Desktop 3D printing of controlled release pharmaceutical bilayer tablets.
Three dimensional (3D) printing was used as a novel medicine formulation technique for production of viable tablets capable of satisfying regulatory tests and matching the release of standard commercial tablets. Hydroxypropyl methylcellulose (HPMC 2208) (Methocel™ K100M Premium) and poly(acrylic acid) (PAA) (Carbopol(®) 974P NF) were used as a hydrophilic matrix for a sustained release (SR) layer. Hypromellose(®) (HPMC 2910) was used as a binder while microcrystalline cellulose (MCC) (Pharmacel(®) 102) and sodium starch glycolate (SSG) (Primojel(®)) were used as disintegrants for an immediate release (IR) layer. Commercial guaifenesin bi-layer tablets (GBT) were used as a model drug (Mucinex(®)) for this study. There was a favourable comparison of release of the active guaifenesin from the printed hydrophilic matrix compared with the commercially available GBT. The printed formulations were also evaluated for physical and mechanical properties such as weight variation, friability, hardness and thickness as a comparison to the commercial tablet and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). All formulations (standard tablets and 3D printed tablets) showed Korsmeyer-Peppas n values between 0.27 and 0.44 which indicates Fickian diffusion drug release through a hydrated HPMC gel layer.


Is medication use by community-dwelling elderly people influenced by cognitive function?
To determine whether medication use differs by cognitive status among community dwelling elderly, a survey was made of a stratified random sample of 4110 black and white participants, aged 65 or older from the Duke Established Populations for Epidemiologic Studies of the Elderly in five adjacent urban and rural counties in the Piedmont area of North Carolina. Main outcome measures were usage of prescription medications, non-prescription medications, and medicines within therapeutic classes in the previous 2 weeks as determined during an in-home interview; and total number of prescription and non-prescription medicines used in the previous 2 weeks. Multivariate analyses, using weighted data adjusted for sampling design, were conducted to assess the association between drug use patterns and cognitive status, as assessed by the Short Portable Mental Status Questionnaire, while adjusting for demographic, health status, and access to health care factors. Participants with cognitive impairment (13.7% of sample) were less likely to use any prescription medications (Adjusted OR = 0.66, 95% CI = 0.48-0.90) or any non-prescription medications (Adjusted OR = 0. 71, 95% CI = 0.56-0.89) than cognitively intact subjects. Both groups took a similar number of prescription and non-prescription medications. Those who were cognitively impaired were less likely to take analgesics (Adjusted OR = 0.66, 95% CI = 0.52-0.83), but were more likely to take central nervous drugs (Adjusted OR = 1.55, 95% CI 1.18-2.04) than those who were cognitively intact. We conclude that drug use patterns by community-dwelling elderly people differ with cognitive status. Future research needs to examine medication use by specific causes of cognitive impairment.


Reviving lithium cobalt oxide-based lithium secondary batteries-toward a higher energy density.
By breaking through the energy density limits step-by-step, the use of lithium cobalt oxide-based Li-ion batteries (LCO-based LIBs) has led to the unprecedented success of consumer electronics over the past 27 years. Recently, strong demands for the quick renewal of the properties of electronic products every so often have resulted in smarter, larger screened, more lightweight devices with longer standby times that have pushed the energy density of LCO-based LIBs nearly to their limit. As a result, with the aim of achieving a higher energy density and lifting the upper cut-off voltage of LCO above 4.45 V (vs. Li/Li+), the development of LCO-based all-solid-state lithium batteries (ASSLBs) with a Li metal anode and LCO-based full cells with high-performance anodes have become urgent scientific and technological requirements. This review summarizes the key challenges of synthesizing LCO-based LBs with a higher energy density from the perspectives of structure and interface stability, and gives an account of effective modification strategies in view of the electrodes, liquid electrolytes, binders, separators, solid electrolytes and LCO-based full cells. The improvement mechanisms of these modification strategies and the controversy over them are also analyzed critically. Moreover, some perspectives regarding the remaining challenges for LCO-based LBs towards a higher energy density and possible future research focuses are also presented.


Does suppression of oscillatory synchronisation mediate some of the therapeutic effects of DBS in patients with Parkinson's disease?
There is growing evidence for exaggerated oscillatory neuronal synchronisation in patients with Parkinson's disease (PD). In particular, oscillations at around 20 Hz, in the so-called beta frequency band, relate to the cardinal symptoms of bradykinesia and rigidity. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can significantly improve these motor impairments. Recent evidence has demonstrated reduction of beta oscillations concurrent with alleviation of PD motor symptoms, raising the possibility that suppression of aberrant activity may mediate the effects of DBS. Here we review the evidence supporting suppression of pathological oscillations during stimulation and discuss how this might underlie the efficacy of DBS. We also consider how beta activity may provide a feedback signal suitable for next generation closed-loop and intelligent stimulators.


Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system.
Netrin 1 is a long-range diffusible factor that exerts chemoattractive or chemorepulsive effects on developing axons growing to or away from the neural midline. Here we used tissue explants to study the action of netrin 1 in the migration of several cerebellar and precerebellar cell progenitors. We show that netrin 1 exerts a strong chemoattractive effect on migrating neurons from the embryonic lower rhombic lip at E12-E14, which give rise to precerebellar nuclei. Netrin 1 promotes the exit of postmitotic migrating neurons from the embryonic lower rhombic lip and upregulates the expression of TAG-1 in these neurons. In addition, in the presence of netrin 1, the migrating neurons are not isolated but are associated with thick fascicles of neurites, typical of the neurophilic way of migration. In contrast, the embryonic upper rhombic lip, which contains tangentially migrating granule cell progenitors, did not respond to netrin 1. Finally, in the postnatal cerebellum, netrin 1 repels both the parallel fibres and migrating granule cells growing out from explants taken from the external germinal layer. The developmental patterns of expression in vivo of netrin 1 and its receptors are consistent with the notion that netrin 1 secreted in the midline acts as chemoattractive cue for precerebellar neurons migrating circumferentially along the extramural stream. Similarly, the pattern of expression in the postnatal cerebellum suggests that netrin 1 could regulate the tangential migration of postmitotic premigratory granule cells. Thus, molecular mechanisms considered as primarily involved in axonal guidance appear also to steer neuronal cell migration.


Producing ethnographies: workplace ethnographies in history.
Data on a large set of workplace ethnographies published from 1940 to 2002, compiled by Randy Hodson, are analyzed to show the trends over time in the production of such ethnographic work, its shifting disciplinary base, the relevance of the personal backgrounds of its authors, the contributions made by academic amateurs, the changing roles of gender and political stances, and the nature of different routes to publication. The definition of what counts as an ethnography is important to the character of the set available and has implications for its potential uses in secondary analysis. It is found that both personal and disciplinary identities and wider social factors have played roles in the production of ethnographic work that need to be understood to account for its history, though it is to be expected that the forms these take will differ for work in different subfields.


Effects of vowel height and vocal intensity on anticipatory nasal airflow in individuals with normal speech.
The purpose of this study was to determine the effects of vowel height and vocal intensity on the magnitude of anticipatory nasal airflow in normal speakers when producing vowel-nasal-vowel (VNV) sequences. Measurements of nasal and oral airflow were obtained from 15 men and 12 women with normal speech during production of the VNV sequences /ini/ and /ana/ at low, medium, and high intensity levels. Ratios of nasal to oral-plus-nasal airflow were calculated for the initial vowel of both utterances at each of the intensity levels. Analysis of variance (ANOVA) procedures indicated a significant main effect of intensity level and a significant vowel-by-sex interaction effect (p < .05) on the airflow ratios. Overall, the airflow ratio was reduced at high as compared to low intensity levels, regardless of sex of the speaker or vowel type. Female speakers exhibited greater airflow ratios during production of /ini/ than during productions of /ana/. Their airflow ratios were also greater during production of /ini/ than were those of male speakers. The results suggest that vocal intensity may affect velopharyngeal (VP) function in an assimilative nasal phonetic context. The results further suggest that anticipatory nasal airflow may be determined by the configuration of the oral cavity to a greater extent in women than in men. Theoretical and clinical implications are discussed.


The Clostridium difficile Protease Cwp84 Modulates both Biofilm Formation and Cell-Surface Properties.
Clostridium difficile is responsible for 15-20% of antibiotic-associated diarrheas, and nearly all cases of pseudomembranous colitis. Among the cell wall proteins involved in the colonization process, Cwp84 is a protease that cleaves the S-layer protein SlpA into two subunits. A cwp84 mutant was previously shown to be affected for in vitro growth but not in its virulence in a hamster model. In this study, the cwp84 mutant elaborated biofilms with increased biomass compared with the parental strain, allowing the mutant to grow more robustly in the biofilm state. Proteomic analyses of the 630Δerm bacteria growing within the biofilm revealed the distribution of abundant proteins either in cell surface, matrix or supernatant fractions. Of note, the toxin TcdA was found in the biofilm matrix. Although the overall proteome differences between the cwp84 mutant and the parental strains were modest, there was still a significant impact on bacterial surface properties such as altered hydrophobicity. In vitro and in vivo competition assays revealed that the mutant was significantly impaired for growth only in the planktonic state, but not in biofilms or in vivo. Taken together, our results suggest that the phenotypes in the cwp84 mutant come from either the accumulation of uncleaved SlpA, or the ability of Cwp84 to cleave as yet undetermined proteins.


