Hyperpolarized 13C metabolic imaging using dissolution dynamic nuclear polarization.
This article describes the basic physics of dissolution dynamic nuclear polarization (dissolution-DNP), and the impact of the resulting highly nonequilibrium spin states, on the physics of magnetic resonance imaging (MRI) detection. The hardware requirements for clinical translation of this technology are also presented. For studies that allow the use of externally administered agents, hyperpolarization offers a way to overcome normal magnetic resonance sensitivity limitations, at least for a brief T(1)-dependent observation window. A 10,000-100,000-fold signal-to-noise advantage provides an avenue for real-time measurement of perfusion, metabolite transport, exchange, and metabolism. The principles behind these measurements, as well as the choice of agent, and progress toward the application of hyperpolarized (13)C metabolic imaging in oncology, cardiology, and neurology are reviewed.


Children's Recognition of Emotional Prosody in Spectrally Degraded Speech Is Predicted by Their Age and Cognitive Status.
It is known that school-aged children with cochlear implants show deficits in voice emotion recognition relative to normal-hearing peers. Little, however, is known about normal-hearing children's processing of emotional cues in cochlear implant-simulated, spectrally degraded speech. The objective of this study was to investigate school-aged, normal-hearing children's recognition of voice emotion, and the degree to which their performance could be predicted by their age, vocabulary, and cognitive factors such as nonverbal intelligence and executive function. Normal-hearing children (6-19 years old) and young adults were tested on a voice emotion recognition task under three different conditions of spectral degradation using cochlear implant simulations (full-spectrum, 16-channel, and 8-channel noise-vocoded speech). Measures of vocabulary, nonverbal intelligence, and executive function were obtained as well. Adults outperformed children on all tasks, and a strong developmental effect was observed. The children's age, the degree of spectral resolution, and nonverbal intelligence were predictors of performance, but vocabulary and executive functions were not, and no interactions were observed between age and spectral resolution. These results indicate that cognitive function and age play important roles in children's ability to process emotional prosody in spectrally degraded speech. The lack of an interaction between the degree of spectral resolution and children's age further suggests that younger and older children may benefit similarly from improvements in spectral resolution. The findings imply that younger and older children with cochlear implants may benefit similarly from technical advances that improve spectral resolution.


A method to predict refractive errors from wave aberration data.
We explored the impact of the eye's higher-order aberrations on subjective refraction comparing two classes of methods for estimating refractive state, one based directly on the wave aberration defined in the pupil plane and another based on the retinal image plane. The method defined in the pupil plane chose the sphere and cylinder that either minimized the wave aberration root mean square or minimized the sum of all the spherical and cylindrical components in the wave aberration. The method defined in the image plane chose the sphere and cylinder that optimized an image-quality metric such as the Strehl intensity ratio, the entropy and the intensity variance of the point-spread function, the volume under the modulation transfer function, or the volume under the contrast-sensitivity function. All these methods were compared in a population of six eyes for which we measured both the wave aberration with a Shack-Hartmann wavefront sensor and the subjective refraction under identical conditions. Pupil plane methods predicted subjective refraction poorly. The mean absolute error of the prediction, in spherical equivalent, was about 0.5 D (range, 0.1 to 0.8 D) and increased with increases in higher-order aberrations. However, for all the retinal image plane methods, the mean error between predicted and subjective refraction was about 0.1 D (range, 0 to 0.25 D). The reliability of the method based on the image-quality optimization was further confirmed in a large population of 146 eyes. In conclusion, higher-order aberrations influence the amount of sphere and cylinder required to correct vision. The results indicate that subjective refraction can be predicted from the eye's optics alone by optimizing computed retinal image quality.


Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta.
The tyrosine kinase Janus kinase 2 (JAK2) binds to the majority of the known members of the cytokine family of receptors. Ligand-receptor binding leads to activation of the associated JAK2 molecules, resulting in rapid autophosphorylation of multiple tyrosines within JAK2. Phosphotyrosines can then serve as docking sites for downstream JAK2 signaling molecules. Despite the importance of these phosphotyrosines in JAK2 function, only a few sites and binding partners have been identified. Using two-dimensional phosphopeptide mapping and a phosphospecific antibody, we identified tyrosine 813 as a site of JAK2 autophosphorylation of overexpressed JAK2 and endogenous JAK2 activated by growth hormone. Tyrosine 813 is contained within a YXXL sequence motif associated with several other identified JAK2 phosphorylation sites. We show that phosphorylation of tyrosine 813 is required for the SH2 domain-containing adapter protein SH2-B beta to bind JAK2 and to enhance the activity of JAK2 and STAT5B. The homologous tyrosine in JAK3, tyrosine 785, is autophosphorylated in response to interleukin-2 stimulation and is required for SH2-B beta to bind JAK3. Taken together these data strongly suggest that tyrosine 813 is a site of autophosphorylation in JAK2 and is the SH2-B beta-binding site within JAK2 that is required for SH2-B beta to enhance activation of JAK2.


Kinetic characterization of the critical step in HIV-1 protease maturation.
HIV maturation requires multiple cleavage of long polyprotein chains into functional proteins that include the viral protease itself. Initial cleavage by the protease dimer occurs from within these precursors, and yet only a single protease monomer is embedded in each polyprotein chain. Self-activation has been proposed to start from a partially dimerized protease formed from monomers of different chains binding its own N termini by self-association to the active site, but a complete structural understanding of this critical step in HIV maturation is missing. Here, we captured the critical self-association of immature HIV-1 protease to its extended amino-terminal recognition motif using large-scale molecular dynamics simulations, thus confirming the postulated intramolecular mechanism in atomic detail. We show that self-association to a catalytically viable state requires structural cooperativity of the flexible β-hairpin "flap" regions of the enzyme and that the major transition pathway is first via self-association in the semiopen/open enzyme states, followed by enzyme conformational transition into a catalytically viable closed state. Furthermore, partial N-terminal threading can play a role in self-association, whereas wide opening of the flaps in concert with self-association is not observed. We estimate the association rate constant (k(on)) to be on the order of ∼1 × 10(4) s(-1), suggesting that N-terminal self-association is not the rate-limiting step in the process. The shown mechanism also provides an interesting example of molecular conformational transitions along the association pathway.


Preoperative and postoperative 1H-MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus.
In a previous study we found significantly decreased N-acetyl aspartate (NAA) and total N-acetyl (tNA) groups in the thalamus of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with healthy individuals (HI). No significant difference between the groups could be found in the frontal deep white matter (FDWM). The primary aim of this study was to investigate if these metabolites in the thalamus were normalised after shunt surgery. The secondary aim was to investigate postoperative metabolic changes in FDWM. Fourteen patients with iNPH, mean age 74 years, and 15 HI, also mean age 74 years, were examined. Assessment of a motor score (MOSs) was performed before and after shunt surgery. Absolute quantitative (1)H-MR spectroscopy (1.5 T, volumes of interest 2.5-3 ml) was performed on the patients in the FDWM and in the thalamus, before and 3 months after shunt surgery, and also once on the HI. The following metabolites were analysed: tNA, NAA, total creatine, total choline (tCho), myo-inositol (mIns), glutamate and lactate concentrations. MRI volumetric calculations of the lateral ventricles were also performed. At 3 months postoperatively, we found no significant changes of tNA or NAA in the thalamus. In contrast, in the FDWM, there was a significant increase of tCho (p=0.01) and a borderline significant decrease of mIns (p=0.06). 12/14 patients were shunt responders (motor function). Median reduction of the lateral ventricle was 16%. A weak correlation between MOS and ventricular reduction was seen. Normalisation of thalamic tNA and NAA could not be detected postoperatively. The increased tCho and decreased mIns in the FDWM postoperatively might relate to clinical improvement.


An unusual case of bacillary angiomatosis in the oral cavity of an AIDS patient who had no concomitant tegumentary lesions - case report and review.
Bacillary angiomatosis (BA) is an angioproliferative disease of immunocompromised patients that usually presents as vascular tumors in the skin and subcutaneous tissues. It is caused by chronic infections with either Bartonella henselae or B. quintana. Oral cavity BA is exceedingly rare and even rarer without simultaneous cutaneous disease. We report herein the case of a 51-year-old HIV-infected man who presented severe odynophagia and an eroded lesion on the hard palate that progressed to an oronasal fistula. No cutaneous lesions were recorded. Doxycycline led to complete resolution. To the best of our knowledge, only six previous cases of oral BA without tegumentary disease have been previously reported and none of them progressed to fistula.


Exploring pathways into and out of amphetamine type stimulant use at critical turning points: a qualitative interview study.
Amphetamine Type Stimulants (ATS) are increasingly used drugs globally. There is limited evidence about what shapes ATS use at critical turning points located within drug using pathways. Using turning point theory, as part of a life course approach, the ATTUNE study aimed to understand which social, economic and individual factors shape pathways into and out of ATS use. Qualitative, semi-structured interviews (n = 70) were undertaken with individuals who had used ATS, or had been exposed to them at least once. Our findings show that turning points for initiation were linked to pleasure, curiosity, boredom and declining mental health; increased use was linked to positive effects experienced at initiation and multiple life-stressors, leading to more intense use. Decreased use was prompted by pivotal events and sustained through continued wellbeing, day-to-day structure, and non-using social networks. We argue that the heterogeneity of these individuals challenges stereotypes of stimulant use allied to nightclubs and 'hedonism'. Further, at critical turning points for recovery, the use of services for problematic ATS consumption was low because users prioritised their alcohol or opioid use when seeking help. There is a need to develop service provision, training, and better outreach to individuals who need support at critical turning points.


