role of transcription factors in B cell survival and differentiation has been delineated during the last years. However, little is known about the intermediate signals and the intracellular pathways that control these events. In this study, we provide evidence both in vitro and in vivo, showing that galectin-3 (Gal-3), a beta-galactoside-binding protein, is a critical mediator of B cell differentiation and survival. Although Gal-3 is not expressed in resting B cells from normal mice, its expression is markedly induced after activation with stimuli such as IL-4 and CD40 cross-linking. These signals promote survival and block the final differentiation of these cells, thus allowing the rising of a memory B cell phenotype. In addition, Gal-3 is expressed in B cells from Trypanosoma cruzi-infected mice, which received signals for activation and differentiation in vivo. By using an antisense strategy, we determined that Gal-3 is a critical signal mediating the effects of IL-4 on B cell fate. Blockade of intracellular Gal-3 in vitro abrogated IL-4-induced survival of activated B cells, favoring the differentiation toward a plasma cell pathway. Moreover, B cells with restrained endogenous Gal-3 expression failed to down-regulate the Blimp-1 transcription factor after IL-4 stimulation. Finally, inhibition of Gal-3 in vivo skewed the balance toward plasma cell differentiation, which resulted in increased Ig production and parasite clearance during T. cruzi infection. Thus, the present study provides evidence of a novel role for Gal-3 as an intracellular mediator of B cell survival and a checkpoint in IL-4-induced B cell commitment toward a memory phenotype.


Switching characteristics of an InP photonic crystal nanocavity: experiment and theory.
The dynamical properties of an InP photonic crystal nanocavity are experimentally investigated using pump-probe techniques and compared to simulations based on coupled-mode theory. Excellent agreement between experimental results and simulations is obtained when employing a rate equation model containing three time constants, that we interpret as the effects of fast carrier diffusion from an initially localized carrier distribution and the slower effects of surface recombination and bulk recombination. The variation of the time constants with parameters characterizing the nanocavity structure is investigated. The model is further extended to evaluate the importance of the fast and slow carrier relaxation processes in relation to patterning effects in the device, as exemplified by the case of all-optical wavelength conversion.


Unravelling the early oxidation mechanism of zinc phosphide (Zn3P2) surfaces by adsorbed oxygen and water: a first-principles DFT-D3 investigation.
Zinc phosphide (Zn3P2) is a novel earth-abundant photovoltaic material with a direct band gap of 1.5 eV. Herein, the incipient oxidation mechanism of the (001), (101), and (110) Zn3P2 surfaces in the presence of oxygen and water, which severely limits the fabrication of efficient Zn3P2-based photovoltaics, has been investigated in detail by means of dispersion-corrected density functional theory (DFT-D3) calculations. The fundamental aspects of the oxygen and water adsorption, including the initial adsorption geometries, adsorption energies, structural parameters, and electronic properties, are presented and discussed. A chemical picture and origin of the initial steps of Zn3P2 surface oxidation are proposed through analyses of Bader charges, partial density of states, and differential charge density isosurface contours. The results presented show that while water interacts weakly with the Zn ions on the Zn3P2 surfaces, molecular and dissociative oxygen species interact strongly with the (001), (101), and (110) surface species. The adsorption of oxygen is demonstrated to be characterized by a significant charge transfer from the interacting surface species, causing them to be oxidized from Zn2+ to Zn3+ formal oxidation states. Preadsorbed oxygen species are shown to facilitate the O-H bond activation of water towards its dissociation, with the adsorbed hydroxide species (OH-) demonstrated to draw a significant amount of charges from the interacting surface sites. Despite the fact that the semiconducting nature of the different Zn3P2 surfaces is preserved, we observe noticeable adsorption induced changes in their electronic structures, with the covered surface exhibiting smaller band gaps than the naked surfaces. The present study demonstrates the importance of the oxygen-water/solid interface to understand the oxidation mechanism of Zn3P2 in the presence of oxygen and water at the molecular level. The study also highlights the need for Zn3P2 nanoparticles to be protected against possible oxidation in the presence of oxygen and moisture via in situ functionalization, wherein the Zn3P2 nanoparticles are exposed to a vapour of organic functional molecules immediately after synthesis.