Rescuer's position and energy consumption, spinal kinetics, and effectiveness of simulated cardiac compression.
Cardiopulmonary resuscitation is often performed in compromised conditions and for long periods. To compare energy expenditure, compression effectiveness, and kinetics of the spine during simulated chest compression with the rescuer in different positions. A 3-group design with 36 nurses (26 females) and 20 male emergency medical technicians was used. Participants performed chest compressions on a mannequin while kneeling on the floor, standing, or kneeling on the bed at the edge of the mattress (bed mount). Oxygen consumption and effectiveness of chest compression were recorded. Muscle moment and power at the lumbosacral joint were determined by recording motions of the lower limbs and pelvis with an electromagnetic tracking device and measuring ground reaction forces with a force plate. A total of 80% of chest compressions delivered by male rescuers (vs 40% delivered by females) were effective, irrespective of position. Male rescuers consumed less oxygen when delivering chest compressions while standing than while kneeling (P = .03), but effective compression ratio also was lower. In female rescuers, effective compressions correlated positively with oxygen consumption in the standing (r = 0.42, P = .04) and bed-mount (r = 0.53, P = .008) positions. Administering chest compressions while standing involved a larger moment magnitude and required more power than doing so while kneeling. Administering chest compressions while standing demands more power but consumes less oxygen than doing so while kneeling, perhaps because fewer cardiac compressions delivered while standing are effective.


Proteome-wide analysis of protein lipidation using chemical probes: in-gel fluorescence visualization, identification and quantification of N-myristoylation, N- and S-acylation, O-cholesterylation, S-farnesylation and S-geranylgeranylation.
Protein lipidation is one of the most widespread post-translational modifications (PTMs) found in nature, regulating protein function, structure and subcellular localization. Lipid transferases and their substrate proteins are also attracting increasing interest as drug targets because of their dysregulation in many disease states. However, the inherent hydrophobicity and potential dynamic nature of lipid modifications makes them notoriously challenging to detect by many analytical methods. Chemical proteomics provides a powerful approach to identify and quantify these diverse protein modifications by combining bespoke chemical tools for lipidated protein enrichment with quantitative mass spectrometry-based proteomics. Here, we report a robust and proteome-wide approach for the exploration of five major classes of protein lipidation in living cells, through the use of specific chemical probes for each lipid PTM. In-cell labeling of lipidated proteins is achieved by the metabolic incorporation of a lipid probe that mimics the specific natural lipid, concomitantly wielding an alkyne as a bio-orthogonal labeling tag. After incorporation, the chemically tagged proteins can be coupled to multifunctional 'capture reagents' by using click chemistry, allowing in-gel fluorescence visualization or enrichment via affinity handles for quantitative chemical proteomics based on label-free quantification (LFQ) or tandem mass-tag (TMT) approaches. In this protocol, we describe the application of lipid probes for N-myristoylation, N- and S-acylation, O-cholesterylation, S-farnesylation and S-geranylgeranylation in multiple cell lines to illustrate both the workflow and data obtained in these experiments. We provide detailed workflows for method optimization, sample preparation for chemical proteomics and data processing. A properly trained researcher (e.g., technician, graduate student or postdoc) can complete all steps from optimizing metabolic labeling to data processing within 3 weeks. This protocol enables sensitive and quantitative analysis of lipidated proteins at a proteome-wide scale at native expression levels, which is critical to understanding the role of lipid PTMs in health and disease.


Dynamics of correlated genetic systems. IV. Multilocus effects of ethanol stress environments.
Four replicate populations of Drosophila melanogaster, two reared on medium supplemented with ethanol and two reared on standard medium, were electrophoretically monitored for 28 generations. During the first 12 generations, allelic, genotypic and gametic frequencies were determined for eight polymorphic enzymes: GOT, alpha-GPDH, MDH, ADH, TO, E6, Ec and ODH. Samples from generation 18 and 28 were electrophoretically typed for ADH and alpha-GPDH. In addition, samples from generation 27 were analyzed for the presence of inversion heterozygotes. The experimental results showed rapid gene-frequency divergence between control and treatment populations at the Adh locus in a direction consistent with the activity hierarchy of Adh genotypes. Gene-frequency divergence between control and treatment populations also occurred at the alpha-Gpdh locus, although the agreement among replicates appeared to have broken down by generation 28. No differential gene-frequency change occurred at any of the six remaining marker loci. Furthermore, values of linkage disequilibria among all linked pairs of genes were initially small and remained small throughout the course of the experiment. Taking these facts into account, it is argued that the gene-frequency response observed at ADH is most probably caused by selection at the Adh locus. The gene frequency response at alpha-Gpdh can also be be accounted for in terms of the effect of ethanol on energy metabolism, although other explanations cannot be excluded.


Post-Synthesis Modifications of Two-Dimensional MoSe2 or MoTe2 by Incorporation of Excess Metal Atoms into the Crystal Structure.
Phase engineering has extensively been used to achieve metallization of two-dimensional (2D) semiconducting materials, as it should boost their catalytic properties or improve electrical contacts. In contrast, here we demonstrate compositional phase change by incorporation of excess metals into the crystal structure. We demonstrate post-synthesis restructuring of the semiconducting MoTe2 or MoSe2 host material by unexpected easy incorporation of excess Mo into their crystal planes, which causes local metallization. The amount of excess Mo can reach values as high as 10% in MoTe2 thus creating a significantly altered material compared to its parent structure. The incorporation mechanism is explained by density functional theory in terms of the energy difference of Mo atoms incorporated in the line phases as compared to Mo ad-clusters. Angle resolved photoemission spectroscopy reveals that the incorporated excess Mo induces band gap states up to the Fermi level causing its pinning at these electronic states. The incorporation of excess transition metals in MoTe2 and MoSe2 is not limited to molybdenum, but other transition metals can also diffuse into the lattice, as demonstrated experimentally by Ti deposition. The mechanism of incorporation of transition metals in MoSe2 and MoTe2 is revealed, which should help to address the challenges in synthesizing defect-free single layer materials by, for example, molecular beam epitaxy. The easy incorporation of metal atoms into the crystal also indicates that the previously assumed picture of a sharp metal/2D-material interface may not be correct, and at least for MoSe2 and MoTe2, in-diffusion of metals from metal-contacts into the 2D material has to be considered. Most importantly though, the process of incorporation of transition metals with high concentrations into pristine 2D transition-metal dichalcogenides enables a pathway for their post-synthesis modifications and adding functionalities.


Modulation of the kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons.
Neurons of the medial nucleus of the trapezoid body, which transmit auditory information that is used to compute the location of sounds in space, are capable of firing at high frequencies with great temporal precision. We found that elimination of the Kv3.1 gene in mice results in the loss of a high-threshold component of potassium current and failure of the neurons to follow high-frequency stimulation. A partial decrease in Kv3.1 current can be produced in wild-type neurons of the medial nucleus of the trapezoid body by activation of protein kinase C. Paradoxically, activation of protein kinase C increases temporal fidelity and the number of action potentials that are evoked by intermediate frequencies of stimulation. Computer simulations confirm that a partial decrease in Kv3.1 current is sufficient to increase the accuracy of response at intermediate frequencies while impairing responses at high frequencies. We further establish that, of the two isoforms of the Kv3.1 potassium channel that are expressed in these neurons, Kv3.1a and Kv3.1b, the decrease in Kv3.1 current is mediated by selective phosphorylation of the Kv3.1b isoform. Using site-directed mutagenesis, we identify a specific C-terminal phosphorylation site responsible for the observed difference in response of the two isoforms to protein kinase C activation. Our results suggest that modulation of Kv3.1 by phosphorylation allows auditory neurons to tune their responses to different patterns of sensory stimulation.


Choosing wisely in anesthesiology: the gap between evidence and practice.
To develop a "top-five" list of unnecessary medical services in anesthesiology, we undertook a multistep survey of anesthesiologists, most of whom were in academic practice, and a consequent iterative process with the committees of the American Society of Anesthesiologists. We generated a list of 18 low-value perioperative activities from American Society of Anesthesiologists practice parameters and the literature. Starting with this list and proceeding with a 2-step survey using a 5-point Likert scale questionnaire, we eventually identified 5 common activities that are of low quality or benefit and high cost and have poor evidence supporting their use. The 2 preoperative practices in the top-five list addressed the avoidance of unindicated baseline laboratory studies or diagnostic cardiac stress testing. The 3 intraoperative practices involved the avoidance of the routine use of the pulmonary artery for cardiac surgery and the use of packed red blood cells or colloid when not indicated.


Cytolytic T lymphocytes raised against a human bladder carcinoma recognize an antigen encoded by gene MAGE-A12.
Human bladder carcinoma line LB831-BLC expresses several distinct Ags that are recognized by different autologous CTL. Here, we show that one of these Ags is presented by HLA-Cw7 and encoded by gene MAGE-A12. This is the first time that CTL directed against a MAGE-encoded Ag have been derived from the lymphocytes of a patient with cancer other than melanoma. This new Ag was found to be nonapeptide VRIGHLYIL, corresponding to position 170-178 of the MAGE-A12 protein. Gene MAGE-A12 is silent in normal tissues except in male germline cells, which do not express HLA molecules. It is expressed in 26-62% of melanomas, infiltrating bladder carcinomas, lung carcinomas, esophageal carcinomas, and head and neck carcinomas. Because HLA-Cw7 is present in 43% of Caucasians, this new Ag is shared by many tumors and should be a useful target for cancer immunotherapy.