The NMR solution structure of a Kunitz-type proteinase inhibitor from the sea anemone Stichodactyla helianthus.
The solution structure of a 55-amino-acid Kunitz-type proteinase inhibitor, ShPI, purified from the Caribbean sea anemone Stichodactyla helianthus, was determined by NMR spectroscopy. Nearly complete sequence-specific 1H-NMR assignments were obtained at pH 4.6 and 36 degrees C, and stereo-specific assignments were determined for 23 pairs of diastereotopic substituents. A data set of 666 upper distance limit constraints and 122 dihedral angle constraints collected on this basis was used as input for a structure calculation with the program DIANA. Following energy minimization with the program OPAL, the average root-mean-square diviation (RMSD) of the 20 DIANA conformers used to represent the solution structure relative to the mean structure is 61 pm for all backbone atoms N, C alpha and C', and 106 pm for all heavy atoms of residues 2-53. This high-quality solution structure of ShPI has a nearly identical molecular architecture as the bovine pancreatic trypsin inhibitor (BPTI), despite a mere 35% of sequence similarity between the two proteins. Exchange rates measured for 48 out of the 51 backbone amide protons showed that the positions of 20 slowly exchanging amide protons correlate well with hydrogen bonds involving these protons in the energy-minimized solution structure. The solution structure of ShPI is compared to the four homologous proteins for which the three-dimensional structure is also available.


Maintenance of the human malarial parasite, Plasmodium falciparum, in scid mice and transmission of gametocytes to mosquitoes.
The study of human malaria has been hampered by the lack of small animal models for the human-infecting malarial parasites. To approach this problem, the erythrocytic stages of the human malarial parasite Plasmodium falciparum were adapted to in vitro growth in the presence of ascites fluid from mice homozygous for the severe-combined immunodeficiency (scid) mutation. Human red blood cells (hRBCs) infected with these adapted parasites were then injected i.p. into nonobese diabetic scid/scid (NOD/LtSz-scid) mice. With daily supplemental intraperitoneal boosts of uninfected hRBCs, parasites were detected in the peripheral circulation of these mice for an average of 7 d after injection. Splenectomy of NOD/LtSz-scid mice increased both the level and duration of parasitemia in the periphery, and it also promoted the circulation of mature sexual stage parasites (gametocytes). When Anopheline mosquitoes were allowed to feed on the splenectomized mice, the gametocytes were ingested by the mosquitoes and developed into oocysts in the mosquito midguts. To our knowledge, these results are the first demonstration of human malarial parasite propagation in mice and transmission of these parasites to the invertebrate vector.


Strong dichroic emission in the pseudo one dimensional material ZrS3.
Zirconium trisulphide (ZrS3), a member of the layered transition metal trichalcogenides (TMTCs) family, has been studied by angle-resolved photoluminescence spectroscopy (ARPLS). The synthesized ZrS3 layers possess a pseudo one-dimensional nature where each layer consists of ZrS3 chains extending along the b-lattice direction. Our results show that the optical properties of few-layered ZrS3 are highly anisotropic as evidenced by large PL intensity variation with the polarization direction. Light is efficiently absorbed when the E-field is polarized along the chain (b-axis), but the field is greatly attenuated and absorption is reduced when it is polarized vertical to the 1D-like chains as the wavelength of the exciting light is much longer than the width of each 1D chain. The observed PL variation with polarization is similar to that of conventional 1D materials, i.e., nanowires, and nanotubes, except for the fact that here the 1D chains interact with each other giving rise to a unique linear dichroism response that falls between the 2D (planar) and 1D (chain) limit. These results not only mark the very first demonstration of PL polarization anisotropy in 2D systems, but also provide novel insight into how the interaction between adjacent 1D-like chains and the 2D nature of each layer influences the overall optical anisotropy of pseudo-1D materials. Results are anticipated to have an impact on optical technologies such as polarized detectors, near-field imaging, communication systems, and bio-applications relying on the generation and detection of polarized light.


Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito.
The Ca(2+)-independent transient outward K(+) current (I(to)) plays an important electrophysiological role in normal and diseased hearts. However, its contribution to ventricular repolarization remains controversial because of differences in its phenotypic expression and function across species. The dog, a frequently used model of human cardiac disease, exhibits altered functional expression of I(to). To better understand the relevance of electrical remodeling in dogs to humans, we studied the phenotypic differences in ventricular I(to) of both species with electrophysiological, pharmacological, and protein-chemical techniques. Several notable distinctions were elucidated, including slower current decay, more rapid recovery from inactivation, and a depolarizing shift of steady-state inactivation in human vs. canine I(to). Whereas recovery from inactivation of human I(to) followed a monoexponential time course, canine I(to) recovered with biexponential kinetics. Pharmacological sensitivity to flecainide was markedly greater in human than canine I(to), and exposure to oxidative stress did not alter the inactivation kinetics of I(to) in either species. Western blot analysis revealed immunoreactive bands specific for Kv4.3, Kv1.4, and Kv channel-interacting protein (KChIP)2 in dog and human, but with notable differences in band sizes across species. We report for the first time major variations in phenotypic properties of human and canine ventricular I(to) despite the presence of the same subunit proteins in both species. These data suggest that differences in electrophysiological and pharmacological properties of I(to) between humans and dogs are not caused by differential expression of the K channel subunit genes thought to encode I(to), but rather may arise from differences in molecular structure and/or posttranslational modification of these subunits.


COVID-19 and Amazonia: Rights-based approaches for the pandemic response.
COVID-19 has shed light on humanity's interconnectedness with nature. The protection of biodiversity is essential to prevent future pandemics and protect human health. With rising deforestation levels, the Amazon basin is a centre stage in this debate. Lacking a regional strategy to protect the rainforest, Amazon countries are failing to protect their rich biodiversity. The transboundary effects of Amazonia's destruction are often overlooked. Simultaneously, the COVID-19 pandemic shows how cooperation between states is more critical than ever. This article examines how Amazon countries have jointly addressed the pandemic, demonstrating the effectiveness of regional agreements and their role in pandemic prevention. The right to a healthy environment is central to this investigation, given the role of forests and biodiversity in preventing zoonotic diseases. This article thus asks: What are the duties of States to protect the environment and indigenous communities during COVID-19 and potentially future pandemics? In this context, it considers the developing jurisprudence of the Inter-American System of Human Rights and its potential effects on regional and national implementation of environmental obligations.


Protocol for audit of current Filipino practice in rehabilitation of stroke inpatients.
Stroke is one of the leading medical conditions in the Philippines. Over 500,000 Filipinos suffer from stroke annually. Provision of evidence-based medical and rehabilitation management for stroke patients has been a challenge due to existing environmental, social, and local health system issues. Thus, existing western guidelines on stroke rehabilitation were contextualized to draft recommendations relevant to the local Philippine setting. Prior to fully implementing the guidelines, an audit of current practice needs to be undertaken, thus the purpose of this audit protocol. A clinical audit of current practices in stroke rehabilitation in the Philippines will be undertaken. A consensus list of data items to be captured was identified by the audit team during a 2-day meeting in 2012. These items, including patient demographics, type of stroke, time to referral for rehabilitation management, length of hospital stay, and other relevant descriptors of stroke management were included as part of the audit. Hospitals in the Philippines will be recruited to take part in the audit activity. Recruitment will be via the registry of the Philippine Academy of Rehabilitation Medicine, where 90% of physiatrists (medical doctors specialized in rehabilitation medicine) are active members and are affiliated with various hospitals in the Philippines. Data collectors will be identified and trained in the audit process. A pilot audit will be conducted to test the feasibility of the audit protocol, and refinements to the protocol will be undertaken as necessary. The comprehensive audit process will take place for a period of 3 months. Data will be encoded using MS Excel(®). Data will be reported as means and percentages as appropriate. Subgroup analysis will be undertaken to look into differences and variability of stroke patient descriptors and rehabilitation activities. This audit study is an ambitious project, but given the "need" to conduct the audit to identify "gaps" in current practice, and the value it can bring to serve as a platform for implementation of evidence-based stroke management in the Philippines to achieve best patient and health outcomes, the audit team is more than ready to take up the challenge.