[Knowledge of obstetricians about the vertical transmission of hepatitis B virus].
Vertical transmission is responsible for 35%-40% of the new cases of hepatitis B worldwide and it is associated with an increased risk of chronic hepatitis B, cirrhosis and hepatocellular carcinoma. To describe obstetricians' knowledge on the recommended measures to the diagnosis of the infection by the hepatitis virus B in pregnant women and to prevent the transmission of this infection to the babies of infected mothers. Obstetricians registered at the 'Sociedade de Ginecologia e Obstetrícia da Bahia', Salvador, BA, Brazil were randomly selected and invited to answer a questionnaire with questions regarding their academic formation, workplace, contact with medical students and their practices about the hepatitis virus B. Individuals who were not currently working as obstetricians or were not living in the state of Bahia were excluded from the study. Data were analyzed with the EpiInfo software with a 95% confidence interval. Three hundred and one obstetricians answered the questionnaire: 90.3% of them recognized that the hepatitis virus B could be transmitted vertically and 81.7% routinely screened their patients for hepatitis virus B infection during prenatal consultations; 66.0% considered HBsAg the best serological marker to be employed on the screening. Only 13.0% systematically recommended the vaccination against hepatitis virus B and the administration of immunoglobulin to the newborns of infected mothers in the first 12 hours of life. The frequency of correct answers about the vertical transmission of hepatitis virus B, the best serological marker for screening and the management of infected mothers and their newborns was higher among professionals who had the 'Título de Especialista em Ginecologia e Obstetrícia (TEGO)' than among the remaining ones (P = 0.018, P = 0.001 and P = 0.002, respectively). We observed that the knowledge of the obstetricians about the diagnosis and management of hepatitis virus B infection during pregnancy is not adequate, reinforcing the need of continuous medical education programs on the infections that can be transmitted vertically.


Influence of grating parameters on the linewidths of external-cavity diode lasers.
We investigate experimentally the influence of the grating reflectivity, grating resolution, and diode facet antireflection (AR) coating on the intrinsic linewidth of an external-cavity diode laser built with a diffraction grating in a Littrow configuration. Grating lasers at 399, 780, and 852 nm are determined to have typical linewidths between 250 and 600 kHz from measurements of their frequency noise power spectral densities. The linewidths are little affected by the presence of an AR coating on the diode facet but narrow as the grating reflectivity and grating resolution are increased, with the resolution exerting a greater effect. We also use frequency noise measurements to characterize a laser mount with improved mechanical stability.


Hematopoietic thymocyte precursors. I. Assay and kinetics of the appearance of progeny.
A quantitative assay for the hematopoietic precursor of thymocytes has been developed. Using this assay the kinetics of appearance of the progeny of transfused bone marrow and spleen cells in the thymus of irradiated (760 R) mice has been studied. Precursor cells are seven to eightfold more common in bone marrow than in spleen and are absent from peripheral lymph nodes. They decline in number as the animals age. When hematopoietic cells are injected immediately after lethal irradiation only a small number of cells actually enter the gland. Their progeny are not detectable in the thymus for 8-12 days. The time of their detection depends both upon the size of the residual endogenous thymocyte population and the number of progenitor cells injected. Evidence has been presented that excludes thymic injury as the basis for the delay in the appearance of donor type cells and indicates that neither the production of a "homing" signal in the irradiated animal nor the development of precursor cells are limiting factors in the rate of thymic repopulation. These studies indicate that only an exceedingly small number (less than 100) of prothymocytes are required to repopulate the thymus of an irradiated mouse. This restricted number of progenitors must produce the entire repertory of T-cell immunologic responsiveness seen in the first weeks after repopulation.


Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective.
The advent of biologic agents has provided a more specific and targeted approach to the treatment of various hematological malignancies and other autoimmune disorders. Such biologic agents have been relatively well tolerated with fewer adverse events reported as compared with many other chemotherapeutic agents. Rituximab is a monoclonal antibody to the B-cell marker CD20 and is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, including rheumatoid arthritis and some vasculitides. However, through randomized controlled trials and post-marketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission. The purpose of this review is to focus on the severe complications that are associated with the use of rituximab and that require critical care. Management and prevention strategies for the most common complications along with some examples of its uses within the critical care setting are also discussed.