Evaluation of the anticonvulsant and anxiolytic-like activities of aqueous leaf extract of Cymbopogon citratus in mice.
Background Anxiety is a common ailment of high co-morbidity with epilepsy, a chronic neurologic disease characterized by recurrent seizures. Current drugs used for these conditions have several limitations such as disabling side effects, relapse, and ineffectiveness in certain population necessitating the search for alternative options. The aqueous leaf extract of Cymbopogon citratus (CYC) is widely used for its various health-promoting effects including relief of seizures and anxiety in ethnomedicine. This present study describes its effects on convulsions, anxiety-like behaviors, and social interaction in mice. Methods Male Swiss mice were pretreated orally with CYC (25, 50, and 100 mg/kg), diazepam (1 mg/kg), or distilled water (10 mL/kg) 60 min before induction of convulsions with intraperitoneal (i.p.) injection of picrotoxin (10 mg/kg), pentylenetetrazole (PTZ; 85 mg/kg), or isoniazid (300 mg/kg). The animals were then observed for the occurrence of seizure for 30 min or 2 h for isoniazid. The effects of CYC on anxiety-like behaviors, social interaction, and spontaneous motor activity (SMA) were evaluated in naive mice. Results CYC (25-100 mg/kg) did not prevent convulsions nor delay the latency to convulsions induced by picrotoxin, PTZ, or isoniazid. Pretreatment with CYC (50 and 100 mg/kg, p.o) produced anxiolytic-like effect, decreased SMA, and also enhanced social interaction behavior in naive mice. Conclusions The results of this study suggest that CYC did not exhibit an anticonvulsant property in mice injected with picrotoxin, PTZ, or isoniazid, but its anxiolytic-like activity and social interaction-promoting effect might be of benefit as an adjuvant in improving the quality of life of epileptic patients.


Priority Setting, Cost-Effectiveness, and the Affordable Care Act.
The Affordable Care Act (ACA) may be the most important health law statute in American history, yet much of the most prominent legal scholarship examining it has focused on the merits of the court challenges it has faced rather than delving into the details of its priority-setting provisions. In addition to providing an overview of the ACA's provisions concerning priority setting and their developing interpretations, this Article attempts to defend three substantive propositions. First, I argue that the ACA is neither uniformly hostile nor uniformly friendly to efforts to set priorities in ways that promote cost and quality. Second, I argue that the ACA does not take a single, unified approach to priority setting; rather, its guidance varies depending on the aspect of the healthcare system at issue (Patient Centered Outcomes Research Institute, Medicare, essential health benefits) and the factors being excluded from priority setting (age, disability, life expectancy). Third, I argue that cost-effectiveness can be achieved within the ACA's constraints, but that doing so will require adopting new approaches to cost-effectiveness and priority setting. By limiting the use of standard cost-effectiveness analysis, the ACA makes the need for workable rivals to cost-effectiveness analysis a pressing practical concern rather than a mere theoretical worry.


GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells.
Celecoxib, a selective cyclooxygenase-2 inhibitor, is known to possess anti-inflammatory activity and also induces apoptosis in various types of cancer cells. Here, we examined the molecular mechanism of celecoxib-induced apoptosis in cervical cancer cell lines (HeLa, CaSki and C33A). Screening of a cDNA microarray chip containing 225 different genes revealed that GADD153 (growth arrest and DNA damage inducible gene), a transcription factor involved in apoptosis, showed the strongest differential expression following celecoxib treatment in all three cervical cancer cell lines. Notably, siRNA-induced silencing of GADD153 suppressed celecoxib-induced apoptosis in all three cell lines, and exogenous expression of GADD153 triggered apoptosis in cervical cancer cells in the absence of other apoptotic stimuli. A luciferase reporter gene assay and mRNA stability tests revealed that the expression of GADD153 was regulated at both the transcriptional and post-transcriptional levels following celecoxib treatment. The region between -649 and -249, containing an intact C/EBP-ATF binding site, is required for celecoxib-induced stimulation of GADD153 promoter activity. In terms of signaling pathway, addition of the NF-kappaB inhibitor, N-tosyl-L-phenylalanyl-chloromethyl ketone, had no effect on GADD153 expression levels. Celecoxib treatment induced Bak expression, whereas cell transfected with siGADD153 showed lower levels of celecoxib-induced Bak upregulation. These novel findings collectively suggest that GADD153 may play a key role in celecoxib-induced apoptosis in cervical cancer cells by regulating the expression of proapoptotic proteins such as Bak.


Increased risk of lung cancer mortality among residents near an asbestos product manufacturing plant.
We investigated whether individuals exposed to asbestos by living near an asbestos-manufacturing facility experienced increased lung cancer mortality. We studied a neighborhood around such a plant in the central Japanese city of Hashima. From 1943 to 1991 this plant produced insulation and packing material using amosite- and chrysotile-type asbestos fibers. The study group was comprised of 577 households. We obtained demographic information by a questionnaire and determined the underlying cause of death for deceased household members from death certificates. Using hourly meteorological data from local observatories, we estimated relative asbestos concentrations in the plant's vicinity, determined the quartile boundaries, and designated each study subject's quartile of ambient exposure. Finally, we calculated standardized mortality ratios to evaluate the association of residential asbestos with lung cancer risk. Our findings strongly suggest that neighborhood asbestos exposure can increase the risk of lung cancer mortality in men and probably in women.


Novel arylimidamides for treatment of visceral leishmaniasis.
Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.


Three-dimensional tomographic reconstruction of an absorptive perturbation with diffuse photon density waves.
A three-dimensional tomographic reconstruction algorithm for an absorptive perturbation in tissue is derived. The input consists of multiple two-dimensional projected views of tissue that is backilluminated with diffuse photon density waves. The algorithm is based on a generalization of the projection-slice theorem and consists of depth estimation, image deconvolution, filtering, and backprojection. The formalism provides estimates of the number of views necessary to achieve a given spatial resolution in the reconstruction. The algorithm is demonstrated with data simulated to mimic the absorption of a contrast agent in human tissue. The effects of noise and uncertainties in the depth estimate are explored.


Moral Challenges for Psychologists Working in Psychology and Law.
States have an obligation to protect themselves and their citizens from harm, and they use the coercive powers of law to investigate threats, enforce rules and arbitrate disputes, thereby impacting on people's well-being and legal rights and privileges. Psychologists as a collective have a responsibility to use their abilities, knowledge, skill and experience to enhance law's effectiveness, efficiency, and reliability in preventing harm, but their professional behaviour in this collaboration must be moral. They could, however, find their personal values to be inappropriate or there to be insufficient moral guides and could find it difficult to obtain definitive moral guidance from law. The profession's ethical principles do, however, provide well-articulated, generally accepted and profession-appropriate guidance, but practitioners might encounter moral issues that can only be solved by the profession as a whole or society.


Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases.
The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis.


Muscle wasting associated with pathologic change is a risk factor for the exacerbation of joint swelling in collagen-induced arthritis in cynomolgus monkeys.
Not only joint destruction but also muscle wasting due to rheumatoid cachexia has been problem in terms of quality of life of patients with rheumatoid arthritis (RA). In the present study, we performed histopathological examination and assessed relationships between characteristic parameters relating to muscle and joint swelling in a collagen-induced arthritis (CIA) model using cynomolgus monkeys (CMs). Female CMs were used and CIA was induced by twice immunizations using bovine type II collagen with Freund's complete adjuvant. Arthritis level was evaluated from the degree of swelling at the peripheral joints of the fore and hind limbs. Food consumption, body weight, and serum biochemical parameters were measured sequentially. Five or 6 animals per time point were sacrificed at 2, 3, 5 and 9 weeks after the first immunization to obtain quadriceps femoris specimens for histopathology. Pimonidazole hydrochloride was intravenously administered to determine tissue hypoxia in skeletal muscle. Gradual joint swelling was observed and the maximum arthritis score was noted at Week 5. In histopathology, necrosis of muscle fiber in the quadriceps femoris was observed only at Week 2 and the most significant findings such as degeneration, atrophy, and regeneration of muscle fiber were mainly observed at Week 5. Food consumption was decreased up to Week 4 but recovered thereafter. Body weight decreased up to Week 5 and did not completely recover thereafter. A biphasic increase in serum cortisol was also observed at Weeks 2 and 5. Histopathology showed that muscle lesions were mainly composed of degeneration and atrophy of the muscle fibers, and ATPase staining revealed that the changes were more pronounced in type II muscle fiber than type I muscle fiber. In the pimonidazole experiment, mosaic pattern in skeletal muscle was demonstrated in the intact animal, but not the CIA animal. Increased arthritis score was accompanied by a decrease in serum creatinine, a marker that reflects muscle mass. Muscle wasting might exacerbate joint swelling in a collagen-induced arthritis model of cynomolgus monkeys.


The risk of child and adolescent overweight is related to types of food consumed.
To investigate the association between the risk of overweight and the consumption of food groups in children and adolescents. We studied 1764 healthy children and adolescents (age 6-19y) attending 16 Seventh-Day Adventist schools and 13 public schools using a 106-item non-quantitative food frequency questionnaire from the late 1980 Child-Adolescent Blood Pressure Study. Logistic regression models were used to compute the risk of overweight according to consumption of grains, nuts, vegetables, fruits, meats/fish/eggs, dairy, and, low nutrient-dense foods (LNDF). The frequency of consumption of grains, nuts, vegetables and LNDF were inversely related to the risk of being overweight and dairy increased the risk. Specifically, the odds ratio (95% CI) for children in the highest quartile or tertile of consumption compared with the lowest quartile or tertile were as follows: grains 0.59(0.41-0.83); nuts 0.60(0.43-0.85); vegetables 0.67(0.48-0.94); LNDF 0.43(0.29-0.63); and, dairy 1.36(0.97, 1.92). The regular intake of specific plant foods may prevent overweight among children and adolescents.