An observational study of ballooning in large spiders: Nanoscale multifibers enable large spiders' soaring flight.
The physical mechanism of aerial dispersal of spiders, "ballooning behavior," is still unclear because of the lack of serious scientific observations and experiments. Therefore, as a first step in clarifying the phenomenon, we studied the ballooning behavior of relatively large spiders (heavier than 5 mg) in nature. Additional wind tunnel tests to identify ballooning silks were implemented in the laboratory. From our observation, it seems obvious that spiders actively evaluate the condition of the wind with their front leg (leg I) and wait for the preferable wind condition for their ballooning takeoff. In the wind tunnel tests, as-yet-unknown physical properties of ballooning fibers (length, thickness, and number of fibers) were identified. Large spiders, 16-20 mg Xysticus spp., spun 50-60 nanoscale fibers, with a diameter of 121-323 nm. The length of these threads was 3.22 ± 1.31 m (N = 22). These physical properties of ballooning fibers can explain the ballooning of large spiders with relatively light updrafts, 0.1-0.5 m s-1, which exist in a light breeze of 1.5-3.3 m s-1. Additionally, in line with previous research on turbulence in atmospheric boundary layers and from our wind measurements, it is hypothesized that spiders use the ascending air current for their aerial dispersal, the "ejection" regime, which is induced by hairpin vortices in the atmospheric boundary layer turbulence. This regime is highly correlated with lower wind speeds. This coincides well with the fact that spiders usually balloon when the wind speed is lower than 3 m s-1.


Heterogeneous hydrogenation of phenylalkynes with parahydrogen: hyperpolarization, reaction selectivity, and kinetics.
Parahydrogen-induced polarization (PHIP) is a powerful technique for studying hydrogenation reactions in gas and liquid phases. Pairwise addition of parahydrogen to the hydrogenation substrate imparts nuclear spin order to reaction products, manifested as enhanced 1H NMR signals from the nascent proton sites. Nanoscale metal catalysts immobilized on supports comprise a promising class of catalysts for producing PHIP effects; however, on such catalysts the percentage of substrates undergoing the pairwise addition route-a necessary condition for observing PHIP-is usually low. In this paper, we present a systematic study of several metal catalysts (Rh, Pt, Pd, and Ir) supported on TiO2 in liquid-phase hydrogenation of different prototypical phenylalkynes (phenylacetylene, 1-phenyl-1-propyne, and 3-phenyl-1-propyne) with parahydrogen. Catalyst activity and selectivity were found to be affected by both the nature of the active metal and the percentage of metal loading. It was demonstrated that the optimal catalyst for production of hyperpolarized products is Rh/TiO2 with 4 wt% metal loading, whereas Pd/TiO2 provided the greatest selectivity for semihydrogenation of phenylalkynes. In a study of liquid-phase hydrogenation reaction kinetics, it was shown that reaction order with respect to hydrogen is nearly the same for pairwise and non-pairwise H2 addition-consistent with a similar nature of the catalytically active sites for these reaction pathways.


Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome.
Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection (P = 0.0002) or in SCID foals (P < 0.0001). In contrast, the CU strain was able to persist despite significantly lower (P < 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion.IMPORTANCE Hepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain-specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host.


A case-control study on the effect of hormone replacement therapy on ischaemic heart disease.
Many clinicians believe that hormone replacement therapy (HRT) protects against coronary heart disease (CHD) in women. However, recent reports have cast some doubt on this because of lack of dose-response or duration-response effects. Since CHD is common in women--about half of all postmenopausal women will get it and about a third of these will die from it--the effect of HRT on CHD is of great public health importance. To determine the degree of cardioprotection conferred by HRT, including the effect of duration, time since last issue, the addition of progestogens, route of administration, and dose. Population-based case-control study. Nine general practices recruited from the Trent Focus Collaborative Research Network. A total of 417 female cases with CHD matched by age and practice to 2435 controls with a case-control ratio of 1:5.8 were studied. The main outcome measure was the odds ratio for CHD calculated by conditional logistic regression adjusted for diabetes, hypertension, body mass index, and smoking. No evidence was found, either from univariate analysis or multivariate analysis, that use of HRT was associated with reduced risk of CHD (odds ratio = 1.32; 95% confidence interval = 0.93 to 1.87). Indeed, the trend was in the opposite direction. There was no association for different types of HRT (opposed or unopposed) or routes of administration. Similarly, there was no association for current or past use and no effect for dose or duration. This study adds to growing evidence that HRT does not confer cardioprotection. Until there is robust evidence to the contrary, general physicians need to assess risks and benefits of HRT independently of any possible reduction in risk of CHD.


Idiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience.
To determine clinical features, natural history, and outcome of a well-defined cohort of 25 consecutive patients with idiopathic systemic capillary leak syndrome (SCLS) evaluated at a tertiary care center. Records of patients diagnosed as having SCLS from November 1, 1981, through April 30, 2008, were reviewed. Descriptive statistics were used to analyze patient demographics, clinical features, complications, and therapeutic interventions. Of the 34 patients whose records were reviewed, 25 fulfilled all diagnostic criteria for SCLS. The median age at diagnosis of SCLS was 44 years. Median follow-up of surviving patients was 4.9 years, and median time to diagnosis from symptom onset was 1.1 years (interquartile range, 0.5-4.1 years). Flulike illness or myalgia was reported by 14 patients (56%) at onset of an acute attack of SCLS, and rhabdomyolysis developed in 9 patients (36%). Patients with a greater decrease in albumin level had a higher likelihood of developing rhabdomyolysis (p=.03). Monoclonal gammopathy, predominantly of the IgG-κ type, was found in 19 patients (76%). The progression rate to multiple myeloma was 0.7% per person-year of follow-up. The overall response rate to the different therapies was 76%, and 24% of patients sustained durable (>2 years) complete remission. The estimated 5-year overall survival rate was 76% (95% confidence interval, 59%-97%). Systemic capillary leak syndrome, a rare disease that occurs in those of middle age, is usually diagnosed after a considerable delay from onset of symptoms. The degree of albumin decrement during an attack correlates with development of rhabdomyolysis. A reduction in the frequency and/or the severity of attacks was seen in nearly three-fourths of patients who were offered empirical therapies. The rate of progression to multiple myeloma appears to be comparable to that of monoclonal gammopathy of undetermined significance.


Trends in Deep Learning for Property-driven Drug Design.
It is more pressing than ever to reduce the time and costs for the development of lead compounds in the pharmaceutical industry. The co-occurrence of advances in high-throughput screening and the rise of deep learning (DL) have enabled the development of large-scale multimodal predictive models for virtual drug screening. Recently, deep generative models have emerged as a powerful tool to explore the chemical space and raise hopes to expedite the drug discovery process. Following this progress in chemocentric approaches for generative chemistry, the next challenge is to build multimodal conditional generative models that leverage disparate knowledge sources when mapping biochemical properties to target structures. Here, we call the community to bridge drug discovery more closely with systems biology when designing deep generative models. Complementing the plethora of reviews on the role of DL in chemoinformatics, we specifically focus on the interface of predictive and generative modelling for drug discovery. Through a systematic publication keyword search on PubMed and a selection of preprint servers (arXiv, biorXiv, chemRxiv, and medRxiv), we quantify trends in the field and find that molecular graphs and VAEs have become the most widely adopted molecular representations and architectures in generative models, respectively. We discuss progress on DL for toxicity, drug-target affinity, and drug sensitivity prediction and specifically focus on conditional molecular generative models that encompass multimodal prediction models. Moreover, we outline future prospects in the field and identify challenges such as the integration of deep learning systems into experimental workflows in a closed-loop manner or the adoption of federated machine learning techniques to overcome data sharing barriers. Other challenges include, but are not limited to interpretability in generative models, more sophisticated metrics for the evaluation of molecular generative models, and, following up on that, community-accepted benchmarks for both multimodal drug property prediction and property-driven molecular design.


Testing the influence of musical expertise on novel word learning across the lifespan using a cross-sectional approach in children, young adults and older adults.
Word learning is a multifaceted perceptual and cognitive task that is omnipresent in everyday life. Currently, it is unclear whether this ability is influenced by age, musical expertise or both variables. Accordingly, we used EEG and compared behavioral and electrophysiological indices of word learning between older adults with and without musical expertise (older adults' perspective) as well as between musically trained and untrained children, young adults, and older adults (lifespan perspective). Results of the older adults' perspective showed that the ability to learn new words is preserved in elderly, however, without a beneficial influence of musical expertise. Otherwise, results of the lifespan perspective revealed lower error rates and faster reaction times in young adults compared to children and older adults. Furthermore, musically trained children and young adults outperformed participants without musical expertise, and this advantage was accompanied by EEG manifestations reflecting faster learning and neural facilitation in accessing lexical-semantic representations.


Information use in space and time: sex allocation behaviour in the parasitoid wasp Nasonia vitripennis.
Behavioural decisions require the appropriate use of relevant information about the environment. However, individuals may have imperfect information, imposing a constraint on adaptive behaviour. We explored how information use influences the sex allocation behaviour of the parasitoid wasp Nasonia vitripennis in response to local mate competition. Optimal sex ratios under local mate competition require females to estimate the number of other females that contribute eggs to a patch. Females rapidly changed their sex allocation in response to changes in the number of females in the environment, suggesting that they are not constrained by how quickly they can respond to new information. Furthermore, females also showed some response to olfactory cues that indicated oviposition by other females, suggesting that such indirect cues may be part of their information repertoire. Both the absolute and the relative size of the patch were important for sex ratio decisions, with sex ratios declining on larger patches in a way that suggests that large patches in effect become more than one patch, with females on larger patches allocating sex increasingly independently of other females. We conclude by highlighting variation among species in whether particular cues are used for sex allocation.