Evaluation of the effectiveness of Face IT, a computer-based psychosocial intervention for disfigurement-related distress.
Some people who have a visible difference (disfigurement) experience psychosocial adjustment problems that can lead to social anxiety and isolation. The aim of this study was to assess the effectiveness of a new computerised CBT-based intervention (Face IT) in reducing anxiety and appearance-related distress for individuals with visible differences. Face IT was tested against a non-intervention control group and standard CBT-based face-to-face delivery. Eighty-three participants were assessed at four time points using the Hospital Anxiety and Depression Scales, Derriford Appearance Scale-24, Body Image Quality of Life Inventory and Fear of Negative Evaluation (FNE). The findings indicate a significant reduction in anxiety and appearance-related distress in both the Face IT intervention and the face-to-face condition. Similar findings were reported for depressive symptoms and FNE. Results at the three and six months follow-up demonstrate increased improvements in psychological functioning with both interventions. This new online psychosocial intervention has been found to be effective at reducing anxiety, depression and appearance concerns amongst individuals with disfigurements, whilst increasing positive adjustment. A remote-access, computer-based intervention offers the potential to provide psychosocial support more easily and in a cost-effective manner to adults with appearance-related distress.


Genetic variation in Australian spotted fever group rickettsiae.
Rickettsiae were isolated by cell culture of buffy coat blood from six patients with spotted fever from southeastern Australia and Flinders Island in Bass Strait. The isolates were genetically compared with two previous Rickettsia australis patient isolates. The genus-specific 17-kDA genes from the isolates were compared after DNA amplification and restriction fragment analysis of the amplified DNA. This comparison revealed that mainland rickettsial isolates from southeastern Australia were identical to two previous isolates of R. australis from northeastern Australia. Rickettsial isolates from Flinders Island were distinct from the mainland isolates. The 16S rRNA gene sequences from the isolates were determined and compared. The Flinders Island rickettsial agent was most closely related (0.3% structural divergence) to Rickettsia rickettsii, Rickettsia conorii, and Rickettsia slovaca. The Flinders Island rickettsial agent was 1.3 and 2.1% structurally divergent from R. australis and Rickettsia akari, respectively. The 16S rRNA gene sequence from the Flinders Island agent shows that this rickettsia is more closely related to the rickettsial spotted fever group than is R. australis. We conclude that there are two populations of spotted fever group rickettsiae in Australia and propose that the genetically distinct causative organism of Flinders Island spotted fever be designated Rickettsia honei. The extent of distribution and animal host reservoirs remain to be elucidated.


Combined pretrauma scopolamine and phencyclidine attenuate posttraumatic increased sensitivity to delayed secondary ischemia.
Fasted Wistar rats were given a mild level of traumatic brain injury (TBI) and then subjected to 6 min of transient forebrain ischemia 24 h posttrauma. One group was given simultaneous 1 mg/kg scopolamine and 4 mg/kg phencyclidine intraperitoneally (IP) 15 min before trauma and another group an equal volume of plasmalyte A solution. After 7 days of postinjury survival, placebo-treated rats demonstrated increased posttraumatic vulnerability to secondary ischemic CA1 neuronal death even 24 h after trauma. This finding confirmed that increased posttraumatic ischemic vulnerability persists for at least 24 h even following mild trauma. Combined muscarinic receptor and N-methyl-D-aspartate (NMDA) receptor coupled ion channel blockade given and present during the mild TBI statistically attenuated this enhanced secondary ischemic CA1 neuronal death and thus posttraumatic increased ischemic vulnerability. Placebo-treated rats had 335.3 +/- 93.6 CA1 neurons/10(6) microns 2 and drug-treated rats had 844.8 +/- 184.9 CA1 neurons/10(6) microns 2. This result suggests that muscarinic and/or NMDA receptor-mediated events confined to TBI and the early posttraumatic period are in part responsible for the phenomenon of increased posttraumatic ischemic vulnerability.


Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure.
Aripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP-HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4-3.6 Å. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs.


Randomized clinical trial of telephone-administered cognitive-behavioral therapy to reduce post-traumatic stress disorder and distress symptoms after hematopoietic stem-cell transplantation.
A significant number of survivors of hematopoietic stem-cell transplantation (HSCT) report enduring adverse effects of treatment, including illness-related post-traumatic stress disorder (PTSD) symptoms and general distress. We report results of a randomized clinical trial that tested the effects of a 10-session, telephone-administered cognitive-behavioral therapy (CBT) intervention on PTSD, depression, and distress symptoms. Survivors who had undergone HSCT 1 to 3 years earlier (N = 408) were assessed for study eligibility. Those who met study eligibility criteria (n = 89) completed a baseline assessment that included a clinical interview and self-report measures of PTSD symptoms (the primary outcome) and depression and general distress (the secondary outcomes). Next, they were randomly assigned to CBT or an assessment-only condition. Survivors in the CBT group completed 10 individual telephone-based CBT sessions (T-CBT) that included strategies to reduce PTSD symptoms, depression, and general distress. Follow-up assessments occurred at 6, 9, and 12 months after the baseline assessment. Linear mixed-model analyses revealed that, compared with HSCT survivors in the assessment-only condition, survivors who completed T-CBT reported fewer illness-related PTSD symptoms, including less avoidance (P < .001) and fewer intrusive thoughts (P < .05) as well as less general distress and fewer depressive symptoms (P < .05) even after controlling for potential demographic and medical covariates. These results were consistent across the three follow-up assessments. A brief, telephone-administered CBT intervention developed for HSCT survivors is an efficacious treatment for reducing illness-related PTSD symptoms and general distress.