Presynaptic CB1 receptors regulate synaptic plasticity at cerebellar parallel fiber synapses.
Endocannabinoids are potent regulators of synaptic strength. They are generally thought to modify neurotransmitter release through retrograde activation of presynaptic type 1 cannabinoid receptors (CB1Rs). In the cerebellar cortex, CB1Rs regulate several forms of synaptic plasticity at synapses onto Purkinje cells, including presynaptically expressed short-term plasticity and, somewhat paradoxically, a postsynaptic form of long-term depression (LTD). Here we have generated mice in which CB1Rs were selectively eliminated from cerebellar granule cells, whose axons form parallel fibers. We find that in these mice, endocannabinoid-dependent short-term plasticity is eliminated at parallel fiber, but not inhibitory interneuron, synapses onto Purkinje cells. Further, parallel fiber LTD is not observed in these mice, indicating that presynaptic CB1Rs regulate long-term plasticity at this synapse.


Genome rearrangement in top3 mutants of Saccharomyces cerevisiae requires a functional RAD1 excision repair gene.
Saccharomyces cerevisiae cells that are mutated at TOP3, a gene that encodes a protein homologous to bacterial type I topoisomerases, have a variety of defects, including reduced growth rate, altered gene expression, blocked sporulation, and elevated rates of mitotic recombination at several loci. The rate of ectopic recombination between two unlinked, homologous loci, SAM1 and SAM2, is sixfold higher in cells containing a top3 null mutation than in wild-type cells. Mutations in either of the two other known topoisomerase genes in S. cerevisiae, TOP1 and TOP2, do not affect the rate of recombination between the SAM genes. The top3 mutation also changes the distribution of recombination events between the SAM genes, leading to the appearance of novel deletion-insertion events in which conversion tracts extend beyond the coding sequence, replacing the DNA flanking the 3' end of one SAM gene with nonhomologous DNA flanking the 3' end of the other. The effects of the top3 null mutation on recombination are dependent on the presence of an intact RAD1 excision repair gene, because both the rate of SAM ectopic gene conversion and the conversion tract length were reduced in rad1 top3 mutant cells compared with top3 mutants. These results suggest that a RAD1-dependent function is involved in the processing of damaged DNA that results from the loss of Top3 activity, targeting such DNA for repair by recombination.


Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients.
Introduction. COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulphate may be efficacious against COVID-19, our hospitals began using zinc sulphate as add-on therapy to hydroxychloroquine and azithromycin.Aim. To compare outcomes among hospitalized COVID-19 patients ordered to receive hydroxychloroquine and azithromycin plus zinc sulphate versus hydroxychloroquine and azithromycin alone.Methodology. This was a retrospective observational study. Data was collected from medical records for all patients with admission dates ranging from 2 March 2020 through to 11 April 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. The study included patients admitted to any of four acute care NYU Langone Health Hospitals in New York City. Patients included were admitted to the hospital with at least one positive COVID-19 test and had completed their hospitalization. Patients were excluded from the study if they were never admitted to the hospital or if there was an order for other investigational therapies for COVID-19.Results. Patients taking zinc sulphate in addition to hydroxychloroquine and azithromycin (n=411) and patients taking hydroxychloroquine and azithromycin alone (n=521) did not differ in age, race, sex, tobacco use or relevant comorbidities. The addition of zinc sulphate did not impact the length of hospitalization, duration of ventilation or intensive care unit (ICU) duration. In univariate analyses, zinc sulphate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulphate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95 % CI 1.12-2.09) and reduction in mortality or transfer to hospice among patients who did not require ICU level of care remained significant (OR 0.449, 95 % CI 0.271-0.744).Conclusion. This study provides the first in vivo evidence that zinc sulphate may play a role in therapeutic management for COVID-19.


A Randomized Placebo-Controlled Study of a Transcranial Photobiomodulation Helmet in Parkinson's Disease: Post-Hoc Analysis of Motor Outcomes.
Emerging evidence is increasingly supporting the use of transcranial photobiomodulation (tPBM) to improve symptoms of neurodegenerative diseases, including Parkinson's disease (PD). The objective of this study was to analyse the safety and efficacy of tPBM for PD motor symptoms. The study was a triple blind, randomized placebo-controlled trial with 40 idiopathic PD patients receiving either active tPBM (635 nm plus 810 nm LEDs) or sham tPBM for 24 min per day (56.88J), six days per week, for 12 weeks. The primary outcome measures were treatment safety and a 37-item MDS-UPDRS-III (motor domain) assessed at baseline and 12 weeks. Individual MDS-UPDRS-III items were clustered into sub-score domains (facial, upper-limb, lower-limb, gait, and tremor). The treatment produced no safety concerns or adverse events, apart from occasional temporary and minor dizziness. There was no significant difference in total MDS-UPDRS-III scores between groups, presumably due to the placebo effect. Additional analyses demonstrated that facial and lower-limb sub-scores significantly improved with active treatment, while gait and lower-limb sub-scores significantly improved with sham treatment. Approximately 70% of participants responded to active treatment (≥5 decrease in MDS-UPDRS-III score) and improved in all sub-scores, while sham responders improved in lower-limb sub-scores only. tPBM appears to be a safe treatment and improved several PD motor symptoms in patients that responded to treatment. tPBM is proving to be increasingly attractive as a possible non-pharmaceutical adjunct therapy.


Hydrotalcite Intercalated siRNA: Computational Characterization of the Interlayer Environment.
Using molecular dynamics (MD) simulations, we explore the structural and dynamical properties of siRNA within the intercalated environment of a Mg:Al 2:1 Layered Double Hydroxide (LDH) nanoparticle. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: COMPASS) is used for the MD simulations of the hybrid organic-inorganic systems. The structure, arrangement, mobility, close contacts and hydrogen bonds associated with the intercalated RNA are examined and contrasted with those of the isolated RNA. Computed powder X-ray diffraction patterns are also compared with related LDH-DNA experiments. As a method of probing whether the intercalated environment approximates the crystalline or rather the aqueous state, we explore the stability of the principle parameters (e.g., the major groove width) that differentiate both A- and A'- crystalline forms of siRNA and contrast this with recent findings for the same siRNA simulated in water. We find the crystalline forms remain structurally distinct when intercalated, whereas this is not the case in water. Implications for the stability of hybrid LDH-RNA systems are discussed.


Empirical observations of the spawning migration of European eels: The long and dangerous road to the Sargasso Sea.
The spawning migration of the European eel (Anguilla anguilla L.) to the Sargasso Sea is one of the greatest animal migrations. However, the duration and route of the migration remain uncertain. Using fishery data from 20 rivers across Europe, we show that most eels begin their oceanic migration between August and December. We used electronic tagging techniques to map the oceanic migration from eels released from four regions in Europe. Of 707 eels tagged, we received 206 data sets. Many migrations ended soon after release because of predation events, but we were able to reconstruct in detail the migration routes of >80 eels. The route extended from western mainland Europe to the Azores region, more than 5000 km toward the Sargasso Sea. All eels exhibited diel vertical migrations, moving from deeper water during the day into shallower water at night. The range of migration speeds was 3 to 47 km day-1. Using data from larval surveys in the Sargasso Sea, we show that spawning likely begins in December and peaks in February. Synthesizing these results, we show that the timing of autumn escapement and the rate of migration are inconsistent with the century-long held assumption that eels spawn as a single reproductive cohort in the springtime following their escapement. Instead, we suggest that European eels adopt a mixed migratory strategy, with some individuals able to achieve a rapid migration, whereas others arrive only in time for the following spawning season. Our results have consequences for eel management.


Metformin treatment does not affect the risk of ruptured abdominal aortic aneurysms.
Diabetes counteracts formation and rupture of abdominal aortic aneurysms, possibly through arterial matrix accumulation. Use of metformin, on the other hand, reduces arterial accumulation of matrix molecules. Consequently, we hypothesized that metformin treatment may reverse the protective role of diabetes on the development and course of aneurysms, that is, that metformin would be associated with aneurysm rupture among individuals with diabetes. Using nationwide Danish registry data, we performed a nested case-control study on the association between long-term use of metformin and ruptured abdominal aortic aneurysm (RAAA). The source population was defined as all individuals in Denmark with diabetes. Cases were all individuals within the source population who were hospitalized with a primary diagnosis of RAAA. For each case, 10 controls matched by age and sex were randomly selected from the source population by risk set sampling. The main exposure measure was a cumulative dispensing of 1000 g of metformin between January 1995 and the index date. We identified 362 cases of RAAA during 1998 to 2013, of which 83.7% occurred in men with a median age of 74 years. In total, 22.4% of the case population were long-term metformin users compared with 28.8% of the controls. We found a statistically nonsignificant protective effect of long-term metformin use toward RAAA with crude odds ratio (OR) of 0.74 (confidence interval, 0.54-1.00). When adjusted for covariates, OR increased to 0.84 (confidence interval, 0.61-1.17). None of the subgroups had ORs deviating substantially from the main result. Metformin use does not increase the risk of RAAA among individuals with diabetes.