Assesment of protein gene product (pgp9.5) enzyme activity against potential Peptide substrate.
PGP9.5 is a human neuron specific ubiquitin carboxyl-terminal hydolase that has been shown by immunuhistochemistry to be present selectively in ubiquitinated inclusions in chronic human degenerative disease. Paraffin sections known to contain ubiquitinprotein conjugate immunureactivity in neurofibrillary tangles (NFT), cortical Lewy bodies, Rosenthal fibres and in Pick bodies were immunostained with PGP9.5. In Alzheimer's disease loosely arranged globose-type neurofibrillary tangles (NFTs) were immunostained together with neuritis surrounding senile plaques (SP). While PGP9.5 has been demonstrated to have ubiquitin carboxy-terminal ethyl esterase activity, there has not been clear identification of its substrate specificity. The main aim was, therefore, to purify PGP9.5 and study its carboxyl-terminal hydrolase activity using, as substrates, synthetic peptides that were chosen to reflect the known possible functions of the enzyme. Ubiquitin is cleaved from conjugates by ubiquitin carboxyl-terminal hydrolases, one of which is protein gene product 9.5 (PGP 9.5). PGP9.5 was purified to homogeneity from human post-mortem brain tissue, its identity confirmed by protein sequence determination. Potential peptide substrates were incubated with PGP 9.5 and assayed by HPLC. Overlap region of ubiquitin in branched gene products were not substrates. Evidence was obtained for cleavage of linearly-conjugated polyubiquitin. Degradation of abnormal proteins by ubiquitin system depends on binding structure of ubiquitins. It has been shown that only linear ubiquitis are substrate for the PGP 9.5. The importance of it is not well understood.


Sperm DNA methylation changes after short-term nut supplementation in healthy men consuming a Western-style diet.
Many environmental and lifestyle factors have been implicated in the decline of sperm quality, with diet being one of the most plausible factors identified in recent years. Moreover, several studies have reported a close association between the alteration of specific sperm DNA methylation signatures and semen quality. To evaluate the effect of tree nut consumption on sperm DNA methylation patterns in healthy individuals reporting eating a Western-style diet. This is a post hoc analysis conducted in a subset of participants (healthy, non-smoking, and young) from the FERTINUTS 14-wk randomized-controlled, parallel trial, recruited between December 2015 and February 2017. The participants included in the current study (n = 72) were randomly selected in a proportion 2:1 from the original FERTINUTS trial between the 98 participants that completed the entire dietary intervention (nut group, n = 48; control group, n = 24). Sperm DNA methylation patterns were examined at baseline and after 14 weeks in 48 individuals consuming 60 g/d of mixed nuts (nut group) and in 24 individuals following the usual Western-style diet avoiding consumption of nuts (control group). Over the course of the trial, no significant changes in global methylation were observed between groups. However, in the nut group, we identified 36 genomic regions that were significantly differentially methylated between the baseline and the end of the trial and 97.2% of the regions displayed hypermethylation. We identified no such change in the control group over the same period of time. We also utilized the recently developed germ line age calculator to determine if nut consumption resulted in alterations to the epigenetic age of cells and no significant differences were found. Adding nuts to a regular Western-style diet subtly impacts sperm DNA methylation in specific regions, demonstrating that there are some sperm epigenome regions that could respond to diet.


An analysis of Australian graduate critical care nurse education.
Preparation of specialist critical care nurses in Australia is at graduate level, although there remains considerable variation in courses offered in relation to qualification, content, assessment and outcomes. As higher education providers must now comply with the Australian Qualifications Framework (AQF) a study was conducted to examine existing critical care courses and graduate practice outcomes. Twenty-two critical care courses were reviewed. Data sources included course provider, websites, course curricula and telephone interviews with course coordinators. A framework approach, was used consisting of five key stages: preliminary immersion of raw data, conceptualising a thematic framework, indexing, charting, mapping and interpretation of data. Analysis revealed considerable variations in course delivery and graduate practice outcomes. Most courses used professional competency standards as a framework for course curricula and clinical assessment, with inconsistency in their translation to graduate practice outcomes. Twenty-one courses included clinical assessment at graduate certificate level with no clinical assessment conducted at master level. The expected practice outcome for fifteen courses was safe practice with graduates not expected to practice at a specialist or team leadership level. Minimum graduate practice standards were not included in three courses as an expected outcome. The AQF requires graduate nurse education to be compliant with academic outcome standards. The findings of our study indicate variations between courses and subsequent graduate practice outcomes. It is therefore timely to establish national critical care education graduate practice standards.


Seasonal forecasting of green water components and crop yields of winter wheat in Serbia and Austria.
A probabilistic crop forecast based on ensembles of crop model output (CMO) estimates offers a myriad of possible realizations and probabilistic forecasts of green water components (precipitation and evapotranspiration), crop yields and green water footprints (GWFs) on monthly or seasonal scales. The present paper presents part of the results of an ongoing study related to the application of ensemble forecasting concepts for agricultural production. The methodology used to produce the ensemble CMO using the ensemble seasonal weather forecasts as the crop model input meteorological data without the perturbation of initial soil or crop conditions is presented and tested for accuracy, as are its results. The selected case study is for winter wheat growth in Austria and Serbia during the 2006-2014 period modelled with the SIRIUS crop model. The historical seasonal forecasts for a 6-month period (1 March-31 August) were collected for the period 2006-2014 and were assimilated from the European Centre for Medium-range Weather Forecast and the Meteorological Archival and Retrieval System. The seasonal ensemble forecasting results obtained for winter wheat phenology dynamics, yield and GWF showed a narrow range of estimates. These results indicate that the use of seasonal weather forecasting in agriculture and its applications for probabilistic crop forecasting can optimize field operations (e.g., soil cultivation, plant protection, fertilizing, irrigation) and takes advantage of the predictions of crop development and yield a few weeks or months in advance.


Complete Genome Sequence of the Wolbachia wAlbB Endosymbiont of Aedes albopictus.
Wolbachia, an alpha-proteobacterium closely related to Rickettsia, is a maternally transmitted, intracellular symbiont of arthropods and nematodes. Aedes albopictus mosquitoes are naturally infected with Wolbachia strains wAlbA and wAlbB. Cell line Aa23 established from Ae. albopictus embryos retains only wAlbB and is a key model to study host-endosymbiont interactions. We have assembled the complete circular genome of wAlbB from the Aa23 cell line using long-read PacBio sequencing at 500× median coverage. The assembled circular chromosome is 1.48 megabases in size, an increase of more than 300 kb over the published draft wAlbB genome. The annotation of the genome identified 1,205 protein coding genes, 34 tRNA, 3 rRNA, 1 tmRNA, and 3 other ncRNA loci. The long reads enabled sequencing over complex repeat regions which are difficult to resolve with short-read sequencing. Thirteen percent of the genome comprised insertion sequence elements distributed throughout the genome, some of which cause pseudogenization. Prophage WO genes encoding some essential components of phage particle assembly are missing, while the remainder are found in five prophage regions/WO-like islands or scattered around the genome. Orthology analysis identified a core proteome of 535 orthogroups across all completed Wolbachia genomes. The majority of proteins could be annotated using Pfam and eggNOG analyses, including ankyrins and components of the Type IV secretion system. KEGG analysis revealed the absence of five genes in wAlbB which are present in other Wolbachia. The availability of a complete circular chromosome from wAlbB will enable further biochemical, molecular, and genetic analyses on this strain and related Wolbachia.


Avoiding hospital admission through provision of hospital care at home: a systematic review and meta-analysis of individual patient data.
Avoidance of admission through provision of hospital care at home is a scheme whereby health care professionals provide active treatment in the patient's home for a condition that would otherwise require inpatient treatment in an acute care hospital. We sought to compare the effectiveness of this method of caring for patients with that type of in-hospital care. We searched the MEDLINE, EMBASE, CINAHL and EconLit databases and the Cochrane Effective Practice and Organisation of Care Group register from the earliest date in each database until January 2008. We included randomized controlled trials that evaluated a service providing an alternative to admission to an acute care hospital. We excluded trials in which the program did not offer a substitute for inpatient care. We performed meta-analyses for trials for which the study populations had similar characteristics and for which common outcomes had been measured. We included 10 randomized trials (with a total of 1327 patients) in our systematic review. Seven of these trials (with a total of 969 patients) were deemed eligible for meta-analysis of individual patient data, but we were able to obtain data for only 5 of these trials (with a total of 844 patients [87%]). There was no significant difference in mortality at 3 months for patients who received hospital care at home (adjusted hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54-1.09, p = 0.15). However, at 6 months, mortality was significantly lower for these patients (adjusted HR 0.62, 95% CI 0.45-0.87, p = 0.005). Admissions to hospital were greater, but not significantly so, for patients receiving hospital care at home (adjusted HR 1.49, 95% CI 0.96-2.33, p = 0.08). Patients receiving hospital care at home reported greater satisfaction than those receiving inpatient care. These programs were less expensive than admission to an acute care hospital ward when the analysis was restricted to treatment actually received and when the costs of informal care were excluded. For selected patients, avoiding admission through provision of hospital care at home yielded similar outcomes to inpatient care, at a similar or lower cost.