Cancer modeling meets human organoid technology.
Organoids are microscopic self-organizing, three-dimensional structures that are grown from stem cells in vitro. They recapitulate many structural and functional aspects of their in vivo counterpart organs. This versatile technology has led to the development of many novel human cancer models. It is now possible to create indefinitely expanding organoids starting from tumor tissue of individuals suffering from a range of carcinomas. Alternatively, CRISPR-based gene modification allows the engineering of organoid models of cancer through the introduction of any combination of cancer gene alterations to normal organoids. When combined with immune cells and fibroblasts, tumor organoids become models for the cancer microenvironment enabling immune-oncology applications. Emerging evidence indicates that organoids can be used to accurately predict drug responses in a personalized treatment setting. Here, we review the current state and future prospects of the rapidly evolving tumor organoid field.


Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy.
Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G-protein Rac1. NADPH oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.


Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation.
Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology ("over-perception"). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness-anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy.


The Incremental Effects of Manual Therapy or Booster Sessions in Addition to Exercise Therapy for Knee Osteoarthritis: A Randomized Clinical Trial.
A factorial randomized controlled trial. To investigate the addition of manual therapy to exercise therapy for the reduction of pain and increase of physical function in people with knee osteoarthritis (OA), and whether "booster sessions" compared to consecutive sessions may improve outcomes. The benefits of providing manual therapy in addition to exercise therapy, or of distributing treatment sessions over time using periodic booster sessions, in people with knee OA are not well established. All participants had knee OA and were provided 12 sessions of multimodal exercise therapy supervised by a physical therapist. Participants were randomly allocated to 1 of 4 groups: exercise therapy in consecutive sessions, exercise therapy distributed over a year using booster sessions, exercise therapy plus manual therapy without booster sessions, and exercise therapy plus manual therapy with booster sessions. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC score; 0-240 scale) at 1-year follow-up. Secondary outcome measures were the numeric pain-rating scale and physical performance tests. Of 75 participants recruited, 66 (88%) were retained at 1-year follow-up. Factorial analysis of covariance of the main effects showed significant benefit from booster sessions (P = .009) and manual therapy (P = .023) over exercise therapy alone. Group analysis showed that exercise therapy with booster sessions (WOMAC score, -46.0 points; 95% confidence interval [CI]: -80.0, -12.0) and exercise therapy plus manual therapy (WOMAC score, -37.5 points; 95% CI: -69.7, -5.5) had superior effects compared with exercise therapy alone. The combined strategy of exercise therapy plus manual therapy with booster sessions was not superior to exercise therapy alone. Distributing 12 sessions of exercise therapy over a year in the form of booster sessions was more effective than providing 12 consecutive exercise therapy sessions. Providing manual therapy in addition to exercise therapy improved treatment effectiveness compared to providing 12 consecutive exercise therapy sessions alone. Trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000460808).


Attraction of mosquitoes to volatiles associated with blood.
Responses of the mosquitoes Aedes aegypti, Culex quinquefasciatus, and Culex nigripalpus to volatiles and compounds associated with bovine and avian blood that were presented in collagen membranes were evaluated in olfactometer and landing assays. The presence of attractants produced by blood was supported by more attraction of all species to blood than water controls in the olfactometer. Females of Ae. aegypti and Cx. quinquefasciatus were more attracted to bovine blood than to avian blood, but there was no difference in Cx. nigripalpus responses. In landing assays, significantly more females of all species landed on casings with blood than on water controls. There was no difference in landing of Ae. aegypti on bovine or avian blood. However, significantly more females of Cx. quinquefasciatus and Cx. nigripalpus landed on avian blood compared to bovine blood. Blood presented in collagen casings was an effective method for evaluating in-flight attraction and landing in all three species. In the olfactometer, several individual compounds elicited attraction in all species, but none were as attractive as blood for all species. In landing assays, several organic acids and sulfides elicited landing, with Ae. aegypti responding to the greatest number of compounds. These assay methods are effective for evaluation of volatile compounds from blood, and although responses were obtained to several compounds, none were as effective as blood in the olfactometer and landing assays.