Effective connectivity associated with auditory error detection in musicians with absolute pitch.
It is advantageous to study a wide range of vocal abilities in order to fully understand how vocal control measures vary across the full spectrum. Individuals with absolute pitch (AP) are able to assign a verbal label to musical notes and have enhanced abilities in pitch identification without reliance on an external referent. In this study we used dynamic causal modeling (DCM) to model effective connectivity of ERP responses to pitch perturbation in voice auditory feedback in musicians with relative pitch (RP), AP, and non-musician controls. We identified a network compromising left and right hemisphere superior temporal gyrus (STG), primary motor cortex (M1), and premotor cortex (PM). We specified nine models and compared two main factors examining various combinations of STG involvement in feedback pitch error detection/correction process. Our results suggest that modulation of left to right STG connections are important in the identification of self-voice error and sensory motor integration in AP musicians. We also identify reduced connectivity of left hemisphere PM to STG connections in AP and RP groups during the error detection and corrections process relative to non-musicians. We suggest that this suppression may allow for enhanced connectivity relating to pitch identification in the right hemisphere in those with more precise pitch matching abilities. Musicians with enhanced pitch identification abilities likely have an improved auditory error detection and correction system involving connectivity of STG regions. Our findings here also suggest that individuals with AP are more adept at using feedback related to pitch from the right hemisphere.


Metal Artifact Reduction in Pelvic Computed Tomography With Hip Prostheses: Comparison of Virtual Monoenergetic Extrapolations From Dual-Energy Computed Tomography and an Iterative Metal Artifact Reduction Algorithm in a Phantom Study.
The aim of this study was to directly compare metal artifact reduction (MAR) of virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (CT) with iterative MAR (iMAR) from single energy in pelvic CT with hip prostheses. A human pelvis phantom with unilateral or bilateral metal inserts of different material (steel and titanium) was scanned with third-generation dual-source CT using single (120 kVp) and dual-energy (100/150 kVp) at similar radiation dose (CT dose index, 7.15 mGy). Three image series for each phantom configuration were reconstructed: uncorrected, VME, and iMAR. Two independent, blinded radiologists assessed image quality quantitatively (noise and attenuation) and subjectively (5-point Likert scale). Intraclass correlation coefficients (ICCs) and Cohen κ were calculated to evaluate interreader agreements. Repeated measures analysis of variance and Friedman test were used to compare quantitative and qualitative image quality. Post hoc testing was performed using a corrected (Bonferroni) P < 0.017. Agreements between readers were high for noise (all, ICC ≥ 0.975) and attenuation (all, ICC ≥ 0.986); agreements for qualitative assessment were good to perfect (all, κ ≥ 0.678). Compared with uncorrected images, VME showed significant noise reduction in the phantom with titanium only (P < 0.017), and iMAR showed significantly lower noise in all regions and phantom configurations (all, P < 0.017). In all phantom configurations, deviations of attenuation were smallest in images reconstructed with iMAR. For VME, there was a tendency toward higher subjective image quality in phantoms with titanium compared with uncorrected images, however, without reaching statistical significance (P > 0.017). Subjective image quality was rated significantly higher for images reconstructed with iMAR than for uncorrected images in all phantom configurations (all, P < 0.017). Iterative MAR showed better MAR capabilities than VME in settings with bilateral hip prosthesis or unilateral steel prosthesis. In settings with unilateral hip prosthesis made of titanium, VME and iMAR performed similarly well.


Prediction models in reproductive medicine: a critical appraisal.
Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis. Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated.


Conservative intrachromosomal recombination between inverted repeats in mouse cells: association between reciprocal exchange and gene conversion.
Recombination in mammalian cells is thought to involve both reciprocal and nonreciprocal modes of exchange, although rigorous proof is lacking due to the inability to recover all products of an exchange. To investigate further the relationship between these modes of exchange, we have analyzed intrachromosomal recombination between duplicated herpes simplex virus thymidine kinase (HSV tk) mutant alleles arranged as inverted repeats in cultured mouse L cells. In crosses between inverted repeats, a single intrachromatid reciprocal exchange leads to inversion of the sequence between the crossover sites and recovery of both genes involved in the event. The majority of recombinant products do not display such inversion and are thus consistent with a nonreciprocal mode of recombination (gene conversion). The remaining products display the sequence inversion predicted for intrachromatid reciprocal exchange. In light of the fact that intrachromatid exchanges occur, the rarity of intrachromatid double reciprocal exchanges strengthens the interpretation that the majority of events in this and previous investigations involve gene conversion. Furthermore, in accord with prediction, one-third of the reciprocal recombinants (inversions) display associated gene conversion. This association suggests that reciprocal and nonreciprocal modes of exchange are mechanistically related in mammalian cells. Finally, the occurrence of inversion recombinants suggests that intrachromosomal recombination can be a conservative (nondestructive) process.


Finite element modelling of contracting skeletal muscle.
To describe the mechanical behaviour of biological tissues and transport processes in biological tissues, conservation laws such as conservation of mass, momentum and energy play a central role. Mathematically these are cast into the form of partial differential equations. Because of nonlinear material behaviour, inhomogeneous properties and usually a complex geometry, it is impossible to find closed-form analytical solutions for these sets of equations. The objective of the finite element method is to find approximate solutions for these problems. The concepts of the finite element method are explained on a finite element continuum model of skeletal muscle. In this case, the momentum equations have to be solved with an extra constraint, because the material behaves as nearly incompressible. The material behaviour consists of a highly nonlinear passive part and an active part. The latter is described with a two-state Huxley model. This means that an extra nonlinear partial differential equation has to be solved. The problems and solutions involved with this procedure are explained. The model is used to describe the mechanical behaviour of a tibialis anterior of a rat. The results have been compared with experimentally determined strains at the surface of the muscle. Qualitatively there is good agreement between measured and calculated strains, but the measured strains were higher.


Impairment of cell adhesion by expression of the mutant neurofibromatosis type 2 (NF2) genes which lack exons in the ERM-homology domain.
Neurofibromatosis 2 (NF2) is an inherited disorder characterized by a predisposition to multiple intracranial tumors. The protein encoded by the NF2 gene has striking similarities to ezrin, radixin and moesin (ERM) proteins which link membrane proteins to the cytoskeleton. Therefore, it can be speculated that the disruption of cytoskeletal organization by alterations in the NF2 gene is involved in the development of tumors. It has been reported that the majority of NF2 mutations were nonsense or frameshift mutations that result in premature termination of translation. To facilitate the detection of these mutations, we performed protein truncation test and found that 11 of 14 NF2 patients had truncational mutations (79%). Seven of the 11 patients (64%) had a splicing abnormality which lead to absence of exons in the ERM homology domain. To examine the biological significance of the exon-missing mutations in the ERM homology domain, we expressed the wild-type (wt-NF2) and the various mutant NF2s (mu-NF2s) in a fibroblast cell line by using both liposome-mediated transfection and nuclear microinjection of the expression plasmids. The wt-NF2 showed intense punctate staining in the perinuclear cytoplasm in addition to overall staining of the submembranous area, whereas the mu-NF2s lacking exons in the ERM homology domain showed granular staining at the perinuclear region without any accumulation at the submembrane region. Microinjection of wt-NF2 cDNA into the nucleus of VA13 cells revealed that wt-NF2 protein induced a progressive elongation of cell processes. Furthermore, cells that expressed mu-NF2 had decreased adhesion, which resulted in detachment from the substratum. These findings suggested that the exon-missing mutations in the ERM-homology domain may affect cell membrane-cytoskeleton signaling and consequently disrupt cell-to-cell or cell-to-matrix interaction.


Five new monotetrahydrofuran ring acetogenins from the leaves of Annona muricata.
Bioactivity-directed fractionation of the leaves of Annona muricata resulted in the isolation of annopentocins A (1), B (2), and C(3), and cis- and trans-annomuricin-D-ones (4, 5). Compounds 1-3 are the first acetogenins reported bearing a mono-tetrahydrofuran (THF) ring with one flanking hydroxyl, on the hydrocarbon side, and another hydroxyl, on the lactone side, that is one carbon away from the THF ring. Compounds 4 and 5 were obtained in a mixture and are new mono-THF ring acetogenins bearing two flanking hydroxyls and an erythro-diol located between the THF and the ketolactone rings. Compound 1 was selectively cytotoxic to pancreatic carcinoma cells (PACA-2), and 2 and 3 were selectively cytotoxic to lung carcinoma cells (A-549); the mixture of 4 and 5 was selectively cytotoxic for the lung (A-549), colon (HT-29), and pancreatic (PACA-2) cell lines with potencies equal to or exceeding those of Adriamycin.


Assessment of the "Weekend Effect" in Lower Extremity Vascular Trauma.
Studies suggest that patients admitted on weekends may have worse outcomes as compared with those admitted on weekdays. Lower extremity vascular trauma (LEVT) often requires emergent surgical intervention and might be particularly sensitive to this "weekend effect." The objective of this study was to determine if a weekend effect exists for LEVT. The National and Nationwide Inpatient Sample Database (2005-2014) was queried to identify all adult patients who were admitted with an LEVT diagnosis. Patient and hospital characteristics were recorded or calculated and outcomes including in-hospital mortality, amputation, length of stay (LOS), and discharge disposition were assessed. Independent predictors of outcomes were identified using multivariable regression models. There were 9,282 patients admitted with LEVT (2,866 weekend admissions vs. 6,416 weekday admissions). Patients admitted on weekends were likely to be younger than 45 years (68% weekend vs. 55% weekday, P < 0.001), male (81% weekend vs. 75% weekday, P < 0.001), and uninsured (22% weekend vs. 17% weekday, P < 0.001) as compared with patients admitted on weekdays. There were no statistically significant differences in mortality (3.8% weekend vs. 3.3% weekday, P = 0.209), amputation (7.2% weekend vs. 6.6% weekday, P = 0.258), or discharge home (57.4% weekend vs. 56.1% weekday, P = 0.271). There was no clinically significant difference in LOS (median 7 days weekend vs. 7 days weekday), P = 0.009. On multivariable regression analyses, there were no statistically significant outcome differences between the groups. This study did not identify a weekend effect in LEVT patients in the United States. This suggests that factors other than the day of admission may be important in influencing outcomes after LEVT.