Amphiregulin-producing γδ T cells are vital for safeguarding oral barrier immune homeostasis.
γδ T cells are enriched at barrier sites such as the gut, skin, and lung, where their roles in maintaining barrier integrity are well established. However, how these cells contribute to homeostasis at the gingiva, a key oral barrier and site of the common chronic inflammatory disease periodontitis, has not been explored. Here we demonstrate that the gingiva is policed by γδ T cells with a T cell receptor (TCR) repertoire that diversifies during development. Gingival γδ T cells accumulated rapidly after birth in response to barrier damage, and strikingly, their absence resulted in enhanced pathology in murine models of the oral inflammatory disease periodontitis. Alterations in bacterial communities could not account for the increased disease severity seen in γδ T cell-deficient mice. Instead, gingival γδ T cells produced the wound healing associated cytokine amphiregulin, administration of which rescued the elevated oral pathology of tcrδ-/- mice. Collectively, our results identify γδ T cells as critical constituents of the immuno-surveillance network that safeguard gingival tissue homeostasis.


Two-Step In Vitro Model to Evaluate the Cellular Immune Response to SARS-CoV-2.
The cellular immune response plays an important role in COVID-19, caused by SARS-CoV-2. This feature makes use of in vitro models' useful tools to evaluate vaccines and biopharmaceutical effects. Here, we developed a two-step model to evaluate the cellular immune response after SARS-CoV-2 infection-induced or spike protein stimulation in peripheral blood mononuclear cells (PBMC) from both unexposed and COVID-19 (primo-infected) individuals (Step1). Moreover, the supernatants of these cultures were used to evaluate its effects on lung cell lines (A549) (Step2). When PBMC from the unexposed were infected by SARS-CoV-2, cytotoxic natural killer and nonclassical monocytes expressing inflammatory cytokines genes were raised. The supernatant of these cells can induce apoptosis of A549 cells (mock vs. Step2 [mean]: 6.4% × 17.7%). Meanwhile, PBMCs from primo-infected presented their memory CD4+ T cells activated with a high production of IFNG and antiviral genes. Supernatant from past COVID-19 subjects contributed to reduce apoptosis (mock vs. Step2 [ratio]: 7.2 × 1.4) and to elevate the antiviral activity (iNOS) of A549 cells (mock vs. Step2 [mean]: 31.5% × 55.7%). Our findings showed features of immune primary cells and lung cell lines response after SARS-CoV-2 or spike protein stimulation that can be used as an in vitro model to study the immunity effects after SARS-CoV-2 antigen exposure.


Pyrethroids differentially alter voltage-gated sodium channels from the honeybee central olfactory neurons.
The sensitivity of neurons from the honey bee olfactory system to pyrethroid insecticides was studied using the patch-clamp technique on central 'antennal lobe neurons' (ALNs) in cell culture. In these neurons, the voltage-dependent sodium currents are characterized by negative potential for activation, fast kinetics of activation and inactivation, and the presence of cumulative inactivation during train of depolarizations. Perfusion of pyrethroids on these ALN neurons submitted to repetitive stimulations induced (1) an acceleration of cumulative inactivation, and (2) a marked slowing of the tail current recorded upon repolarization. Cypermethrin and permethrin accelerated cumulative inactivation of the sodium current peak in a similar manner and tetramethrin was even more effective. The slow-down of channel deactivation was markedly dependent on the type of pyrethroid. With cypermethrin, a progressive increase of the tail current amplitude along with successive stimulations reveals a traditionally described use-dependent recruitment of modified sodium channels. However, an unexpected decrease in this tail current was revealed with tetramethrin. If one considers the calculated percentage of modified channels as an index of pyrethroids effects, ALNs are significantly more susceptible to tetramethrin than to permethrin or cypermethrin for a single depolarization, but this difference attenuates with repetitive activity. Further comparison with peripheral neurons from antennae suggest that these modifications are neuron type specific. Modeling the sodium channel as a multi-state channel with fast and slow inactivation allows to underline the effects of pyrethroids on a set of rate constants connecting open and inactivated conformations, and give some insights to their specificity. Altogether, our results revealed a differential sensitivity of central olfactory neurons to pyrethroids that emphasize the ability for these compounds to impair detection and processing of information at several levels of the bees olfactory pathway.


Lactogenic and somatogenic hormones regulate the expression of neuropeptide Y and cocaine- and amphetamine-regulated transcript in rat insulinoma (INS-1) cells: interactions with glucose and glucocorticoids.
Lactogenic hormones stimulate food intake in rodents, ungulates, and birds. To test the hypothesis that lactogens regulate expression of neuropeptides that control appetite, we used the prolactin (PRL)-responsive rat insulinoma (INS-1) cell line as an experimental paradigm. INS-1 cells express mRNA for neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) but little or no agouti-related peptide or proopiomelanocortin. As in the hypothalamus in vivo, the levels of NPY mRNA in INS-1 cells were increased by glucose deprivation. Conversely, high media glucose concentrations (11 mm) reduced the levels of NPY mRNA and increased levels of CART mRNA. Rat PRL stimulated a 4- to 7-fold increase in NPY mRNA in INS-1 cells (P < 0.001) and reduced by 50-80% the levels of CART mRNA (P < 0.001). The effects of PRL on NPY mRNA were time and dose dependent and potentiated by glucose deprivation or exogenous dexamethasone (Dex). Hormonal induction of NPY mRNA was accompanied by increased secretion of NPY peptide into cellular conditioned media. PRL stimulated a 1.8- to 3.5-fold increase in expression of AMP-activated protein kinase (AMPK), which mediates in part the effects of hypoglycemia on NPY expression in the hypothalamus in vivo. Pharmacological inhibition of AMPK activity blunted slightly the effects of PRL on NPY and CART but reversed entirely the effects of Dex or of PRL plus Dex on CART mRNA. The effects of PRL on NPY, CART, and AMPK mRNA were mirrored by those of other lactogens and somatogens including placental lactogen and GH. Rat PRL and rat GH in combination had no additive or synergistic effects, suggesting that lactogenic and somatogenic hormones regulate neuropeptide gene expression through similar mechanisms. We conclude that lactogens act in concert with glucose deprivation and glucocorticoids to induce NPY expression and inhibit CART. We speculate that the lactogens facilitate food intake in response to fasting or nutrient deprivation, when glucose levels decline and cortisol levels rise.


A Guanidine-Based Synthetic Compound Suppresses Angiogenesis via Inhibition of Acid Ceramidase.
Angiogenesis generates new blood vessels from pre-existing vessels. Tumors induce the formation of new blood vessels to ensure sufficient oxygen and nutrients for their growth. Normally, angiogenesis is induced by various pro-angiogenesis factors, including vascular endothelial growth factor (VEGF). Inhibition of VEGF is a promising approach to cancer treatment. A guanidine-based synthetic compound, E2, was identified as a potent hit from 68 guanidine-based derivatives by screening for angiogenesis inhibitors showing antiproliferative activity in human umbilical vein endothelial cells (HUVECs). To explore the mode of action of E2, target proteins were investigated using phage display biopanning, and acid ceramidase 1 (ASAH1) was identified as an E2-binding protein. Drug affinity responsive target stability (DARTS) and ASAH1 activity assays revealed the direct binding of E2 to ASAH1. Moreover, siRNA knockdown of ASAH1 demonstrated its role as an angiogenesis factor. Consequently, E2 inhibited chemoinvasion and tube formation of HUVECs in a dose-dependent manner. E2 also potently suppressed neo-vascularization of chorioallantoic membranes in vivo. Collectively, these data suggest that E2 is a novel angiogenesis inhibitor and ASAH1 is proposed to be a new antiangiogenesis target.


CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors.
Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b. Previous studies have reported shank3 morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of shank3b mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. CRISPR/Cas9 was applied to generate a shank3b loss-of-function mutation (shank3b-/- ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in shank3b mutant zebrafish. shank3b-/- zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of shank3b-deficient zebrafish. We generated the first inheritable shank3b mutant zebrafish model using CRISPR/Cas9 gene editing approach. shank3b-/- zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human SHANK3 function and ASD.


Promoting LGBT health and wellbeing through inclusive policy development.
In this paper we argue the importance of including gender and sexually diverse populations in policy development towards a more inclusive form of health promotion. We emphasize the need to address the broad health and wellbeing issues and needs of LGBT people, rather than exclusively using an illness-based focus such as HIV/AIDS. We critically examine the limitations of population health, the social determinants of health (SDOH), and public health goals, in light of the lack of recognition of gender and sexually diverse individuals and communities. By first acknowledging the unique health and social care needs of LGBT people, then employing anti-oppressive, critical and intersectional analyses we offer recommendations for how to make population health perspectives, public health goals, and the design of public health promotion policy more inclusive of gender and sexual diversity. In health promotion research and practice, representation matters. It matters which populations are being targeted for health promotion interventions and for what purposes, and it matters which populations are being overlooked. In Canada, current health promotion policy is informed by population health and social determinants of health (SDOH) perspectives, as demonstrated by Public Health Goals for Canada. With Canada's multicultural makeup comes the challenge of ensuring that diverse populations are equitably and effectively recognized in public health and health promotion policy.