Pericardiocentesis in trauma: a systematic review.
Pericardiocentesis (PCC) had been taught as a mandatory skill in the Advanced Trauma Life Support (ATLS®) course as a bridge to definitive surgical therapy for traumatic pericardial tamponade since its inception in 1978. Immediate thoracotomy for penetrating trauma to the heart and chest has resulted in the decreased use of PCC in trauma. PCC is now offered as an optional skill in the ninth edition of the ATLS®. A review of the literature regarding the use and effectiveness of PCC in traumatic pericardial tamponade in the modern era is necessary to better define its current role in trauma care. Scientific publications from 1970 to 2010 involving PCC after trauma were identified. The Preferred Reporting Items for Systematic reviews and Meta-Analyses was used. Human studies describing acute traumatic tamponade were included. Publications involving nontraumatic or chronic pericardial tamponade from effusions caused by inflammatory, infectious, or neoplastic etiology were excluded. Publications were categorized by level of evidence. Of the 135 publications identified, 27 were included, composing of 2,094 trauma patients with suspected cardiac tamponade. The reported use of PCC decreased from 45.9% of patients in the period 1970 to 1979 down to 6.4% of patients in the period between 2000 and 2010 (p < 0.05). Reported rates describing the use of PCC as the sole intervention decreased from 13.7% in the period 1970 to 1979 to 2.1% in the period 2000 to 2010 (p < 0.05). Survival analysis after PCC was possible for 380 patients. Overall survival following PCC was 83.4% (n = 317) and 91.8% (n = 145) when used as the sole intervention. In patients who received PCC then thoracotomy, survival rate was 79.5% (n = 178). Studies on the use of PCC for trauma are limited and biased toward survivors. The reported survival rate is high. There remains a limited role for PCC in nontrauma centers where definitive surgical management is not immediately available and transport time to a higher level of care facility supports the use of temporary decompression by PCC. Systematic review, level III.


Di-(2 ethylhexyl) phthalate and flutamide alter gene expression in the testis of immature male rats.
We previously demonstrated that the androgenic and anti-androgenic effects of endocrine disruptors (EDs) alter reproductive function and exert distinct effects on developing male reproductive organs. To further investigate these effects, we used an immature rat model to examine the effects of di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on the male reproductive system. Immature male SD rats were treated daily with DEHP and Flu on postnatal days (PNDs) 21 to 35, in a dose-dependent manner. As results, the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD) decreased significantly in response to high doses of DEHP or Flu. Testosterone (T) levels significantly decreased in all DEHP- treated groups, whereas luteinizing hormone (LH) plasma levels were not altered by any of the two treatments at PND 36. However, treatment with DEHP or Flu induced histopathological changes in the testes, wherein degeneration and disorders of Leydig cells, germ cells and dilatation of tubular lumen were observed in a dose-dependent manner. Conversely, hyperplasia and denseness of Leydig, Sertoli and germ cells were observed in rats given with high doses of Flu. The results by cDNA microarray analysis indicated that 1,272 genes were up-regulated by more than two-fold, and 1,969 genes were down-regulated in response to DEHP, Flu or both EDs. These genes were selected based on their markedly increased or decreased expression levels. These genes have been also classified on the basis of gene ontology (e.g., steroid hormone biosynthetic process, regulation of transcription, signal transduction, metabolic process, biosynthetic process...). Significant decreases in gene expression were observed in steroidogenic genes (i.e., Star, Cyp11a1 and Hsd3b). In addition, the expression of a common set of target genes, including CaBP1, Vav2, Plcd1, Lhx1 and Isoc1, was altered following exposure to EDs, suggesting that they may be marker genes to screen for the anti-androgenic or androgenic effects of EDs. Overall, our results demonstrated that exposure to DEHP, Flu or both EDs resulted in a alteration of gene expression in the testes of immature male rats. Furthermore, the toxicological effects of these EDs on the male reproductive system resulted from their anti-androgenic effects. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of EDs, in regards to anti-androgenic effects in humans and wildlife.