Pain-Reducing Effects of Physical Therapist-Delivered Interventions: A Systematic Review of Randomized Trials Among Older Adults With Dementia.
Pain is common among older adults with dementia. There are nonpharmacological options for managing pain in this population. However, the effects of physical therapist-delivered interventions have not been summarized. The purpose of this systematic review was to summarize the literature on physical therapist-delivered interventions in randomized trials for reducing pain among older adults with dementia. A systematic search of MEDLINE/PubMed, CINAHL, PsycINFO, and Web of Science was conducted for randomized trials of pain management in individuals 60 years or older with medically diagnosed dementia of any severity. Included studies addressed the effects of nonpharmacological physical therapist-delivered interventions on pain outcomes. Pain outcomes included patient or caregiver self-report, observational or interactive measures. Independent reviewers extracted relevant data and assessed methodological quality using the PEDro scale. Three studies (total = 222 participants; mean age range = 82.2-84.0 years; 178 [80.2%] females) met inclusion criteria. PEDro scores ranged from 4 to 8/10. Interventions included passive movement and massage. Pain outcomes included the observational measures Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC), Pain in Advanced Dementia (PAINAD), and Doloplus-2 Scale. Passive movement did not show better results when compared with no treatment, while massage showed pain-reducing effects in 1 study compared with no treatment. The evidence supporting pain-reducing physical therapy interventions for patients with dementia is limited. There is a clear gap in knowledge related to evidence-based physical therapy for managing pain in this population. Future studies should examine active physical therapist-delivered interventions and utilize interactive pain measures.


Dinitrobenzene detection by use of one-color laser photolysis and laser-induced fluorescence of vibrationally excited NO.
Trace concentrations of 1, 4-dinitrobenzene (DNB) are detected by a combination of laser photolysis and laser-induced fluorescence. A one-color laser is applied to induce DNB photodissociation and for subsequent detection of NO photofragments by excitation and emission through A(v' =0) <-- X(v" = 0 - 2) and A(v' =0) --> X(v" = 0,1) transitions, respectively. The resulting NO rovibrational excitation spectra serve as markers for the presence of DNB. The NO is produced in vibrational ground and excited states with peak height ratios of (v" = 0):(v" = 1):(v" = 2) = 1:0.5:0.13. The limits of detection of DNB mixed with 100 or 500 Torr of air with v" = 2 excitation at 248 nm are 13 and 11 parts in 10(9) by weight, respectively, for a 30-s integration time. The application of this scheme for DNB detection has the advantage that no ambient ground state NO interferes and that the fluorescence is collected at shorter wavelengths than the exciting radiation, precluding background fluorescence.


Post-weaning Environmental Enrichment in Male CD-1 Mice: Impact on Social Behaviors, Corticosterone Levels and Prefrontal Cytokine Expression in Adulthood.
Environmental enrichment is typically associated with enhanced well-being, improved cognitive function and stress resilience. However, in some instances grouping adult male mice in enriched conditions promoted a stressful environment, which resulted in elevated endocrine, monoamine and inflammatory outcomes in response to subsequent stressor exposure. The current investigation examined whether raising male mice in an enriched environment (EE) would modulate social and anxiety-like behaviors in early adulthood and influence brain expression of pro-inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Immediately after weaning (postnatal day [PD] 21), CD-1 male mice were housed with their siblings (3/cage) for 6 weeks in an EE or a standard (SE) environment. Body weights and aggressive interactions were monitored weekly. Social avoidance behaviors in the social interaction test and anxiety-like behaviors in the elevated-plus maze were examined in early adulthood. Ninety minutes following the behavioral tests, mice were sacrificed and a blood sample and the prefrontal cortex (PFC) were collected for the determination of plasma corticosterone levels as well as cytokine and BDNF mRNA expression. Mice raised in an EE exhibited more wounds and gained less weight than mice housed in a SE. Enriched mice also spent a greater amount of time in proximity of a social target in the social interaction test and made fewer transitions into the closed arms of the elevated-plus maze. Interestingly, the elevated plasma corticosterone and upregulated prefrontal interleukin (IL)-1β expression observed after the social interaction test among the SE mice were not apparent among those housed in an EE. Enrichment also increased prefrontal BDNF expression, especially among mice that experienced the social interaction test. These results suggest that although raising male mice in an EE may elicit aggressive interactions between sibling cage-mates (as indicated by a high number of wounds), this environment also enhances social behaviors and limits the corticosterone and cytokine impacts of mild social stressors encountered in early adulthood.


Increased Default Mode Network Connectivity in Obsessive-Compulsive Disorder During Reward Processing.
Objective: Obsessive-compulsive disorder (OCD) is characterized by anxiety-provoking, obsessive thoughts (i.e., obsessions) which patients react to with compulsive behaviors (i.e., compulsions). Due to the transient feeling of relief following the reduction of obsession-induced anxiety, compulsions are often described as relieving or even rewarding. Several studies investigated functional activation during reward processing in OCD, but findings are heterogeneous up to now and little is known about potential alterations in functional connectivity. Method: Against this background we studied OCD patients (n = 44) and healthy controls (n = 37) during the receipt of monetary reward by assessing both activation and functional connectivity. Results: Patients showed a decreased activation in several frontal regions and the posterior cingulate (PCC, BA31) together with a stronger connectivity between the PCC and the vmPFC (BA10). Conclusion: Present findings demonstrate an increased connectivity in patients within major nodes of the default mode network (DMN)-a network known to be involved in the evaluation of internal mental states. These results may indicate an increased activity of internal, self-related processing at the expense of a normal responsiveness toward external rewards and incentives. This, in turn, may explain the constant urge for additional reinforcement and patients' inability to inhibit their compulsive behaviors.


Spatial-spectral modulating snapshot hyperspectral imager.
Experimental results are presented for a computed tomography imaging spectrometer (CTIS) with imposed spatial-spectral modulation on the image scene. This modulation structure on the CTIS tomographic dispersion created substantial gains in spectral reconstruction resolution after standard iterative, nonlinear, inversion techniques were used. Modulation limits system ambiguities, so high-frequency spectral and low-frequency spatial scene data could be recovered. The results demonstrate how spatial modulation acts as a high-frequency spectral deconvolver for the snapshot hyperspectral imager technology.


Structured learning of human interactions in TV shows.
The objective of this work is recognition and spatiotemporal localization of two-person interactions in video. Our approach is person-centric. As a first stage we track all upper bodies and heads in a video using a tracking-by-detection approach that combines detections with KLT tracking and clique partitioning, together with occlusion detection, to yield robust person tracks. We develop local descriptors of activity based on the head orientation (estimated using a set of pose-specific classifiers) and the local spatiotemporal region around them, together with global descriptors that encode the relative positions of people as a function of interaction type. Learning and inference on the model uses a structured output SVM which combines the local and global descriptors in a principled manner. Inference using the model yields information about which pairs of people are interacting, their interaction class, and their head orientation (which is also treated as a variable, enabling mistakes in the classifier to be corrected using global context). We show that inference can be carried out with polynomial complexity in the number of people, and describe an efficient algorithm for this. The method is evaluated on a new dataset comprising 300 video clips acquired from 23 different TV shows and on the benchmark UT--Interaction dataset.


Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion.
Group 3 innate lymphoid cells (ILC3s) have demonstrated roles in promoting antibacterial immunity, maintaining epithelial barrier function, and supporting tissue repair. ILC3 alterations are associated with chronic inflammation and inflammatory disease; however, the characteristics and relevant regulatory mechanisms of this cell population in HIV-1 infection are poorly understood due in part to a lack of a robust model. Here, we determined that functional human ILC3s develop in lymphoid organs of humanized mice and that persistent HIV-1 infection in this model depletes ILC3s, as observed in chronic HIV-1-infected patients. In HIV-1-infected mice, effective antiretroviral therapy reversed the loss of ILC3s. HIV-1-dependent reduction of ILC3s required plasmacytoid dendritic cells (pDCs), IFN-I, and the CD95/FasL pathway, as targeted depletion or blockade of these prevented HIV-1-induced ILC3 depletion in vivo and in vitro, respectively. Finally, we determined that HIV-1 infection induces CD95 expression on ILC3s via a pDC- and IFN-I-dependent mechanism that sensitizes ILC3s to undergo CD95/FasL-mediated apoptosis. We conclude that chronic HIV-1 infection depletes ILC3s through pDC activation, induction of IFN-I, and CD95-mediated apoptosis.


Mapping transcription factor interactome networks using HaloTag protein arrays.
Protein microarrays enable investigation of diverse biochemical properties for thousands of proteins in a single experiment, an unparalleled capacity. Using a high-density system called HaloTag nucleic acid programmable protein array (HaloTag-NAPPA), we created high-density protein arrays comprising 12,000 Arabidopsis ORFs. We used these arrays to query protein-protein interactions for a set of 38 transcription factors and transcriptional regulators (TFs) that function in diverse plant hormone regulatory pathways. The resulting transcription factor interactome network, TF-NAPPA, contains thousands of novel interactions. Validation in a benchmarked in vitro pull-down assay revealed that a random subset of TF-NAPPA validated at the same rate of 64% as a positive reference set of literature-curated interactions. Moreover, using a bimolecular fluorescence complementation (BiFC) assay, we confirmed in planta several interactions of biological interest and determined the interaction localizations for seven pairs. The application of HaloTag-NAPPA technology to plant hormone signaling pathways allowed the identification of many novel transcription factor-protein interactions and led to the development of a proteome-wide plant hormone TF interactome network.