Volatile Drosophila cuticular pheromones are affected by social but not sexual experience.
Recognition of conspecifics and mates is based on a variety of sensory cues that are specific to the species, sex and social status of each individual. The courtship and mating activity of Drosophila melanogaster flies is thought to depend on the olfactory perception of a male-specific volatile pheromone, cis-vaccenyl acetate (cVA), and the gustatory perception of cuticular hydrocarbons (CHs), some of which are sexually dimorphic. Using two complementary sampling methods (headspace Solid Phase Micro-Extraction [SPME] and solvent extraction) coupled with GC-MS analysis, we measured the dispersion of pheromonal CHs in the air and on the substrate around the fly. We also followed the variations in CHs that were induced by social and sexual interactions. We found that all CHs present on the fly body were deposited as a thin layer on the substrate, whereas only a few of these molecules were also detected in the air. Moreover, social experience during early adult development and in mature flies strongly affected male volatile CHs but not cVA, whereas sexual interaction only had a moderate influence on dispersed CHs. Our study suggests that, in addition to their role as contact cues, CHs can influence fly behavior at a distance and that volatile, deposited and body pheromonal CHs participate in a three-step recognition of the chemical identity and social status of insects.


Importance effects on age differences in performance in event-based prospective memory.
Most laboratory-based studies on prospective memory show a decline with increasing age. Theoretical explanations for age differences focus on the allocation of attentional resources to support prospective remembering. The recruitment of prospective memory target monitoring seems to be influenced by perceived task importance. In the present study, we investigated the influence of task importance on the magnitude of age differences in event-based prospective memory. Healthy younger (n = 25) and older (n = 25) adults were instructed a priori to prioritize either the ongoing or the prospective memory task before performing an event-based prospective memory task. We found an interaction between age and task importance: instructed higher importance of the ongoing task compared to the prospective memory task component produced significant age-related declines in prospective remembering. By contrast, if older adults treated the prospective memory task component as more important than the ongoing task, they achieved equivalent levels of prospective memory performance as their younger counterparts, but did so at a cost to ongoing task performance. The present data indicate that task importance is one of the factors determining the presence or absence of age deficits in prospective remembering. Findings are discussed in the context of limited processing resources in old age and theoretical frameworks of event-based prospective memory. © 2013 S. Karger AG, Basel.


A systematic review of prognostic factors for return to work following work-related traumatic hand injury.
Systematic review. Traumatic hand injuries are frequent cause of work related injuries and can result in prolonged durations of time loss from work. To systematically review available evidence to determine which prognostic factors predict return-to-work (RTW) following work-related traumatic hand injuries. We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO from 1980 to September 2013 and reference lists of articles. Studies investigating any prognostic factors of RTW after traumatic hand injury were included. Two reviewers performed study selection, assessment of methodological quality and data extraction independently of each other. Identified factors were grouped into conceptual prognostic factor categories. We assessed 8 studies, which addressed 11 potential prognostic factors (i.e., sociodemographic factors, occupation, work compensation status, treatment related factors, impairment severity, location of injury, etc.). The quality of the studies was low to moderate. Across all included studies, RTW (original or modified work) occurred in over 60% of individuals by 6 months. There was consistent low-moderate quality evidence that individuals with more severe impairments and lower pre-injury income were less likely to RTW, and low-moderate quality evidence that age, gender and level of education had no impact on RTW. Evidence on other commonly cited prognostic factors were limited in the literature. Impairment severity and lower pre-injury income showed a consistent association with RTW following occupational hand injury, while other factors demonstrated no or variable effects across studies. Additional high-quality studies are warranted toward improving our understanding of the complex factors that mediate RTW following a traumatic work-related hand injury. 2a.


Development of a multiwavelength aerosol and water-vapor lidar at the Jungfraujoch Alpine Station (3580 m above sea level) in Switzerland.
The Jungfraujoch Research Station (46.55 degrees N, 7.98 degrees E, 3580 m above sea level) for decades has contributed in a significant manner to the systematic observation of the Earth's atmosphere both with in situ measurements and with trace gas column detection. We report on the development of a lidar system that improves the measurement potential of highly resolved atmospheric parameters in both time and space, with the goal of achieving long-term monitoring of atmospheric aerosol optical properties and water-vapor content. From the simultaneously detected elastic-backscatter signals at 355, 532, and 1064 nm, Raman signals from nitrogen at 387 and 607 nm, and water vapor at 408 nm, the aerosol extinction and backscatter coefficients at three wavelengths and a water-vapor mixing ratio are derived. Additional information about particle shape is obtained by depolarization measurements at 532 nm. Water-vapor measurements by use of both nitrogen and water-vapor Raman returns from the 355-nm laser beam are demonstrated with a vertical range resolution of 75 m and an integration time of 2 h. The comparison to the water-vapor profile derived from balloon measurements (Snow White technique) showed excellent agreement. The system design and the results obtained by its operation are reported.


Genetic control of branching pattern and floral identity during Petunia inflorescence development.
A main determinant of inflorescence architecture is the site where floral meristems are initiated. We show that in wild-type Petunia bifurcation of the inflorescence meristem yields two meristems of approximately equal size. One terminates into a floral meristem and the other maintains its inflorescence identity. By random transposon mutagenesis we have generated two mutants in which the architecture of the inflorescence is altered. In the extra petals- (exp) mutant the inflorescence terminates with the formation of a single terminal flower. Phenotypic analysis showed that exp is required for the bifurcation of inflorescence meristems. In contrast, the aberrant leaf and flower- (alf) mutant is affected in the specification of floral meristem identity while the branching pattern of the inflorescence remains unaltered. A weak alf allele was identified that, after bifurcation of the inflorescence meristem, yields a 'floral' meristem with partial inflorescence characteristics. By analysing independent transposon dTph1 insertion alleles we show that the alf locus encodes the Petunia FLORICAULA/LEAFY homolog. In situ hybridisation shows that alf is expressed in the floral meristem and also in the vegetative meristem. Differences and similarities between these Petunia mutants and mutations affecting inflorescence architecture in other species will be discussed.


Evaluation of tenogenic differentiation potential of selected subpopulations of human adipose-derived stem cells.
Identification of a suitable cell source and bioactive agents guiding cell differentiation towards tenogenic phenotype represents a prerequisite for advancement of cell-based therapies for tendon repair. Human adipose-derived stem cells (hASCs) are a promising, yet intrinsically heterogenous population with diversified differentiation capacities. In this work, we investigated antigenically-defined subsets of hASCs expressing markers related to tendon phenotype or associated with pluripotency that might be more prone to tenogenic differentiation, when compared to unsorted hASCs. Subpopulations positive for tenomodulin (TNMD+ hASCs) and stage specific early antigen 4 (SSEA-4+ hASCs), as well as unsorted ASCs were cultured up to 21 days in basic medium or media supplemented with TGF-β3 (10 ng/ml), or GDF-5 (50 ng/ml). Cell response was evaluated by analysis of expression of tendon-related markers at gene level and protein level by real time RT-PCR, western blot, and immunocytochemistry. A significant upregulation of scleraxis was observed for both subpopulations and unsorted hASCs in the presence of TGF-β3. More prominent alterations in gene expression profile in response to TGF-β3 were observed for TNMD+ hASCs. Subpopulations evidenced an increased collagen III and TNC deposition in basal medium conditions in comparison with unsorted hASCs. In the particular case of TNMD+ hASCs, GDF-5 seems to influence more the deposition of TNC. Within hASCs populations, discrete subsets could be distinguished offering varied sensitivity to specific biochemical stimulation leading to differential expression of tenogenic components suggesting that cell subsets may have distinctive roles in the complex biological responses leading to tenogenic commitment to be further explored in cell based strategies for tendon tissues.


Tracking chemical reactions on the surface of filamentous phage using mass spectrometry.
Chemical modification of phage libraries has allowed the in vitro evolution of ligands having properties not provided by natural polypeptides. The development of novel and more diverse chemical reactions on phage was hampered by the lack of analytical methods to efficiently monitor the reaction products on the more than 10 000 kDa large filamentous phage particles. Herein, we present a strategy to detect chemically modified peptides on phage based on enzymatic release of peptide from phage and mass spectrometry analysis.


Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons.
Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48-96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.


DNA methylation profiles of airway epithelial cells and PBMCs from healthy, atopic and asthmatic children.
Allergic inflammation is commonly observed in a number of conditions that are associated with atopy including asthma, eczema and rhinitis. However, the genetic, environmental or epigenetic factors involved in these conditions are likely to be different. Epigenetic modifications, such as DNA methylation, can be influenced by the environment and result in changes to gene expression. To characterize the DNA methylation pattern of airway epithelial cells (AECs) compared to peripheral blood mononuclear cells (PBMCs) and to discern differences in methylation within each cell type amongst healthy, atopic and asthmatic subjects. PBMCs and AECs from bronchial brushings were obtained from children undergoing elective surgery for non-respiratory conditions. The children were categorized as atopic, atopic asthmatic, non-atopic asthmatic or healthy controls. Extracted DNA was bisulfite treated and 1505 CpG loci across 807 genes were analyzed using the Illumina GoldenGate Methylation Cancer Panel I. Gene expression for a subset of genes was performed using RT-PCR. We demonstrate a signature set of CpG sites that are differentially methylated in AECs as compared to PBMCs regardless of disease phenotype. Of these, 13 CpG sites were specific to healthy controls, 8 sites were only found in atopics, and 6 CpGs were unique to asthmatics. We found no differences in the methylation status of PBMCs between disease phenotypes. In AECs derived from asthmatics compared to atopics, 8 differentially methylated sites were identified including CpGs in STAT5A and CRIP1. We demonstrate STAT5A gene expression is decreased whereas CRIP1 gene expression is elevated in the AECs from asthmatic compared to both healthy and atopic subjects. We characterized a cell specific DNA methylation signature for AECs compared to PBMCs regardless of asthmatic or atopic status. Our data highlight the importance of understanding DNA methylation in the epithelium when studying the epithelial contribution to asthma.