Microcystin-LR Binds Iron, and Iron Promotes Self-Assembly.
The microcystin-producing Microcystis aeruginosa PCC 7806 and its close strain, the nonproducing Microcystis aeruginosa PCC 7005, grow similarly in the presence of 17 μM iron. Under severe iron deficient conditions (0.05 μM), the toxigenic strain grows slightly less than in iron-replete conditions, while the nonproducing microcystin strain is not able to grow. Isothermal titration calorimetry performed at cyanobacterial cytosol or meaningful environmental pHs values shows a microcystin-LR dissociaton constant for Fe2+ and Fe3+ of 2.4 μM. Using atomic force microscopy, 40% of microcystin-LR dimers were observed, and the presence of iron promoted its oligomerization up to six units. Microcystin-LR binds also Mo6+, Cu2+, and Mn2+. Polymeric microcystin binding iron may be related with a toxic cell colony advantage, providing enhanced iron bioavailability and perhaps affecting the structure of the gelatinous sheath. Inside cells, with microcystin implicated in the fitness of the photosynthetic machinery under stress conditions, the toxin would be involved in avoiding metal-dependent Fenton reactions when photooxidation causes disassembly of the iron-rich photosystems. Additionally, it could be hypothesized that polymerization-depolymerization dynamics may be an additional signal that could trigger changes (for example, in the binding of microcystin to proteins).


How accurate are quotations and references in medical journals?
The accuracy of quotations and references in six medical journals published during January 1984 was assessed. The original author was misquoted in 15% of all references, and most of the errors would have misled readers. Errors in citation of references occurred in 24%, of which 8% were major errors--that is, they prevented immediate identification of the source of the reference. Inaccurate quotations and citations are displeasing for the original author, misleading for the reader, and mean that untruths become "accepted fact." Some suggestions for reducing these high levels of inaccuracy are that papers scheduled for publication with errors of citation should be returned to the author and checked completely and a permanent column specifically for misquotations could be inserted into the journal.


CEO stabilized frequency comb from a 1-μm Kerr-lens mode-locked bulk Yb:CYA laser.
We report the first Kerr-lens mode-locked (KLM) bulk frequency comb in the 1-μm spectral regime. The fundamental KLM Yb:CYA laser is pumped by a low-noise, high-bright 976-nm fiber laser and typically provides 250-mW output power and 57-fs pulse duration. Only 58-mW output pulses were launched into a 1.3-m photonic crystal fiber (PCF) for one octave-spanning supercontinuum generation. Using a simplified collinear f-2f interferometer, the free-running carrier-envelope offset (CEO) frequency was measured to be 42-dB signal-to-noise ratio (SNR) for a 100-kHz resolution and 9.6-kHz full width at half maximum (FWHM) under a 100-Hz resolution. A long-term CEO control at 23 MHz was ultimately realized by feeding the phase error signal to the pump power of the oscillator. The integrated phase noise (IPN) of the locked CEO was measured to be 316 mrad with an integrated range from 1 Hz to 10 MHz. The standard deviation and Allan deviation for more than 4-hour recording are 1.6 mHz and 5.6 × 10(-18) (for 1-s gate time), respectively. This is, to the best of our knowledge, the best stability achieved among the 1-μm solid-state frequency combs.


Surface photochemistry of bromoform on ice: cross section and competing reaction pathways.
The 266 nm photodissociation of bromoform adsorbed on an amorphous solid water (ASW) layer has been investigated for the first time under well-defined ultrahigh vacuum conditions. Time-of-flight (TOF) measurements indicate direct release of gas-phase Br, CHBr2, Br2, and CHBr species, with potential implications for stratospheric chemistry. Furthermore, new, ice-surface-mediated C-C (C2H2Br2) and C-O (CHBrO, CO) species are revealed in postirradiation temperature programmed desorption (TPD) and reflection absorption infrared (RAIR) spectra. A cross section of approximately 5 x 10(-20) cm2 is determined for bromoform photodissociation at 266 nm based on the integrated area of both the TOF spectra of Br and Br2 and the postirradiation TPD curves of CHBr3. The involvement of the free, non-hydrogen-bonded water groups at the ASW surface in the formation of the photoproducts is evident from the RAIRS results.


Action to Improve Social Determinants of Health: Outcomes of Leadership and Advocacy Training for Community Residents.
Racial and ethnic disparities remain a public health problem and are largely due to social determinants of health (SDOH). Using an adapted 36-hour community health worker (CHW) curriculum, we trained 42 lay community residents in New Orleans, Louisiana, neighborhoods experiencing disparities in leadership and advocacy skills to address SDOH. Six months posttraining, 29 participants completed a follow-up survey and interview. Participants described increases in knowledge, self-efficacy, and activities related to leadership and advocacy at all levels of the social ecological model. We also found a significant increase in communicating with Louisiana state senators or representatives (p < .0339). Our findings show that an adapted CHW training curriculum focused on SDOH, leadership, and advocacy can be used to train lay community residents in how to make changes in the community conditions that affect health and prompt new engagement to address SDOH at all levels of the social ecological model. Future efforts to increase lay community participation in addressing SDOH may benefit from providing ongoing support to participants such as organizing meetings with residents interested in similar topics, offering opportunities to "shadow" experienced CHWs, or hosting additional skills building workshops.


Family influences on children's physical activity and fruit and vegetable consumption.
There is evidence of a clustering of healthy dietary patterns and physical activity among young people and also of unhealthy behaviours. The identification of influences on children's health behaviors, particularly clustered health behaviors, at the time at which they develop is imperative for the design of interventions. This study examines associations between parental modelling and support and children's physical activity (PA) and consumption of fruit and vegetables (FV), and combinations of these behaviours. In 2002/3 parents of 775 Australian children aged 10-12 years reported how frequently their child ate a variety of fruits and vegetables in the last week. Children wore accelerometers for eight days during waking hours. Parental modelling and parental support (financial and transport) were self-reported. Binary logistic and multinomial logistic regression analyses examined the likelihood of achieving >/= 2 hours of PA per day (high PA) and of consuming >/= 5 portions of FV per day (high FV) and combinations of these behaviors (e.g. high PA/low FV), according to parental modelling and support. Items of parental modelling and support were differentially associated with child behaviours. For example, girls whose parents reported high PA modelling had higher odds of consuming >/= 5 portions of FV/day (OR = 1.95, 95% CI = 1.32-2.87, p < 0.001). Boys whose parents reported high financial support for snacks/fast foods had higher odds of having 'high PA/low FV' (OR = 2.0, 95% CI = 1.1-3.7). Parental modelling of and support for physical activity and fruit and vegetable consumption were differentially associated with these behaviours in children across behavioural domains and with combinations of these behaviours. Promoting parents' own healthy eating and physical activity behaviours as well encouraging parental modelling and support of these behaviours in their children may be important strategies to test in future research.


Scenarios of energy reduction potential of zero energy building promotion in the Asia-Pacific region to year 2050.
Building energy consumption in the Asia-Pacific region continues to rise. It is important to understand the energy use and future trends of 21 members of Asia-Pacific Economic Cooperation (APEC) and to find more effective ways to achieve APEC's dual goals of reducing energy intensity by 45% of 2005 levels by 2035 and doubling the share of renewable energy in the energy mix between 2010 and 2030. Recently, promoting building toward ultra-low energy, nearly zero energy and zero energy is becoming a consensus trend. This paper aims to explore how zero energy building promotion could influence the total energy demand in the mid to long term. An EUPP (Economic, Urbanization, Population and Purchasing power parity) model was established to show the relationship between building energy consumption and its influencing factors, and the potential development path of building energy consumption in APEC was predicted by using the model. The results show that in the Business As Usual (BAU) model, building energy demand will increase from 1387.4 Mtoe in 2016 to 2456.8 Mtoe in 2050 while in the CAP model, building energy demand will be constrained to under 2000 Mtoe before 2050. In the ZEB promotion model, 897.8 to 1945.3 Mtoe could be saved separately. The share of end demand supplied by onsite renewable energy production could reach 11%-54%. The building sector has the potential to become the largest contributor to achieve the APEC energy goal and thus to the climate change goal.


Deciphering cellular states of innate tumor drug responses.
The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment. Transcriptional profiles of clinical samples collected from CRC patients prior to their exposure to a combined chemotherapy of folinic acid, 5-fluorouracil and irinotecan were established using microarrays. Vigilant experimental design, power simulations and robust statistics were used to restrain the rates of false negative and false positive hybridizations, allowing successful discrimination between drug resistance and sensitivity states with restricted sampling. A list of 679 genes was established that intrinsically differentiates, for the first time prior to drug exposure, subsequently diagnosed chemo-sensitive and resistant patients. Independent biological validation performed through quantitative PCR confirmed the expression pattern on two additional patients. Careful annotation of interconnected functional networks provided a unique representation of the cellular states underlying drug responses. Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses. These broad-spectrum cellular signatures represent a starting point from which by-pass chemotherapy schemes, targeting simultaneously several of the molecular mechanisms involved, may be developed for critical therapeutic intervention in CRC patients. The demonstrated power of this research strategy makes it generally applicable to other physiological and pathological situations.