Cytotoxic effect of substitution at 2-, 6-, and 2,6-positions in ascorbic acid on malignant cell line.
In recent years L-ascorbic acid (AA) and its isomers have raised considerable interest as anticancer agents, although the mechanism has remained largely unknown. AA isomers are nearly identical in their physical and chemical properties but differ widely in their biological properties. AA, a lactone sugar, has a number of reactive positions, especially at 2- and 6-. Although there are a number of reports on the cytotoxic effect of AA and its isomers on malignant and nonmalignant cell lines, no work has been reported on the comparative effects of substitutions at these active sites. This study, then, investigates the comparative cytotoxicity of such substitutes on the malignant leukemia P388 cell line in culture. We tested a series of 2-, 6- and 2,6- disubstituted AA-derivatives, comprising the following: i) substitution at 2-position: -PO4, -SO4, O-Me, O-octadecyl; ii) substitution at 6-position: -PO4, -SO4, -palmitate, -stearate; and iii) substitution at 2,6-position: -dipalmitate. About 50,000 P388 cells/ml were incubated with and without AA derivatives in a final concentration of 1000, 500, 100, 10 and 1 microg/ml in triplicate and counted after 72 hrs. All 2-substituted and the 2,6-substituted AA derivatives tested were nontoxic and ineffective in preventing cell growth. In contrast, all 6-substituted AA derivatives were very toxic at all levels, even at the lowest concentration. These results suggest that substitution at 2-, 6- and 2,6-positions in AA have a different effect on toxicity. The 2-, and 2,6-substituted AA derivatives are stable compounds, resistant to hydrolysis which render them inactive. The cytotoxicity of the 6-substituted derivatives may be explained by one of the following mechanisms, yet to be explored: i) the hydrolysis rate may differ; or ii) the chemical structure itself may affect toxicity. Further studies are in progress to understand the mechanism.


Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database.
To test the hypothesis that exenatide twice daily reduces the relative incidence of cardiovascular disease (CVD) events among patients with type 2 diabetes compared with other glucose-lowering agent(s). A retrospective database analysis was performed of the LifeLink database of medical and pharmaceutical insurance claims for June 2005 through March 2009. Patients with no history in the preceding 9 months of myocardial infarction, ischemic stroke, or coronary revascularization procedure were assigned to the exenatide-initiated or non-exenatide-initiated cohorts based on the first new prescription filled and reassigned if exenatide was prescribed or discontinued. Incident CVD events (myocardial infarction, ischemic stroke, or coronary revascularization procedure) were identified by ICD-9-CM diagnosis codes. Patient outcomes were adjusted for differences in clinical and demographic characteristics and compared using propensity score-weighted discrete time survival analysis with time-varying exposure to exenatide. A total of 39,275 patients with type 2 diabetes were treated with exenatide twice daily, and 381,218 patients were treated with other glucose-lowering therapies. Patients who initiated exenatide were more likely to have prior ischemic heart disease, obesity, hyperlipidemia, hypertension, and/or other comorbidities at baseline. Exenatide-treated patients were less likely to have a CVD event than non-exenatide-treated patients (hazard ratio 0.81; 95% CI 0.68-0.95; P = 0.01) and lower rates of CVD-related hospitalization (0.88; 0.79-0.98; P = 0.02) and all-cause hospitalization (0.94; 0.91-0.97; P < 0.001). Exenatide twice-daily treatment was associated with a lower risk of CVD events and hospitalizations than treatment with other glucose-lowering therapies.


The impact of upright radiographs of midshaft clavicle fractures on treatment recommendations.
Clavicle fractures' treatment recommendations are based on displacement. The goal of this paper is to determine upright clavicle radiographs at initial presentation changes timing and method of treatment. Retrospective study in a level 1 trauma center. 356 patients with clavicle fractures were reviewed. Patients with only supine radiographs (Group 1, 285 patients) were compared to patients with supine and upright radiographs (Group 2, 71 patients). Higher proportion of fractures in the upright vs supine radiographs were displaced 100% or more of the clavicle width, (52.1% vs. 33.5%, p =0.004). Treatment assignment changed from nonoperative to operative treatment more commonly in the Group 2 compared to Group 1 (43.7% vs 21.9%, p =0.019). The most common reason for surgery in Group 1 was presence of continued pain or failure to develop radiographic evidence of callus on serial radiographs (17, 53.1%) as compared to Group 2 (2, 14.2%, p =0.014). In Group 2 the most common cause for treatment change was displacement (12, 85.7%) as compared to Group 1 (15, 46.9%, p =0.014). Patients with upright x-rays are more likely to have a change in treatment because of displacement while patients that had supine x-rays have more delayed/nonunion.


A study on the thermal conversion of scheelite-type ABO4 into perovskite-type AB(O,N)3.
Phase-pure scheelite AMoO4 and AWO4 (A = Ba, Sr, Ca) were thermally treated under an ammonia atmosphere at 400 to 900 °C. SrMoO4 and SrWO4 were shown to convert into cubic perovskite SrMoO2N and SrWO1.5N1.5, at 700 °C and 900 °C respectively, and to form metastable intermediate phases (scheelite SrMoO4-xNx and SrWO4-xNx), as revealed by X-ray diffraction (XRD), elemental analysis and FTIR spectroscopy. High-temperature oxide melt solution calorimetry reveals that the enthalpy of formation for SrM(O,N)3 (M = Mo, W) perovskites is less negative than that of the corresponding scheelite oxides, though the conversion of the scheelite oxides into perovskite oxynitrides is thermodynamically favorable at moderate temperatures. The reaction of BaMO4 with ammonia leads to the formation of rhombohedral Ba3M2(O,N)8 and the corresponding binary metal nitrides Mo3N2 and W4.6N4; similar behavior was observed for CaMO4, which converted upon ammonolysis into individual oxides and nitrides. Thus, BaMO4 and CaMO4 were shown to not provide access to perovskite oxynitrides. The influence of the starting scheelite oxide precursor, the structure distortion and the degree of covalency of the B-site-N bond are discussed within the context of the formability of perovskite oxynitrides.


Present-day African analogue of a pre-European Amazonian floodplain fishery shows convergence in cultural niche construction.
Erickson [Erickson CL (2000) Nature 408 (6809):190-193] interpreted features in seasonal floodplains in Bolivia's Beni savannas as vestiges of pre-European earthen fish weirs, postulating that they supported a productive, sustainable fishery that warranted cooperation in the construction and maintenance of perennial structures. His inferences were bold, because no close ethnographic analogues were known. A similar present-day Zambian fishery, documented here, appears strikingly convergent. The Zambian fishery supports Erickson's key inferences about the pre-European fishery: It allows sustained high harvest levels; weir construction and operation require cooperation; and weirs are inherited across generations. However, our comparison suggests that the pre-European system may not have entailed intensive management, as Erickson postulated. The Zambian fishery's sustainability is based on exploiting an assemblage dominated by species with life histories combining high fecundity, multiple reproductive cycles, and seasonal use of floodplains. As water rises, adults migrate from permanent watercourses into floodplains, through gaps in weirs, to feed and spawn. Juveniles grow and then migrate back to dry-season refuges as water falls. At that moment fishermen set traps in the gaps, harvesting large numbers of fish, mostly juveniles. In nature, most juveniles die during the first dry season, so that their harvest just before migration has limited impact on future populations, facilitating sustainability and the adoption of a fishery based on inherited perennial structures. South American floodplain fishes with similar life histories were the likely targets of the pre-European fishery. Convergence in floodplain fish strategies in these two regions in turn drove convergence in cultural niche construction.


Fabrication of glucose fiber sensor based on immobilized GOD technique for rapid measurement.
The concentration and pH value of the immobilized glucose oxidase (GOD) are critical parameters in a glucose sensor. In this study, we develop a glucose fiber sensor integrated with heterodyne interferometry to measure the phase difference arising from the chemical reaction between glucose and GOD. Our studies show that the response time and resolution of this sensor will be strongly affected by the pH and concentration properties of GOD. In addition, the results show good linearity between the calibration curve for the glucose solution and serum based sample. The response time of this sensor can be shorter than 3 seconds and best resolutions are 0.1 and 0.136 mg/dl for glucose solution and serum based sample, respectively.