Achieving Effective Universal Health Coverage And Diagonal Approaches To Care For Chronic Illnesses.
Health systems in low- and middle-income countries were designed to provide episodic care for acute conditions. However, the burden of disease has shifted to be overwhelmingly dominated by chronic conditions and illnesses that require health systems to function in an integrated manner across a spectrum of disease stages from prevention to palliation. Low- and middle-income countries are also aiming to ensure health care access for all through universal health coverage. This article proposes a framework of effective universal health coverage intended to meet the challenge of chronic illnesses. It outlines strategies to strengthen health systems through a "diagonal approach." We argue that the core challenge to health systems is chronicity of illness that requires ongoing and long-term health care. The example of breast cancer within the broader context of health system reform in Mexico is presented to illustrate effective universal health coverage along the chronic disease continuum and across health systems functions. The article concludes with recommendations to strengthen health systems in order to achieve effective universal health coverage.


Divergent V1R repertoires in five species: Amplification in rodents, decimation in primates, and a surprisingly small repertoire in dogs.
The V1R gene family comprises one of two types of putative pheromone receptors expressed in the mammalian vomeronasal organ (VNO). We searched the most recent mouse, rat, dog, chimpanzee, and human genome sequence assemblies to compile a near-complete repertoire of V1R genes for each species. Dog, human, and chimpanzee have very few intact V1Rs (8, 2, and 0, respectively) compared to more than a hundred intact V1Rs in each of the rat (106) and mouse (165) genomes. We also provide the first description of the diversity of V1R pseudogenes in these species. We identify at least 165 pseudogenes in mouse, 110 in rat, 102 in chimpanzee, 115 in human, and 54 in dog. Primate and dog pseudogenes are distributed among almost all V1R subfamilies seen in rodents, indicating that the common ancestor of these species had a diverse V1R repertoire. We find that V1R genes were subject to strikingly different fates in different species and in different subfamilies. In rodents, some subfamilies remained relatively stable or underwent roughly equivalent expansion in mouse and rat; other subfamilies expanded in one species but not the other. The small number of intact V1Rs in the dog genome is unexpected given the presumption that dogs, like rodents, have a functional VNO, and a complex system of pheromone-based behaviors. We identify an intact transient receptor potential channel 2beta in the dog genome, consistent with a functional VNO in dogs. The diminished V1R repertoire in dogs raises questions about the relative contributions of V1Rs versus other candidate pheromone receptor genes in the establishment of complex pheromone systems in mammals.


Shortened constraint-induced movement therapy in subacute stroke - no effect of using a restraint: a randomized controlled study with independent observers.
To examine the effect of using a mitt during shortened constraint-induced movement therapy for patients in the subacute phase after stroke. Twenty-four patients with stroke (mean age 57.6 (standard deviation (SD) 8.5) years; average 7 weeks post-stroke) with mild to moderate impaired hand function. The patients were randomized to mitt use or no mitt use on the less affected hand for 90% of waking hours for 12 days. All patients received 3 h of arm and hand training per day for 2 weeks. Assessments were made by blinded observers using the modified Motor Assessment Scale, the Sollerman hand function test, the 2-Point Discrimination test and Motor Activity Log test. Patients in both groups showed significant improvements in arm and hand motor performance and on self-reported motor ability after 2 weeks of therapy and at 3 months follow-up. However, no statistically significant differences between the groups were found in any measures at any point in time. In this study, no effect of using a restraint in patients with subacute stroke was found. Thus, this component in the constraint-induced therapy concept seems to be of minor importance for the outcome.


New phosphine-diamine and phosphine-amino-alcohol tridentate ligands for ruthenium catalysed enantioselective hydrogenation of ketones and a concise lactone synthesis enabled by asymmetric reduction of cyano-ketones.
Enantioselective hydrogenation of ketones is a key reaction in organic chemistry. In the past, we have attempted to deal with some unsolved challenges in this arena by introducing chiral tridentate phosphine-diamine/Ru catalysts. New catalysts and new applications are presented here, including the synthesis of phosphine-amino-alcohol P,N,OH ligands derived from (R,S)-1-amino-2-indanol, (S,S)-1-amino-2-indanol and a new chiral P,N,N ligand derived from (R,R)-1,2-diphenylethylenediamine. Ruthenium pre-catalysts of type [RuCl2(L)(DMSO)] were isolated and then examined in the hydrogenation of ketones. While the new P,N,OH ligand based catalysts are poor, the new P,N,N system gives up to 98% e.e. on substrates that do not react at all with most catalysts. A preliminary attempt at realising a new delta lactone synthesis by organocatalytic Michael addition between acetophenone and acrylonitrile, followed by asymmetric hydrogenation of the nitrile functionalised ketone is challenging in part due to the Michael addition chemistry, but also since Noyori pressure hydrogenation catalysts gave massively reduced reactivity relative to their performance for other acetophenone derivatives. The Ru phosphine-diamine system allowed quantitative conversion and around 50% e.e. The product can be converted into a delta lactone by treatment with KOH with complete retention of enantiomeric excess. This approach potentially offers access to this class of chiral molecules in three steps from the extremely cheap building blocks acrylonitrile and methyl-ketones; we encourage researchers to improve on our efforts in this potentially useful but currently flawed process.


Lattice and continuum modelling of a bioactive porous tissue scaffold.
A contemporary procedure to grow artificial tissue is to seed cells onto a porous biomaterial scaffold and culture it within a perfusion bioreactor to facilitate the transport of nutrients to growing cells. Typical models of cell growth for tissue engineering applications make use of spatially homogeneous or spatially continuous equations to model cell growth, flow of culture medium, nutrient transport and their interactions. The network structure of the physical porous scaffold is often incorporated through parameters in these models, either phenomenologically or through techniques like mathematical homogenization. We derive a model on a square grid lattice to demonstrate the importance of explicitly modelling the network structure of the porous scaffold and compare results from this model with those from a modified continuum model from the literature. We capture two-way coupling between cell growth and fluid flow by allowing cells to block pores, and by allowing the shear stress of the fluid to affect cell growth and death. We explore a range of parameters for both models and demonstrate quantitative and qualitative differences between predictions from each of these approaches, including spatial pattern formation and local oscillations in cell density present only in the lattice model. These differences suggest that for some parameter regimes, corresponding to specific cell types and scaffold geometries, the lattice model gives qualitatively different model predictions than typical continuum models. Our results inform model selection for bioactive porous tissue scaffolds, aiding in the development of successful tissue engineering experiments and eventually clinically successful technologies.


Audiovisual links in endogenous covert spatial attention.
In 7 experiments we investigated cross-modal links for endogenous covert spatial orienting in hearing and vision. Participants judged the elevation (up vs. down) of auditory or visual targets regardless of their laterality or modality. When participants were informed that targets were more likely on 1 side, elevation judgments were faster on that side, even if the modality of the target was uncertain. When participants expected a target on a particular side in just 1 modality, corresponding shifts of covert attention also took place in the other modality, as evidenced by faster elevation judgments on that side. However, it was possible to "split" auditory and visual attention when targets in the 2 modalities were expected on constant but opposite sides throughout a block, although covert orienting effects were larger when targets were expected on the same side in both modalities. These results show that although endogenous covert attention does not operate exclusively within a supramodal system, there are strong spatial links between auditory and visual attention.


Magnetic Resonance Imaging in degenerative disease of the lumbar spine: Fat Saturation technique and contrast medium.
To examine both anterior and posterior elements of the lumbar spine in patients with low back pain using MRI T2-weighted sequences with Fat Saturation (FS) and contrast enhanced T1-weighted sequences with FS. Two thousand eight hundred and twenty (2820) patients (1628 male, 1192 female, mean age 54) presenting low back pain underwent MRI standard examination (Sagittal T1w TSE and T2w TSE, axial T1 SE) with the addition of sagittal and axial T2w Fat Sat (FS) sequences. Among all the patients, 987 (35%) have been studied adding Contrast Enhanced (CE) T1w FS sequences after administration of contrast medium. Among 987 patients studied with contrast medium, we found: active-inflammatory intervertebral osteochondrosis in 646 (65%) patients; degenerative-inflammatory changes in facet joints (facet joint effusion, synovitis, synovial cysts) in 462 (47%); spondylolysis in 69 (7%); degenerative-inflammatory changes of the flava, interspinous and supraspinous ligaments in 245 (25%); inflammatory changes of posterior perispinal muscles in 84 (8%) patients. In patients with suspected no-disc-related low back pain, the implementation of T2w FS and CE T1w FS sequences to the standard MR protocol could allow a better identification of degenerative-inflammatory changes more likely associated to the pain.


Ultrasound-Guided Hydrodissection With Corticosteroid Injection in the Treatment of Carpal Tunnel Syndrome: A Pilot Study.
Corticosteroid injections can provide (temporary) relief in patients with mild to moderate carpal tunnel syndrome (CTS). Hydrodissection as part of an injection has been associated with positive clinical outcomes but data for CTS so far has been scarce. This study is designed to assess patient tolerance and secondarily provide pilot data on the added effect of hydrodissection. Twenty CTS patients were randomized to an ultrasound-guided betamethasone injection with hydrodissection (5 mL) or without (2 mL). Patient tolerance was assessed directly after intervention and patient-reported outcome after 4 and 24 weeks. Intra-group data were compared using Wilcoxon Signed Rank and inter-group with Wilcoxon rank-sum tests. Tolerance and pain scores did not differ between the two groups. Symptom scores decreased in both groups, but to a lesser extent in the hydrodissection group with a mean difference of -0.8 versus -1.5 in the control group at 4 weeks (P = .02). At 6 months, this difference was no longer present (P = .81). No statistically significant differences were found between the hydrodissection and control groups in the function or pain scores at follow-up at either time point. After injection, both symptomatic and functional scores improved, but the hydrodissected group did not show additional improvement. Data presented can be used to support larger studies to assess the value of hydrodissection in CTS management.