Angular Ectopic Pregnancy Presenting as Rupture of Lateral Wall of the Uterus: Late Presentation in Gestation Week 20.
The differential diagnosis of acute abdominal pain in pregnancy is broad and can be complicated by atypical manifestations that are due to the anatomic distortions and physiologic changes of pregnancy. Due to the lack of clinical understanding, angular pregnancy does not appear to be recognized as a clinical entity and many cases are likely to go undiagnosed. This is a case report of a 34-year-old woman who was referred to the obstetrics emergency department with sudden abdominal pain and in a state of hypovolemic shock. She had 20 weeks amenorrhea with a positive blood pregnancy test. She underwent laparatomy with internal hemorrhage diagnosis. During the emergency laparotomy, the authors were surprised to encounter the conceptus of 20 weeks angular pregnancy extruded through the left lateral angulation of uterine cavity. The placenta and amnion were removed and the uterine was repaired. Angular pregnancy is rare, but it should be fully understood since its clinical management, outcomes, and maternal mortality are different.


Surgical management of craniopharyngiomas. A review of 74 cases.
A series of 74 patients with craniopharyngiomas were treated during a 15-year period. Of the 74 patients, 40 were males and 34 were females, with a mean age of 27 years (range 3 to 65 years). Twenty-eight patients (38%) were less than 18 years of age. Remission was defined as clinical improvement with stable ophthalmological and neurological status, radiological evidence of a decrease in tumor size, and either a continued decrease or a stable tumor size on follow-up radiological evaluations. A fair result was considered remission with new neurological deficits related to surgical intervention. All other results were considered a failure. The mean follow-up period in this study was 4 years, with 100% of the patients monitored. In children, the most common presentation was that of growth failure (93%). In adults, sexual dysfunction was the most common presentation, with 88% of males presenting with impotence or marked decrease in sexual drive, and 82% of females presenting with primary or secondary amenorrhea, often associated with galactorrhea. Considering the pediatric and adult populations together, the most common presenting symptom was visual dysfunction, with 71% of patients presenting in this manner. Fifty percent of patients presented with severe headache. The most frequent preoperative finding was a visual field defect, with 72% of patients so affected; 42% of patients had preoperative hypothyroidism and 24% had hypoadrenalism. Diabetes insipidus was present preoperatively in 23%. Hydrocephalus was uncommon, being present in only 15%. A subfrontal craniotomy was used in 47% of patients, a transsphenoidal approach in 39%, a subtemporal approach in 11%, a transcallosal approach in 5%, and a suboccipital craniectomy in 2%. Multiple procedures were required in 15% of patients in order to provide significant relief of compressive symptomatology. The results of therapy indicate that total tumor removal was deemed to have been achieved in only seven patients, six of whom have had no recurrence. However, 91% of patients are in remission, one had a fair result, and two died as a direct result of surgical intervention. One patient died from uncontrolled disease, and three patients died from unrelated causes. The results of this study indicate that radical subtotal removal followed by radiotherapy is an acceptable treatment for craniopharyngioma.


Emergence of connectivity motifs in networks of model neurons with short- and long-term plastic synapses.
Recent experimental data from the rodent cerebral cortex and olfactory bulb indicate that specific connectivity motifs are correlated with short-term dynamics of excitatory synaptic transmission. It was observed that neurons with short-term facilitating synapses form predominantly reciprocal pairwise connections, while neurons with short-term depressing synapses form predominantly unidirectional pairwise connections. The cause of these structural differences in excitatory synaptic microcircuits is unknown. We show that these connectivity motifs emerge in networks of model neurons, from the interactions between short-term synaptic dynamics (SD) and long-term spike-timing dependent plasticity (STDP). While the impact of STDP on SD was shown in simultaneous neuronal pair recordings in vitro, the mutual interactions between STDP and SD in large networks are still the subject of intense research. Our approach combines an SD phenomenological model with an STDP model that faithfully captures long-term plasticity dependence on both spike times and frequency. As a proof of concept, we first simulate and analyze recurrent networks of spiking neurons with random initial connection efficacies and where synapses are either all short-term facilitating or all depressing. For identical external inputs to the network, and as a direct consequence of internally generated activity, we find that networks with depressing synapses evolve unidirectional connectivity motifs, while networks with facilitating synapses evolve reciprocal connectivity motifs. We then show that the same results hold for heterogeneous networks, including both facilitating and depressing synapses. This does not contradict a recent theory that proposes that motifs are shaped by external inputs, but rather complements it by examining the role of both the external inputs and the internally generated network activity. Our study highlights the conditions under which SD-STDP might explain the correlation between facilitation and reciprocal connectivity motifs, as well as between depression and unidirectional motifs.


SLEAP: A deep learning system for multi-animal pose tracking.
The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal.


Deaf community analysis for health education priorities.
Deaf persons' access to health-related information is limited by barriers to spoken or written language: they cannot overhear information; they have limited access to television, radio, and other channels for public information; and the average reading level of Deaf adults is at a 3rd to 4th grade level. However, literature searches revealed no published reports of community analysis focusing specifically on health education priorities for Deaf communities. A seven-step community analysis was conducted to learn the health education priorities in Arizona Deaf communities and to inform development of culturally relevant health education interventions in Deaf communities. The word "Deaf" is capitalized to reflect the cultural perspective of the Deaf community. A 14-member Deaf Health Committee collected data using multimethods that included review of state census data, review of national health priorities, key informant interviews, discussions with key community groups, a mail survey (n = 20), and semistructured interviews conducted in sign language with 111 Deaf adults. The community diagnosis with highest priority for health education was vulnerability to cardiovascular disease (CVD). Following completion of the community analysis, a heart-health education intervention (The Deaf Heart Health Intervention) was developed using a train-the-trainer, community health worker model. If this model proves to be effective in addressing vulnerability to CVD, then a similar protocol could be employed to address other health concerns identified in the Deaf community analysis.


A hybrid temporal and spatial speckle-suppression method for laser displays.
We propose a system that reduces laser display speckles by vibrating the light pipe. A small displacement of the light pipe appears to allow the total reflection of the laser, thereby resulting in a homogenized speckle field that changes with time. In this case, the speckle interference generated by the pattern projected by the laser through the light pipe destroys the spatial homogenization of the laser beams when the light pipe is vibrated. Moreover, when the light pipe begins the sequential vibration, the phases and paths of the beams are changed after the beams traverse the light pipe. Consequently, temporal speckle wavefront superposition can homogenize the luminous intensity distribution of the speckle pattern. This process reduces the speckle contrast to less than 4% while maintaining a luminous intensity of greater than 70%.


Increased activity of mitochondrial aldehyde dehydrogenase (ALDH) in the putamen of individuals with Alzheimer's disease: a human postmortem study.
For decades, it has been acknowledged that oxidative stress due to free radical species contributes to the pathophysiology of aging and neurodegenerative diseases. Aldehyde dehydrogenases (ALDH) not only transform aldehydes to acids but also act as antioxidant enzymes. However, little is known about the implications of the enzymatic family of ALDH in the context of neurodegenerative processes such as Alzheimer's disease (AD). We therefore examined the enzymatic activity of the mitochondrial ALDH-isoform in different regions of the postmortem brain tissue isolated from patients with AD and controls. We found that the mitochondrial ALDH activity was significantly increased only in the putamen of patients suffering from AD compared to controls. This is of particular interest since mediators of oxidative stress, such as iron, are increased in the putamen of patients with AD. This study adds to the body of evidence that suggests that oxidative stress as well as aldehyde toxicity play a role in AD.


Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway.
Low plasma B-vitamin levels and elevated homocysteine have been associated with cancer, cardiovascular disease and neurodegenerative disorders. Common variants in FUT2 on chromosome 19q13 were associated with plasma vitamin B12 levels among women in a genome-wide association study in the Nurses' Health Study (NHS) NCI-Cancer Genetic Markers of Susceptibility (CGEMS) project. To identify additional loci associated with plasma vitamin B12, homocysteine, folate and vitamin B6 (active form pyridoxal 5'-phosphate, PLP), we conducted a meta-analysis of three GWA scans (total n = 4763, consisting of 1658 women in NHS-CGEMS, 1647 women in Framingham-SNP-Health Association Resource (SHARe) and 1458 men in SHARe). On chromosome 19q13, we confirm the association of plasma vitamin B12 with rs602662 and rs492602 (P-value = 1.83 x 10(-15) and 1.30 x 10(-14), respectively) in strong linkage disequilibrium (LD) with rs601338 (P = 6.92 x 10(-15)), the FUT2 W143X nonsense mutation. We identified additional genome-wide significant loci for plasma vitamin B12 on chromosomes 6p21 (P = 4.05 x 10(-08)), 10p12 (P-value=2.87 x 10(-9)) and 11q11 (P-value=2.25 x 10(-10)) in genes with biological relevance. We confirm the association of the well-studied functional candidate SNP 5,10-methylene tetrahydrofolate reductase (MTHFR) Ala222Val (dbSNP ID: rs1801133; P-value=1.27 x 10(-8)), on chromosome 1p36 with plasma homocysteine and identify an additional genome-wide significant locus on chromosome 9q22 (P-value=2.06 x 10(-8)) associated with plasma homocysteine. We also identified genome-wide associations with variants on chromosome 1p36 with plasma PLP (P-value=1.40 x 10(-15)). Genome-wide significant loci were not identified for plasma folate. These data reveal new biological candidates and confirm prior candidate genes for plasma homocysteine, plasma vitamin B12 and plasma PLP.